>> GOOD MORNING, EVERYONE. WELCOME TO THE 134th MEETING OF RECOMBINANT DNA ADVISORY COMMITTEE OF THE NIH. I'M YOU MAN FONG, CHAIR OF THE COMMITTEE AND -- YUMAN FONG, I WOULD LIKE TO CALL THIS MEETING TOWARD. LET'S INTRODUCE OURSELVES, GO AROUND THE TABLE AND BRIEFLY SAY A SHORT INTRODUCTION. LET'S START DOWN IN THIS END. >> WALLY KOCH, TEMPLE UNIVERSITY. >> NORM POST, UNIVERSITY OF WISCONSIN MADISON. >> LORI (INDISCERNIBLE) NORTHWESTERN UNIVERSITY. >> (INDISCERNIBLE) HARVARD SCHOOL PUBLIC HEALTH. (INDISCERNIBLE) >> DAVID (INAUDIBLE) WAKE FOREST UNIVERSITY. >> SUSAN ROSS, UNIVERSITY OF PENNSYLVANIA. >> JOE PLEWS SKI, UNIVERSITY OF -- PILEWSKI, UNIVERSITY OF PITTSBURG. >> YUMAN FONG, MEMORIAL SLOAN-KETTERING CANCER CENTER. >> JACQUELINE CORRIGAN KORY, NIH. >> ANDREW BADLY MAYO CLINIC. >> PAULA CANON, UNIVERSITY SOUTHERN CALIFORNIA. >> (INAUDIBLE) KIEM UNIVERSITY OF WASHINGTON SEATTLE. >> DENISE GAVIN, FDA. >> COULD THE RAC MEMBERS ON THE PHONE INTRODUCE THEMSELVES? >> MARGARET M OBJECTIONLINO. (INAUDIBLE) PUBLIC MEMBER. >> NEXT ORDER OF BUSINESS IS JACKIE WILL READ TO US THE NOTICE OF MEETING AN CON IN THIS CASE OF INTEREST GUIDANCE. >> WELCOME, EVERYBODY. AS IS WE ALWAYS DO DURING THE MEETING, REMIND YOU ABOUT YOUR -- THE RULES OF CONDUCT AND CONFLICT OF INTEREST SO AS MEMBER OF THIS COMMITTEE YOU ARE A SPECIAL GOVERNMENT EMPLOYEE AND THEREFORE STUDENT RULES THAT APPLY TO GOVERNMENT EMPLOYEES. THE RULE AND REGULATIONS ARE EXPLAINED IN A REPORT TITLED STANDARDS OF ETHICAL CONDUCT FOR EMPLOYEES AT THE EXECUTIVE BRANCH YOU RECEIVE THIS DODGE WHEN APPOINTED TO THE COMMITTEE. AT EVERY MEETING IN ADDITION THE REMINDING YOU THE IMPORTANCE OF FOLLOWING THETICS RULE WE LIKE TO REVIEW THE STEPS WE TAKE TO EBB SURE ANY CONFLICT OF INTEREST ARE ADDRESSED. KNOW BEFORE EVERY MEETING YOU PROVIDE US WITH INFORMATION ABOUT YOUR PERSONAL PROFESSIONAL AND FINANCIAL INTERESTS. WE USE THIS INFORMATION TO BASIS OF ASSESSING WHETHER YOU HAVE ANY REAL POTENTIAL OR APPARENT CONFLICT OF INTEREST TO COMPROMISE YOUR ABLE TO BE OBJECTIVE AND GIVING ADVICE DURING COMMITTEE MEETINGS. WHILE WE WAIVE CONFLICT OF INTEREST FOR GENERAL MATTERS BECAUSE WE BELIEVE YOUR ABILITY TO BE OBJECTIVE WILL NOT BE AFFECTED BY YOUR INTEREST IN SUCH MATTERS, WE ALSO RELY TO A GREAT DEGREE ON THE (INAUDIBLE) DURING OUR MEETINGS AND POSSIBILITY THEN COULD AFFECT OR APPEAR TO AFFECT INTERESTS IN A SPECIFIC WAY. AT THE TIME WE ASK YOU TO RECUSE YOURSELF FROM THE DISCUSSION. IF IFFY YES, SIR ABOUT RULES OF CONDUCT OR CONFLICT OF INTEREST OUR MANAGEMENT OFFICER WILL BE HAPPY TO ADDRESS THEM. >> THANK YOU VERY MUCH. WE WILL NOW MOVE ON TO REVIEW OF THE MINUTES FROM THE LAST MEETING AND TWO REVIEWSER FROM THE RAC WHO LOOKED OVER MINUTES IN DETAIL DR. HAMMARSKJOLD AND MS. MOLINO. MS. MOLINO. SFROM >> YES, I REVIEWED THE MINUTES AND FOUND THEM TO BE A FAIR REFLECTION OF THE -- I'M SORRY, THE MEETING. >> WITHOUT -- I WOULD MOVE THAT THE MENS BE APPROVED -- MINUTES BE APPROVED UNLESS THERE'S OBJECTIONS. ANY ADDITIONS TO THE MINUTES OR CHANGES TO THE MINUTES ANYBODY PROPOSES? THANK YOU. LET'S MOVE ON TO THE ORDER THE FIRST ORDER OF BUSINESS THIS MORNING WHICH IS THE FIRST PROTOCOL AND DISCUSSION. IT IS HUMAN GENE TRANSFER PROTOCOL NUMBER 1304-1230, A PHASE 1 ASCENDING DOSE TRIAL OF SAFETY AND TOLERABILITY OF TOCA 511, A RETROVIRAL REPLICATING VECTOR ADMINISTERED INTRAVIEIOUSLY TO SUBJECTS UNDERGOING SUBSEQUENT RESECTION FOR RECURRENT HIGH GRADE GLIOMA FOLLOWED BY TREATMENT OF TOCA FC EXTENDED RELEASE 5-FC. THE PI FOR THIS PROTOCOL IS ON THE PHONE, HE IS DR. STEVEN KALKANIS WHO IS VICE CHAIR DEPARTMENT OF NEUROSURGERY AT THE HENRY FORD HOSPITAL AT DETROIT, MICHIGAN. THE PRESENTATIONS WILL BE DONE BY THE PRIMARY PRESENTER WILL BE DANIEL PERSEK, VICE PRESIDENT OF CLINICAL DEVELOPMENT AT TOCAGEN. HE PRACTICED MEDICINE TEN YEARS BEFORE THE BIOFARM SUECAL INDUSTRY WITH WHERE HE SPENT 20 YEARS DOGGING CLINICAL TRIALS. HE RECEIVED HISTOM.D. FROM UNIVERSITY OF PENNSYLVANIAFUL ALSO FOR SCIENTIFIC QUESTIONS IS DOUG JOLLY, EXECUTIVE VICE PRESIDENT OF RESEARCH AND PHARMACEUTICAL DEVELOPMENT AT TOCAGEN. HE RECEIVED HIS Ph.D. AT UNIVERSITY OF GLASCOW AND PERFORMED POST GRADUATE RESEARCH IN MOLECULAR BIOLOGY HARVARD, UCSD AND INTERIM, NUMEROUS PUBLICATIONS COVERED LENTIVIRAL AND RETROVIRAL RESEARCH AND ALSO BEEN FOUND SCIENTIFIC HEAD OF SCIENTIFIC COMPANIES BASED ON VIRAL VECTOR BIOLOGIC PRODUCTS SO DR. PERCEK IF YOU COULD INTRODUCE ANY OTHER INDIVIDUALS IN YOUR TEAM THAT ARE PRESENT OR ON THE PHONE FOR DISCUSSIONS. >> I DON'T THINK THERE'S ANYONE ELSE ON THE PHONE. AMANDA FROM REGULATORY IS HERE WITH US, TO KEEP US FROM GETTING TOO NERVOUS. I WOULD LIKE TO THANK THE COMMITTEE MEMBERS FROM THE OPPORTUNITY TO PRESENT OUR PROTOCOL THIS MORNING. WITHOUT FURTHER ADIEU, WE'LL TAKE OFF. THESE ARE TOPICS TO ADDRESS, CAN EVERYBODY HEAR ME OKAY? FIRST TOCA 511 REFRESHER. UPDATE ON THE ONGOING STUDIES. TG-511-0801 AND TG 511-1101. THE RATIONALE FOR PROPOSED DOSING PROTOCOL. THE E DO SIGN OF THAT PROTOCOL AND BRIEF WRAPUP. SO TOCA 511 IS RETROVIRAL REPLICATING VECTOR BASED ON A MURINE LEUKEMIA VIRUS WHICH THE ENVELOPE IS CHANGEED TO AN AMPA TROPIC ENVELOPE. A DEAMINASE GENE SINISTERRED BETWEEN 3 PRIME TR AN CATALYZES THE CONVERSION OF THE ANTI-FUNGAL DRUG TO THE ANTI-NEOPLASTIC DRUG 5 FU AND RIBOSOME ENTRY SEQUENCES FACILITATES TRANSGENE EXPRESSION. HERE IS A SCHEMATIC OF THE VECTOR SHOWING PLACEMENT OF THE ICE AND CD GENE AND ENZYMATIC CONVERSION OF 5 FC AVAILABLE FOR MANY YEARS.vq TO TREAT SERIOUS FUNGAL BRAIN INFECTIONS AND METABOLITE ANTI-NEOPLASTIC DRUG 5 FU. THAT'S COMMON THEMES OF ALL TOCA 511 STUDIES INVOLVE DELIVERY OF THE VECTOR, SECOND WE ALLOW TIME FOR VECTOR TO INTEGRATE AND THIRD AD MINUTE STIR CYCLES OF ORAL 5 FC. THIS IS A SUMMARY EACH PREVIOUSLY PRESENTED TO THE RECOMBINANT DNA ADVISORY COMMITTEE IN THE PAST. FIRST IS THE TG 511-0801 STUDY, REFERRED TO AS THE INTRATUMORAL STUDY AND THE TG 51 #-11 STUDY, SURGICAL RESECTION STUDY. YOU CAN SEE THAT THE INDICATION FOR EACH STUDY THE SAME RECURRENT HIGH GRADE GLIOMAVMENT VECTOR IS THE SAME, TOCA 511. ADMINISTRATION IS DIFFERENT IN THE L 801 -- 0801 STUDY IT'S TRANSCRANIALLY WITH A BURR HOLE WITH SMALL INJECTION UNDER REAL TIME MRI GUIDANCE. IN THE SURGICAL RESECTION STUDY THE VECTOR IS INJECTED INTO THE WALL OF THE RESECTION CAVITY AT TIM OF OPEN CRANEIOTMY AND REMOVAL OF THE TUMOR. THE TOP DOSE IS STUDIED IN EACH PROTOCOL ARE THE SAME. HALF LOG DOSE ESCALATION SCHEME AND STANDARD THREE PLUS THREE DESIGN AND THE PRODRUG IS THE SAME 5 FC WITH CYCLE OF 5 IF,C IN 0801 STUDY BEING SIX DAYS O OF EVERY MONTH AND 11 WILL BE 01 STUDY, 8 DAYS OUT OF EVERY SIX WEEKS. THE OBJECTIVES OF BOTH STUDIES ARE SAFETY, TOLERABILITY AND ESTABLISHED MAXIMUM TOLERATED DOSE OF VECTOR. NOW, HERE IS A DOSING SUMMARY TO DATE BY STUDY AND BY DOSING COHORT. YOU CAN SEE THAT IN THE INTRATUMORAL STUDY WE ENROLLED 25 SUBJECTS AND RESECTION STUDY 22 SUBJECT. ENROLLMENT IS ON GOING AND TOP DOSE ONE TIME 10 TO THE 6 PER GRAM. HERE IS A LIST OF DOSE LIMITING TOXICITIES AGAIN BY STUDY AN DOSING COHORT AND YOU CAN SEE THAT IN THE INTRATUMORAL STUDY NO DOSE LIMITING TOXICITIES OBSERVED IN THE SURGICAL RESECTION STUDY THERE'S A SINGLE DOSE LIMBING TOXICITY AND ONE TIMES 10 TO THE 5TH PER GRAM COHORT. THIS DLT WAS REVIEWED WITH THE COMMITTEE AT ITS MARCH 2013 MEETING BUT JUST BRIEFLY WE'LL REREVIEW I HERE. THIS WAS A 70-YEAR-OLD MAN WITH RECURRENT GBM. ENROLLED IN 10 TO TO 5 TU PER GRAM DOSING COHORT. THE DLT REPORTED GRADE 3 WEAKNESS WHICH CODES PREFERRED TIME ISCHEMIA WHICH OCCURRED FOUR WEEKS AFTER SURGERY. RT PCR PLASMA SHOWED 103,000 COPIES OF VIRUS AND INTERCURRENT MEDICAL CONDITIONS OF UPPER RESPIRATORY INFECTION AND PULMONARY EMBOLISM. HE WAS DISCHARGED ON HOSPITAL DAY 4 PETE RTPCR TEN DAYS AFTER FIRST SHOWED VIRUS BELOW LEVEL OF QUANTITATION WITHOUT ANY SPECIFIC THERAPY HAVING BEEN AD MINISTERED. AND RT PCR REMAINS NEGATIVE MORE THAN NINE MONTHS AFTER ADMINISTRATION. IN TERMS OF TOCA 511 BIODISTRIBUTION IN GENERAL, 6 OF 47 SUBJECTS HAD VIREMIA, POSITIVE RT PCR IN PLASMA, NOT A DOSE DEPENDENT FINDING, IN OTHER WORDS NOT BECOME MORE FREQUENT OR HIGHER TITER AS DOSE IS ESCALATEDDED. ALL SUBJECTS WITH VIREMIA CONTROLLED WITHOUT ANTIRETROVIRAL THERAPY. ASYMPTOMATIC. ONLY TWO SHED VECTOR IN SALIVA LOW TITER AND TRANSYENLY AND AT TIME OF SHEDDING SUGGEST SHEDDING IS NOT INDEPENDENT EVENT. HERE IS A TYPICAL GRAPH OF SUBJECT WITH WITH VIREMIA IN SURGICAL RESECTION STUDY,K SEE ABOUT 50 DAYS AFTER ADMINISTRATION THE PATIENT HAS AN RT PCR SPIKE OF 32,000 COPY PER ML. FOLLOWED BY A DNA SPIKE PCR AND BOTH WHICH DROP PRECIPITOUSLY WITH APPEARANCE OF ANTIVIRAL ANTIBODIES SHOWN IN GREEN TRIANGLES. IN TERMS OF SAFETY, NO SUBJECT IS REQUIRED TREATMENT WITH ANTIRETROVIRALS. AT THE RECOMMENDATION OF RECOMBINANT DNA ADVISORY COMMITTEE WE DID MEET WITH INFECTIOUS DISEASE EXPERTS TO DEFINE A MULTI-DRUG REGIMEN USED IF REQUIRED. I WOULD LIKE TO POINT OUT THAT 5 FC IS NOT CONSIDERED THE FAILSAFE FOR THIS STUDY AS THIS WAS A QUESTION THAT WAS BROUGHT UP BY A NUMBER OF REVIEWERS. NO HEALTHCARE WORKER IS EXPERIENCED INADVERTENT EXPOSURE TO VECTOR. THEREFORE WE HAVE NOT HAD THE NEED TO USE POST EXPOSURE PROPHYLAXIS. THE RATIONALE FOR THE IV DELIVERY PROPOSED IS AS FOLLOWS. GLIAL BLASTOMA IS A HETEROGENEOUS TUMOR WITH NECROTIC POORLY VASCULARIZED CENTER AND PERIPHERY. THE HALLMARK OF GBM AND HIGH GRADE GLIOMA IN GENERAL IS ENHANCED GADOLINIUM ON MRI. IT GETS INTO THE TUMOR THROUGH ABNORMAL TUMOR VESSELS AN PRE-CLINICAL DATA SUGGEST THE VECTOR CAN ENTER ENTERTHE TUMOR THROUGH THE SAME LEAKY VESSELS. HERE IS FROM AN INTRACRANIAL MOUSE TUMOR MODEL WITH A GFP VERSION OF VECTOR UX SEE THE CENTER PANEL WHEN THE VECTOR IS INJECTED INTRAVIEIOUSLY, 14 DAYS LATER 73% ARE EXPRESSING GFP AND OPT RIGHT HAND PICTURE YOU CAN SEE THE FLUORESCENCE IN THE BRAIN TUMOR OF THE MOUSE THAT RECEIVED THE VECTOR INTRAVENOUSLY. IN ADDITION IV DOSING HAS COME PRABBLE SURVIVAL INTRACRANIAL DOSING, 2449 TUMOR MODEL AND B 6 F 31 MOUSE. TOP CURVE IN PURPLE IS INTRAVIEIOUS DOSING ON FIVE CONSECUTIVE DAYS APPROXIMATE SIMILAR SURVIVAL TO THE BLUE CURVE INTRACRANIAL DOSING BOTH WHICH ARE STATISTICALLY SUPERIOR TO THE PINK CURVE WHICH IS A CONTROL GROUP. INTERESTINGLY THE ORANGE CURVE IS A GROUP OF MICE THAT RECEIVEDDED INTRAVENOUS VECTOR THREE DAYS ON AN EVERY OTHER DAY BASIS AND THEY DIDN'T DO AS WELL. THIS SUGGESTED DOSE AND SCHEDULE ARE IMPORTANT FOR THIS MODE OF DELIVERY AND WILL HAVE MORE TO SAY ABOUT THAT LATER WHEN WE DISCUSS THE PROPOSED PROTOCOL. TOCA 511 IS ADMINISTERED INTRAVENOUSLY TO MICE AN DOGS IN PRE-CLINICAL WORK. AS YOU KNOW BIOPSY MICE HAVE IMMUNE TOLERANCE TO MLV AND DEVELOP LYMPHOMA 15 TO 30% OF THE TIME AFTER EITHER INTRACRANIAL OR INTRAVENOUS DOSING. THEY HAVE SIMILAR CLINICAL OBSERVATIONS GROSS PATHOLOGY BIODISTRIBUTION WITH IV COMPARED TO INTRACRANIAL DELIVERY OF VECTOR BUT INTERESTINGLY NO LYMPHOMA IS OBSERVED WHEN MICE ALSO RECEIVE 5 FC. INTERESTINGLY B 6 C 3F 1 MICE DIDN'T DEVELOP LYMPHOMA OR OTHER TOXICITY SUGGESTING LYMPHOMA GENESIS HAS BOTH STRAIN AND SPECIES SPECIFIC BEHAVIOR. DOGS HAD NO LYMPHOMA OR TOXICITY AFTER IV DOSING AND IV DOSE IS GIVEN TO MICE IN STUDIES ARE 3 TO 4 LOGS HIGHER THAN PROPOSED HUMAN STARTING DOSE. HERE IS A TYPICAL ENHANCING GBM ON MRI SCAN, FOLLOWING AD MENSTRUATION OF GADOLINIUM, YOU CAN SEE THE VASCULAR ENHANCING PERIPHERY AND YOU CAN SEE NON-ENHANCING CENTER. WE HAVE SUCCESSFULLY DELIVERED TOCA 511 TO CENTER OF TUMORS, HERE IS ONE OF OUR CASES, THE ASTERISK MARKS THE PRIOR RESECTION CAVITY AND THE TUMOR IS NOW GROWN BACK HERE, THE REASON YOU DON'T SEE IT CHEERILY IS THAT COMBAT RUN ALMOST IS NOT ADMINISTERED TO THIS PATIENT AT THIS POINT. YOU ALSO SEE THE LONG CERAMIC MRI COMPATIBLE CANNELLA, AT THE TIP YOU SEE A WHITE DOT WHICH IS VECTOR TO WHICH GADOLINIUM IS ADDED WHICH IS JUST STARTING TO BE INFUSED TO CENTER OF THE TUMOR. THIS PATIENT TOOK ONE COURSE OF 5 FC AND UNFORTUNATELY EXPIREDDED A MONTH LATER BUT WE WERE ABLE TO OBTAIN AUTOPSY WHICH YIELDED VERY IMPORTANT INFORMATION. WE RECEIVE CONTRA LATERAL NORMAL BRAIN IPSA LATERAL NORMAL BRAIN, BRAIN TUMOR, ABOUT FOUR SEN METERS FROM SITE OF INJECTION AND BRAIN TUMOR AT SITE OF INJECTION. THIS IS Q PCR TESTING ON THE CONTRA LATERAL NORMAL BRAIN, NO VECTOR DETECTEDDED AS YOU WOULD EXPECT GIVEN SPECIFICITY OF THIS CONSTRUCT FOR DIVIDING TUMOR CELLS, SAME ON IPSA LATERAL NORMAL BRAIN, NO VECTOR DETECTED. ON THE BRAIN TOW MORE FOUR CENTIMETERS FROM SITE OF INJECTION, JUST TRACE OF THE TRANSGENE DNA WAS DETECTED. BUT AT THE SITE OF INJECTION WE SEE 97 MILLION COPY OF VECTOR DNA SHOWING THE VECTOR DOES INTEGRATE AND PERSIST AND ABOUT A CENTIMETER AAWAY WE SEE 8570 COPIES PER MICROGRAM WHICH GIVES AN IDEA OF SPREAD CHARACTERISTICS OF THE VIRUS. NOW, DESPITE THE FACT THAT THIS PATIENT RECEIVED A COURSE OF 5 FC YOU SEE THE TRANSGENE DNA IS ALSO PRESENT. WHEN WE ARE ABLE TO TARGET THE CENTER, WE GET INTERESTING RESULTS. YOU CAN SEE THE TUMOR THERE, IMMEDIATELY FOLLOWING 5 FC, 12 DAYSś/Ö FOLLOWING 5 FC YOU SEE THE NECROTIC AREA IN THE CENTER OF THE TUMOR. BUT UNFORTUNATELY THE ENHANCING PERIPHERY STILL REMAINS. SO THE AIM OF IV DELIVERY IS TARGET RAPIDLY EXPANDING PERIPHERY OF TUMOR TO DELIVER WITHOUT NEED FOR COMPLEX NEUROSURGICAL INTERVENTION. ONE OF THE OTHER ADVANTAGES OF THIS PROTOCOL IS WE FEEL WE CAN OBTAIN A QUICK READ OUT OF THE OUTCOME OF INTRAVENOUS DELIVERY BY RESECTING THE TUMOR 11 DAYS AFTER IV ADMINISTRATION. ULTIMATELY WE HOPE TO COMBINE BOTH INTRAVENOUS AND INTRATUMORAL INJECTION TO TARGET ON TWO SEPARATE FRONTS. THE DESIGN OF THE IV STUDY IS AS FOLLOWS. THIS IS A MULTI-CENTER PHASE 1 ASCENDING DOSE STUDY. ADULT SUBJECTS WITH RECURRENT HIGH GRADE GLIOMA UNDER REPEAT RESECTION WITH APPROPRIATE CANDIDATES. STARTEST DOSE IS HIGHEST SAFE TOLERATED DOSE IN ONGOING PHASE 1 STUDIES AT THE TIME WRITTEN WAS 3.2 TIMES 10 TO THE 5TH TU PER GRAM. THAT DOSE IS SPLIT IV AND HALF GIVEN AT TIME OF RESECTION. HERE IS A STUDY SCHEMATIC. YOU SEE SUBJECTS ARE SCREENED. TOCA 511 IS ADMINISTERED INTRAVENOUSLY, THE TUMOR IS RESECTED AND WALLS OF THE RESECTION CAVITY ARE INJECTED WITH REMAINING TOCA 51 #. WE WAIT FOUR WEEKS FOR INTEGRATION AND BEGIN CYCLES OF 5 FC STUDY TEN DAYS OUT OF EVERY 5 WEEKS. HERE IS SUMMARY OF THE PROPOSED DOSING SCHEME, THERE'S A LOT OF INFORMATION ON THE SLIDE SO I'LL TAKE IT COLUMN BY COLUMN. ON THE LEFT HAND COLUMN YOU SEE THERE ARE FIVE PROPOSED DOSING COHORTS, EACH HALF LOG ESCALATION FROM PRIOR DOSE. THE NUMBER OF PLANNED SUBJECTS CAN BE SEEN IN COLUMN 2 YOU SEE WE PROPOSE ONE SUBJECT IN EACH OF THE FIRST THREE COHORTS, IN OTHER WORDS AN ACCELERATED DOSE ESCALATION FORMAT. THE REASON FOR THIS IS THAT WE KNOW BECAUSE OF THE DELUSION EFFECT OF THE BLOOD ON THE VIRUS THAT WE'RE NOT LIKELY TO REACH EFFICACIOUS DOSES UNTIL WE REACH HIGHER DOSES SO WE'D LIKE TO MINIMIZE EXPOSURE OF SUBJECTS TO DOSES THAT ARE LIKELY TO NOT TO BE EFFICACIOUS. WHEN WE GET TO THE FOURTH AND FIFTH DOSING COHORTS WE RESORT TO THREE PLUS THREE DESIGN. IN THE THIRD COLUMN YOU SEE THE NUMBER OF IV INJECTIONS YOU SEE FOR THE FIRST THREE COHORTS, SUBJECTS RECEIVE SINGLE INTRAVENOUS INJECTION FOR THE FOURTH AND FIFTH COHORTS MULTIPLE INJECTIONS FOR THE FOURTH. THEY RECEIVE THREE INJECTIONS ON -- ONE INJECTION ON THREE CONSECUTIVE DAYS AND FOR THE FIFTH COHORT FIVE INJECTIONS ONE INJECTION OF FIVE CONSECUTIVE DAYS. REASON FOR THIS IS TWOFOLD. THE HIGHER COHORTS THE VOLUME OF VECTOR AD MINISTERED MAKES A SINGLE ADMINISTRATION LESS FEASIBLE BUT MORE IMPORTANTLY AS I SHOWED IN THE SURVIVAL CURVE THERE'S SUGGESTION THAT MULTIPLE REPEATED DOSING HAS GREATER EFFICACY THAN SINGLE OR LOWER DOSES FREQUENCY ADMINISTRATION. THE REASON FOR THIS IS POSSIBLY BECAUSE THE VIRUS ONLY INFECTS DIVIDING CELLS AND BY ADMINISTERING THE DRUG ON MULTIPLE DAYS THE VECTOR WOULD THEREFORE EXPOSED TO DIFFERENT POPULATIONS OF DIVIDING CELLS ON DIFFERENT DAYS. FOURTH COLUMN SHOWS THE TOTAL INTRAVENOUS DOSE TO BE DELIVERED IN TO TUs P PER ML OF BLOOD. IN THE FIFTH COHORT WE WOULD BE GIVING 4.8 TIMES TEN TO THE TEN TU WHICH SCALES TO 9.5 TIMES 10 TO THE 6 TU PER ML OF BLOOD AND 20 FOLD LOWER DOSE THAN ADMINISTERED TO MICE. AS I MENTION, THAT DOSE WOULD BE DIVIDED INTO FIFTHS WITH A FIFTH BEING GIVEN ON EACH OF FIVE CONSECUTIVE DAYS. THE LAST COLUMN SHOWS THE INTRACRANIAL DOSING TU PER GRAM OF BRAIN THE WAY THE FDA ASKED US TO SCALE THE INTRACRANIAL DOSING THE FIRST COHORT RECEIVE 1 PONTIUS PILATE 6 TIMES TEN TO THE 5TH TUs PER GRAM OF BRAIN AND 3 PONTIUS PILATE 3 TIMES 10 TO THE 5 TU PER GRAM OF BRAIN WHICH IS THE HIGHEST DOSE THAT HAD BEEN SAFELY ADMINISTERED TO THE RESECTION CAVITY AT THE TIME THIS PROTOCOL WAS WRITTEN. WE DO NOT FURTHER ESCALATE THAT DOSE AFTER THAT. SO IN SUMMARY TOCA 5115 FC DELIVERED 47 SUBJECTS, IT'S SAFE AND WELL TOLERATED TO DATE ESPECIALLY CONSIDERING THE CANCER INDICATION. ALL SUBJECTS CONTROL THE VIRUS WITHOUT NEEDTOR ANTIRETROVIRAL THERAPY. WE'RE ABLE TO SUCCESSFULLY TARGET THE CENTER OF THE TUMOR BUT FEEL DELIVERING THE VECTOR THE VASCULAR PERIPHERY WILL HELP WITH OUR CLINICAL EFFICACY. PRE-CLINICAL DATA SUPPORT THE USE OF INTRAVENOUS DELIVERY AND I WOULD LIKE TO REMIND YOU RECURRENT HIGH GRADE GLIOMA HAS A POOR PROGNOSIS MAKING THERYK BENEFIT RATIO OF THIS TYPE OF STUDY APPROPRIATE. THANK YOU. >> THANK YOU VERY MUCH. LET'S GO THROUGH THE REVIEWS BY REVIEWER. AND THEN I WILL REMIND THE REVIEWERS PLEASE GO THROUGH THE POINTS THAT YOU BROUGHT UP EVEN IF THEY HAVE BEEN ADEQUATELY ADDRESSED BY THE SPONSOR AS WELL AS PI SO THAT WE HAVE IT ON RECORD. LET'S STARTS WITH DR. PAULA CANON. >> THANK YOU. THE FIRST QUESTION I HAD ACTUALLY CAME FROM MY MY MISUNDERSTANDING OF YOUR PROTOCOL SO I APOLOGIZE FOR THAT. I HAD THE IMPRESSION ACTUALLY BASED ON THE TITLE OF YOUR PROTOCOL THAT YOU ARE PROPOSING JUST TO DO IV INJECTION AND I NOW UNDERSTAND IT'S IV KNOWED BY TUMOR RESECTION. THEN INJECTION INTO THE TUMOR BED. IS A LOT OF MY CONCERNS ARE NOW NO LONGER MAKE SENSE TO ME. HOWEVER, I DO STILL HAVE A CONCERNN'T YOUR TITLE BECAUSE YOUR TITLE JUST SAYS ADMINISTERED INTRAVENOUSLY, IT DOESN'T STIPULATE TYPE THAT'S GOING TO BE ADDITIONAL TUMOR BED INJECTION AFTER RESECTION. SO THAT WOULD BE A SUGGESTION TO THINK ABOUT THE TITLE. >> THANKS. >> ANOTHER QUESTION I DIP PUT IN MY INITIAL REVIEW BUT NOW I HAVE THIS QUESTION IS IF YOU'RE GOING TO BE DELIVERING VIRUS IN TWO WAYS INTRAVENOUS AND FOLLOWING RESECTION, IS THERE ANY WAY FOR EXAMPLE TO TAG YOUR VIRUSES DIFFERENTLY MAYBE WITH AN RFLP SO THAT SHOULD ANY VIREMIA ARISE YOU CAN GO BACK AND SAY THIS CAME FROM THE IV DELIVERED VIRUS, THIS CAME FROM THE INTRACREPEIAL VIRUS. THAT WOULD BE A SUGGESTION TO THINK ABOUT IT. >> WE HAVE ENROLLED 22 PATIENTS IN THE SURGICAL RESECTION STUDY SO THINK OF THIS PROTOCOL AS IDENTICAL TO THE SURGICAL RESECTION STUDY WITH A FRONT PART WHERE THEY GET THE VIRUS INTRAVENOUSLY. SO WE HAVE A GOOD HANDLE ON THE TIME COURSE AND THE EXTENT OF VIREMIA WE SEE IN SURGICAL CASES, AS I SAID IT'S NOT CLEARLY DOSE DEPENDENT, NOT 100% CLEAR WHY SOME PATIENTS GET VIREMIA IN THE RESECTION AND OTHERS DONE. HOWEVER IT LOOKS LIKE SOME WHO GET VIREMIA HAVE A BETTER COURSE AND SO THE SUGGESTION IS THAT THE VIRUS IS BEING -- REPLICATING IN TUMOR AND SPILLING TO THE BLOODSTREAM AND WE SEE NICE SHRINKAGE OF TUMOR AND THE RESECTION CAVITY. SO THE TIME COURSE ALLOWS US TO SOMEWHAT DIFFERENTIATE WHETHER VIREMIA COMES FROM THE INTRAVENOUS PORTION OR SURGICAL RESECTION PART. BUT I DON'T KNOW, DOUG, DO YOU WANT TO COMMENT OPT SUGGEST? >> IT WOULD BE A COOL EXPERIMENT BUT ISSUE WITH WITH CARRYING OUT ANY SPEED IS THAT YOU HAVE TO SET UP A WHOLE NEW MANUFACTURING PROCESS. UNLIKELY TO DO THAT RIGHT AWAY BUT AN INTERESTING IDEA. >> A FOLLOW-UP QUESTION WHEN THE PATIENT WHOSE HAVE SEEN VIREMIA, YOU MAKE -- YOU MADE A STATEMENT IN RESPONSE TO ONE OUR REVIEWS THAT YOU DIDN'T -- THAT YOU BELIEVE VIREMIA IS COMING FROM TUMOR AND NOT FOR EXAMPLE FROM T CELLS, THE NATURAL HOST IN THE MOUSE, HOWEVER I BELIEVE IN THE RESPONSE TO DR. KIEM'S COMMENTS, YOU MENTION PBMC AND SORT INTO T-CELL B CELL AND MYELOID CELLS, THE POSITIVE PCR SIGNAL WAS IN THE T-CELL FRACTION. I WAS A LITTLE CONCH FUSED BECAUSE ONE HAND YOU ARGUE INNATE RESTRICTIONS SUCH AS APOBEC WILL PREVENT THIS REPLICATING FROM INFECTING T CELLS BUT IT WOULD SEEM YOU HAVE DATA TO SAY ACTUALLY WHEN YOU HAVE POSITIVE PCR SIGNAL, IT IS IN T-CELLS. >> INTERESTING QUESTION, I'LL LET DOUG ANSWER THE PART TO TALK ABOUT. THE REASON I SAY THE REASON I SHE YOU THE GRAPH IS RNA SPIKE BEFORE WE SEE THE DNA SPIKE. SO IF THE VIREMIA WERE COMING FROM CELLULAR ELEMENTS, I WOULD EXPECT TO SEE IT IN REVERSE ORDER ABOUT THE SAME TIME. SO WE SEE VIRUS APPEARS FREE IN THE BLOODSTREAM FIRST INTEGRATED FASHION, USUALLY LATER SIGNIFICANTLY LATER, WEEKS LATER. THE OTHER THING IS WE HAVE SEEN VIRTUALLY NO GI OR TOXICITY SO THE OTHER ORGANS WITH RAPID CELL TURN OVER IS HAVING SIGNIFICANT INTEGRATION IN THE BONE MARROW THE GI TRACK WE EXPECT TO SEE SOME TOXICITY AFTER 5 FC. THIS COUPLED WITH THE FACT OF INTERESTING RESPONSES IN PATIENTS WHO HAVE BEEN VIREMIC LEADS US TO BELIEVE THE VECTOR IS MOST LIKELY BEING PRODUCED IN THE DIVIDING TUMOR CELLS. >> ONE PATIENT, PATIENT WITH LARGEST VIRAL SPIKE IS DNA NEVER GONE ABOVE VLOQ, >> JUST THE RNA. THE OTHER THING, IF YOU TRY AND INFECT P PBMC, OBVIOUSLY NON-REPLICATING RETROVIRAL VECTORS GET INTO T-CELLS REACTIVELY EFFICIENTLY. SO OUR PICTURE IS THAT THE TUMOR IS PROBABLY MAKING MOST OF THE VIRUS AND YOU GET INFECTION BECAUSE APOBEC DOESN'T TYPICALLY STOP INCOMING VIRUSES, STOPS OUTGOING VIRUS THEREFORE YOU PROBABLY DON'T GET SPREAD IN THE WAY YOU MIGHT EXPECT. IN VITRO TRYING TO INFECT HUMAN PBMC, IT'S DIFFICULT TO GET BEYOND THE FIRST INFECTION EVENT, GET IT TO SPREAD. SO THE RATIONALE WOULD BE THE VIRAL KINETICS PLUS THE OBSERVATIONS IN VITRO. >> OKAY. THANK YOU. WE ALSO -- WE HAD A QUESTION ABOUT THE ANTIVIRAL REGIMEN YOU PROPOSE. MY UNDERSTANDING IS YOU PROPOSE TANOVOFIV AND YOU STATED AZT WORKS AGAINST TOCA 511. I WANT TO ASK YOU SPECIFICALLY HAVE YOU DEMONSTRATED THE TAGLAVIR AND TO NOVEMBER VEER WORK AGAINST THIS VIRUS O IS THIS AN EXTRAPOLATION OF LITERATURE ON XMRV? >> THE LATTER. >> WE HAVE DATA WITH THEIR OWN VIRUS AND AZT BUT LAST TIME WE WERE HERE THE COMMITTEE FELT THE EMERGENCE OF RESISTANCE IT WAS IMPORTANT TO HAVE MULTI-DRUG REGIMEN. SO WE MET WITH WITH EXPERTS AND THAT'S WHAT THEY RECOMMENDED WE DO. I'M HAPPY TO SAY WE HAVEN'T NEEDED TO USE THE REGIMEN THUS FAR. DOUG, DO YOU WANT TO COMMENT MORE HOW IT WAS DEVELOPED? >> I WAS GOING TO SAY WE TALKED TO A COUPLE OF INFECTIOUS DISEASE EXPERTS AND THEY FELT THE EVIDENCE FOR INHIBITION OF XMRV PASS ON TO VIRUSES AS WELL, BUT WE HAVEN'T DONE THE EXPERIMENT. >> I WOULD STRONGLY RECOMMEND DOING THE EXPERIMENT, IT WAS TRIVIAL TO DO IN THE LITTLE CRAZY TO BE RECOMMENDING THE DRUG REGIMEN, YOU HAVEN'T TESTED. >> OKAY. >> THANK YOU. >> I HAD A QUESTION ABOUT STABILITY OF RETRO VIRUS AND MAINTENANCE OF THE IRSVD AND YOU ANSWERED THAT QUITE WELL WHEN YOU ESTIMATE COPY NUMBER BASED ON MLV GENOME AND THE RSVD BECAUSE THAT IS COMPARABLE SO AT LEAST SHORT TERM IT LOOKS REASONABLY UNSTABLE AND I ACCEPT YOUR CORRECTIONS OF 5 FC NOT SEEN AS THE PRIMARY WAY TO STOP UNWANTED VIREMIA, ANTIRETROVIRAL. THIS COMES BACK TO THE FACT IT'S QUITE IMPORTANT TO DEMONSTRATE ANTIRETROVIRALS DO INDEED WORK. FINALLY I HAD MINOR POINTS ABOUT INFORMED CONSENT, SUGGESTIONS TO IMPROVE THE LANGUAGE WHICH YOU ACCEPTED. WHICH IN THE REVIEW THEY WERE QUITE (INAUDIBLE), I HAVE NO FURTHER QUESTIONS. >> THANK YOU. >> DR. CAMNAN T ONLY UNRESOLVED ISSUE IS YOU WANT ACTUAL DATA SUPPORTING THE USE OF DRUG REGIMEN TREATMENT. >> YES. >> LET'S MOVE TO DR. THE HANS PETER KIEM. >> THANK YOU VERY MUCH, NICE PRESENTATION. I CLEARLY UNDERSTAND THE RATIONALE FOR GOING WITH THE IV APPROACH BUT AS PROBABLY A LOT OF PEOPLE GIVING THIS IV REPLICATION RECOMBINANT VIRUS (INAUDIBLE) MOST OF MY POINTS SO LET ME START READING DOWN WHAT I SENT YOU. GIVEN THESE REPLICATION COMPETENT RETRO VIRUS WOULDN'T BE INTEGRATION IN OTHER PROLIFERATIVE CELLS LIKE HEMATOPOIETIC CELLS OR OTHER TISSUES, PROGENITOR CELLS OR STEM CELLS OR OTHER TISSUES LIKE TARGET. WHAT TYPES OF ASSAYS WILL YOU BE LOOKING FOR OR BELIEVE WOULD BE USING FOR INTEGRATION, WHAT IS THE SENSITIVITY OF THESE ASSAYS. YOU HAVE MADE SOME OF IT IN THE GUT THERE WAS NO TOXICITY. HAVE YOU ACTUALLY LOOKED IN OTHER TISSUES WHETHER THERE'S ANY VIRUS? GET BACK TO SYSTEM OF THESE QUESTIONS. >> IN HUMANS, NO. OBVIOUSLY WE EF DONE A LOT OF WORK IN MICE AN DOGS. IF YOU LOOK IN MICE WHICH GET VIREMIC YOU FIND IT IN MORE TISSUES. CAUSES MORE MICE FOR PCR HE SURE.S SO WE WEREN'T ABLE TO CLEANLY PROFUSE THE ANIMALS SO WE CAN'T SEPARATE THAT CLEANLY FROM THE BLOOD LEVELS. BUT THERE WERE THE USUAL -- SO WE SCANNED ABOUT 30 ODD TISSUES AND MAIN ONES WERE LYMPHOID TISSUES THAT WERE IN THYMUS. THERE WERE HIGH COUNT IN THE ESOPHAGUS BUT NOT IN THE GUT ITSELF. OBVIOUSLY. >> IN THE MICE DID YOU SEE ANY LYMPHOMAS? >> IN THE BIOPSY MICE, BIOLOCALIZATION IN GOP TOX STUDIES LYMPHOMAS SICK MONTHS AT HIGHEST DOSES AT DEPENDING ON THE PROTOCOL, BETWEEN 15 AND 30%. THE B-6 C 3F 1 MICE CROSS OF CC 7 BLACK 6 WE HAVE BEEN NEVER BEEN ABLE TO MAKE THEM VIREMIC THOUGH THEY GET A FEW COUNTS. THEY HAVEN'T EVER GOT LYMPHOMA. THESE ARE TYPICALLY 8 WEEK OLD MICE. ACTUALLY I'LL LEAVE IT AT THAT. >> LET ME MOVE ON TO MY NEXT QUESTION, GIVEN VIRUS BE INTRAVENOUSLY WILL INCREASE THE POTENTIAL RISK AND I MEAN OBVIOUSLY CAN THE MOUSE PREDICT WHAT YOU'RE GOING TO SEE IN PATIENTS, INFECTIVITY OF MOUSE CELLS, DIFFERENT THAN HUMAN CELLS OR DOG CELLS IN THE STUDY. THE BIGGEST QUESTION THERE, MAYBE HOPEFULLY MONITOR THESE PATIENTS FOR INNEXT OTHER IT SHALL SHOE OUTSIDE THE BRAIN. >> HANS, WILL YOU SPEAK INTO THE MICROPHONE? WE'RE HAVING A LITTLE TROUBLE HEARING. I'M SORRY. >> SO I GUESS I WOULD SAY FIRST OF ALL THAT THE BEST PREDICTION I DON'T THINK IS THE MICE ANY MORE NOW THAT WE HAVE HAD MULTIPLE VIREMIC SUBJECTS SOME WHICH ARE HIGHLY VIREMIC, THE BEHAVER YOUR OF THOSE SUBJECTS WOULD LIKELY BEST PREDICT WHAT HAPPENS TO SUBJECTS IN THIS INTRAVENOUS DOSING PROTOCOL. THE WAY WE MONITOR IS I THINK THERE ARE TEN TIME POINTS WHICH WE GET TCR AND RTPCR ON BLOOD. WE CHECK FOR SHEDDING AT MULTIPLE TIME POINTS, WITH WE CHECK ANTIBODIES BUT OBVIOUSLY WE'RE NOT OBTAINING TISSUE, EXCEPT BRAIN TUMOR, ONE OF THE NICEST FEATURES OF THIS PROTOCOL. ONE OF THE FRUSTRATING THINGS ABOUT GLIOMA RESEARCH I'M SURE YOU KNOW, IT'S SOMEWHAT A BLACK BOX, YOU CAN SEE WHAT YOU PUT IN AND WHAT YOU GET OUT. SO BY SELECTING PATIENT WHOSE SIGNEDED UP TO HAVE ANOTHER CRANEIOTMY AND TUMOR RESECTION, WE SHOULD BE ABLE TO TELL QUICKLY WHETHER THE INTRAVENOUS METHOD IS SEEDING THE TUMOR. WE DON'T COLLECT TISSUE FROM ORGANS BUT WE CHECK CAREFUL ADVERSE EVENT DATA AND WE DO A LOT OF SAFETY BLOOD TESTING WITH WITH CBC AND CHEMISTRY PANELS AT MANY TIME POINTS IN THE PROTOCOL. AND LOOK FOR CHANGES FROM BASELINE. SO BETWEEN ADVERSE EVENTS, AND FOR CURRENT STUDIES WE HAVE A MEETING FOR DATA MONITORING COMMITTEE AFTER DOSE COHORT TO REVIEW THE DATA. >> MY THIRD QUESTION IS THEY RECEIVE B -- (INDISCERNIBLE) PRONE TO CANCER OR LYMPHOMA. THEN IT GETS BACK TO CAREFUL ANALYSIS AND MONITORING OF THESE PATIENTS. BUT I THINK YOU ANSWERED THAT APPROPRIATELY. THE FOURTH QUESTION WAS FOR INVESTIGATORS TO PRE-TREATMENT SCREENING OF PATIENTS WHETHER THERE'S SERUM INACTIVATION OF REPLICATION COMPETENT VIRUS. >> THAT'S AN INTERESTING QUESTION. WE DON'T. BUT WE -- I THINK I'LL LET DOUG TELL YOU B ABOUT ANIMAL WORK WE HAVE DONE EVALUATE WHETHER THAT MIGHT HAVE ANY IMPACT ON SURVIVAL OF THE VECTOR. >> SO FIRST YOU SCREEN 100 PEOPLE FOR ANTIBODIES AGAINST MLV, THERE'S THIS KIND OF RUGGED BACK GROUND THAT'S NOT ZERO AND IN FACT WE HAVE AN ELISA WE FOLLOW PATIENTS WITH AN SCREEN 200 PATIENTS TO FIND SOMEONE WHO IS REALLY VERY POSITIVE SO WE USE THE POSITIVE CONTROL BUT THOSE PEOPLE OCCUR BUT ONCE – IN 100 PEOPLE. SO THERE IS SOME BACKGROUND THOUGH UP CLEAR WHY. YOU LOOK AT THAT BACKGROUND, IT'S NOT PARTICULARLY NEUTRALIZING. IN TERMS OF ACTIVATION I THE QUESTION I ANSWERED WITH NON-REPLICATIVE RETROVIRAL VECTORS IF YOU MAKE IT IN THE MATCHING SPECIES, IT'S MUCH REDUCED. WE HAVE DONE EMPERIMENTS LOOKING IN BOTH DOGS AND MICE AT T THE HALF LIFE OF THE VIRUS AND IT'S BIPHASIC. SO YOU GET A DROP TO 1,000 FOR THE DOSE. IN ABOUT AN HOUR, IT TRAILS OFF OVER THE NEXT FEW DAYS IN THE MICE. THE DOGS COULDN'T PUT ENOUGH IN TO SEE THE SECOND PHASE. WE HAVE DONE A STUDY WHERE WE PRE-IMMUNIZE MICE AND SURVIVAL OF THOSE MICE UPON READMINISTRATION, VECTOR WAS NOT SIGNIFICANTLY DIFFERENT FROM MICE THAT WEREN'T PREIMMUNIZED SO HAVING SOME IMMUNITY TO VECTOR DOESN'T NECESSARILY -- THE VIRUS DOESN'T NECESSARY HI LOSE EFFICACY. >> ANTIBODY, INTERESTINGLY ANTIBODIES THAT WE GET TO THE VIRUS IN PEOPLE DOESN'T APPEAR NATURALIZING THOUGH NEUTRALIZING >> I WAS WONDERING TO CORRELATE ANY VIREMIA WITH THESE PATIENTS. Q. NUMBER 5, WHAT WILL HAPPEN TO PATIENTS WITH VIEW REAMIA AND TUMOR PROGRESSION? TREATMENT OF THE TUMOR COULD RESULT IN ENHANCED SIDE EFFECTS. THE EFFICACY OF ANTIRETROVIRAL IS LIKELY NOT KNOWN IN THIS SETTING. SO YOU TREAT -- SOMEBODY HAS VIREMIA, HAS PROGRESSIVE DISEASE WE'LL GIVE CHEMOTHERAPY. >> WE WILL TREAT -- THERE ARE RULES IN THE PROTOCOL THAT SPECIFY IF A PATIENT IS OBVIOUSLY NOT RESPONDING TO THE PROTOCOL TREATMENT THEN THEY CAN BE CANDIDATE TO RECEIVE ANTIRETROVIRAL THERAPY, WE HAVEN'T HAD TO DO THAT BECAUSE PATIENTS HAVE CONTROLLED VIREMIA WITH THEIR OWN IMMUNE SYSTEM. >> BUT THE ANN RETROVIRAL THERAPY, ANTITUMOR THERAPY. THEY GO TO ANOTHER PROTOCOL LIKELY OR HAVE ANOTHER RESECTION. >> I THINK YOU'RE TALKING POTENTIAL ANTI-LYMPHOMA DRUGS IS THAT RIGHT? >> THIS IS ANTITUMOR, GLIAL BLASTOMA. I THINK YOU ALSO ADDRESSED COMMON USE OF STEROIDS IN THE STUDY AFTER PATIENTS ARE INJECTIONED WITH THE VIRUS CH Q. AS YOU KNOW STEROIDS HAVE AN INTERESTING AFFECT, STEROID RESPONSE ELEMENT, IN VITRO VIRAL KINETICSR>„ ACCELERATING DEX METH ZONE, ALL GET DEX METH ZONE AT SOME POINT BUT WE PURPOSELY AVOIDED THE DEX METH ZONE DURING INTRAVENOUS DOSING BECAUSE IT WORKS TO RAPIDSLY DECREASE PERITUMORAL EDEMA AND HAS THIS AFFECT ON THE VASCULATURE AND SINCE WE'RE DEPENDING ON THAT LEAKY VASCULATURE TO GET VIRUS TO TUMOR, WE DECIDED WE SHOULDN'T DURING ENTER VENOUS WE DECIDED TO TROY THE SUM -- IN THE SURGICAL RESECTION PART THE SURGEON IS FREE TO USE HIS OR HER STANDARD REGIMEN WHICH IS USUALLY 4 MILLIGRAMS OF DEXAMETHASONE EVERY SIX HOURS IN THE IMMEDIATE PERIOPERATIVE PERIOD. >> PATIENTS HAVE PROGRESSIVE DISEASE POTENTIALLY NEEDING STEROIDS -- >> THEY WOULD GET IT. >> THEY WOULD GET IT. >> YES. >> SO MY LAST QUESTION, I WAS HERE THAT I SENT TO, FAMILY MEMBERS BE SCREENED IN PATIENTS WITH VIREMIA, YOU SHOW THAT TWO PATIENTS HAD SHEDDING. >> THEY HAD SOL VARY SHEDDING BE AS YOU KNOW PATIENTS SHED HIV IN THE SALIVA BUT NOT CONSIDERED INFECTIOUS BECAUSE OF THE LOW AMOUNT. GENERALLY I'LL REMIND YOU THIS IS A RISK GROUP 2 ORGANISM AND WE HAVE PEOPLE WALKING THROUGH THE HOSPITAL AND COMMUNITY WITH RISK GROUP 3 ORGANISMS IN THEIR BLOOD. AGAIN AT THE SUGGESTION OF THE COMMITTEE, WE HAVE STRONG LANGUAGE IN THE PROTOCOLS AND IN THE CONSENT TO ADVISE PATIENTS TO USE THE SAME PRECAUTIONS WE ADVISE PATIENTS TO USE WHO HAVE HIV. SO CONDOMS, UNTIL THERE'S NO EVIDENCE OF VIRUS IN THE BLOOD, NOT SHARING RAISERS NOT GETTING BODY PIERCINGSES TATTOOING, DONATING ORGANS, THINGS LIKE THAT, SEEMS LIKE THE MOST CONSERVATIVE THING WE CAN DO RIGHT NOW. >> I THINK IT'S REASONABLE. I WAS GOING TO ADD WE HAVE DONE FAIRLY EXTENSIVE CO-HABITING STUDIES WHERE WE TOOK THE BALD C MICE, CHECKED HIGHLY VIREMIC. PUT TWO MICE IN WITH THREE NAIVE MICE AND 8 DIFFERENT CAGES. AND FOLLOWED THE -- BOTH SETS OF MICE FOR OVER 100 DAYS AND P THEN THE NAIVE MICE OUT 180 DAYS AND WE DONE SEE TRANSMISSION TO MICE SO IT'S RELATIVELY NON-TRANSMISSIBLE. >> THE OTHER POINT THE MAKE IS WITH SHEDDING DOESN'T OCCURREN PENDENT FROM VIREMIA SO IF YOU'RE FOLLOWING THE BLOOD, THAT'S PROBABLY THE BEST PREDICTOR, AND YOU CAN TELL THE PATIENT YOU'RE VIREMIC SO YOU'RE GOING TO HAVE SAUL RELATIONS YOU HAVE TO USE CONDOMS. WE KNOW WHEN IT GOES AWAY IT DOESN'T COME BACK SO AT THAT POINT WE CAN ADVISE THE PATIENT WHAT TO DO. >> ARE THERE GUIDELINES ON YOUR PROTOCOL, REQUIRING ANTIRETROVIRAL THERAPY WILL YOU ADJUST THE PROTOCOL? >> THERE ARE STOPPING RULES FOR PATIENTSER FOR THE STUDY WE HAVE WORKED OUT WITH THE FDA. AND SO THE ANSWER IS YES, THERE ARE LOTS OF STOPPING RULES ON THE STUDY. AS I SAID FORTUNATELY WE'RE AT THE (INAUDIBLE) (INDISCERNIBLE) >> SOMEONE ON THE PHONE IS IN TRAFFIC YOU CAN MUTE YOUR PHONE. (INDISCERNIBLE) >> THAT WAS A A GOOD DIAGNOSIS. I HAD NO IDEA MAYBE I HAD UPSET THE GODS. >> ANOTHER QUESTION I HAD IS SO IF YOU WAIT TWO WEEKS AFTER THE IN VIVO INJECTION OF THE VIRUS, THEN I ASSUME PATIENTS WILL KNOW THEY HAVE TO WAIT TWO WEEKS, WILL THAT DELAY ANY POTENTIAL TREATMENT FOR THE PATIENT? THEY COULD HAVE GOTTEN EARLIER? >> YOU'RE SAYING BETWEEN INTRAVIEIOUS INJECTION AN SURGERY? >> YES. >> YES. THAT'S WHY THE PROTOCOL SPECIFIES 11 PLUS OR MINUS 3 DAYS, IT GIVES THE SURGEON A LITTLE LEEWAY TO TAILOR THE TREATMENT. IF IT'S A PATIENT HE OR SHE FEELS CAN'T WAIT 14 DAYS. OBVIOUSLY THE LONGER WE WAIT THE MORE LIKELY IT IS WE'LL GET A GOOD READ HOW MUCH VECTOR THERE IS AN WHERE IT IS BUT IF THE PATIENT CAN'T WAIT THE TOW MORE CAN BE REMOVED AS EARLY AS 8 DAYS. (INDISCERNIBLE). >> YEAH. >> OKAY. THESE WERE MY QUESTIONS. THANK YOU. >> ANY UNRESOLVED QUESTIONS MANY >> NO. >> LET ME FOLLOW-UPs6l ON SOMETHING YOU BROUGHT UP ABOUT THE GUIDELINES FOR USING ANTIVIRALS. AS I READ THE PROTOCOL RIGHT NOW THE GUIDELINES ARE REALLY TWO PARTS. PEOPLE VIREMIC WITH WITH MORE THAN 30,000 COPIES AND WHO HAVE NO TUMOR RESPONSE AND THEREFORE YOU'RE GOING TO GIVE THE APT VIRALS REGARDLESS L OF SYMPTOMS, PEOPLE WITH VIREMIA AND RESPONSE TO THERAPY AND THEREFORE MUCH BIGGER DEAL TO GIVE ANTIVIRALS YOU LEAVE IT AT DISCRETION OF INVESTIGATORS, SHOULDN'T IT BE BASED ON SYMPTOMTOLOGY TO RELATE TO THE VIRUS? >> THAT'S A GREAT QUESTION. I MEAN, ALL THIS WE'RE FEELING OUR WAY, WE DIDN'T KNOW WHETHER VIREMIA WOULD BE SYMPTOMATIC OF THE SIX PATIENTS THAT HAVE HAD SIGNIFICANT VIREMIA THE ONE SUBJECTS WITH WEAKNESS AND P ADMITTED THAT I DISCAN YOUS HERE AND ONE OTHER SUBJECT HAD SOME UNDOCUMENTED LOW GRADE FEVERS, THE OTHERS ARE ASYMPTOMATIC. SO I DON'T KNOW THAT WE COULD -- SHOULD PIN ANYTHING ON SYMPTOMS BECAUSE THEY SEEM TO BE PRETTY INCONSISTENT. WE DID WORK OUT WITH FDA SOME RULES FOR AD HOC VIRALGFSTING SO WHEN PATIENTS ARE ADMITTED, WHEN PATIENTS HAVE VIREMIA, WE CAN DO MORE FREQUENT TESTING TO TRY TO GET A BETTER HANDLE ON THE ACTUAL TIME COURSE VIREMIA. THAT TESTING IS BASED ON SYMPTOMS SO IF THEY'RE ASYMPTOMATIC WILL TEST MORE FREQUENTLY IF THERE'S 25,000 COPIES PER ML BUT IF SYMPTOMATIC WE TEST MORE FREQUENTLY AT 10,000. BUT WE HAVEN'T NEEDED TO DO THAT EITHER BECAUSE IT'S -- IT GOES AWAY SO RAPIDLY. SO I DON'T KNOW THE ANSWER TO YOUR QUESTION. AND I THINK YOU CORRECTLY POINT OUT THAT THOSE CRITERIA WERE WRITTEN YEARS AGO WHEN WE HAD NO IDEA WHAT WOULD BE HAPPENING. WE WOULD BE HAPPY TO TAKE SUGGESTIONS ABOUT WAYS TO REFINE OR MAKE THEM MORE MEANINGFUL BUT NOT SURE WHAT THEY WOULD BE. >> THERE MUST BE A WAY FOLKS WHO WORK IN RETROVIRAL WORK COME TO A CONSENSUS AS TO WHAT THE GUIDELINES FOR TREATMENT SHOULD BE. AND THAT'S BECAUSE AGAIN, THE TWO SIDES OF IT REALLY ARE YOU DONE WANT TO GIVE ANTIVIRALS IF SOMEBODY ASYMPTOMATIC AND IT'S WORKING. IN TERMS OF WHATEVER TARGET IT'S GOING AGAINST. AT THE SAME TIME, YOU WANT TO MAKE SURE THAT EVERYONE WHO IS SYMPTOMATIC FROM VIREMIA IS TREAT SOD THEY'RE NOT HARMED FROM THE PROTOCOL. SO HOW TO PUT THAT IN A GUIDELINE THAT'S USEFUL FOR EVERYONE DOING WORK LIKE THIS WOULD BE USEFUL. I JUST WONDER WHAT THAT FORUM WOULD BE TO COME UP WITH SUCH GUIDELINES THAT I WOULD MAKE AND MUCH MORE UNIFORM. ANY SUGGESTION FROM OTHER RAC MEMBERS? I JUST -- READING IT, IT JUST LITTLE LOSS FOR ME. >> THE REASON IT WAS LOOSE IS BECAUSE WE DIDN'T KNOW -- IF YOU READ THE PROTOCOL VIREMIA IS NOT REALLY A TOXICITY AT THIS POINT. IT'S SORT OF -- IT'S OUR EQUIVALENT OF OF IT IS OURER EQUIVALENT, A BIODISTRIBUTION PHENOMENA, WE DIDN'T KNOW IF IT WOULD BE A TOXICITY, IT'S LIKE MEASURING PK AND PD IN STUDIES OF SMALL MOLECULES CH WE HAVE TO HAVE SOMETHING TO MEASURE SO WE MEASURE IT BUT IT DOESN'T APPEAR TO BE A TOXICITY AND NOT DIFFERENT IN OTHER VIRAL ILLNESSES WHERE PATIENTS ARE VIREMIC AND ASYMPTOMATIC. THE BIG CONCERN IS OBVIOUSLY ABOUT DOES VIREMIA OR SOME WAY PLACE THE SUBJECT AT RISK FOR LYMPHOMA. AND THE DEVELOPMENT OF LYMPHOMA WOULD TAKE A SIGNIFICANT AMOUNT OF TIME WHICH THESE PATIENTS DON'T USUALLY HAVE. AND SO I DON'T KNOW HOW THAT ENTERS THE EQUATION EXCEPT LAST TIME WE DISCUSSED THE FACT THERE ARE SIGNIFICANT DIFFERENCES BETWEEN OUR PROTOCOL AND THE PROTOCOLS IN WHICH INSERTIONAL ONCOGENESIS IS OBSERVED. THESE WERE NOT TREATING EXVIVO, NOT TREATING HEMATOPOIETIC STEM CELLS, NOT USING CYTOKINE EXPANSION, NOT USING MARROW CONDITIONING WITHOUT LEADING AGENTS, THESE ARE NOT KIDS WITH IMMATURE IMMUNE SYSTEMS, THE CDG IS NOT A KNOWN ONCOGENE AND DOESN'T CONFER SURVIVAL ADVANTAGE ON CELLS THAT IS INFECTED WITH WITH. AND IN FACT JUST THE OPPOSITE. IN THE MICE IF THEY GET 5 FC THEY DON'T GET LYMPHOMA. IS THERE'S DIFFERENCES BETWEEN WHAT WE'RE DOING AN INSERTIONFUL MUTAGENESIS IS OBSERVED. SO I DON'T REALLY KNOW WHAT TO TELL YOU ABOUT VIREMIA, I OOHs SOMETHING WE MEASURE, IT'S INTERESTING, DOESN'T APPEAR TO BE IN AND OF ITSELF A TOXICITY. BUT I AGREE, IF A PATIENT WERE SYMPTOMATIC OR HAVING SOME ORGAN PROBLEM, I THINK YES, THEY SHOULD BE TREATED. I ASSUME THE PI AND PATIENT AND OUR INPUT WOULD AGREE TO THAT KIND OF THING. >> ANDREW, DID YOU HAVE A COMMENT? >> I THINK IT'S A INTERESTING DISCUSSION WHAT VIRAL LOAD SHOULD BE A SET POINT OR TRIGGER FOR STARTING ANTIRETROVIRAL THERAPY. IN THE HIV WORLD, HIGH GRADE VIE REMARKS IS NOT A ASYMPTOMAT YOU CAN CONDITION. IN THE ACUTE RETROVIRAL SYNDROME YOU SEE IMMEDIATELY POST INFECTION, IT'S A MONOLIKE ILLNESS WITH HIGH (INAUDIBLE) AND THOSE KIND OF THINGS. BACK IN THER RA WHEN WE DID PER THERAPEUTIC TREATMENT, PATIENTS FORMERLY SUPPRESSED AND STOPPED ON THERAPY STOPPED DEVELOPED A SIMILAR ACUTE RETROVIRAL SYNDROME COUNSEL DENT WITH HIGH LEVEL VIREMIA. WHAT IS HIGH LEVEL VIREMIA, IT'S DIFFERENCE FOR EVERYONE BUT MY EXPERIENCE IN THOSE DAYS, 30,000 COPIES WASN'T HIGH WAS SEVERAL HUNDRED THOUSAND COPIES OR A MILLION COPIES. SO I AGREE WITH THE COMMENT VIREMIA IS NOT A TOXICITY. GIVEN VIREMIA CAN BE A TOXICITY WITH RETROVIRAL SYNDROMES, IT IS APPROPRIATE THE LEAVE AT DISCRETION OF VISITOR WITH CONSULTING HIV EXPERTS WHEN THERAPY SHOULD BE STARTED. FROM MY OWN VIEW POINT THOSE SYMPTOMS SHOULD BE THE TRIGGER. THE CONCERN ABOUT INSERTIONAL MUTAGENESIS BEING MORE LIKELY WITH HIGH VIREMIA VERSUS LESS LIKELY WITH LOW GRADE VIREMIA, NOT SURE I BUY THAT AS A TRIGGER FOR THERAPY. >> VERY GOOD. THIRD REVIEW E DR. DAWN WOOLEY. >> HI, MY FIRST QUESTION WAS ON DOSING. I THINK THAT YOU CLARIFIED THAT SO I HAVE NO FURTHER QUESTIONS ON THAT. THEN THE SECOND QUESTION WAS ON THE RATIONALE FOR THE INTRAVENOUS VERSUS INTRACRANIAL, YOU ADDRESSED THAT FOR REALLY IN YOUR PRESENTATION. IN THE CURRENT STUDY, BOTH ROUTES ARE GOING TO BE DONE THEN THE IV FIRST SO YOU CAN ASSESS HOW MUCH IS GETTING TO THE PERIPHERY AFTER THE RESECTION. EVENTUALLY THOUGH YOU WOULD LIKE TO MOVE TO INTRAVIEIOUS ONLY, IS THAT CORRECT? OR YOU ENVISION THAT? >> AS I SAID WE WOULDN'T BE AGAINST COMBINING THE INTRATUMORAL WHICH HAS THE ABLE TO TARGET, THERE AREN'T A LOT OF ACTIVE BLOOD VESSELS IN THE TUMORS, NOT SURE HOW WELL INTRAVENOUS ALONE WOULD WORK. I CAN IT WILL YOU AFTER STANDING 8, 10 HOURS IN THE OPERATING ROOM WATCHING THESE SERVICES BE PERFORMED I WILL LOVE THIS TO SWITCH OVER INTRAVENOUS DOSING THOUGH I DON'T THINK PATIENTS APPRECIATE THAT. NOT POSITIVE'S AN ASSUMPTION WE CAN MAKE NOW. >> YOU ENVISION BOTH MAYBE NEEDED. >> WE HAVE MAY HAVE TO TARGET ON TWO SEPARATE FRONTS. >> ON THE TWO FRONTS. >> I WAS JUST ENVISIONING WHAT YOU WANTED TO DO IS WHITTLE L IT FROM THE OUTSIDE IN BY GETTING THAT HIGHLY VASCULAR PERIPHERY. WHEN THESE TUMORS REAPPEAR ON THE SLIDE YOU SHOWED IT REOCCURRED NEXT TO THE ORIGINAL? >> 85% OF THE TIME IT OCCURS WITHIN A 1 CENTIMETER ZONE NEXT TO RESECTION CAVITY. >> OKAY. ALL RIGHT. SO I THINK THAT THE RATIONALE WAS THOROUGH. NO OTHER QUESTIONS ON THAT. I WAS THINKING THE DELIVERY METHOD AND I ASKED ABOUT THE SHUNT BECAUSE I WAS ENVISIONING WHITTLING AWAY FROM THE INSIDE OUT. YOU DIDN'T HAVE MUCH SUCCESS IN THE MOUSE WITH THE SHUT, YOU TRIED THAT. >> SHUNTS, ACTUALLY IT -- -- IN HUMANS AS WELL WITH A VARIETY OF AGENTS. SHUNTS ARE LIMITED TO DIFFUSION AND THEY GO A COUPLE OF MILLIMETERS DEEP AND UNFORTUNATELY IT'S NOT ENOUGH TO TAKE ALL THE, THESE ARE RAPIDLY INFILTRATING TUMORS SO IT HASN'T WORKED, WHETHER IT WOULD WORK WITH A VECTOR THAT HAS ABILITY TO MOVE AND DIVIDE, I DON'T KNOW THE ANSWER TO THAT. THE OTHER PROBLEM WITHELas;– THE SHUNT APPROACH, THE ADVANTAGE IS ARC, YOU CAN TEST BY PULLING STUFF OUT OF SHUNT AND B, YOU CAN DO MULTIPLE INJECTIONS WHICH MAYBE BENEFICIAL BUT THE CAVITY FILLS VERY RAPIDLY WITH WITH CEREBRAL SPINAL FLUID VERY OFTEN SO YOU HAVE DELUSIONAL EFFECT AS WELL. SO IF YOU BURY YOUR SHUT IN ONE AREA OF THE RESECTION CAVITY YOU JUST DONE KNOW WHICH AREA IS GOING TO BE THE ONE THAT WHERE THE RECURRENCE POPS UP SO IF YOU ONLY HAVE ONE OR TWO RESERVOIRS IN PLACE AND YOU HAVE TO BURY THAT CATHETER TO KEEP THE VECTOR FROM BEING DILUTEED TO THE CSF, YOU'RE PICKING ONE OR O TWO SURES IF OF SPHERE RECURRENCE CAN OCCUR. >> THAT'S MY QUESTION, WHEN YOU DO A SHUT HOW MANY LOCATIONS CAN YOU APPLY? >> SHUNTS GENERALLY HAVE A RESERVOIR IN A SINGLE CATHETER THAT YOU HAVE TO BURY SOMEWHERE. >> YOU CAN'T HAVE MULTIPLE -- >> RIGHT. >> WHEN YOU DO -- AFTER THE RESECTION AND YOU DO INJECTIONS, HOW MANY POINTS DO YOU INJECT THE AGENTS? >> SO IT DEPENDED ON DOSING COHORT BUT RIGHT NOW WE'RE DOING BETWEEN 25 AND 30 INJECTIONS AT ABOUT .1 ML EACH. WE DID LEARN SOMETHING BY CAREFULLY TALKING TO PHYSICIANS WHO HAD BEEN INVOLVED IN OTHER STUDIES LIKE THIS. THEY DIDN'T LIKE TAKING SHARP NEEDLES AND MAKING BLIND INJECTIONS TO THE BRAIN SO WE'RE USING A BLUNT TIP SIDE FIRING NEEDLE WITH CENTIMETER MARKERS THAT SURGEONS TELL US THEY LIKE. WE HAVE HAD NO INTRAOPERATIVE COMPLICATIONS THUS FAR SO WORKING WITH WELL. >> SO QUITE A FEW DIFFERENCE LOCATIONS. >> UH-HUH. >> I THINK YOU FAIRLY ANSWERED THAT QUESTION ON THE DELIVERY AN WHY A SHUNT MIGHT NOT WORK IN THIS CASE. MY FOURTH QUESTION WAS JUST IN YOUR RESPONSES TO APPENDIX M, ARGUMENT ABOUT SELECTIVITY. AND I THINK THAT YOU ADEQUATELY ANSWERED THAT BECAUSE YOU STILL BELIEVE THAT THE AGENT'S GOING TO TARGET THE TUMOR BECAUSE OF HOW RAPIDLY IT'S DIVIDING AND THERE'S OTHER DIVIDING CELLS, STILL GOING THE HONE IN ON THE TUMOR AND STILL IN THE IMMUNOPRIVILEGED ENVIRONMENT OF THE BRAIN PRIMARILY. >> I THINK THAT ANSWER WAS A GOOD ONE AND I ACCEPT THAT. NOW, QUESTION NUMBER 5, I SEE WHERE YOU'RE GOING, YOU WERE JUST TRYING TO REFER MLV AS NON-LYTIC VIRUS AND EMPHASIZING IT BUDS OUT OF THE CELL. I WAS SEEING AS ENGINEERED THAT ONCE IN THE PRESENCE OF THE PRODRUG IT WILL KILL THE CELL. I THINK THAT'S JUST A WORDING ISSUE THERE. CLARIFIED THAT ANSWER. THE NEXT QUESTION WAS JUST ON HOW INTACT IMMUNE SYSTEM CAN CONTROL THIS VIRUS. DEMONSTRATED IN ANIMAL MODELS. I THINK YOU HAD REFERENCED ONE OF THE PAPERS THAT JUST USED THE INTRACRANIAL. YOU FURTHER CLARIFY YOU HAVE DONE STUDIES IN MICE AND DOGS NOT YET PUBLISHED SO YOU BELIEVE THAT BY AN INTACT IMMUNE SYSTEM WILL CONTROL THIS VIRUS. IN THESE PATIENTS, ARE THEY RECEIVING ANY OTHER TREATMENTS THAT MAY COMPROMISE THEIR IMMUNE SYSTEM? SO THEY DON'T HAVE THE NORMAL INTACT IMMUNE SYSTEM. I THINK YOU ALSO HAD SAID IT'S A MATURE IMMUNE SYSTEM UNLIKE A CHILD, BUT IS THERE ANYTHING YOU CAN THINK OF THAT AGAIN MAY COMPROMISE THEIR ADULT IMMUNE SYSTEM? >> ALL THESE PATIENTS IN ORDER TO GET INTO OUR STUDY HAVE FAILED PRIOR RADIATION TEMAZOLAMIDE. MOST HAVE MILD LYMPHOPENIA WHEN THEY ENTER THE STUDY. SURGEONS FREQUENTLY USE CORTICO STEROIDS IN THE PERIOPERATIVE PERIOD WHICH FURTHER REDUCES LYMPHOCYTES BUT DESPITE THAT, AS I SAID, ALL THE PATIENTS HAVE BEEN ABLE TO CONTROL THE VIRUS THROUGH THEIR OWN IMMUNE MECHANISM, EVERY PATIENT HAS DEVELOPED IMMUNE RESPONSE IN THIS STUDY. >> THAT HAS BEEN ABLE TO CONTROL IT. >> YES. EVEN THE PARENTS THAT DON'T HAVE VIREMIA HAVE ALL DEVELOPED MORE THAN A FOUR, FIVE FOLD INCREASE IN ANTIBODIES OVER TIME. >> OKAY. AND THEN MY NEXT QUESTION WAS JUST ON THE LIMITS OF DETECTION. SO I'M ALWAYS CONCERNED ABOUT SHEDDING AND THERE'S A LOT OF DIFFERENT KINDS OF SECRETIONS AND EXCRETIONS AND SOUNDS LIKE YOU TESTED A NUMBER OF THEM. A LOT OF TIMES PROTOCOLS ARE INTERNAL. WE DON'T SEE THEM PUBLISHED. I CAN'T READ THE TECHNICAL DETAILS. AND I DO SOME OF THIS WORK MYSELF. I'M SPIKING SOME SAMPLES. IT IS TRICKY AND SOMETIMES I'M CONCERNED WE'RE UNDERESTIMATING THE SHEDDING. BECAUSEqAÖ IT'S DEPENDING ON WHEN YOU DO CONTROLS HOW THE SAMPLES ARE SPIKED, WHEN THEY'RE SPIKED, AND SOME OF THESE STAMM SAMPLES LIKE URINE AND STOOL ARE HARSH ENVIRONMENTS SO ONCE YOU PERFORM ALYSIS STEP AND NUCLEIC ASITS ARE EXPOSED AND THERE'S INHIBITORS OF PCR. YOU DID LIST NUMBER OF LIMITS OF DETECTION HERE. AND I SEE THAT FOR THE BLOOD AND URINE IT'S PER ML. A TISSUE IS PER MICROGRAM OF TOTAL DNA THAT YOU HAVE THERE. IF YOU DO THE FECAL SAMPLES, I THINK YOU HAVE THAT LIMIT DETECTION OF COPIES PER MICROGRAM BUT IN FETAL SAMPLE IT'S PER MICROGRAM OF WHAT? THAT'S A TRICKY SAMPLE TO TRY TO DO A SHEDDING. >> THAT'S DNA SO IT'S JUST COPIES PER MICROGRAM OF, >> SO FROM A STOOL SAMPLE YOU ISOLATE TOTAL DNA. >> YEAH. >> BUT I THINK YOU ADDRESSED IN RESPONSE TO THE LAST REVIEWERS, THAT THESE PATIENTS ARE GOING TO BE ADVISED TO BEHAVE AS IF THEY HAVE HIV? >> THE HOSPITAL WILL HAVE THESE WRITTEN GUIDELINES, WE'LL JUST SAY GIVE HEM THE SAFE SHEET WITH EVERYBODY THAT GETS HIV THAT LEAVE IT IS HOSPITAL BECAUSE THE GUIDELINES ARE ESSENTIALLY THE SAME. >> RIGHT. NOW, HOW LONG ARE THEY ADVISED TO FOLLOW PRECAUTIONS? >> FOR EXAMPLE, THE CONDOMS ARE FOR SIX MONTHS OR UNTIL THEIR BLOOD IS NEGATIVE FOR VECTOR, WHICHEVER IS LONGER. FOR THE FOR BODY PIERCING APPROXIMATE ORGAN DONATION, I WOULD SAY IT'S FOR LIFE. >> RIGHT. ARE YOU CONCERNED LIKE WITH WITH HIV THERE ARE RESERVOIRS IN THE BODY, ARE YOU CONCERNED THAT WITH THIS AGENT THAT DOWN THE ROAD THERE COULD BE SOME REACTIVATION OR REPLICATION DOWN THE ROAD AFTER A PERIOD OF APPEARING TO BE NEGATIVE IN THE BLOOD? >> ONE OF THE THINGS WE WORKED ON VERY ASSIDUOUSLY WITH FDA WHEN WE STARTED PROTOCOLS FIVE YEARS AGO WAS THIS CONTINUATION STUDY SO THAT EVERY SUBJECT P WEATHERED IS ENCOURAGED TO ROLL INTO THE CONTINUATION STUDY AND WE FOLLOWED PEOPLE FOR QUITE -- UP TO 18 MONTHS. UNFORTUNATELY MOST ARE STILL DYING. BUT WE HAVE NOT SEEN REAPPEARANCE OF VECTOR. WHEN THOSE PATIENTS ARE DYING, THEY'RE ON HIGH LEVEL -- HIGH DOSE OF STEROIDS TO CONTROL BRAIN SWELLING OR PERITUMORAL EDEMA, SO DESPITE THAT WE HAVE PN'T SEEN REOCCURRENCE OF VIREMIA. >> BUT AS TREATMENT BECOMES MORE SUCCESSFUL YOU MIGHT HAVE YOUNGER PATIENTS WHO ARE NOW LIVING LONGER AND THIS MAY BE AN ISSUE DOWN THE ROAD. >> ABSOLUTELY. WE'RE AWARE GENE TRANSFER GUIDELINES WHICH REQUIRE FOLLOW-UP FOR 15 YEARS, WE HAVE DONE OUR BEST TO MAKE SURE THAT WE TAKE THAT SERIOUSLY. >> MY NEXT QUESTION IS ANTIRETROVIRALS WE DISCUSSED A LOT. I WAS WONDERING WHY INTEGRATION INHIBITOR WAS CHOSEN INSTEAD OF A PROTOYEAH INHIBITOR. WHAT'S THE RATIONALE FOR THAT ONE? >> THERE'S ACTIVITY AGAINST MLV SO MOST HIV DRUGS DESPITE THE FACT AZT THE FIRST ONE DID CAUSE -- INHIBIT QUITE WELL MOST DOPE WORK AGAINST MLB SO THESE ARE THE THREE THAT WORK THE BET BEST. >> BECAUSE EMPIRICALLY IT WAS SHOWN TO AGAINST THE OTHER VIRUS, THE XMRV. >> XMRV. >> I WOULD ALSO THOUGH HIGHLY RECOMMEND TESTING THIS REGIME AGAINST YOUR ACTUAL AGENT. SO I WOULD LIKE THAT INCLUDED. >> WE'LL DO THAT. >> OKAY. THEN MY NEXT QUESTION WAS JUST -- YOU HAD A LOT OF ANIMAL DATA JUST SUMMARIZE WHAT HAD BEEN DONE IN THE MICE AND DOG MODELS. YOU COVERED A LOT OF THAT. WHAT WAS THE DIFFERENCE BETWEEN BIOPSY, STRAIN? WHAT ARE THE PRIMARY DIFFERENCE BETWEEN THE TWO? >> GENETICALLY OR BIOLOGICALLY? >> IN TERMS OF ACTUAL IMMUNE SYSTEMS, THE MICE THEMSELVES. >> PHARMACO LOGICALLY IT'S KNOWN C-57 BLACK 6 IS RELATIVELY RESISTANT TO MLV. YOU CAN TOCA MLV THAT IS. AND ALL NEWBORN MICE IF YOU INJECT GET RYE REAMIC. C-67 BLACK SIX MICE AN HYBRID (INDISCERNIBLE) B-6 MICE, ARE QUITE RESISTANT TO MLR, WHEREAS BIOPSIES KNOWN TO BE PERMISSIVE. THE BASIS FOR THAT IS NOT COMPLETELY UNDERSTOOD BUT IS PRESUMABLY SOMEWHERE AT LEAST A COUPLE OF COMPONENTS, ONE THAT BIOPSY MICE TEND TO MAKE RELATED VIRUSES TO MLV NATURALLY. SO ARE SOMEWHAT TOLLERRIZED TO IT. SECONDLY, THERE IS DATA SHOWING SPLICING ALLELE OF APOBEC THAT MICE MAKE, THE ONE IN C-57 BLACK SICK MAKES THE CELLS AND ANIMAL MORE RHESUS TAN TO MLV THAN SPLICING BALD MICE, THAT'S NOT MEETLY NAILED DOWN EXPLANATION OF THE DIFFERENCE BUT PHENOMENON LOGICALLY IT'S BEEN KNOWN A LONG TIME. >> IN THE RESPONSE THERE WAS A CHART YOU HAVE B-6 F #, 90, 150 AND 180 DAYS. 19 -- IN THAT STRAIN THE LOAD WENT DOWN AND BIOPSY JUST KEPT GOING UP TO ALMOST # .5 MILLION. >> SO THAT'S -- SO COUPLE OF COMMENTS. ESPECIALLY IN THE BALD C MICE, IT'S A PUZZLE BECAUSE THEY'RE HIGHLY INBRED MICE, THIS IS ONE VIRUS, YOU GET A HIGHLY HETEROGENEOUS RESPONSE. TYPICAL A WEEK OF BIOPSY MICE YOU GET ONE THAT DOESN'T INFECT AND YOU GET THREE THAT GETS INFECTED A BIT AND ANOTHER GROUP THAT GETS MORE INFECTED AND THREE MORE THAT SHOOT OFF THE CHARTS BUT YOU CAN SEE THEY'RE STARTING TO GO UP IN THAT PARTICULAR EMPERIMENT. WHEREAS THE B-6 MICE PEAK AROUND 30 DAYS THEN GOES AWAY. >> IN THE BEOPC IT NEVER WHEN DOWN, DO YOU EVER SEE IT START TO GO DOWN? >> WE HAVE NOT FOLLOWED MICE THAT MUCH PAST 180 DAYS. WE DID SOME 210 DAY EXPERIMENTS. WE HAVE NEVER SEEN IT GO SIGNIFICANTLY DOWN, IT BOUNCES AROUND A BIT FOR SOME OF THE ANIMALS. >> OKAY. SO FOR ONE STRAIN IT JUST KEEPS GOING UP AND THE OTHER SO IN TERMS OF HUMAN STUDY, WHAT IF THEY BEHAVE MORE LIKE THE BIOP C? >> THEY -- SO FAR THEY DONE. >> YEAH. >> >> INTERESTINGLY IN THE BIOP C MICE THEY DOPE GET LYMPHOMA. THEY DONE. SO WE'RE TREATING OUR SUBJECTS WITH 5 FC. >> MY NEXT QUESTION ON THE MONKEY STUDY, A CLARIFICATION TO MAKE SURE IT WAS STATED THAT THAT WAS A SHORT TERM EXPERIMENT. UP TO TWO YEARS AN LONG TERM EFFECTS WERE UNKNOWN. YOU HAD TAKEN THAT ADVICE AND YOU WERE GOING TO AMOUNT IT AND ADD THAT LONG TERM EFFECTS WERE NOT KNOWN. >> THAT'S CORRECT. >> THE NEXT QUESTION WAS YOUR RESPONSE TO APPENDIX M, EXAMINING THE DNA ACROSS THE IRIS CD REGION, YOUR STATEMENT HAS SAID THE VIRUS BUT LARGELY INTACT WHICH JUST MADE ME BELIEVE THERE WERE OTHER THINGS GOING ON, THERE WERE OTHER POPULATIONS WITH SOME REARRANGEMENTS, WE DID SEE MINOR FRACTIONS WITH SIGNIFICANT DELETIONS. >> THAT WAS AN EXPERIMENT PCRED ACROSS THE IRS CD, I WITHIN INTO DETAIL THERE. THE RESULTS WERE MOSTLY REASSURING BUT WE DID SEE SOME THINGS THAT LOOKED LIKE SMALLER BANDS ON GEL AND MOST OF THOSE ARE MAJORITY OF THOSE SEEM TO BE JIB RUSH WHEN WITH SEQUENCE THEM BUT SOME HAD DELETIONS IN THEM. THE CONFUSING THING WAS WE HAVE SEEN IN THAT EXPERIMENT WE HAVE SEEN THAT WITH A PLASMID. SO IT WAS DIFFICULT TO INTERPRET BECAUSE THE QUESTION BECOMES DELETION OF PLASMID SO WE NEVER WORK THAT BECOME WARDS, WE DECIDED TO CLONE THE VIRUS AND SEQUENCE IT. >> ANY NEXT QUESTION WAS IcV’RR'K THERE WAS A STATEMENT THAT YOU MADE THAT RISK OF VIRAL DISSEMINATION OUTSIDE THE TUMORS THEORETICAL BUT YOU ARE GIVING IT SYSTEMICALLY. I REALIZE YOU'RE ASSAYING IT WILL HONE IN AND GO THERE BE YOU SAID YOU'LL CLARIFY YOUR RESPONSE TO INDICATE. IT'S OVER INITIALLY AND HONE IN ON THE TUMOR. YOU SAID YOU WERE GOING TO CLARIFY YOUR RESPONSE ON THAT. I JUST WHEN YOU REFER TO THE TOCA 5 # 1 AS A DRUG, I JUST WAS CONCERNED THAT MAY BE MISLEADING BECAUSE THERE'S REPLICATING VIRUS. SO I PREFER AGENT BUT YOU CLARIFY FOR THE REGULATORY PURPOSES IT WILL BE CALLED A DRUG PRODUCT. BUT THE PATIENTS WILL BE MADE AWARE IT IS A REPLICATING VIRUS. ON THE CONSENT FORM JUST A CLARIFICATION THERE WAS A STATEMENT THAT IT'S A SMALL LIVE VIRUS. I'M PICTURING MYSELF AS LAY PERSON READING THIS AND THINKING MAYBE IT'S SAFER BECAUSE IT'S SMALL. SMALLER THAN OTHER AND YOU SAID YOU WOULD CLARIFY THAT, JUST PUT IN THAT IT'S A LIVE VIRUS. I DIDN'T WANT ANY MISUNDERSTANDING OF THE PATIENTS. THEN I THINK MY LAST ONE WAS ON THE RISKS OF THE STUDY, I THINK YOU HAD A SEPARATE SECTION, TRANSMITTING TO OTHERS BUT AS I WAS READING IT ONE POINT I THOUGHT MIGHT BE WORTH MENTIONING IN ANOTHER PART OF THE CONSENT FORM. BECAUSE IT SEEMED TO BE APPROPRIATE THERE BUT YOU ADDRESSED IN THE OTHER SECTION LATER. SO I'M OKAY WITH THAT. THAT'S ALL I HAVE. >> THANK YOU. SO ANY UNRESOLVED ISSUES? >> NO BUT I DID WANT THE RECOMMENDATION OF TESTING ON ANTIRETROVIRAL DRUGS. >> SOCIETY WILL E ME CLARIFY AN INTERCHANGE IN THAT DISCUSSION. OBVIOUSLY ONE MOST IMPORTANT THING PIECE OF DATA WE COULD GET IS LONG TERM WHETHER THERE'S REACTIVATION PARTICULARLY UNDER STEROID CONDITIONS. PEOPLE WITH HIGH GRATE GLIOMAS HAVE BAD OUTCOME AND MANY DIE WITHIN A SHORT PERIOD OF TIME AFTER TREATMENT. SO MY QUESTION TO YOU, SINCE THAT DATA IS IMPORTANT AND BETTER THAN DOING PRIMATE DATA WITH LONG TERM FOLLOW-UP AND NEWSPAPER SUPPRESSION TO LOOK FOR REACTIVATION, THIS IS ACTUALLY HUMAN DATA, IS THERE A MECHANISM WHEREBY YOU MEASURE REACTIVATION IN THOSE TERMINAL PATIENTS AT T THE END OF THEIR LIVES? IS THERE A WAY YOU'RE LOOKING AT TITERS IN THOSE PATIENTS? SO HOW OFTEN ARE YOU GETTING IT AND WHEN ARE YOU GETTING THOSE SAMPLE? >> THE CONTINUATION PROTOCOL, OR LONG TERM SAFETY PROTOCOL, IF YOU HAVE NEGATIVE RTPCR YOU GET EVERY THREE MONTHS FOR THE FIRST YEAR TWICE A YEAR AFTER THAT, THROUGH YEAR FIVE. IF YOU ARE POSITIVE RTPCR YOU CONTINUE THE MONTHLY CHECK. WE HAD A COUPLE OF LONG TERM SURVIVORS, WE FOLLOWED SOME OUT 18 MONTHS SO WE HAVE SOME DATA. BUT IT'S VERY DIFFICULT TO GET PEOPLE NEAR THE EPIOF THEIR LIVES TO DO THINGS THAT ARE MORE FOR SCIENTIFIC PURPOSES THAN THEIR OWN BENCH WE WORK HARD AT IT. OUR INVESTIGATORS UNDERSTAND THAT AN ARE GOOD ABOUT IT TOO. >> THERE'S LOT OF BLOOD DRAWN MANY TIMES IN TREATMENT AN PALLIATION WOULD BE GREAT TO GET SAMPLES. IF YOU'RE COVERED BY A PROTOCOL TO LOOK, WOULD LOVE TO SEE THAT DATA AND KNOW THE TITERS AT THE END OF LIFE CITY PATIENTS IN YOUR STUDY? >> WE HAVE FEW, I DON'T KNOW IF THERE ARE ANY TOLL BODY AUTOPSIES. WE HAVE PROBABLY TWO OR THREE BRAIN ONLY AUTOPSIES. WHAT WAS INTERESTING AND SURPRISING TO ME WAS NUMBER OF RERESECTIONS WE HAVE AFTER AD MEN STRAIGHT, WE HAVE 8, 10 RERESECTIONS WHICH HAS GIVEN US VALUABLE INFORMATION ON TUMOR, SPREAD CHARACTERISTICS, LOCATION, PRESENCE OF CD GENE, ET CETERA. WE HAVE THOSE DATA, WOULD BE HAPPY TO SHARE THEM. THOSE RESECTION DATA WERE SOME OF THE FIRST DATA THAT CLUED US IN WE NEEDED TO START ADMINISTERING THE b]% VECTOR WITH REAL TIME MRI GUIDANCE TO GUARANTEE WE WERE TARGETING THE TOW TUMOR. THAT'S WHAT WE DO NOW IN THE INTRATUMORAL PROTOCOL. >> LOOK FORWARD TO SEEING THAT IN PUBLICATION SO THE FIELD CAN SHARE THAT DATA. THAT WOULD BE WONDERFUL. ANY OTHER COMMENTS FROM RAC MEMBERS? MARSHALL. >> I COMPLETELY AGREE TREATING THE RY WITH INTRAVENOUS MEDICATION IS POTENTIALLY GOING TO HAVE BENEFIT. CAN YOU I ALSO AGREE -- >> CAN YOU SPEAK INTO THE MICROPHONE? >> IT'S NOT LIKELY TO HAVE A MAJOR AFFECT AT THE CORE OF THE TUMOR WHERE YOU HAVE RELATIVELY LIMITED BLOOD SUPPLY. SO DO YOU HAVE ANY STUDIES OF SIGH MULL TAPEIOUS INTRAVENOUS AND INTRATUMORAL INJECTION AND SEEING WHAT HAPPENED? >> IN HUMANS NO. IN MICE WE HAVE DONE MULTIPLE ADMINISTRATION DATA. MICE WE HAVE DONE IT WITH DIFFERENT COLORED MARKERS SO YOU CAN SEE WHO IS WHERE. WE GO TO SOMEWHAT DIFFERENT CELLS. >> WHAT HAPPENS WITH THAT RELATIVE TO EITHER ONE IN ISOLATED FASHION, ARE THE RESULTS BETTER? >> THEY LOOK ABOUT THE SAME ACTUALLY. YOU GET SOME OVERLAP. WITH THE IV ADMINISTRATION IN THE MICE, THEN YOU GET A SPREAD THROUGHOUT THE TUMOR MORE EVENLY WITH THE INTRATUMORAL, IT WAS ONE OF THE REASONS DIFFICULT TO INTERPRET BECAUSE WE KNOW IN THE MICE THAT RELATIVE VOLUMES WERE GIVEN YOU GET REFLECT AND IT GOES AROUND THE OUTSIDE OF THE TUMOR. SO YOU SEE A DIFFERENT DISTRIBUTION. >> BECAUSE THE QUESTION IS, IF THAT'S THE THEORETICAL ADVANTAGE, I AGREE WITH IT, YOU SAID IN THE FUTURE YOU DO HAVE SOME DATA WHY NOT ANOTHER ARM TO THIS STUDY? YOU DO THIS IV, YOU GET SOME DATA ALL THAT TAKES TIME, THESE ARE PATIENTS THAT DOPE HAVE A LOT OF TIME AND IF YOU IN THEORY THINK YOU'RE GOING TO HAVE ADDITIONAL BENEFIT, WHICH I DO, BY SIGH MULL TAPEIOUS TREATMENT OF BOTH REGIONS, WHY WAIT? >> THIS PROTOCOL IS REALLY A TWO REGION ADMINISTRATION. WE'RE DOING INTRAVENOUS AND INJECTING -- >> NOT AT THE BEGINNING. >> NOT AT THE BEGINNING. >> THAT COULD CLEARLY HAVE SOME ADVANTAGE. YOU ARE PRE-SELECTING THE CELLS THAT ARE RHESUS TAN. I THINK IF YOU DO WORK WITH TUMORS YOU GIVE IT EVERYTHING YOU HAVE UP FRONT. SO THERE IS LESS LIKELIHOOD FOR THAT TO OCCUR. AND BACK HERE IN SIX MONTHS CAN I DO BOTH AT THE SAME TIME? >> I ASK -- THERE IS RAC FREQUENT FLYER AWARD. BUT THE REAL ANSWER TO YOUR QUESTION IS, WE FELT IT WAS IMPORTANT TO DEMONSTRATE THE INTRAVENOUS DELIVERY SEEDD THE TUMOR. WE CAN'T DO AN EFFICACY STUDY IF THAT PREMISE IS NOT MET. >> ABSOLUTELY BUT YOU CAN HAVE ANOTHER ARM OF THE STUDY. >> TAKE YOU UP ON THAT. Q. ANY OTHER COMMENTS FROM RAC MEMBERS? ANY COMMENTS FROM PEOPLE ON PHONE? ANY PUBLIC COMMENTS? WHY DONE WE TAKE A FIVE MINUTE BREAK AND WE WILL READ THE RECOMMENDATIONS BACK TO THE INVESTIGATORS. >> OVERALL I THINK THE ALL THE CONCERNS OF THE REVIEWERS HAVE BEEN ADDRESSED. DIRECTLY. AND THERE REALLY IS JUST ONE RECOMMENDATION FROM THE RAC FOR THIS MORNING'S PROTOCOL. AND I WILL READ THE RECOMMENDATION. THE PROTOCOL PROPOSES TO USE ANTIVIRAL AZT TANOVOFIR TO ADDRESS VIREMIA OR IF NEEDED POST EXPOSURE PROPHYLAXIS. WHILE THE ANTIVIRAL ACTIVITY OF AZT AGAINST TOCA 511 IS CONFIRMED THE PROPOSAL TO USE THE OTHER ANTIVIRALS BASED ON EXTRAPOLATION ON DATA THIS SHOWS APT VIRAL ACTIVITY AGAINST THE MURINE RETROVIRAL XMRV, THE ANTIVIRALS TONOFOVIR AGAINST TOCA 511 SHOULD BE DIRECTLY TESTED SO THAT WOULD BE THE ONLY RECOMMENDATION WE HAVE. ARE THERE ANY ADDITIONS OR CHANGES FROM OTHER MEMBERS AT THE TABLE? ANDREW? >> ONLY ONE, IF ACTIVITY IS NOT DEMONSTRATED FOR TWO AGENTS, ADDITIONAL AGENT (INAUDIBLE). >> OKAY. DID WE FIND A DIFFERENT REGIMEN DID YOU SAY IN IS >> YES. >> CAN WE TEST THOSE INDIVIDUALLY OR DO YOU WANT TO TEST IN COMBINATION? >> INDIVIDUAL IS FINE. >> OKAY. THANK YOU. >> ANY OTHER RECOMMENDATIONS? ANY COMMENTS? THEN LET'S TAKE A VOTE ON THE RECOMMENDATIONS. LET'S START WITH DR. KOCH. >> KOCH APPROVE. >> (INAUDIBLE) YES. >> KIEM. YES. >> CHIACCI. YES. >> ORNELLES, YES. >> ROSS, YES. >> PILEWSKI, YES. >> KOHN, YES. >> FONG, YES. >> (INDISCERNIBLE) YES. >> (INAUDIBLE) YES. >> CANON. YES. >> STROME, YES. >> KIEM, YES. >> (INAUDIBLE), YES. (OFF MIC) >> MEMBERS ON THE PHONE? >> MALLINO, YES. >> ANYBODY ELSE ON THE PHONE? THANK YOU VERY MUCH FOR SHARING YOUR INFORMATION WITH US THIS MORNING. >> THANK YOU. WE WILL TAKE ANOTHER FIVE MINUTES WHILE SLIDES ARE BEING LOADED. THEN WE E WILL RESUME WITH THE NEXT PROTOCOL. >> WHY DON'T WE GET STARTED. THE NEXT PROTOCOL IN THE DISCUSSION THIS MORNING IS PROTOCOL NUMBER 1304-1219. IT'S ENTITLED A PHASE 1/2 OPEN LABEL DOSE ESCALATION STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SINGLE DOSE OF TT-034 IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION. THE PI WILL BE PRESENTING TO US THIS MORNING, IT IS DR. KEYUR PATEL WHO IS ASSOCIATE PROFESSOR OF MEDICINE FROM THE DEPARTMENT OF GASTROINTEROLOGY DUKE UNIVERSITY MEDICAL CENTER. THE SPONSOR OF THIS PROTOCOL IS TACERE THERAPEUTICS INC.. YOU WILL LIKE TO INTRODUCE YOUR COLLABORATORS OR ASSOCIATES FOR US THIS MORNING? >> THANK YOU TO THE ADVISORY COMMITTEE FOR ALLOWING US TO PREP OUR PROTOCOL ENTITLED FACE 1, 2 OPEN LABEL DOSE escalation study to evaluate the safety and efficacy of single doses of TT-034 in patients with chronic Hepatitis infection if. KEY PERSONNEL LISTED HERE, MYSELF AS PRINCIPLE INVESTIGATOR AND FROM UCSD ON THE WEB AND TACERE, DAVE SEELY, DR. FRAZIER WRIGHT, STAYTY (INAUDIBLE) AND DR. SCRIBNER AS WELL. SO THE BACKGROUND 130 TO 150 MILLION CHRONIC INFECTED HEPATITIS C PATIENTS WORLD WIDE. WE KNOW IT'S LEADING CAUSE OF CIRRHOSIS, HEPATOCELLULAR CARCINOMA AND LIVER TRANSPLAINATION IN DEVELOPED NATIONS. CURRENT STANDARD OF CARE FOR HEPATITIS # IS TRIPLE THERAPY BROUGHT TO 48 WEEKS. WE KNOW SBR RATES ARE UP TO 5% IN CIRCUMSTANCES BUT HAVING THERAPIES INTERFERON BASED APPROXIMATE P ASSOCIATED WITH SEVERE SIDE EFFECTS AND THERE ARE ISSUES OF COMPLIANCE. HOWEVER, NEW THERAPIES ON HORIZON ARE AIMED INTRAFOREIGN TREATMENT FOR 8 TO 12 WEEKS AND WE HAVE SEEN CURE RATES OF BETWEEN 40 TO 90% IN EARLY CLINICAL TRIALS. HOWEVER, BENEATH THE BEAR TREATMENTS DOES REMAIN, IDEAL TREATMENT WOULD BE VERY SHORT DURATION, HAVE HIGH CURE RATES, ALMOST NO SIDE EFFECTS AND PROVIDE BROAD COVERAGE FOR ALL POPULATIONS WITH CHRONIC HEPATITIS C INFECTION. SO TT-034 HAS MANY ATRY BUYS OF IDEAL THERAPY FOR HEPATITIS C INFECTION, THIS IS AN RNAi THERAPEUTIC INTENDED AS A ONE SHOP CURE. INCLUDES A RECOMBINANT A B ADENOASSOCIATED GENE DELIVERED BY ARCAV 8 RECTOR WITH HIGH LIVER TROPISM. CONTINUOUSLY PRODUCES REPLENISHING POOL OF SHORT -- FOR 180 DAYS CH THESE SHORT PAIR PIN RNAs TIDE THREE SEPARATE HIGHLY COB SERVED REGIONS OF THE GENOME AND HAS A CAPABILITY FOR NEAR COMPLETE HEPATOCYTE TRANSDUCTION. THE GOAL IS TO ACHIEVE COMPLETE ELIMINATION OF VIRUS OR SUSTAINED VOLATILE RESPONSE WITH SINGLE INFUSION TO ELIMINATE LONG TREATMENTS IN PATIENT CLIENT ISSUES IN CLINIC. WE HAVE SEEN LOW TOXICITY AND ANIMAL STUDIES TO KATE. THERE'S POTENTIAL IN COMBINATION WITH SMALL MOLECULE THERAPIES AND NON-RESPONDERS TO THIS AGENT CAN GO ON TO STANDARD THERAPIES. HOWEVER, ONCE ADMINISTERED THERE IS NO ABILITY TO WITHDRAW THIS TREATMENT. SO OVERVIEW OF EXPRESSION FROM TT-034, WE HAVE THREE INDEPENDENTLY TRANSCRIBED RNAi ELEMENTS THAT TARGET THREE SEPARATE HIGHLY CONSERVED REGIONS OF THE GENOME. YOU CAN SEE SH RNA IS 19 AND 22 TARGET NOT OVERLAPPING REGIONS OF THE NS 5B POLYMERASE REGION AND IT TARGETS FIVE PRIME UTR OF THE HOPE C GENOME TO PREVENT GENERATION OF ESCAPE MUTANTS. ALSO ALLOWS THE IDEA OF COMBINATION DRUG IN ONE THERAPEUTIC ENTITY AS MUCH IN COMBINATION THAT WE'RE SEEING IN DEVELOPMENT. THIS PROVIDES BROAD PATIENT APPLICABILITY WHILE MAINTAINING SPECIFICITY. LOOKING AT MODE OF TT-034 AGAINST HEPATITIS INFECTIOUS CYCLE, LOOK AT THE REPLICATION CYCLE OF HEPATITIS C VIRUS. THE ENTIRE LIFE CYCLE IS WITHIN THE CYTOPLASM. FOLLOWING RECEPTOR MEDIATED ENDOCYTOSIS, IT UNDERGOES TRANSLATION, PROCESSING, THEREAFTER ASSEMBLY THROUGH NEGATIVE STRAND INTERMEDIATE PACKAGES AND EXOCYTOCYTOSIS. INTO THE NUCLEUS, WHERE THE HOSTS TRANSCRIPTIONAL MACHINERY PRODUCES THREE INDEPENDENT SHORT RNAs WHICH THEN EXPORTED INTO THE CYTOPLASM THROUGH EXPORTING 5, UNDERGO CLEAVAGE WITH THE RNA DICER INTO DOUBLE STABBED RNA AND THE GUIDE STRANDERRED IS LINKED ON TO THE RISK COMPLEX WHICH THEN LOCATES THE TARGET mRNA ON THE HEPATITIS C POSITIVE AND NEGATIVE STRANDS RESULTING SUBSEQUENT CLEAVAGE OF THE VIRAL RNA WITH IS THEN CLEARED THROUGH HEPATOCYTES, THIS WAS RESULTS IN NO PACKAGING AND NO REPLICATION COMPLEX NOT CLEARANCE OF THE HEPATITIS C VIRUS. SO TT-034 IS ONMIZED FOR SAFETY AND EFFICACY. THE FIRST GENERATION COMPOUND TT-034 -- TT-0 # 3 WAS NEGATIVE TO TOXICITY IN ANIMAL MODELS, ASSOCIATED WITH VERY HIGH SH RNA LEVELS. MODIFICATIONS TO THE (INAUDIBLE) ENGINEER TRANSDUCTION OF HEPATOCYTES AND BIODISTRIBUTION OF PROPERTIES. TT-034 ACTIVITY GENES 1B REPLY CON MODELS APPROXIMATE INP FACTIOUS TISSUE CULTURE SYSTEM SHOWN HERE, ONE ISSUE WITH DRUG DEVELOPMENT IN HEPATITIS C INFECTION THE ABOUT SEN OF SMALL ANIMAL MODEL OF HEPATITIS C INFECTION THUS WE USE THE INDUSTRY STANDARD OF REPLY CON HERE ON THE LEFT. LOOKING AT REPLY CON MODELS 1A AND B SHOWING ACTIVITY AGAINST 1 A AND 1B REPLY CONS ON THE RIGHT. WE CAN SEE A FISH THE SHOE CULTURE SYSTEM USING (INDISCERNIBLE) TT-034 MAINTAINS ACTIVITY IN CELL CULTURE MODELS. THIS SLIDE I'LL WALK YOU THROUGH, IT'S A LITTLE COMPLEX BUT TT-034 LOOKS CLINICALLY RELEVANT DOSES THAT PRODUCE EFFICACIOUS SHORT HAIR PIN ION LEVELS IN ABSENCE OF TOXICITY SO ON THE LEFT THIS IS A REPLY CON MODEL SHOWING PERCENTAGE OF INHIBITION. ALONG WITH THE EXPRESSION OF SH RNA 6, 19 AND 22 SHOWN IN RED, GREEN AND BLUE RESPECTIVELY. WE CAN 20 TO 220 COPIES OF SH RNA PER CELL IS ENOUGH TO RESULT IN 100% INHIBITION OF THE REPLY CON. LOOKING OVER TO THE RIGHT, WE CAN SEE A DOSE DEPENDENT INCREASE IN EXPRESSION OF SH RNA 6, 22 AN 19. WITH INCREASING DOSES. REMEMBERING THAT REPLY CON MODEL CONTAINS BETWEEN 800 AND 1,000 GENOMES PER CELL. COMPARED TO HEPATOCYTE WHICH WE BELIEVE CONTAINS 15 TO 20 GENOME COPIES PER CELL. SO THE RESULTING EXPRESSION OF SH RNA 22 AND 19, HUNDREDS THOUSANDS LEVELS WOULD BE EXPECTED TO ACHIEVE INEXHIBITION OF VIRAL REPLICATION. THE MIDDLE GRAPH HERE, SHOWS THE RISK OF LIVER TOXICITY WITH ALT FOLLOWED IN THE NON-HUMAN PRIMATE MODELS, WE CAN SEE IT WAS REALLY MINIMAL LIVER TOXICITY NOTED OVER 50 DAY PERIOD IN THE NON-HUMAN PRIMATE MODELS. SO SUMMARY OF TT-034 GLP DATA, SUSTAINED PREFERENTIAL TRANSDUCTION OF HEPATOCYTES AND SH RNA EXPRESSION. 180 DAY GLP STUDIES IN 520 MICE APPROXIMATE 80 NON-HUMAN PRIMATES THREE DOSE LEVELS. MINIMAL TRANSIENT ADVERSE EVENTS, NO TEST ARTICLE RELATED FINDINGS AND CLINICAL OBSERVATION, BODY WEIGHTS, FOOD CONSUMPTION, GRACE PATHOLOGY ORGAN WEIGHTS AND NON-HUMAN PRIMATE IT IS HIGHEST DOSE ONLY AT ONE TIMES TEN TO THE 13 VECTOR GENOMES WAS ASSOCIATED WITH TRANSIENT INCREASE THE LIVER TRANSAMINASES ON DAY 4. THIS WAS UNLIKELY TO DUE TO TRANSGENE EXPRESSION AND RESULT BY THREE WEEKS. IN MICE MINIMAL (INAUDIBLE) ADRENAL GLANDS IN ONE OF 15 MALES AT MIDDLE DOSE RANGE, ONE TIMES TEN TO THE 12 VECTOR GENOMES PER KILOGRAM AND FOUR OUT OF 15 MLs AT HIGH DOSE ONE TIMES TEN TO THE 13 VECTOR GENOMES PER KILOGRAM. NECROPSY THIS IS CONSIDERED NON-ADVERSE AND NO SIGNIFICANT MICRORNA SAFETY FINDINGS. SO I'LL GO THROUGH THE CLINICAL PROTOCOL OUTLINE, THIS IS PHASE 1, 2 STUDY DESIGNED OPEN LABEL, SINGLE DOSE SAFETY STUDY IN HEPATITIS C PATIENTS. FIVE DOSAGE COHORTS ARE PLANNED. THERE IS A DATA SAFETY AND MONITORING BOARD REVIEW AFTER THE FIRST PATIENT IN EACH COHORT AND BETWEEN COHORTS. EXTENSIVE SAFETY MONITORING DURING 24 SUBS WEAPON OBSERVE VISION AND LIVER WHICH COIN SIDES WITH EXPECTED PEAK OF SHORT HAIR PIN EXPRESSION WHICH INCLUDES ASSAYS FOR DNA TRANSDUCTION SH RNA EXPRESSION AND HISTOPATHOLOGY. SO END POINTS THROUGH WEEK 24. THE PRIMARY END POINTS, IS SAFETY. INSTANCE OF TREATMENT ADVERSE ETCHES AN CHANGES IN CLINICAL PARAMETERS. SECOND END POINTS INCLUDE EFFICACY, PK AND PD MEASURES, ASSESSED THROUGH CHANGES IN RNA, ASSOCIATED WITH VIRAL VECTOR, LAS VEGAS BIOPSY, AS WELL AS BLOOD VECTOR SH RNA EXPRESSION LEVELS IN THE EXSOMES AN SERUM. SO THESE ARE THE KEY INCLUSION CRITERIA, STUDYING ADULT PATIENTS AND CHRONIC HEPATITIS C GENE INFECTION, TREATMENT FAILURES OR RELAPSES TO CURRENT STANDARD CARE, TRIPLE THERAPY OR INELIGIBLE OR UNWILLING TO RECEIVE STANDARD OF CARE TRIPLE THERAPY WITH NERVE AND CIRRHOSIS AT SCREENING. KEY EXCLUDING CRITERIA SHOWN HERE. WHICH MAY ABROGATE TRANSDUCTION, SEVERE DISEASE OR HISTORY OF HE PATH CELLULAR CARCINOMA OR SUSPICION OF HCC AND CO-INFECTION WITH WITH HIV ONE OR TWO OR HEPATITIS B INFECTION. SO THIS TABLE SHOWS A DOSE ESCALATION SCHEME PLANNED COHORT, ONE WILL BE STARTED AT DOSE OF FOUR TIMES TEN TO THE TEN VECTOR GENE COPIES PER KILOGRAM. THIS DOSE IS 250 FOLD LESS THAN THE OBSERVED SURVEILLANCE IN NON-CLINICAL STUDIES, THIS IS FIRST IN HEIM STUDY AND SAFETY IS OUR PRIMARY MEASURE IN THIS STUDY. SO EEL START WITH DOSE OF 4 TIMES TEN TO THE TEN. THERE'S TWO SUBJECTS WHO ARE SEQUENTIALLY, OBSERVATION PERIOD OF SIX WEEKS. BETWEEN COHORTS BEFORE DOSE ESCALATION, .5 BLOGS FOUR TIMES TEN TO THE 12 VECTOR GENOME COPIES PER KILOGRAM. NOTE COHORTS FOUR AND FIVE IS A TEN WEEK OBSERVATION PERIOD BETWEEN SUBJECTS AND COHORTS. THIS COIN SIDES WITH EXPECTED PEAK OF T-CELL INDUCTION WHICH IS IS SEEN PRIOR STUDIES BETWEEN 7 AND 9 WEEKS, REFERRING TO THE THE AAVA VECTOR STUDIES IN HEMOPHILIA B. PRE-TRIAL SCREEN ASSESSMENTS ARE SHOWN HERE, CLEARLY INFORMED CONSENT FOR CLINICAL AND LABORATORY ASSESSMENTS CARRIED OUT WITH IMPORTANTLY NEUTRALIZING ANTIBODIES AS WELL AS T-CELL RESPONSES USING THE INTERFERON GAMMA ELISPOT ASSAY TO AAV-8. THE ASSESSMENTS THE ASSESSMENTS INCLUDE COMPREHENSIVE CLINICAL LABORATORY ASSESSMENTS AND IMPORTANTLY THIS WILL INCLUDE LIVER ENZYMES AND FUNCTION,TRY POE ANYONE, NEUTRALIZING ANTIBODIES TO AAV-8, T-CELL USING ELLE SPOT ASSAYS TO AAV-8. VECTOR BODY FLUIDS AND SOME ASSESSMENT IN EFFICACY THROUGH HCV RNA MEASUREMENT AND TARGET SEQUENCING, AND LIVER BIOPSY DAY 21 AS MENTIONED PREVIOUSLY TO ASSESS DNA TRANSDUCTION SH RNA TRANSDUCTION HISTOPATHOLOGY. SO THIS SHOWS DOSE ESCALATION STOPPING RULE TONS LEFT. THE DOSE EXCALATION CRITERIA, IT CAN BE EXTENDED IN THE EVENT OF ONE EPISODE OF DOSE LIMITING TOXICITY. IF THEY EXPERIENCE DIFFERENT DOSE LIMBING TOXICITIES THE DOSING IS SPECIFIC LEVEL WILL BE STOPPED IN TWO EPISODES OF THE SAME DLT. FROM YOU CAN SEE THE STOCKING RULES, DOSING WILL BE STOPPED THE FOLLOWING DEATH GRADE 3ER 4 TOXICITY POSSIBLY RELATED TO STUDY DRUG. AND BILIRUBIN INCREASED AS SHOWN POSSIBLY RELATED TO THE STUDY DRUG OR ANY OTHER SERIOUS ADVERSE EVENTS POSSIBLY RELATED TO THE STUDY DRUG. SO THE SUMMARY FOR THIS COMPOUND IS A NOVEL TREATMENT FOR HEPATITIS INFECTION, IT IS AN RNAi BASED WITH GENE VECTOR WHICH PRODUES SH RNA LONG TERM. NOT OVERLAPPING HIGHLY CONSERVED REGIONS OF THE GENOME REDUCE IT IS LIKELIHOOD OF ESCAPE MUTANTS. WE HAVE EXTENSIVE NON-CLINICAL DATA SUPPORTING PROGRESS OF TTA-3 TO CLINICAL DEVELOPMENT. THIS IS A PHASE 1, 2 STUDY WITH CAREFUL DOSE EXTENSIONSIVE MONITORING. IT'S ONE HOCK CURE FOR HEPATITIS INFECTION. IF ACHIEVED THIS PROVIDES POTENTIAL FOR A PARADOX SHIFT IN HEPATITIS C TREATMENT. THANK YOU FOR YOUR ATTENTION. >> VERY GOOD. THANK YOU, VERY MUCH. WE HAVE TWO INVITED REVIEWERS FOR THIS PROTOCOL THAT FIRST IS DR. WILLIE MADDREY FROM THE UNIVERSITY OF TEXAS SOUTH WESTERN MEDICAL CENTER IN DALLAS. HE IS A HOFFMAN DISTINGUISHED CHAIR IN MEDICAL SCIENCETIS AND ASSISTANT PRESIDENT OF UNIVERSITY OF TEXAS SOUTH WESTERN. RECEIVED HIS MEDICAL DEGREE IN BALLET MOORE COMPLETED RESIDENCY AT THE JOHNS HOPKINS HOSPITAL. FROM 1982 TO 1990 HE WAS THE MCGHEE PROFESSOR AND CHAIRMAN DEPARTMENT OF MEDICINE JEFFERSON MEDICAL COLLEGE. HE HAS PUBLISHED EXTENSIVELY ON AREAS OF CHRONIC VIRAL HEPATITIS DRUG INDUCED LIVER DISEASE ALCOHOL INDUCED LIVER DISEASE, LIVER TRANSPLANTATION AND PRIMARY BILLION RUBIN CIRRHOSIS. SO DR. MADDREY, IF YOU CAN BRING UP YOUR POINTS OF REVIEW AND THEN LET US KNOW WHETHER THEY HAVE BEEN SATISFACTORILY ADDRESSED BY THE INVESTIGATORS. >> THANK YOU FOR INVITING ME TO PARTICIPATE. WHEN I REVIEWED THIS MATERIAL, I KEPT THINKING BACK TO MY AREA OF EXPERTISE WHICH IS IN VIRAL HEPATITIS, NOT IN THIS BRANCH OF SCIENCE. SO I WENT TO SOME OF MY FRIENDS AND GOT A QUICK COURSE AFTER MY FRIENDS DECIDED THAT A QUICK COURSE WOULD BE AS GOOD AS A LONG COURSE FOR ME WITH MY CAPACITY. I WENT BACK TO MY AREA OF EXPERTISE WHICH IS VIRAL HEPATITIS. THERE IS NO QUESTION THERE IS A NEED FOR THE EQUIVALENT OF A ONE SHOT APPROACH. BECAUSE WE FEEL NOW WITH THE CURRENT MEDICATIONS WE HAVE GONE TO ONLY APPROACH A GROUP OF INDIVIDUALS, THEY'RE NOT APPROACHABLE WITH THE TYPES OF DRUGS BEING DEVELOPED. SO I'M ALL FOR THIS ONE SHOT IDEA IF IT WORKS OUTS. THE QUESTIONS THAT I HAD WERE FIRST OFF, IS THIS LOCATED ONLY IN THE HEPATOCYTES? OBVIOUSLY SOMETHING THAT GOT INTO THE COPPOLA CELLS ARE CONCERNED AS FAR AS CHANGES IN OTHER TYPES OF KUPLA CELL FUNCTION AND REGULATORY FUNCTION. I WAS SATISFIED THE ANSWERS SENT BACK THAT THIS IS VIRTUALLY ONLY IN HEPATOCYTES AND THEY SPECIFICALLY WERE I BELIEVE TO RECOUP THE CELLS, HAVE BEEN WORRIED ABOUT THAT BECAUSE THERE WERE A FEW CELLS THAT SEEMED TO BE INFECTED THAT YOU COULD NOT TOTALLY IDENTIFY. THE ONE I WOULD BE MOST WORRIED ABOUT WOULD BE THE SO CALLED (INAUDIBLE) CELL THAT LEADS TO PRODUCTION OF FIBROSIS. I DONE KNOW IF YOU'LL BE ABLE TO SEE ANYTHING ON THAT 21 DAY BIOPSY. I'M ALL FOR THAT. BECAUSE I THINK WHAT YOU'RE TRYING TO DO, SURE YOU'LL HAVE EXPERTS REVIEW THIS LOOKING SPECIFICALLY AT WHETHER THERE ARE ANY ABERRANT PRODUCTIONS OF FIBROSIS OR FOCAL AREAS OF NECROSIS NOT EXPECTED. OF COURSE EVEN SUCH SIMPLE THINGS AS EOSINOPHILIA WOULD BE ABLE TO BE IDENTIFIED BECAUSE WHICH WOULDN'T EXPECT THAT IN A VIRAL HEPATITIS SETTING. AS FAR AS FOLLOW-UP INTERVALS, AFTER READING THE RESPONSE TO HAVE THE SPONSOR, IT'S CERTAINLY REASONABLE 180 DAYS, ONE THING THAT'S INTERESTING TO ME IS HOW MUCH WILL BE LEFT, HOW MUCH ACTIVE INVOLVEMENT OF CELLS WILL BE AVAILABLE AFTER SEVERAL MONTHS? IT'S OBVIOUS THIS IS NOT LIFETIME. BUT WHAT IS THE PREDICTION HOW LONG SOME CELLS WILL BE PROTECTIVE? WE FULLY RECOGNIZE IN THIS FIELD FOR A LONG TIME, MINORITY OF CELLS ARE INFECTED AT ANY GIVEN MOMENT. PROBABLY THE NUMBER IS ONE IN FIVE TO ONE IN THREE. SO WE HAVE GOT TO BE SURROUNDING INFECTED CELLS WITH A LOT OF OTHER CELLS THAT ARE BEING GIVEN A BLUNTLY A VACCINE TO PREVENT INFECTION. AND I THOUGHT THIS THE MATERIAL REVIEWED RELATED TO MICE AND MONKEYS ALL SUGGESTED THIS IS GOOD OUT TO SEVERAL MONTHS, ABOUT TO MAYBE SIX MONTHS. BUT IF THE DRUG DOES WHAT IT'S SUPPOSED TO, THERE WON'T BE ANY VIRUS LEFT AFFAIRLY SHORT TIME. I HAD THE MOST TROUBLE MY FRIEND NORM FAUST IS HERE WHO MAY WANT TO COMMENT ON. THIS I HAD THE MOST TROUBLE WITH ONE THING. THIS LOOKED TO BE WIDE GOOD. I DON'T KNOW WHO WOULD BE THE TYPE OF PATIENT WHO WOULD VOLUNTEER TO BE AMONGST THE FIRST TWO AND SINCE THIS IS A ONE TIME DEAL. ONCE YOU HAVE TAKEN YOUR SHOT IT WILL BE AN UNUSUAL PERSON I THINK WHO HAS FAILED ALL THE UNUSUAL TREATMENT AND YOU TAKE ON THE DRUG KNOWING IN ADDITION THERE IS A NORMAL NEGATIVE REACTION TO ANY LIVER BIOPSIES IN CLINICAL STUDIES. WE USED TO DO THEM MUCH MORE THAN WE DO THEM NOW BECAUSE LONG TERM -- ALTERNATIVES BUT THIS SHOULD BE DONE. SO MY MAJOR REQUEST TO THE UPON SR.S, WHY NOT GIVE THE LOWEST DOSE YOU THINK MIGHT BE OF SOME GOOD. I KNOW AND I READ YOUR ANSWER, AND I AGREE WITH CONSERVATISM, HAVING TO LOOK CAREFULLY AT A NUMBER OF OTHER STUDIES INCLUDING GOING BACK TO LITERATURE OF THE HEMOPHILIA TREATMENT AND I UNDERSTAND WHAT YOU'RE DOING BUT I STILL HAD THAT A OPEN WORRY GIVING PERSON SOMETHING ONE TIME HE OR SHE CAN NEVER GET AGAIN, AND MAYBE HAVE THE TANTALIZING SITUATION OF THAT DOSE ALMOST HELPING. THAT WAS A CONCERN. I'M SPEAKING FROM POINT OF VIEW OF A CLINICIAN WHICH IS THE ONLY POINT OF VIEW I HAVE HERE. BECAUSE WE TAUPE HAVE EXPERTISE IN THE REST OF THIS. I THINK THE PLANS FOR WHAT YOU WOULD DO IF YOU INITIATED A RESPONSE, I THINK IF YOU DID ADVERSE RESPONSE IT WOULD LOOK LIKE AUTOIMMUNE HEPATITIS. I THINK THAT IF THAT WERE THE CASE WE WOULD USE THE GENERAL GOOD APPROACH WE HAVE MAINLY BASED ON CORTICOSTEROID AND OTHER IMMUNOREGULATORS, WE CAN USUALLY TAKE CARE OF THAT. WHICH SHOULD BE SELF-LIMITED, DRUG INDUCED HEPATITIS THAT OCCURS WITH MINI CYCLINE, THE DRUG OF CHOICE FOR CAUSING THAT, WE FINE IF WE COME TO THE PATIENT WITH EFFECTIVE IMMUNOSUPPRESSION, USUALLY CORTICOSTEROID BASED AND TREAT FOR SIX MONTHS OR SO, ONCE ALL THE DRUGS ARE OUT OF THE SYSTEM, DRUG INDUCED CHRONIC -- DRUG INDUCED AUTOIMMUNE HEPATITIS WILL RESOLVE. SO I THINK THAT IS A SAFETY ENOUGH FACTOR. I NOTICE NO DIFFERENCES IN GENE TYPE 1A AND 1B, THIS IS VERY IMPORTANT BECAUSE IF WE LOOK AT THE WORLD, IT'S REMARKABLE HOW WE USED TO SAY GENOTYPE ONE BUT NOW REALIZE THE DIFFERENCES IN POPULATION DYNAMICS GENOTYPE 1 AND 2 ARE REALLY QUITE STRIKING. I WOULD BE INTERESTED AND DID NOT ASK THE QUESTION, I WOULD BE INTERESTED IN THE RESPONSES LOOKED PARTICULARLY GENOTYPE 3, THE FORGOTTEN GENOTYPE HERE AND COMING UP A Z AN IMPORTANT WORLD WIDE ISSUE THAN WE ANTICIPATED, LIKE TO ASK THE SPONSOR TO COMMENT ON THAT. THE ADVANTAGES ARE SO OBVIOUS BECAUSE THEY'RE MILLIONS OF PEOPLE IN ISOLATED PARTS OF THE WORLD WHOM YOU WILL NOT BE ABLE TO GET ANY KIND OF LONG TERM THERAPIES INTO THEM FOR A PERIOD OF TIME. EVERYBODY HAS TO REALIZE THAT THERE ARE TWO GOOD THINGS HAPPENING HERE RIGHT NOW. ONE, DRUGS ARE GETTING BETTER. YOU ONLY HAVE TO FOLLOW THE NEWSPAPERS YOU DON'T HAVE TO READ THE JOURNALS. BECAUSE MANY OF THE COMPANIES ARE DEVELOPING THEIR DRUGS THROUGH THE NEWSPAPERS. WE WILL SEE BY THE FIRST OF 15 AND I THINK PROBABLY MID 14 NEW INTERFERON-FREE REGIMENS. I ALSO ON THAT COST WILL BE AN ISSUE AND GETTING TO THOSE POPULATIONS THAT WE CAN'T GET TO. THE OTHER THING ABOUT THIS, NOW IS THE TIME TO DO THIS BECAUSE P SOME REASON HEPATITIS C IS RESOLVING ITSELF, WE'RE GETTING A NEW CASES THAT AM TO ANYTHING, DR. HARVEY, ONE OF THE FOREMOST EXPERTS IN THE WORLD WORKS HERE AND MANY LOOKED TO THE EPIDEMIOLOGY AND THAT DISEASE IS GOING AWAY, IT'S TRULY GOING WAY WAY. WE HARDLY ARE SEEING ANY NEW CASES ADDEDED TO THE POOL. SO YOU WILL BE TREATING AN EVER OLDER POPULATION WORLDWIDE, EVER OLDER SO WHEREAS THIS USED TO BE A DISEASE OF THE YOUNG IT'S NOW A DISEASE OF THE MIDDLE. SO, THAT'S -- MORE THAN I KNOW AND ALL THAT I NEED TO KNOW. >> THANK YOU VERY MUCH, DR. MADDREY, IN RESPONSE TO WHETHER YOU TEST AGAINST GENOTYPE 3. >> THE TYPICAL REPLY CON NOELS USED ARE GENOTYPE 1 AND ONLY WHEN HCVCC SYSTEMS CAN SWITCH TO GENE TYPE 2. WE HAVE NOT YET ATTEMPTED TO TEST THE ACTIVITY OF TT-034 AGAINST GENOTYPE 3 OR BEYOND. BUT AGREE IT IS PERFORM FOR THE FUTURE. >> NEXT WE'LL MOVE TO DON KOHN TO MY LEFT. >> THANK YOU. OVERALL I THOUGHT THE PROTOCOL WAS VERY WELL WRITTEN AS CONSENT WAS TWO. MY BIGGEST CONCERN WHICH IS NOT A QUESTION BUT POTENTIAL PERMITS ARE LONG LASTING EFFECT AND EVEN THOUGH VECTOR USING HAS DECREASED EXPRESSION AND NO DETECTABLE TOXICITY OUT 180 DAYS, THERE IS POTENTIAL REFLECTED IN CONSENT FOR A LOW LEVEL CHRONIC HEPATOTOXICITY THAT CAN OCCUR OVER MONTHS AND YEARS AND I THINK THE WAY TO KNOW THAT IS TO DO THE TRIAL. THATRYK IS EXPLAINED TO SUBJECTS INCLUDING WORST CASE SCENARIO YOU COULD NEED A LIVER TRANSPLANT IS IN THE CONCEPT. THAT'S THE WAY TO DO IT, TO PRESENT THE WORST THOUGH YOU SAY IT'S NOT. SO MY SPECIFIC QUESTIONS WERE NOT AS COMPLEX AS THAT, ONE BUT ABOUT ANTIBODY THE TO AAV-8 ASSAY, WHICH IS OBVIOUSLY CRITICAL TO ENROLLMENT, IT WASN'T DESCRIBED THAT I COULD SEE. SO IN YOUR RESPONSE TO MY QUESTION YOU DESCRIBE AS A NEUTRALIZATION ASSAY FOR AVA 8 THAT SEEMS FINE DEVELOPED CHARACTERIZE OR QUALIFIED ASSAY WHICH WILL BE FINE. MY SECOND RELATED TO THAT, THE ISSUE OF LONGERRER -- LONG TERM EFFECTS. THAT IS WHETHER LONG TERM STUDIES WERE PLANNED IN NON-HUMAN PRIMATES THE DATA TODAY IN MICE AN MONKEYS WENT TO 180 DAYS WHERE THERE WAS NO SIGN OF TOXICITY. THE ANSWER, NOTHING CURRENTLY IS PLAN AS PART OF YOUR LASER PHASE DEVELOPMENT YOU MAY DO SOME LONG TERM CAR SEW GENESIS BASED ASSAY, I THINK THAT WILL BE FINE. MY THIRD COMMENT WAS MINOR, IT WAS JUST THE WAY STOPPING RULES WERE WRITTEN, YOU GOT A STOPPING RULE IF PATIENTS HAD INCREASED ENZYMES OR COAGULOPATHY FOR ANY REASON I THOUGHT YOU SHOULD MAKE SURE IT WAS DRUG RELATED SO YOU DIDN'T BOX YOURSELF IN A CORNER IF THEY NEED ANTI-CO-ING ALATED, YOU WOULD CHANGE THAT. SO CONCERNS THAT I RAISE THEY ADDRESSED THEM ALL. >> THANK YOU. >> THANK YOU VERY MUCH, DON. WE'RE GOING TO MOVE TO LORI ZOLOTH FOR THE NEXT REVIEW. >> I SHARED THE CUR I DON'T SAYTIES AND P COMPLAINTS A OTHER REVIEWERS. LIKE EVERYONE THIS IS A WONDERFUL TARGET, A CHRONIC HEPATITIS IS A HORRIBLE AND CURABLE DISEASE AFFECTING THE ABJECT POOR AND IN PARTS OF THE WORLD WHERE IT'S DIFFICULT TO GET ONGOING TREATMENT SO I LIKE THE ONE SHOT ONE DOSE INTERVENTION OF THIS. INTERFERON IS PROVEN EX-- (INAUDIBLE) WITH SIDE EFFECTS SO IT WOULD BE A TRUE BREAK THROUGH TO SUPPORT. THE QUESTION I HAD WAS (INAUDIBLE) THE SAME ONE, THE ETHICAL ONE, IT'S A ONE TIME TREATMENT, IT'S ALL OR NOTHING. EARLY ESCALATION PROCESS ARE NOT GOING TO GET ANOTHER CHANCE. THAT IS, IT'S PROBLEMATIC. ISSUE BUT IT'S ALSO PROBLEMATIC WHEN IT'S GOING TO BE GIVEN BECAUSE THERE'S ALWAYS (INAUDIBLE) VARIATION. SO THE QUESTION IS, SINCE IT CAN NEVER BE REDONE AND SHOULDN'T THAT BE WHAT (INAUDIBLE) INEVITABLE TREATMENT PROTOCOL. THERE'S NO PLAN B IN THIS. THE FOOD NEWS IS ONE SHOT, BAD NEWS IS ONE SHOT, NO GOING BACK. THE OTHER QUESTION I HAD DID IT SHIP (INAUDIBLE) COULD YOU BE QUITE DIFFERENT (INAUDIBLE) AND COULD THAT LEAD TO OTHER MISCHIEF AND YOU THOUGHT PERHAPS NO, DR. FONG AND I BOTH WONDERED WHAT HAPPENED TO THIS, WHAT HAPPENS TO DISEASE REEMERGE AFTER THAT AS WELL. I RAISE THE QUESTION ABOUT DOING THE STUDY WITH WIDER INTERNATIONAL SAMPLE, THE REASON I LIKE THIS IS BECAUSE OF ITS -- ATTENTION TO JUST ISSUES AROUND DISEASE AND YOU RESPONDED THAT YOU WANTED A CONTROLLED DOSE BUT I URGE YOU TO -- IF YOU'RE SUCCESSFUL TO GO ALMOST IMMEDIATELY TO A CONTROLLED AREA BUT (INAUDIBLE). LOCATED (INAUDIBLE) DID WANT TO SAY THE CONSENT FORM WAS CLEAR, IT WAS EASY TO READ AN GOOD ONE. IT'S HUMBLE IN ITS CLAIM WHICH IS REARE FRESHING AND OFFERED EACH PATIENT TO TAKE CHANCE TO TAKE IT IMHOME AND TALK T OVER WITH FAMILIES WHICH I HAVEN'T SEEN AND SHOULD BE PART OF THE CONSENT FORM PROCESS. THE ANIMAL DATA IS HARD TO FIGURE IF THERE -- BECAUSE THEY KILLD THE ANIMALS TO DO THE AUTOPSY. SO I WOULD URGE YOU TO KEEP SOME AROUND ALIVE TO SEE WHAT HAPPENS INSTEAD OF KILLING THEM ALL BECAUSE WE HAVE NOD WHERE. THIS IS A 15 YEAR TRIAL. SO QUESTION IS WHAT DOES IT LOOK LIKE? AFTER TIME. I THINK THE -- THE CONSENT[x COULD STRESS MORE ROBUSTLY THE IDEA, PROBLEM PREGNANCIES 15 YEAR TRIAL SO IT HAS TO SAY OVER AN OVER AGAIN. AND THEY -- YOU SAID I HAD NOTED THEY'RE ALSO NO OTHER MEDICATIONS DURING THIS TIME. IT'S NOT CLEAR WHETHER IT'S ENTIRE 15 YEARS WITH SHORTER DURATION. YOU SAID YOU WERE GOING TO CLARIFY THAT. SO IT'S -- THE PROTOCOL IS FOREVER, IT'S NOT JUST EVERY GENE INTERVENTION, NOT JUST 15 YEARS, ONCE YOU HAVE DONE THIS THERE'S NO GOING BACK FOR ANY PROTOCOLS. YOU NEED TO MAKE THAT CLEAR. THE QUESTION IS THERE'S STOPPING RULES THAT HAD TO DO WITH DOSE ESCALATION IS THES TO WILL BE ESCALATED UNTIL THE SIDE EFFECTS ARE TOO BURDENSOME OR TELLS US IT'S EFFECTIVE, WHICHEVER IS FIRST BUT I'M WONDERING ABOUT THIS POPULATION. THIS IS PATIENTS WHO ARE IN THE PROTOCOL BUZZ THEY FOUND THERE'S SIDE EFFECTS ON INTERFERON WAS TOO BURDEN S&P WHICH MIGHT BE THE SIDE EFFECTS TOO BURDENSOME BUT LOW TOLL RAPT FOR BAD SIDE EFFECTS WHICH STOP THE TRIALS, IF IT'S THE LATTER THEY STOP THE TRIAL TOO SOON. I DON'T KNOW HOW YOU SORT THAT OUT BUT WANTED TO DRAW YOUR ATTENTION TO THAT AS A PROBLEM. THEN YOU GAVE CLEAR ANSWERS KNOWING WHETHER TREATMENT IS EFFECTIVE USING LABORATORY DATA. SO IT'S NOT (INAUDIBLE) SO THOSE ARE MY QUESTIONS AND I THINK YOU DID A GOOD JOB ANSWERING. AND PROMISING TO ANSWER THE ONES YOU COULDN'T IN YOUR STUDIES IN THE FUTURE. >> ANY UNRESOLVED ISSUE? >> THEY CAN'T RESOLVE THEM IN THE STUDY IN THE NEXT STUDY WHEN -- I WANT THEM TOE THAT'S -- NOT SURE IF I CAN DO ANYTHING MORE THAN GESTURE TOWARDS THE NEED TO TRY THIS IN INTERNATIONAL SETTINGS. AND CLARIFY THOSE, THE ISSUES I RAISE THE INFORMED CONSENT PROCESS. >> VERY GOOD. FOLLOW-UP ON STOPPING RULES. I NOTICE IN STOPPING RULES DEATH FROM ANY REASON IS PART OF THE STOPPING RULES. SHOULD THAT BE CHANGED TO DEATH FROM -- THOUGHT TO BE RELATED TO AGENT? >> WE AGREE. >> ONE OF THE EXTERM REVIEWERS WAS SCOTT HARPER, HE HAD EMERGENCY TODAY AND CANNOT BE WITH US, SO HE SENT ALONG COMMENTS FOR ME TO READ TO THE INVESTIGATORS AND THE COMMITTEE. DR. HARPER IS AN ASSISTANT PROFESSOR AT PEDIATRICS AT OHIO STATE UNIVERSITY AND PRINCIPLE INVESTIGATOR IN THE CENTER FOR GENE THERAPY AT THE RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL IN COLUMBUS P. HE HAS HELD BOTH POSITIONS SINCE JUNE OF 2007 AND PRIOR TO THIS DR. HARPER OWNED A Ph.D. IN CELLULAR MOLECULAR BIOLOGY FROM THE UNIVERSITY OF MICHIGAN IN 2002 FOLLOWED BY FIVE YEAR POST-DOCTORAL FELLOWSHIP UNIVERSITY OF IOWA. HE IS AN INDEPENDENT INVESTIGATOR DEVELOPING RNAi BASED THERAPIES FOR DOMINANTLY INHERITED NEUROMUSCULAR DISORDERS AND HE WAS ONE OF THE REVIEWERS. OVERALL, I'M GOING TO READ HIS COMMENTS. AND A LOT OF HIS ORIGINAL REVIEW IS ON RECORD AND THESE ARE HIS RESPONSES TO THE COMMENTS BACK FROM THE INVESTIGATORS. OVERALL, I AM SATISFIED WITH THE APPLICATION AND THINK THIS WILL BE AN IMPORTANT FIRST IN HUMAN TRIAL OF SH RNA FOR CHRONIC VIRAL INFECTION IN THE LIVER. MY ISSUES HERE MOSTLY STEM FROM WHAT I CONSIDER OVERSTATEMENTS WITH RESPECT TO SOME DATA IN APPARENT WILLINGNESS TO STATE CERTITUDE ISSUES WHILE MINIMIZING SOME OTHER POTENTIAL OUTCOMES. FROM A SELFISH STANDPOINT AS RNAi THERAPY RESEARCH E, I WILL LOVE TO SEE STRATEGY PROVE SUCCESSFUL AND SAFE. THE MAJOR CRITICISM FROM MY OWN WORK WITH WITH CHRONICK PRESENTATION OF U-6 DRIVEN SH RNA AN MI RNAs RELATES TO THE FACT THAT WE CANNOT TURN THIS TREATMENT OFF. FROM RECENT HISTORICAL DATA AS WELL AS EXPERIENCE WITH TT-033 RANI CAN OCCUR WITH OVEREXPRESSION. WE NEED THE PAY HEED TO THE FACT SH RNA LEVELS REPORTED HERE MAY SEEM SAFE THIS ANIMALS BUT THAT THEY ARE STILL -- THERE COULD STILL BE ACCUMULATION OF MATERIAL PRODUCTS THAT SATURATES THE ENDOGENOUS MI RNA BIOGENESIS PATHWAY IN CAUSE CELLULAR STRESS. I THEREFORE THINK IT CRITICAL TO PROCEED WITH FIRST IN HUMAN THERAPY CAUTIOUSLY AND NOT MINIMIZE THE POTENTIAL FOR REACHING SATURATION AND A POINT OF NO RETURN FOR SH RNA EXPRESSION. IN THE SHORT TERM TOXICITY COULD HAVE IMPACTS ON PATIENTS AND LONG TERM COULD HAVE BROAD IMPLICATIONS ON FUTURE RNAi TRIALS FOR HOST OF OTHER DISORDERS. IN TERMS OF HIS COMMENTS TO THE REVIEWERS, HIS QUESTION ONE WAS BASICALLY TO SIMPLIFY THE JARGON WHICH HE'S SATISFIED WITH WITH FROM THE REVIEWERS, QUESTION # WAS ON WHY USING AAV-8 INSTEAD OF ORIGINAL SEROTYPE AND HE WAS VERY SATISFIED. QUESTION 3, HE ASKED FOR FURTHER CHARACTERIZATION OF PROMOTER USED AND HE WAS HAPPY WITH THAT. QUESTION FOUR BRINGS UP THE FOLLOWING POINT. THE APPLICANTS DID NOT ANSWER MY QUESTION BUT I REALIZE NOW THAT THIS IS MY FALL, AS MY QUESTION WAS POORLY WORDED. I UNDERSTAND AND AGREE WHAT THE ANSWER PROVIDED WHICH CENTERS AROUND USING INDIVIDUAL PROMOTERS TO DRIVE EACH SH RNA INSTEAD OF USING ONE P PROMOTER TO DRIVE A POLYCISTRON OF THREE SH RNAs. WHEN EXAMINEED FROM THIS STAND POINT THE JUSTIFICATION IS REASONABLE AN CORRECT. WHAT I MEANT TO ASK WAS THIS. WHY DID THE OFFICE USE THREE DIFFERENT PROMOTERS TO DRIVE EACH SH RNA INSTEAD OF THE THREE OF THE SAME PROMOTER TO ACCOMPLISH THE SAME THING. IN OTHER WORDS WHY NOT USE 3 U-7 PROMOTERS FOR SH RNA INSTEAD OF THREE DIFFERENT PROMOTERS HERE, THIS IS NOT A CRITICAL QUESTION FOR THE APPROVAL BUT MORE TECHNICAL CURIOSITY, THEY SEEM TO ADDRESS THIS POINT IN RATER RESPONSE. SO WHAT WOULD BE APPLICANTS AND HOW WOULD THEY ANSWER TO THIS? >> ULTIMATELY REWORRIED VECTOR RECOMBINATION DURING HAVE BEENTOR MANUFACTURING. AND IT'S KNOWN THAT MULTIPLE SEQUENCES OF THE SAME TYPE CAN AT TIMES PROMOTE RECOMBINATION. GIVEN THE FACT DIFFERENT MEMBER OF THE U-6 FAMILY HAD DIFFERENT SEQUENCES BUT STILL USE THE SAME PROMOTER AND HAVE RELATIVELY SAME ACTIVITY, WE DECIDED TO GO WITH THE THREE DIFFERENCE SEQUENCES. >> VERY GOOD. QUESTION 5 ASKS THE SPECIES OF ORIGIN AND HE WAS SATIIED. QUESTION 6 HE WRITES THE RESPONDENT CITE FIGURE 20 TO BABB UP THE ASSERTION THAT LIVER SH RNA LEVELS WERE SIGNIFICANTLY LOWER IN ANIMALS ADMINISTERED TT-034 COMPARED TO TT-33. BASED ON DATA PROVIDED NOT SURE THIS IS A COMPLETELY ACCURATE STATEMENT. AND THERE ARE INCONSISTENT NQ PCR DATA ON SH RNA 22 EXPRESSION LEVELS CALLS INTO QUESTION ACCURACY OF THEIR ACUTE PCR METHOD. CERTAINLY THE NORTHERN BLOT DATA SUPPORT THE ASSERTION THAT TT-034 DERIVED SH RNA ARE LOWER THAN THOSE DERIVED FROM TT-033 WITH RESPECT TO RNA 6 AND 19. IF ONE ASSUMES THAT THE ABSENCE OF SIGNAL ON THE TT-034 NORTHERN BLOT IS INDICATIVE OF LOWER LEVELS OF PROCESS SH RNA, WHICH IS A SAFE ASSUMPTION CONSIDERING THE REST OF THEIR DATA. THERE MAYBE A SIGNAL IN THE 1.25 E-13 LANE OF A 19. HOWEVER, OTHERWISE THERE'S NO DIRECT EVIDENCE OF TT-034 6 OR 19 EXPRESSION BY NORTHERN. THE QPCR DATA WHICH SHOULD BE MORE SENSITIVE SEEMS TO DETECT THESE TRANSCRIPTS, THEY ARE MARKEDLY LOWER THAN CORRESPONDING 6 OR 19 GENERATED FROM T-33 AS CLAIMED BY AUTHORS. NEVERTHELESS THOUGH I HAVE EMBRACED QPCR AN UNDERSTAND ITS POWER BEING AN OLD SCHOOL MOLECULAR BIOLOGIST I WOULD HAVE LIKE TO SEE TT-034 SIGNAL ON THE PROVIDED GEL IMAGES. MY RATIONALE FOR THIS CAN BE ILLUSTRATED IN THE PANEL BOTTOM PANEL OF THIS FIGURE. REGARDING THE BOTTOM PANEL SH RNA 22 EXPRESSION IS HIGHER IN TT-034 THAN IN TT-33 BASED ON NORTHERN BLOT. QPCR DATA SHELLED OPPOSITE REPORT SO WHICH DATA IS CORRECT? THIS SPEAKS TO MY EARLIER POINT ABOUT LIKING GELS BETTER THAN QPCR IN INSTANCES LIKE THIS, SO YOU CAN SEE THE RAW DATA VERSUS LOOKING A T A NUMBER SEPARATED BY QPCR CALCULATIONS. CAN THE AUTHOR COMMENT ON THESE DISCREPANCIES AND HOW THEY USE THIS DATA TO JUSTIFY THE BROAD STATEMENT THAT LIVER SH RNA LEVELS WERE SIGNIFICANTLY LOWERS IN ANIMALz'„ ADMINISTERS IN 34 VERSUS 33 COMPOUND. THIS DISCUSSION RELEVANT TO OVEREXPRESSION RELATED TO OFF TARGET EFFECTS OF SH RNAs SINCE THE TEAM HAS ALREADY SHOWN THAT THE IDENTICAL PRODUCT IS CAPABLE OF CAUSING TOXICITY IF EXPRESSED IN HIGH ENOUGH LEVELS. IN THE TABLE THEY PROVIDED THAT ACCOMPANIES THIS DATA, SH RNA LEVELS CONTINUE TO INCREASE THROUGHOUT THE COURSE OF THE STUDY. WITH RESPECT TO THIS FIGURE WHY ARE APPARENT DIFFERENT PRODUCTS SH RNA NORTHERN GEL IN THE TT-33 VERSUS THE TT-34 EXPERIMENTS. >> I THINK I REMEMBER ALL THE QUESTIONS IN RESPONSE TO DR. HARPER'S COMMENTS ENTREPRENEUR BLOT, WE ARE SOMETHING LIKE 25 MICROGRAMS PER WELL WHICH IS ABOUT THE SAITH AGO PIPE YOU CAN REASONABLY GET ON THE GEL. IT WOULD BE NICE TO VISUALIZE REDUCED SH RNA HE CAN PRESENTATION ON THE NORTHERN BLOT ANALYSIS, VERY CHALLENGING ESPECIALLY CONSIDERING THE PROBES QUESTION USE TO DECK THESE SHORT SPECIES VERY SHORT SO THERE'S NOT THE ABILITY TO OVERLABEL SPECIFIC PROBE N. REGARDS TO SH RNA 22 QFCR ASSAY ASSAYS, STUDIES WERE PERFORMED, MATERIALS WERE SPENT BY NORTHERN BLOT ANALYSIS OR QPCR. FIRST GENERATION QPCR ASSAY BASED WHICH RECOGNIZE THREE PRIME ENDS, MODIFICATION OF THE STEM LOOP ASSAY. BUT APPLIED BIOSYSTEMS DEVELOP FOR MICRORNAs. THE PROBLEM FOR PROCESS THE LOOPS OF SH RNA LIKE DICER, LIKE ENZYMES THAT PRODUCES A WIDE VARIETY OF THREE PRIME ENDS, IT PRODUCED A WIDER VARIETY OF THREE PRIME ENDS THAN ORIGINALLY ANTICIPATE SOD THE QPCR DATA DISCOVER RANT -- DISCORDANT. SO DR. HARPER IS CORRECT THAT THAT SHOULD BE THE DATA PROPERLY INTERPRETED. IN TERMS OF WHY SH RNA 22 DIDN'T SHOW THE SAME DOWN REGULATION AS SH RNA 6 AND 19, ESSENTIALLY WHAT HAPPENED WAS, THIS IS DURING THE CLOTHING PROCESS, WE SWAPPED A DOWN STREAM TITER BOX NORMALLY MEANT A U 69 TITER BOX CORRESPONDING PROMOTER TO U 68 PROMOTER. IN DOING SO IT CHANGE IT IS TRANSCRIPTIONAL START SITE AND HENCE WHY THE PRODUCTS APPEAR SLIGHTLY DIFFERENT ON THE NORTHERN BLOT ANALYSIS. BUT ALSO IT DID NOT SIGNIFICANTLY REDUCE SH RNA 22. WE AGREE WITH DR. HARPER, CERTAINLY NOT ALL SH RNAs ARE DOWN REGULATED APPROPRIATE BY BUT CERTAINLY WHEN WE GO BACK AND TO THE PRE-CLINICAL TESTING, MURINE AND NON-HUMAN PRIMATES WE SEE AN ELIMINATION OF TOXICITY ASSOCIATED WITH ORIGINAL TT-033 EXPRESSION. >> YOUR PRODUCT THEN IN THIS TRIAL, IS IT EXPECTED TO KNOCK DOWN 22? TRYING TO FIGURE OUT, IS IT A TRIPLE PRODUCT THEN? >> IT IS A TRIPLE PRODUCT. AND I KNOW THAT DR. HARPER ASKS A QUESTION LATER IN HIS SERIES OF QUESTIONS, ASKING RELATIVE CONTRIBUTION OF SH RNA 22 TO 6 AND 19. I ANTICIPATE WE'LL GET TO THAT QUESTION, MAYBE WE CAN HEAD IT OFF AT THE PASS SAYING THAT WHILE CERTAINLY SH RNA 22 IS PRODUCED IN MORE ABUNDANCE THAN 6 AND 19, WE KNOW THEY'RE BOTH ACTIVE IN HOPE C REPLY CONS BECAUSE WE DO FIVE PRIME RACE ANALYSIS WHICH VERY CLEARLY DEFINES WHERE THE TARGET HAS BEEN CLEAVED AND THE TARGET IN THIS CASE IS THE HCV GENOME. WE SEE SPECIFIC CLEAVAGE POINTS FOR SH RNA 6, SH RNA 19 AS WELL AS SH RNA 22. IN ADDITION THE THAT, WHEN WE TRANSFECT IN REPORTER CONSTRUCTS, INDIVIDUAL REPORTER CON TRUCKS IN THE CONTEXT OF EXPRESSING ALL THREE SH RNA, EACH OF THOSE REPORTER CONTRACTS IS CORRESPONDINGLY DOWN REGULATED. SH RNA 22 IS NOT ASSESSING OUT RISK AND TAKING AWAY ABILITY OF 6 AND 19 TO HAVE CLEAVAGE POINTS WITHIN THE TARGET. Q. HE GOES ON TO ASK ADDITIONAL QUESTIONS RELATED TO QUESTION 7 AND 8 IN THE REVIEW. I UNDERSTAND APPLICANT ABOUT DIFFICULTIES OF TRANSFECTION HAVING AN IMPACT ONSET OF EXPERIMENTS IN VITRO. ALSO NO DOUBT EACH THREE SH RNA IS WORKING AS INTENDED. I'M NOT CONVINCED THAT THE OTHER TWO SH RNAs ARE AVOIDING EXERTING SELECTIVE PRESSURE BASED ON CURRENT DATA. IT COULD BE THEY ARE NOT -- THEY AREN'T EXPRESSED HIGH ENOUGH IN THE SYSTEMS USED HERE. REGARDLESS, I THINK THE RATIONALE FOR USING ALL THREE TO HELP ELIMINATE ANY ESCAPE MUTANTS IS SOUND, I SIMPLY THINK THE NOTION THAT SH RNA 22 IS THE ONLY PRODUCT CAPABLE OF ELICITING THE PRESSURE IS OVERINTERPRETATION OF THE DATA PRESENTED. I HAVE A FEW MORE QUESTIONS RELATED TO EXPRESSION OF SH RNA. FIRST, THUS DOES SH RNA 22 HAVE HYPERFUNCTIONAL ACTIVITY OR IS IT JUST EXPRESSED HIGH ENOUGH LEVELS TO ELICIT BETTER GENE SILENCING EFFECTS? IS SH RNA LESS FUNCTIONAL IF CONSIDERED RELATIVE TO ITS EXPRESSION LEVEL. IN OTHER WORDS, IS IT NECESSARY TO EXPRESS SH RNA 22 AT HIGH LEVELS TO ACHIEVE SILENTING OR IF YOU SWAP OUT THE PROMOTER DRIVING IT FOR ANOTHER WEAKENED U-6 PROMOTER, WOULD IT PRODUCE LESS AND BE EFFECTIVE? >> TWO QUESTIONS. FIRST IS HYPERFUNCTIONALTY OF SH RNA 22, INDEED IT IS HYPERFUNCTIONAL, WE WERE ABLE TO TEST THROUGH TRANSFECTION STUDIES WHICH YOU HAVE A CONSTANT AM OF REPORTER APPROXIMATE YOU DROP THE AMOUNT OF SH RNA EXPRESSION CONSTRUCT. AS YOU DROP THE RNA EXPRESSION CONSTRUCT YOU SEE DECREASE IN THE REPORTER ACTIVITY WITH SH RNA 22, AS WE DROP LEVEL OF SH RNA EXPRESSION CONSTRUCT IT BASICALLY STAYED SUSTAINED INHIBITION LEVEL CONSIDERABLY LONGER PROBABLY SEVERAL -- AT LEAST ONE ORDER OF MAGNITUDE RELATIVE TO THE OTHER TWO. SO I HAVE BEEN DEED SH RNA 22 IS HYPERFUNCTIONAL. I'M SORRY. I LOST THE SECOND QUESTION. >> CAN YOU SWAP OUT FOR A MORE WEAKENED PROMOTER AND BE OKAY? >> POTENTIALLY. WE HAVE NOT PERFORMED THOSE EXPERIMENTS. THE CONSTRUCTS THAT WE MOVED FORWARD WITH TESTED WELL IN TERMS OF ACTIVITY AS WELL AS SAFETY. ONCE WE HAD DONE A LARGE NUMBER OF ANIMAL STUDIES WE DIDN'T SEE GIVEN THE DATA SETS WE HAD IN HAND WE DIP SEE THE NEED TO GO BACK AND TRY TO FIX >> OKAY. >> HE GOES ON TO ASK, IN THE RESPONSE AUTHORS STATE THIS IS A VERY DIFFERENT SITUATION FROM IN VIVO APPLICATION WHICH TT-034 CONTINUOUSLY PRODUCES A POOL OF SH RNAs AT LEVELS WHICH CAN BE MORE ADEQUATELY CONTROLLED BY DOSE, THAT IS ADMINISTERED. CERTAINLY THIS IS TRUE VECTOR DOSE HAS IMPACT ON EXPRESSION LEVELS BUT THE NORTHERN BLOT DATA FROM FIGURE 20, SEEMS THERE WILL BE RELATIVELY HIGHER SH RNA 22 COMPARED TO THE OTHER TWO. MY OVERALL CONCERN IS SH RNAs TARGET CELLS AND AT SOME POINT IT CAN REACH A LEVEL CONCERNING. SO YOUR RESPONSE TO THIS? >> WE WOULD DISAGREE WITH DR. HARPER. THERE'S THE ANIMAL DATA WHICH WE HAD CYNAMOLOGOUS MONKEYS. WE LOOK A BIOPSY OF ANIMALS HARVESTED AT EITHER DAY 60 OR DAY 180. CERTAINLY AT DAY 15 LIVER BIOPSY THERE WAS -- AT LEAST TWO, THREE, FOUR FEEL MORE SH RNA DAY 15 THAN DAY 180. AS A WHOLE, WE THOUGHT THAT PERHAPS DR. HARPER WAS TRYING TO INTERPRET GROUP AVERAGES OF INDIVIDUAL ANIMALS WHICH IS ALWAYS TRICKY. CERTAINLY THERE WAS A LARGE NUMBER OF ANIMALS ON THE STUDY. THE CHANGES OR THE NOTED INCREASES FOR INSTANCE FROM DAY 60 TO DAY 180 WERE NOT SIGNIFICANT. CERTAINLY WITHIN THE SCOPE OF VARIABILITY FROM GROUP TO GROUP AT LEAST OUR INTERPRETATION. >> OKAY. THEN FINALLY FOR QUESTION NINE, HE HAS THE FOLLOWING REMAINING QUESTIONS. WE DO NOT -- QUOTE, WE DO NOT ANTICIPATE AN EVER INCREASING AND CONTINUOUS LONG TERM BUILD UP OF SH RNA LEVELS BUT 180 DAYS AS YOU STATED. LOOKING OVER THE DATA FROM FIGURE 27 TO 32, THERE DOES APPEAR TO BE INCREASING AND CONTINUOUS LONG TERM BUILD UP OF SH RNA OVER TIME. MY INTERPRETING THIS DATA CORRECTLY? HIS READING OF YOUR FIGURES FROM 27 TO 32 THINKS THERE IS INCREASING. >> WE WOULD DISAGREE. WE THINK IT FALLS WITHIN THE ANIMAL TO ANIMAL VARIABLE. ON ON OF THAT THERE'S HEPATOCYTE TURN OVER LONG TERM WHICH HAS ABILITY TO DECREASE TRANSDUCE VECTOR AND CON COME TAN SH RNA PRODUCTION. >> THE LAST COMMENT, THE AUTHORS ADDRESS THIS POINT IN E BY REFERRING TO A DISCUSSION IN POINT C. THE RESPONDENTS REFER TO SECTION M 2 B 2D TO ADDRESS THE POINT OF ETCH OF SH RNA ON MERE 122 EXPRESSION AND PROCESSING. I MAYBE MISSING IT. IS THERE A FIGURE OR DATA TABLE THAT CORRESPONDS TO THIS? THEY STATE THAT THERE WAS NO SIGNATURE CAP CHANGES IN MERE 122 LEVELS IN TT-034 MONKEYS OR MICE VERSUS CONTROL SAMPLES. IT WAS NOT CLEAR TO ME HOW THIS WAS MEASURED. PLEASE STATE THE METHODOLOGY. ALSO ARE THERE -- ARE THEY REFERRING TO PRIMARY MERE 122 AND PROCESS MATURE FORMS ONLY MA WHICH ARE FORMS. IS THERE A CHANGE IN TO PROCESSING FROM FULL LENGTH TO MATURE. >> SO THESE WERE DONE ON CHIP BASED STUDIES FOR DETECTION OF MATURE MICRORNAs, WE DID NOT LOOK AT PREPROCESSED MICRORNAs, LOOKED AT THE MATURE MICRORNAs LEVELS. MERE 122 IS OBVIOUSLY A CONCERN SINCE IT'S THE PRIMARY MICRORNA FOUND WITHIN LIVER, PRESSED 170,000 COPIES PER CELL. IT WAS STATED IN THE TEXT OR RESPONSE TO THE QUESTION, WE DIDN'T SEE CHANGES SPECIFICALLY IN MERE 122. LEVELS. IN EITHER MOUSE OR THE CYNAMOLOGOUS MON CAN KY MODEL. -- CYNAMOLOGOUS MONKEY MODEL. >> I WAS ALSO PRIVY TO THIS PROTOCOL AS I COME MY QUESTIONS. MY FIRST QUESTION ON THE OFF TARGET EFFECTS OF THE VECTOR AND SH RNAs, AGAIN IN THE PRE-CLINICAL TALKS THERE DOES SEEM TO BE EXPRESSION IN ADRENAL AN SPLEEN AND OTHER THINGS. VISITORS ADDRESSED THAT. THIS IS A PHASE 1 STUDY AND WE'LL KNOW IN PEOPLE WHAT THE OFF TARGET AFFECTS WILL BE. MY OTHER QUESTIONS, CENTER AROUND DELIVERY OF THIS. THIS IS OBVIOUSLY A VERY EXCITING THERAPY THAT IF WE -- YOU CAN ACTUALLY GO AND DELIVER AN AGENT A SINGLE TIME AND ONE OUT HOPE C REPLICATION AN PROPAGATION IN THE LIVER WOULD BE WONFUL, THERE'S 3 TIMES TEN TO THE 1159’ HEPATOCELLS IN HEPATOCYTES IN THE LIVER. THEY LIVE FIVE MONTHS SO IF YOU HAVEN'T WHIPPED OUT HOPE C VIRUS, ANY OTHER NEW HEPATOCYTE WILL GET INFECTED AND SINCE THIS IS A THERAPY THAT IS THOUGHT TO ONLY BE USEFUL ONCE, HOW -- WHAT'S GOING TO HAPPEN AT THIS POINT? SO MY OTHER QUESTION REALLY CENTERS AROUND THOSE THREE ISSUE S. ONE TRYING TO DELIVER ENOUGH VECTORS SO THAT YOU'RE EFFECTIVE. SO MY QUESTION WAS WHY NOT DELIVER IT LOCALLY? BECAUSE WE ALL KNOW FROM OTHER GENE THERAPY DELIVERY, IF WE GO AN PERFUSE AN ORGAN WITH A VECTOR THAT WE CARE ABOUT, WE GENERALLY WILL CONCENTRATE VECTORS AND MULTI-LOG LOWER DOSES BE ABLE TO GET MUCH HIGHER INFECTION OF THE TARGET ORGAN. THE ONLY ORGAN YOU CARE ABOUT IS LIVER. IN EVERY HOP AND LIVER CENTER IN AMERICA, PEOPLE ARE CAN LATING THE HEPATIC ARTERY EVERY DAY FOR THERAPIES AS WELL AS DIAGNOSIS, THOSE CANLATIONS ARE QUITE SAFE. AND SO YOU RESPOND THAT YOU WORRY ABOUT THROMBO SEES IN THE HEPATIC ARTERY, I HAVE PERMLY NEVER SEEN ONE, AND I HAVE BEEN IN PRACTICE OVER 20 YEARS. I HAVE SEEN DEFECTIONS OF THE ARTERY BUT NOT JUST SIMPLE THROMBOSIS. BUT EVEN THOSE ARE VERY RARE EVENTS, WHY NOT TRY TO DELIVER THIS LOCALLY SO YOU CAN ADD A MUCH LOWER DOSE, PROVIDE FOR A HIGHER TRANSFECTION OF THE HEPATOCYTES, SINCE THAT'S THE TARGET ORGAN AND THERAPY. >> WE APPRECIATE THE COMMENTS. WE WANT TO LIMIT THE INVASIVENESS OF THIS PROCEDURE. AND BROAD APPLICABILITY. AND WHILE WE AGREE ACADEMIC MEDICAL CENTERS ARE CERTAINLY DUE EMBOLIZATION FOR HEPATIC ARTERIES AND CANLATION OF THE HEPATIC VEIN IS DONE ROUTINELY, ULTIMATELY WE WANTED TO LIMIT INVASIVENESS AND POTENTIAL FOR LIVER INJURY THROMBOSIS BEING ONE CONSENT. BUT INFARCTION OF THE LIVER PARTICULARLY THROUGH EMBOLIZATION HEPATIC ARTERY OR INFUSION, WE WANT TO LIMIT POTENTIAL FOR FURTHER LIVER INJURY IN THESE PATIENT WHOSE MAY HAVE SIGNIFICANT FIBROSIS. ALSO IN OUR ANIMAL DATA WHERE WE LOOK AT INFUSION THROUGH PERIPHERY, HEPATIC VASCULATURE, AND THERE'S SIMILAR EXPRESSION OF SH RNA THROUGH THOSE BOTH DIALYSIS DELIVERED. >> I THINK IT'S A VERY IMPORTANT POINT, VERY IMPORTANT QUESTION, I WOULD PERHAPS FOCUS A BIT ON THE EXTENT OF HOW MUCH HIGHER I FIREBASE COULD BE ACHIEVED SOMEONE MORE INVASIVE PROTOCOL. I THINK IN HUMANS WITH ARCAV VECTORS, I CAN POINT TO TRIALS DONE ONE ARCAV-2, DELIVERING FACTOR 9 FOR THE HEMOPHILIA, HEPATIC ARTERY, DIRECT VASCULATURE ADMINISTRATION. VERSUS SIMILAR TRIAL WITH AV-8 VECTOR, LED BY UCL ST. JUDE GROUP. AT THE SAME DOSE THOUGH SEROTYPES ARE DIFFERENT T SAME DOSE LED TO APPROXIMATELY THE SAME LEVEL OF TRANSDUCTION TRANSDUCTION AS DETERMINED BY LEVEL OF FACTOR SICK LATING. OF COURSE IN THE TRIAL TRANSIENT EXPRESSION. IT'S OVERSTATING TO SAY IT WOULD BE MUCH LOWER DOSE USED PERHAPS SOME FULL LOWER DOSE BUT MAYBE WITHIN ABOUT FIVE FOLD BASED ON BOTH ANIMAL STUDIES, WE'RE FAMILIAR WITH WITH AS WELL AS THE HUMAN STUDIES THAT ARE AVAILABLE. >> SO DO YOU HAVE DATA WITH YOUR VECTOR AS TO LOCAL VERSUS SYSTEMIC? >> WE DO NOT. >> I WANT YOU GUYS TO SUCCEED. IT WOULD BE A MAJOR HELP TO HUMAN HEALTHCARE. INSTEAD OF HAVING TO COME BACK AND HAVE ANOTHER PROTOCOL THAT SAYS LOCAL DELIVERY, WOULD LOVE TO SEE ADDITIONAL ARM IN THIS STUDY, THAT YOU MAY OR MAY NOT GO ON TO. IF YOU ARE SUCCESSFUL YOU DON'T HAVE TO GO THERE. WHETHER IT'S HERPES VECTOR VACCINIA VECTORS, MANY VECTORS WHEN WE SEND TO THE LIVER WE GET HIGHER TUMOR AND CELL TRANSDUCTION THAN GIVING IT SYSTEMICALLY. AND SO JUST AS A THOUGHT. AND THE OTHER REASON I BRING THAT UP IS BECAUSE NOW THERE ARE MANY BALLOON CATHETER PROFUSION TECHNIQUES YOU CAN DELIVER VECTOR INTO THE LIVER AND OTHER ORGANS. AND WHERE YOU CAN TAKE ALL THE BLOOD OUT. WHERE YOU CAN ACTUALLY TAKE THE IMMUNE CIRCULATING IMMUNE CELLS AN ANTIBODIES CIRCLING AN REDELIVER A VECTOR TO THIS SPECIAL ORGAN WHERE WE HAVE TECHNICAL WAYS OF DELIVERING WITHOUT THE BLOOD BEING THERE. SO THE POSSIBILITY YOU CAN ACTUALLY REDELIVER THE VEHICLE ALSO EXISTS. SO I TISSUE CONSIDER IT AND DO ANIMAL TRAILS TO SEE IF YOU GET HAY HIGHER LEVEL CELL TRANSDUCTION. >> WE APPRECIATE THE COMMENTS AND IT STIMULATED INTERNAL DISCUSSION AROUND THAT SPECIFIC ISSUE AS WE HEAD TO ADDRESS IT. >> OVERALL, I HAD NO OTHER COMMENTS ARE THERE OTHER COMMENTS FROM THE MEMBERS OF THE RAC? >> I WANT TO RESPOND TO DR. DR. MADDREY'S CONCERN ABOUT PATIENTS RECEIVING ENEFFECTIVE DOSE. NOT JUST PATIENTS IN THAT THAT ARE GETTING INFECTEDS TO, IT'S HIGHLY LIKELY EVERYBODY WILL RECEIVE AN INEFFECTIVE DOSE. 95% OF PHASE 1 STUDIES NEVER GET ONLY 5% GET TO MARKET. IT'S THE NATURE, DESPITE THE ENTHUSIASM, YOU DOPE DO STUDIES UNLESS U YOU PUT IN A TREMENDOUS AM OF WORK AND YOU'RE OPTIMISTIC THAT'S TRUE OF ALL PHASE 1 STUDIES YOU WOULDN'T DO UNLESS YOU THOUGHT THEY WERE GOING TO WORK AND 95% DONE GET TO MARKET BECAUSE THEY'RE UNSAFE OR INEFFECTIVE. I SUSPECT THAT AVERAGE IS WAY LOWER THAN THAT IN GENE THERAPY TRIALS. SO DESPITE ENTHUSIASM AND HOPE AN OPTIMISM, THE PROSPECTS OF ANYBODY IN THIS TRIAL BENEFITING FROM IT ARE EXTREMELY LOW, NOT JUST PEOPLE THAT'S POINT 1. POINT 2, HUMAN SUBJECTS RESEARCH HAS NO CONCEIVABLE BENEFIT, THAT IS SO CALLED NON-THERAPEUTIC RESEARCH, IS IT AN IMPORTANT PART OF DEVELOPMENT OF CLINICAL CARE. SO MANY PATIENTS SUBJECTS HEALTHY AN ILL, VOLUNTEER FOR STUDIES WITH NO CONCEIVABLE PROSPECT OF BENEFIT. AND THE CONSENT FORM IS AS DR. ZOLOTH SAID IS VERY CANDID ABOUT THAT. SO THE PEOPLE ENTERING THIS TRIAL NOT ONLY ONES IN THE SO-CALLED INEFFECTIVE DOSE BUT ALL KNOW THERE HAS BEEN NO PROSPECT OF BENEFIT BUT PARTICULARLY ONES IN THE COOR KNOW THAT. THEY HAVE TO BE VOLUNTEERS AN CARE ENOUGH ABOUT ADVANCING DISEASE DISEASE TO SAY YEAH, I BENEFITED FROM WHAT OTHERS HAVE DONE. SO SAY ORS RESPONSE ABOUTING BEING CONSERVATIVE AND MAKING SURE ABOUT SAFETY, THIS IS PRIMARILY SAFETY TRIAL, CORRECT TIME HONORED APPROACH THE PHASE 1 TRIALS AND FACT THAT SOME PATIENTS WILL NOT BENEFIT IS TRUE OF ALMOST ALL COHORTS NOT JUST THOSE. FDA FIGURES 95% OF DRUGS INTRODUCED HUMAN TESTING NEVER GET TO MARKET. AFTER 20 YEARS OF GENE THERAPY HAS TO BE A LOWER NUMBER. >> 100. THERE'S NO MARKETABLE PRODUCT. RIGHT. SO THE CHANCES ARE EMPIRICALLY ZERO. >> LORI, CAN YOU TURN ON YOUR MICROPHONE IN >> JUST POINTING OUT WITH 100% FAILURE WHICH YOU HAD SO FAR IF YOU GET TO MARKET DOES NOT MEAN THE NEXT IS NOT ENTIRELY LIKE -- >> YOU HAVE TO HAVE A DREAM HOW YOU'RE GOING -- DREAMS COME TRUE. >> OTHER COMMENTS? DAWN. >> I HAVE A BRIEF QUESTION. ARE THESE ACTING SYNERGISTICALLY AND IF SO, WHATS TO THE LEVEL OF SYNERGISM? >> GOOD QUESTION. WE HAVE NOT DONE ANY STUDIES CONCERNING THE RELATIVE CONTRIBUTION OF SH RNA TOWARDS CLEAVAGE WITHIN THE CONTEXT OF BEING EXPRESSED ALL THREE. SO WE JUST HAVEN'T HAVEN'T DONE THAT DETERMINATION. >> ANDREW. >> JUST A QUESTION, LOOKING TO YOUR COMMENT ON. THIS THE REASON THERE WAS A REPORT ABOUT USING MICRORNA 122 PRETTY IMPRESSIVE RESULTS IN HOPE C. WONDERING WHERE YOU THINK YOUR PROPOSED THERAPEUTIC WILL LOOP UP AND SYNERGY (INAUDIBLE). >> THANKS FOR THAT QUESTION, I THINK THE PROGRAM IS DIFFERENT FROM THIS APPROACH. KNOCKING DOWN A VIABLE HOST TARGET, THIS EMPLOYS THREE S RNAs SO ANY DIFFERENT MECHANISM OF ACTION BUT WE ENVISION IF WE CAN SHOW SAFETY AND DEGREE OF EFFICACY IN THIS TRIAL THAT WE DO HAVE POTENTIAL TO COMBINE WITH ALL DAA AGENTS, CERTAINLY WE HAVEN'T CONSIDERED A COMBINATIONS WITH OTHER NUCLEIC ACID TARGETS, ANTI-SENSE STRATEGIES SUCH AS (INAUDIBLE) -- BUT WE ENVISION OR PRODUCT TO COMBINE POSSIBLY WITH ONE MORE POTENT OLD AS THEY MERGE THE ULTIMATE AIM TO ACHIEVE SUSTAINED LARGE RESPONSE IN A MINIMAL TIME AS POSSIBLE. >> OTHER COMMENTS FROM MEMBERS OF THE RAC? ANY COMMENTS FROM PEOPLE ON THE PHONE? ANY PUBLIC COMMENTS? PLEASE IDENTIFY YOURSELF. >> MY NAME IS LLOYD CLICKSTEEN FROM NOVARTIS INSTITUTES. A KEY ELM OF YOUR PROPOSAL IS TO ACHIEVE SUBSTANTIAL EXPOSURE OF MAJORITY OF HEPATOCYTES TO YOUR THERAPY. HAVE YOU OR OTHERS TESTED WHETHER THIS IS GOING TO BE TRUE IN A FIBROTIC AND ANATOMICALLY ABNORMAL LIVER? >> VERY GOOD QUESTION. WE HAVE NOT DIRECTLY TESTED ABILITY TO TRANSDUCE FIBROTIC LIVERS WE HAVE COLLABORATORS WITH WITH UNPUBLISHED DATA THAT SHOW EXCELLENT TRANSDUCTION OF FIBROTIC LIVER. THE ISSUE IS THAT AT SOME POINT THE HEPATOCYTES ARE SO DAMAGED THAT THEY TURN OF VERY RAPIDLY. SO IT'S HARD TO ESTABLISH LONG TERM TRANSDUCTION IN SEVERELY DISEASED ORGANS. THAT'S PART OF THE REASON I WHO WE SET OUR INCLUSION EXCLUSION CRITERIA TO ONLY INCLUDE PATIENTS WITH MED VEER SCORES UP TO F-3. AGAIN, THE EVIDENCE WE HAVE FROM UNPUBLISHED EVIDENCE FROM OUR COLLABORATORS IS YOU CAN'T TRANSDUCE ORGANS, JUST HARD TO BE ABLE TO MAINTAIN LONG TERM TRANSDUCTION. >> QUESTION IS, ARE YOU GETTING A SUBSTANTIAL MAJORITY OF THIS HEPATOCYTES TRANSDUCED DURING THE IN THE NEXT SEVERAL DAYS AFTER ADMINISTRATION? >> OUR STUDYS WE DID WITH ANIMALS AN NON-FIBROTIC MODELS, YES. WE CAN ACHIEVE NEAR COMPLETE TRANSDUCTION OF ALL HEPATOCYTE WITNESS THE LIVER WITH CLINICALLY RELEVANT DOSES. >> THANK YOU. >> DR. CHATERGEE. >> IF YOU GET MORE RAPID TURN OVER WITH HEPATOCYTES IN INBROUGHTIC LIVER WOULD YOU LOSE EPISOMEAL GENOME? >> YES, WE BELIEVE THAT'S TRUE. >> DO YOU HAVE A STRATEGY TO ADDRESS THIS? >> AGAIN, THE STRATEGY IS TO LIMIT THE THE FIBROSIS, TRY TO STAY WITHIN POPULATIONS WITH MINIMAL FIBROSIS COMPARATIVELY. >> WILLIS, DID YOU HAVE ANOTHER COMMENT? >> I WOULD LIKE THE COMMENT ON THAT. I THINK THE POINT I TRIED TO MAKE IS WE'RE GETTING MORE FIBROSIS, BECAUSE WE'RE GETTING OLDER POPULATIONS. MAYBE NOT IN THIS PHASE BUT I WOULD BE PLANNING SOON TO HAVE A POPULATION OF CIRRHOTICS BECAUSE THIS IS A GROUP THAT HAS DESPERATE NEED. THESE ARE PEOPLE WE'RE TRYING TO GET RID OF THE VIRUS SO WE CAN -- WELL, POSSIBLY INFLUENCE LESS CANCER. I THINK IT'S TRUE, I WANT T IT TO BE TRUE. BUT I DO AGREE WITH WHAT DR. CRICKSTEEN SAID, I'M CONCERNED HOW HEALTHY THESE HEPATOCYTES ARE AS FAR AS ABLE TO DO ANYTHING IN ADVANCE DISEASE. WE WILL I BELIEVE WHEN YOU GET TO FURTHER PHASE YOU OUGHT TO HAVE RUN OF THE MILL SHORT TERM INFECTIONS AND THEN YOU OUGHT TO HAVE GROUP OF PEOPLE FOR WHOM THE END IS IN SIGHT AS FAR AS TRANSPLANTATION OR DEVELOPMENT OF CANCER. >> ANY OTHER COMMENTS? WHY DON'T WE TAKE A FIVE MINUTE BREAK THEN READ OUR RECOMMENDATIONS TO THE INVESTIGATORS. >> LET'S GET STARTED. ONCE AGAIN, THANK YOU, VERY MUCH FOR PRESENTING TO US TODAY, A VERY EXCITING PROTOCOL AND LET ME READ FOR YOU THE REMAINING SUGGESTIONS FROM THE RAC. THIS HAD BEEN IN DRAFT FORM. PRE-CLINICAL. AS TARGET ORGAN IS DELIVERED CONSIDER FURTHER ANIMAL STUDIES TO SEE HOW -- VIA HEAR INTRAVENOUS ADMINISTRATION. FOCUS LIVER DELIVERY SHOULD MINIMIZE DISTRIBUTION TO TISSUES FOR WHICH THERE IS NO THERAPEUTIC NEED. THIS DATA MAY LED TO A DO SESSION TO AMEND YOUR AD MENSTRUATION ROUTE OR ADD ADDITIONAL COHORT FOR DIRECT COMPARISON. NUMBER TWO. CLINICAL. IT IS IMPORTANT TO LOOK AT THE BIOPSY TO IDENTIFY UNUSUAL AREAS OF FIBROSIS OR NECROSIS NOT EXPECTED WITH CHRONIC HEPATITIS C INFECTION OR OTHER SIGNS OF INFLAMMATION NOT EXPECTED WITH CHRONIC HOPE C FOR EXAMPLE EOSINOPHILIA. SUGGESTIONS THAT THE -- NUMBER TWO, SUGGEST THE STOPPING RULES BE AMENDED TO CLARIFY THAT ONLY A DEATH POSSIBLY RELATED TO STUDY AGENT WILL BE A STOPPING RULE AS IT IS QUITE POSSIBLE THAT SUBJECTS MAY DIE OF UNRELATED CAUSES. ETHICAL. THE CONCEPT FORM SHOULD STRONGLY DISCUSS RISK OF PREGNANCY BEYOND THE IMMEDIATE PROTOCOL PERIOD BUT ALSO IN THE LONG TERM FOLLOW-UP PERIOD. NEXT. HEPATITIS C IS INTERNATIONAL PROBLEM AND GIVEN COST AN LENGTH OF TREATMENT WITH TRADITIONAL THERAPIES COUNTRIES WITH LIMITED RESOURCES MAY NOT HAVE ACCESS TO TRADITIONALL TREATMENTS. IF THIS IS SUCCESSFUL, CONSIDER INCLUDING INTERNATIONAL SITES IN YOUR NEXT PHASE OF CLINICAL DEVELOPMENT. NEXT, THE POTENTIAL ADVANTAGES OF THIS APPROACH IS AT THE -- VIRUS ERADICATION MAY OCCUR WITH ONE TIME ADMINISTRATION. HOWEVER, THIS IS ALSO A POTENTIAL KISS ADVANTAGE SINCE THE DOSE RECEIVED IF THE DOSE RECEIVED IS NOT EFFICACIOUS, READMINISTRATION WILL NOT BE POSSIBLE AND IF THERE IS ANY ADVERSE EVENT IT MAYBE DIFFICULT TO REVERSE THIS DRUG. THE INFORMED CONCEPT SHOULD SPECIFICALLY DISCUSS THESE CONCEPTS IN MORE DETAIL. ANY ADDITIONS TO THE RECOMMENDATIONS OR CHANGE? ANY RESPONSES FROM THE INVESTIGATORS IN? >> WE THINK THAT THE COMMITTEE -- THANK THE COMMITTEE FOR THE COMMENTS AND WE'LL LOOK INTO THIS. >> GOOD. ANY MOTION FOR A VOTE? THEN WHY DOPE WE START DR. KOCH. >> KOCH. YES. >> POST. YES. >> ZOLOTH. YES. >> CHAT ERGEE, YES. >> ORNELLES, YES. >>S ARE, YES. >> PILEWSKI, YES. >> KOHN, YES. >> FONG, YES. >> CHIOCCA, YES. >> BADLY, YES. >> CANON, YES. STROME, YES. >> KIEM, YES. >> WOOLEY, YES. >> ON PHONE. >> MALLINO, YES. >> I THANK DR. MADDREY FOR BEING WITH US THIS MORNING AND SCOTT HARPER FOR HIS THOROUGH REVIEW OF THIS PROTOCOL. AND I THANK THE INVESTIGATORS FOR PRESENTING TO US. WE ARE WAY AHEAD OF SCHEDULE. WE ARE AN HOUR AHEAD OF SCHEDULE AT PRESENT SO WE'RE TRYING TO GET THE PRESENTERS FOR THE NEXT SESSIONS TO START EARLIER. WE'RE GOING TO TAKE A 15 MINUTE BREAK ABOUT RECONVENE AT 11:15. >> LET EAT RECONVENE. -- LET'S RECONVENE. THE NEXT ITEM ON THE AGENDA IS REPORT OF THE GENE TRANSFER SAFETY ASSESSMENT BOARD, HANS PETER KIEM WAS GOING TO PRESENT THAT FOR US. >> THIS IS THE REPORT FROM THE LAST GENE TRANSFER SAFETY ASSESSMENT BOARD. PROPERTY COTS SUBMITTED FOR SECOND QUARTER 2013, THE TOTAL OF 24 SUBMISSIONS, DISEASE END CRAG FOR 17 PROTOCOLS NOT SELECTED FOR CANCER. INFECTIOUS DISEASES AND ONE FOR PARKINSON'S DISEASES AUING YOU TO SEW THE DIFFERENCE VECTOR SYSTEMS USE TO RETROVIRAL STUDIES FOR ADENOVIRAL STUDIES ONE AAV ONE HERPES SIMPLEX THREE PASS MID, ONE RNA AND ONE TRANSPOSEON STUDY. 14 ADVERSE EVENTS REVIEWED BY TEN DIFFERENT PROTOCOLS INCLUDING INITIAL AND FOLLOW-UP REPORTS WE WILL NOT REVIEW AND DISCUSS THESE EVENTS TODAY. THERE WILL BE MORE INFORMATION AVAILABLE SHORTLY ON SOME OF THESE EVENTS AND MORTIS DUGS ESPECIALLY ON -- MORE DISCUSSIONS ON THERAPY RELATED EVENS DISCUSSED AT THE LATER MEETING IN SEPTEMBER PROTOCOLS NOTIFIED OF ENROLLMENT THE FOLLOWING HIGHLIGHTS FROM TWO PUB WILL BELY REVIEWED PROPERTY COGS. THIS IS THE FIRST -- PROTOCOLS. THIS HIGHLIGHTS A FADES 1, 2 STUDY OF ADOPTIVE IMMUNOTHERAPY AFTER ALLO GENETIC CELL TRANSPLANTATION WITH VIRUS C 8 T-CELLS TRANSDUCED TO EXPRESS WT-1 SPECIFIC RECEPTOR FOR PATIENTS WITH HIGH RISK OR RELAPSE ARCML MDS OR CMO. THE RECOMMENDATIONS FOR PLASMA SAMPLES ARE STORED FOR FUTURE SITE KEEP ANALYSIS IN THE EVENT A SYSTEMIC INFLAMMATORY REACTION WILL OCCUR. AND THE CONSENT FORM IS MODIFIED TO EXPLICITLY STATE THAT APPROXIMATELY ONE HALF OF INDIVIDUALS PARTICIPATE IN THIS TRIAL TRIAL NOT LIKELY TO RELAPSE AND NOT REQUIRE FURTHER TREATMENT. THE OTHER STUDY PHASE 2 RANDOMIZED OPEN LABEL STUDY IL-12 MONOTHERAPY AN COMBINATION IN SUBJECTS ACTABLE LESIONS IN TUMOR LESION LYMPH NODE, PATHOLOGIC MAYBE INJECTED, IN ADDITION TO FURTHER STUDIES WILL BE CONDUCTED ON INJECTED LYMPH NODES TO DETERMINE TYPES OF CELLS L TRANSDUCED. THE BIODISTRIBUTION OF THOSE CELLS AND PERSISTENCE OF THE VECTOR IN THOSE CELLS AND IN LIGHT OF STET OF SUBJECT FROM INDEX -- DEATH OF SUBJECT FROM MELANOMA, INVESTIGATORS ARE INSTRUCTED TO DETERMINE ANALYSIS IF INJECTABLE LESION IS HARBORING INFECTION AND I VOID INJECTION. SLIDE 2 ALSO REMIND PEOPLE THERE WILL BE A T-CELL IMMUNOTHERAPY OPTIMIZING TRIAL DESIGN MEETING LATER THIS YEAR IN SEPTEMBER, ON THE 11th OF SEPTEMBER OTHER AT THE HYATT REGENCY IN BETHESDA. WE WILL DISCUSS MANY T-CELL IMMUNOTHERAPIES, TRIAL COSIGNS AN ADVERSE EFFECTS -- DESIGNS APPROXIMATE ADVERSE EFFECTS FROM THE T-CELL IMMUNOTHERAPIES. ANY QUESTIONS? >> FOLLOW-UP ON THAT FOR THE RAC MEMBERS, THE T-CELL CONFERENCE RUNS FROM 10TH TO THE 1 #th TO AROUND NOON, THE RAC MEETING WILL IMMEDIATELY START THEREAFTER ABOUT NOON FOR THE NEXT DAY. (INAUDIBLE). >> >> THANK YOU VERY MUCH DR. KIEM. NEXT WE WILL HAVE A PRESENTATION ON AN UPDATE OF A HUMAN GENE TRANSFER PROTOCOL, PROTOCOL NUMBER 510-738 TITLED A PHASE 1 DOSE ESCALATION STUDY OF INTRATUMORAL HERPES SIMPLEX VIRUS 1 MUTANT HSV 1716 WITH IN PATIENTS WITH REFRACTORY SARCOMA OR NEUROBLASTOMA. PRESENTING ON THE PHONE WILL BE TIM CRIPE, CHIEF OF THE DIVISION OF HEMOTOLOGY ONCOLOGY AND BONE MARROW TRANSPLANTATION AT THE NATIONWIDE CHILDREN'S HOSPITAL AND MEMBER OF THE FACULTY AT THE OHIO MEDICINE. BEFORE COMING NATION WEED CHILDREN'S HE WAS MEDICAL DIRECTOR FOR CLINICAL TRANSLATIONAL RESEARCH, FOUNDER OF THE COMPREHENSIVE MOUSE SKEW LOW SKELETAL PROGRAM AT CINCINNATI CHILDREN'S MEDICAL CENTER. HIS RESEARCH FOCUSES ON DEVELOPING AND TESTING THERAPIES FOR PEDIATRIC SOLID TUMORS AN TRANSLATING THOSE FINDINGS IN CLINICAL STUDIES. THANK YOU FOR BEING WITH US. YOU INDUCE COLLABORATORS ALSO OPT PHONE WITH YOU TODAY? >> YES, ACTUALLY I HAVE A SLIDE WITH THEIR NAMES SO ASSUMING THE SLIDES ARE UP. I WANT TO THANK THE RAC TO GIVE UPDATE AND SINCE WE ARE PROPOSING SIGNIFICANT CHANGE IN THE PROTOCOL THROUGH AMENDMENT. I ASSUME YOU'LL INTERRUPT ME IF SOMETHING IS WRONG WITH THE SOUND. THE NEXT SLIDE SHOWN NO, THE PRIMARY STUDY TEAM SOME WHOM ARE ON THE PHONE. SO FROM VIRTUE BIOLOGIC IN THE UNITED KINGDOM, THE RISK OFFCAST PERSONNEL, ROBERT SPAVIN IS ON, JOE CON NOR SIGN SCIENTIFIC OFFICER IS ON, SAUCE GOALS BORROW, THOSE THREE HAVE JOINED US. FROM CINCINNATI CHILDREN'S WHERE I BEGAN THIS WORK, A NUMBER OF YEARS AGO, WE'RE NOW CURRENTLY JIM GOALER IS SITE PI THERE, ONE MEDICAL COLLEAGUES, I BELIEVE OPT PHONE P IS MARY AN BRUNER, NOT SURE IF SHE HAS SEEN THE SLIDES. THERE ARE OTHER PEOPLE THAT HAVE BEEN KEY PLAYERS AS WELL LISTED ON THE SLIDE. HERE AT NATIONWIDE I MOVEDDED A YEAR AND A HALF AGO, MYSELF, WE HAVE SEVERAL KEY PEOPLE MICHELLE VAUGHN MAYBE DIALING IN. WE'RE RUNNING SOUPER THAN WE THOUGHT SO NOT SHOWER SHE JOINED US YET. I BELIEVE THAT'S THE TEAM THAT'S CURRENTLY DIALED IN. SO WHAT I THOUGHT I WOULD RUN THROUGH TODAY RELATIVELY BRIEFLY, A QUICK REVIEW OF CHILDHOOD ADOLESCENT SR. COMA WITH USINGS SARCOMA IS AN INVENTORY EXAMPLE, REVIEW FROM ONCOLYTIC VIRUS STUDIES PEDIATRIC AND REGARDING HSV DRUG VECTORS. BRIEF DESCRIPTION OF THE BACKGROUND OF 1716 SEPARATEVERE STUDY UPDATE AND PROPOSED MAJOR AMMENT. SO MANY OF YOU KNOW ABOUT THE SUCCESS IN CHILDHOOD CANCER THERAPY MOST WHICH HAVE BEEN FOR LEUKEMIA, FOR STANDARD LYMPHOBLASTIC LEUKEMIA AND HODGKIN'S DISEASE AND A FEW OTHER TUMORS SUCH AS WILL.'S TUMOR BUT MANY CANCERS WE SEE IN PEDIATRICS AND YOUNGcoLr ADULTS, PROGRESS IS SLOWS, THIS IS AN EXAMPLE FROM USINGS SARCOMA, A JUMP IN SURVIVAL CURVES WITH THE ADDITION IN THE 80s OF (INDISCERNIBLE) TO A THREE DRUG BACKBONE SO USING FIVE DRUGS WE SAW A BIT OF A JUMP BUT DESPITE NUMEROUS CLINICAL TRIALS SINCE THEN THERE'S REALLY BEEN LITTLE PROGRESS IN THE EARLY PART OF THIS PAST DECADE AND EARLY 2000 WE DID SEE SOME INCREASE IN SHORT TERM METRICS USING A COMPRESSED CHEMOTHERAPY DOSING REGIMEN, INSTEAD OF THREE WEEKS EVERY TWO WEEKS SO WE HOPE THAT WILL TRANSLATE TO A LITTLE MORE LONG TERM SURVIVAL BUTTY SPITE LOTS OF WORK PROGRESS HAS BEEN SLOWED SUGGESTING THE NEED FOR OTHER KINDS OF THERAPIES, IN PARTICULAR FOR THOSE WHO RELAPSE OR FOR THOSE WITH METASTATIC DISEASE SURVIVAL IS ESSENTIALLY ZERO. SO WE ARE PURSUING ONCOLIT VIRAL THERAPY AS ALTERNATIVE OR ADJUNCT TO CHEMOTHERAPY. AS YOU WILL THE KNOW, USE OF LIVE VIRUSES TO INFECT AND KILL TUMOR CELLS THAT POTENTIALLY INDUCE ANTITUMOR IMMUNE RESPONSE AND EXPRESS TRANSGENES TO INDUCE VARIOUS THERAPEUTIC EFFECTS. I DID A SEARCH ON CLINICALTRIALS.GOV FOR HSV DERIVED VECTORS AND CAME UP WITH FOLLOWING LIST OF DIFFERENT VECTORS. THEY HAVE DIFFERENT STRAIN BACKGROUNDS AND DIFFERENCE MUTATIONS. SOME OF WHICH MAY HARBOR TRANSGENES, MANY OF YOU ON THE COMMITTEE ARE FAMILIAR WITH THESE VARIOUS VECTORS ONE I'M TALKING TODAY, 1716 DOES NOT CONTAIN TRANSGENES, IS A DELETION, AND THERE HAVE BEEN SIX COMPLETED STUDIES IN EUROPE NOT ON CLINICALTRIALS.GOV AND TWO INCLUDING OURS THAT ARE ON CLINICAL TRIALS D&O GOVERNOR. -- CLINICALTRIALS.GOV. REVIEWING PEDIATRICSK WITH ONCOLYTIC THERAPY, SENECA VALLEY VIRUS TRIAL, REAL LICENSE TRIAL, CUP TRIALS 1716 AND THEN ONE THAT I WAS INVOLVED WITH WITH GENERIX VACCINIA TRIAL ON HOLE NOW. THE FIRST TWO CHILDREN'S ONCOLOGY GROUP PHASE ONE CONSORTIUM AND A FEW OTHER SELECTED SITES SO THOSE ARE SOMEWHERE BETWEEN 15 AND 20 SITES. THE 1716 IS CURRENTLY ONLY OPEN AT CINCINNATI CHILDREN'S AND WE'RE PUTTING IT THROUGH THE REGULATORY PROCESSES TO OPEN IT HIRE AT NATIONWIDE IN COLUMBUS. THE GENEREF WAS OPEN IN CINCINNATI. THESE ENROLLED PATIENTS OF VARYING AGES DOWN TO AGE 2 OR 3 IN SOME CASES, THE CURRENT TRIAL THAT WE'RE DISCUSSING TODAY IS OPEN FROM AGE 7 TO AGE 30. THIS IS MAINLY BECAUSE THE PATIENTS WITH SARCOMAS SPAN ADOLESCENT YOUNG ADULT RANGE. CURRENT TRIAL IS OPEN INTRATUMORAL INJECTION AND INTRAVENOUS INJ AND THERE ARE CERTAIN MINIMAL SIZE LEAGUES REQUIRED FOR THE INTRATUMORAL DOSING TO HAHN IT WILL VOLUME OF DOSE WE'RE GIVING. I PUT PUT A RED AROAR ON THE DOSE ESCALATION SCHEMA FOR EACH TRIAL WHERE THE TRIAL IS CURRENTLY AT ENROLLING. MOST TRIALS HAVE BEEN OPEN FOR A COUPLE OF YEARS AND THEY'RE ALL THE OTHERS ARE ALL OPEN AT THE TOP, DOSING RANGE AT THE MOMENT SO DOSE ESCALATED SAFELY TO THOSE RANGES. THE HSV ARROW WAS THE TOP DOSE PRIOR TO CURRENT AMENDMENT WE ARE PROPOSING. THAT'S WHY WE'RE NOT YET AT THE TOP DOSE. P IN TERMS OF NUMBER OF INJECTIONS SENECA VALLEY IS A ONE HOUR INFUSION. THE REAL LICENSE IS A ONE HOUR INFUSION DAILY FOR FIVE DAYS. BOTH REPEATABLE. THAT ONE ON A MONTHLY COURSE UP THERE, UP TO 12 DOSES. THE SENECA VALLEY ONE IS AMENDED TO INCLUDE A COHORT B WHICH REPEAT DOSES PRIOR AFTER A CYCLOPHOSPHOMAID DEEING ON DAYS 28 AND 9. CURRENT STUDY FOR 1716 HAS BEEN OPEN TO REPEE DOSING UP TO THREE MORE DOSES FOR INTRATUMORAL IF PATIENTS HAD ASTABLE DISEASE OR -- STABLE DISEASE OR BEAR RESPONSE. GENEREX STUDY IS ORIGINALLY OPEN TO INCLUDE UP TO FOUR TOTAL DOSESES. JUST BRIEFLY, THE GENOMIC MAPS OF THESE HSVs IN CLINICAL TRIAL THE HSV GENOME IS 150 BASE PAIRS, A UNIQUE LONG REGION, A UNIQUE SHORT REGION FOLLOWED -- VOND BY UNIQUE REPEATS. IT WAS ORIGINALLY IN CLINICAL TRIALS IS A DOUBLE DELETION, 34.5 GENE DELETEDDED IN REPEAT AS WITH WELL AS ICP-6 GENE DEFECTIVE. THE 1716 HAS THE IP 6 GENE INTACT, BOTH COPIES RO-1 GENE THAT ENCODES ICP 30.5, ALSO IN SOME CIRCLES KNOWN AS NEUROVIRULENCE GENE. THE OTHER VECTORS I ELICIT ARE IN CLINICAL TRIALS, WE CAN DISCUSS IF ANYONE HAS QUESTIONS. FOCUS NOW ON THE 1716 STORY. THERE ARE A FAIR AMOUNT OF PRE-CLINICAL DATA, TOXICOLOGY AND BIODISTRIBUTION STUDIES. THAT HAVE BEEN PERFORMED LD-50 IS HIGH FOR INTRACRANIAL INJECTION AND XENOGRAPH MODELS SHOWING EFFICACY WITH INTRATUMORAL INJECTIONS AND A COUPLE THAT I'LL SHOW YOU WITH INTRAVENOUS INJECTION. THIS VIRUS HAS BEEN IN ADULT TRIAL THIS IS EUROPEMENT FIRST FOUR WITH INTRATUMORAL INJECTION OF ADULT HIGH GRADE GLIOMAS. YOU CAN SEE THE PATIENTS THERE. THERE WAS A MELANOMA TRIAL AND A TRIAL OF SQUAMOUS CELL CARCINOMA, INTRATUMORAL INJECTION AND A NEW TRIAL WAS OPENED RECENTLY INDICATION WITH MESOTHELIOMA WHERE PLURAL AN TWO PATIENTS ENROLLED TO DATE. OF THOSE TRIALS THE CONCLUSIONS THAT MOST WHICH HAVE BEEN PUBLISHED THERE WERE NO VIRUS RELATED TOXICITIES THAT ANY DOSE OR ROUTE OF ADMINISTRATION NO VIRUS SHED WAS DETECTED BY BUTCAL SWAB OR URINE. THE ADMINISTRATION INTRATUMORALLY WAS TOLERATED. THERE WAS VIRAL REPLICATION WITH RESECONDED TISSUE RETAINED POST ADMINISTRATION IN A COUPLE OF TRIALS. TISSUE WHEN TESTED EXVIVO REMAIN SUSCEPTIBLE TO REPLICATION. IN THE BRAIN TUMOR TRIAL IN PARTICULAR, THIS WERE MANY NOTABLE INDIVIDUAL CASE REPORTS PROLONG SURVIVAL BEYOND WHAT ONE EXPECTS FOR DIAGNOSIS. THAT STUDY THAT'S OPEN, THE MESOTHELIOMA STUDY IS GOING UP TO A DOSE OF 10 TO THE 7TH CALL INTERNATIONAL UNITS WHICH IS ESSENTIALLY EQUIVALENT TO PLAQUE FORMING UNITS. MORE DETAIL ABOUT THAT STUDY OPEN, AGE 18 AND ABOVE. THOSE PLURAL CATHETERS FOR ADMINISTRATION. THERE'S SINGLE AND REPEAT DOSING. ON A THREE BY THREE DESIGN WITH DOSES ONE WEEK APART UP TO A TOLL OF FOUR DOSES. TWO PATIENTS SO FAR NO DLT OR SAE. BOTH PATIENTS HAVE HAD PROGRESSIVE DISEASE FOLLOWING THE FIRST DOSE. WE AB AD PEDIATRIC STUDY BECAUSE I'M A PEDIATRIC ONCOLOGIST, THOSE ARE THE PATIENTS I SEE. WE ALSO HAD PRE-CLINICAL DATA WITH 1716 AND SOME SARCOMA MODELS AGAIN, USING SARCOMA IS AN EXAMPLE. THIS IS A DOSE ESCALATION STUDY OF INTRATUMORAL COLLECTION SINGLE DOSE AT TIME ZERO, WHERE YOU SEE VOLUMES RANGE BETWEEN 250 TO 500-MILLIMETERS CUBED, THREE DOSES AND SURVIVAL IN A MOUSE XENOGRAPH FLANK MODEL. IN ACCUMULATION DATA PHASE 1 STUDY ORIGINALLY INTRATUMORAL DOSING FOR REASONS I'LL DISCUSS LATER WE AMENDED TO PROPOSE AN INTRAVENOUS DOSING COOR. THIS WAS FOUR PATIENTS WITH NON-CENTRAL NERVOUS SOLID TUMORS. PARTLY BECAUSE THAT'S MY CLINICAL PRACTICE AN PARTLY BECAUSE THAT'S WHERE WE HAD PRE-CLINICAL DATA DETERMINE SAFETY AND DECEMBER LIMITING TOXICITIES AN SECONDARILY MONITOR ANTIVIRAL IMMUNE RESPONSE, VIREMIA, VIRUS SHEDDING AND ANTITUMOR ACTIVITY WITHIN THE CONFINES OF A PHASE 1 STUDY. THIS SHOWS THE ORIGINAL STUDY DESIGN, WE HAD TWO PARTS TO IT. SINGLE INTRATUMORAL DOSE, THAT'S BASED ON MOST PRE-CLINICAL DATA, AND PRE-CLINICAL TEXT DOG DATA THAT TESTED A SINGLE DOSE. BECAUSE OF POSSIBILITY OF TUMOR RESPONSE IF THERE WERE ONE WE FEEL UNETHICAL NOT OFFERING A SECOND OUTHIRE DOSE SO THE FDA WAS AGREEABLE TO ADDING THREE ADDITIONAL DOSES. AT LEAST FOUR WEEKS APART, WE BUILT IN AN OPTIONAL BIOPSY, BEING INTRATUMORALLY WITH A NEEDLE ALREADY THERE THAT WE TAKE A POSE OF TISSUE IF PATIENT HAD PRIOR INJECTION AND LOOK FOR VIRUS IN THE TISSUE. NO PATIENTS HAVE UNDERGONE A SECOND INJECTION, GIVE YOU THAT AHEAD OF TIME TESTIMONY DOSE LEVELS WERE TWO. WITHIN TIMES TEN THE 10TH AND TWO TIMES 10 TO THE 6TH ON AVAILABLE SIZES FROM DSP MANUFACTURING AND ALSO BECAUSE THOSE WERE WELL BELOW THE ON A PER KILO BASIS, THE DOSES TESTED IN THE TOX STUDIES. THE PLAN WAS ORIGINALLY THREE PATIENTS AT THE FIRST DOSE LEVEL, THREE PATIENTS AT EACH OF THREE SITE CLASSIFICATIONS HIGH CLASS -- CENTRAL PERITONEAL. SUPERFICIAL DEEP OR INTRAPULMONARY. THAT WAS A TYPO. OUTCOME SAFETY AND EFFICACY. >> SO THE STUDY IS THAT SUS IS FIVE PATIENTS ARE ENROLLED TO DATE. THREE WERE ENROLLED AT DOSE LEVEL 1, TWO AT DOSE LEVEL 2, THE DIAGNOSIS HERE NON-TOW MORE SOLID TUMORS IN CHILDREN, RHABDOMYOSARCOMA, THE SOFT TISSUE SARCOMA, MALIGNANT NERVE SHEET TUMOR PATIENT WITH WITH NF-1 AND KNEW FIBROMATOSIS TYPE 1, OSTEOSARCOMA AND CORRIDOR MA, NO TREATMENT RELATED SERIOUS ADVERSE Ek]U-5„ÖAv OR MAJOR TOXICITIES HAVE BEEN OBSERVED. I WANTED TO ILLUSTRATE ONE OF THE CASES FOR YOU AND I DO HAVE A SIMILAR SET OF SLIDES AND IMAGES FOR ALL THE CASES IF YOU'RE INTERESTED THAT ARE BUILT IN AT THE END OF THE TALK. BUT JUST TO SHOW YOU THE KINDS OF PATIENTS THAT WE GET ON THIS TRIAL, THEY HAVE BEEN COPPING TO THIS TRIAL LAST DITCH EFFORT AFTER HAVING BEEN ENROLLED IN MULTIPLE OTHER PHASE 1 STUDIES IN MANY CASES. CERTAINLY HAVING BEEN ON MULTISALVAGE CHEMOTHERAPY REGIMENS THIS IS THE FOURTH PATIENT, 19-YEAR-OLD WITH RECURRENT OSTEOSARCOMA OF HIS SPINE. HE HAD MULTIPLE SURGERIES BEFORE THAT, MULTIPLE CHEMOTHERAPY RECOMMENDATION MENS AND ON STUDIES WITH TARGETED AGENTS INCLUDING IGF-1 ANTIBODY RECEPTOR ANTIBODY COMBINED WITH (INDISCERNIBLE). FAMILY HISTORY WAS NOTABLE FOR P-53 GERM LINE MUTATIONS. HE WAS ALSO IN THE HOSPITAL SUBSEQUENTLY PASSED AWAY FROM HIS LEUKEMIA, SISTER DIAGNOSED WITH WITH LYMPHOMA AN BROTHER PASSED FROM OSTEOSARCOMA, HIS CONDITION AT THE TIME OF STUDY ENTRY WAS PARAPLEA JIK FROM TUMOR EXTENSION TO THE SPINAL CANAL AMERICA HAD KIDNEY PROBLEMS FROM PRIOR CHEMOTHERAPY, CHRONIC PAIN AN SKID BREAKDOWNS BUT NOTHING INELIGIBLE BASED ON STUDY CRITERIA. THIS IS AN EXAMPLE, IT SHOWS CHEST X-RAY, PRIOR RIB RESECTIONS AS YOU CAN SEE, HE HAD SPINAL FUSIONS AS YOU CAN SEE, FROM PREVIOUS TUMOR RESECTIONS. AND ON PET SCAN YOU CAN SEE THE TUMOR RECURRED SURROUNDING SPINAL FUSION RODS PERIPHERY PET CAN BUT QUITE EXTENSIVE THROUGHOUT HIS SPINAL REGION. SO HE -- I'M GOING BACK TO THAT A SECOND. SO WE PICKED OUT A SPOT THAT WAS FAIRLY ACCESSIBLE, TURNED OUT TO BE VERY MUCH SUPERFICIAL BENEATH THE SKIN ON HIS BACK. IT CORRESPONDS TO A REGION AROUND HERE, WE CO-REGISTER PET AND IMAGING AN INTERVENTIONAL RADIOLOGISTS TO INJECT -- THE VIRUS REPLICATES ABOUT SPREADS AND TAKE HOLD AND SPREAD THE REST OF THE TUMOR BUT IN THESE CASES WEAVER NOT INJECTING HIGH TITERS, WE HAVE QUITE EXTENSIVE TUMOR PROGRESSION IN THESE PATIENTS, TOO LITTLE TOO LATE. BUT THAT IS THE THEME FROM ALL FIVE PATIENTS, HAPPY TO SHOW YOU THE DETAILS IF INTERESTED. SUMMARIZE HERE IS A DAY 28 VISIT , NONHAVE BEEN OBSERVED. THERE WERE ADVERSE HE WANTS POSSIBLY RELATED TO 1716 BUT ALL ARE MILD AND TRANSIENT. ALL CULTURE RESULTS BUTCAL URINE AND BLOOD ARE NEGATIVE. THERE ARE LOW SOME INSTANCES OF LOW PCR RESULTS IN TWO PATIENTS WITHOUT CLINICAL -- WITHOUT ANY CLINICAL EVIDENCE OF HSV INFECTION. MOST CONVERTED IF THEY WERE NEGATIVE BASE HYPE THEY CONNIVERRED DAY 28 TO POSITIVE. YOU CAN SEE THE 1, 2, 3, 4 PATIENTS CONVERTED BUT THE FIFTH PATIENT WHICH WAS THE CORRIDOR MA WHICH WAS A TUMOR IN THE PARASINUS REGION, THAT PATIENT DID NOT COP VERT. BUT THE OTHER CONVERTED SUGGESTING THEY HAD SOME EXPOSURE TO HSE ANTIGENS. ONLY ONE OF OUR FIVE PATIENTS WERE POSITIVE BASELINE. SO THE SUMMARY OF EFFICACY DATA FOR INITIAL EVIDENCE OF EFFICACY AT DAY 14 OR DAY 28, AT MRI. THE FIRST FOUR SUBJECT DETERMINED THE TO HAVE PROGRESSIVE DISEASE, FIFTH WAS DETERMINEED TO HAVE STABLE DISEASE AT DAY 14 BUT PROGRESSIVE AT DAY 28 AND ALTHOUGH TECHNICALLY ELIGIBLE THIS PATIENT CHOSE TO SEEK OTHER TYPES OF THERAPY. WE HAVE HAD A TOTAL OF 284 ADVERSE EVENTS, 21 ASSOCIATED WITH SERIOUS ADVERSE EVENTS REPORTING, MOST WERE METABOLIC OR LABORATORY SOME PAIN, UP IN OF THESE WERE POSSIBLY TO THE UNDERLYING VIRUS BUT THE LIMITATIONS OF THE STUDY, THERE'S SLOW ENROLLMENT, WE HAVE BEEN OPEN SINCE 2010. WE DID STREAM 23 PATIENTS BUT ONLY FIVE ENROLLED. MOST PREFERRED TO OFFER OTHER STUDIES THAT WERE OPEN OR OFF STUDY SALVAGE REGIMENS SYSTEMIC TREATMENT BUZZ MOST EITHER HAVE EXTENSIVE DISEASE AND THE REGION WE'RE ABLE TO INJECT IS QUITE SMALL. OR THEY HAD METASTATIC DISEASE AND DIDN'T WANT TO OPT FOR SOMETHING THAT WAS A LOCALIZED TYPE OF THERAPY. SEVERAL HAD RAPID DISEASE PROGRESSION THAT PRECLUDED ENROLLING. WE HAVE SHOWN EFFICACY LIKELY IN PART DUE TO LOW DOSE THOUGH THERE MAYBE OTHER EFFECTS THAT ARE DIFFERENT FROM MOUSE STUDIES TO HUMANS. WE HAVE PROPOSED A HIGHER INTRATUMORAL DOSE. AND INTRAVENOUS DOSE COHORT BECAUSE OF SOME DATA I'LL SHOW YOU NEXT. AND BECAUSE OF THE POOR ACCRUAL AND REALLY NEED TO ADDRESS PATIENT POPULATIONS MORE EXTENSIVE TOW MORE BURDEN INCLUDING METASTATIC DISEASE. PROVIDED I HAVE SUFFICIENT TIME I WANT TO SHOW YOU SLIDES ABOUT IV TOXICOLOGY STUDY OR BIODISTRIBUTION STUDY AND IV EFFICACY STUDY ONE SLIDE EACH. IN TERMS OF TOX STUDY WITH IND THERE WAS INTRAPERITONEAL ADMINISTRATION TO STIMULATE TYPE TISSUE INJECTION OF VIRUS. THERE WAS ALSO AN INTRAVENOUS COHORT CONSISTING OF 66 AN HALLS GIVEN APPROXIMATELY 7 MILLION PLAQUE FORMING UNITS PER KILOGRAM WHICH IS 3 UNFOLD ABOVE FROM POSED HIGH ISODOSE IN THIS TRIAL. THERE WAS 100 PEST SURVIVAL TO RESPECTIVE TIME POINTS, EARLY MID AN LATE TIME POINTS SET UP PRIOR TO THE EXPERIMENT. WE DID OBSERVATIONS WEIGHT, CHEMISTRY, BLOOD COUNTS, HISTOPATHOLOGY FROM EACH MOUSE. THERE ARE CONSISTENT CHANGES THAT PATHOLOGISTS NOTED OR TAIL NECROSIS OR ABSESSES. THESE WERE ALSO SEEN IN MICE GIVEN EXCIPIENT, THE STRANGE WE USE HAD REPORTED BASELINE EPICARDIAL CALCIFICATIONS THAT WE THOUGHT WERE CONSISTENT WITH REPORTED PREVIOUS REPORTS.nUns ELEVATED BILIRUBIN WITH UP INCONSISTENT IN THE EXCIPIENT MICE. SORRY FOR TITLE BUT BIODISTRIBUTION STUDY THAT EXPRESSES LUCIFERASE, THIS IS A FLANK XENOGRAPH OF OF HEPATOCELLULAR CARCINOMA AND IV ADMINISTRATION OF ONE TIMES TEN TO THE 7TH AND THE TUMOR APPEARS TO BE EXPRESSING VIRAL GENES LUCIFERASE AND PRIMARILY AT THE SITE OF TUMOR AND SEEN PERSISTING UP TO 21 DAYS. WHEN LOOKING AT THE ORGANS FOR EVIDENCE OF VIRUS, THERE WAS NO VIRUS DECKED IN ANY ORGANS IN THIS PARTICULAR STUDY EXCEPT IN THE TUMOR. AT THE VARIOUS TIME POINT AND SEEN TO PERSIST BEYOND THREE TO FOUR WEEKS. FINALLY EFFICACY DATA IV AD MINISTERED -- VIRUS AD MINISTERED BY INTRAVENOUSLY ON DAY #, 14, 29 IN THIS CURVE. DIFFERENCE IN GROWTH WAS TREATED HIGHLY IN THE HUMANS THAT WERE GIVEN TO THE MICE ON A PER KILO BASIS IS FAR EXCEEDED WHAT WE'RE PROPOSING TO GET TO THE HUMANS. YOU CAN SEE THAT IN TWO OUT OF SIX MICE WITH 10 TO THE 5TH CURED AND FOUR OF 6, 10 TO THE 6 WERE CURED SO THE VIRUS HOMES TO AN REPLICATE IN TUMOR WHEN GIVEN INTRAVENOUSLY. SO BASED ON DATA WE PROPOSED A NUMBER OF AMENDMENTS. THE CURRENT AMMENT THAT'S BEEN APPROVED BY THE IRB APPROXIMATE THE AT CINCINNATI THIS VERSION 12.2. THIS ADDS IN ADDITION TO THE INTRATUMORAL DOSINGING A SECOND COHORT INTRAVENOUS DOSE, WHEN WE FILED THIS WE THOUGHT WE WOULD INCREASE THE DOSE INTRATUMORAL BUT THAT IS ACTUALLY WHAT WE CALL VERSION 13. BUT THIS DOES INCLUDE INTRAVENOUS DOSE ESCALATION THAT IS CALCULATED ON A PER KILO BASIS. BUT EQUIVALENT IN A 40 CELL GRAM PERSON BY TWO TIMES TECH TO THE 6, EQUIVALENT TO THE DOSE GIVING NOW THAT WE NEED ONE MORE PATIENT TO I CREW TO. AND THEN A FURTHER DOSE ESCALATION ONE TIMES TEN TO THE 7TH. WE ACTUALLY THE ONE TO APPROVE NEXT VERSION 13 DOES VAN DOSE LEVEL BECAUSE OF UP ADEQUATE SUPPLIES. SAME OUTCOMES AS BEFORE VIRUS SHEDDING ANTIVIRAL RESPONSE. >> SOME OF THE SAFEGUARDS AN DISCUSSIONINGS WITH THE FDA WE HAVE INCORPORATED INTO THE CURRENT AMENDMENT IS THE FIRST THREE PATIENTS TO BE GIVEN INTRAVENOUS DOSING WOULD BE ADULTS OVER 18. A 28 DAY ON OBSERVATION PERIOD BETWEEN EACH OF THE PATIENTS AND YOU CAN HAVE IRB REVIEW REQUESTED BY BOTH FDA AND IRB. REVIEW OF THOSE THREE PATIENTS PRIOR TO ENROLLING ANY YOUNGER PATIENTS. WE RESTRICT YOUNGER PATIENTS TO THOSE GREATER TO OR EQUAL TO SEVEN YEARS OLD. NO SECOND DOSE. UNTIL FIRST THREE RECEIVED A SINGLE DOSE AN COMPLETED DLT OBSERVATION PERIOD. THESE WERE PUT IN PLACE BECAUSE THIS WOULD BE THE FIRST IN HUMAN INTRAVENOUS DOSING 1716. SO STATUS ARMAMENTS FOR INTRATUMORAL IV DOSING FOR ACCRUAL AT CINCINNATI. IBC APPROVED IT, THE FDA CBER APPROVED BUT ASKED TO HOLE ON MULTIPLE IV DOSING PENNING REVIEW OF THE FIRST THREE PATIENTS ADMINISTERED TO SINGLE DOSE, TODAY IS OUR UPDATE FOR YOU. WE WOULD LIKE TO OPEN AND PUT IN ACTUALLY VERSION 13 HERE AT NATIONWIDE AND DEP THEN DOWN CINCINNATI, THAT REVISE IT IS DOSE LEVELS GETS RID OF THE TOP IV DOSE AND ADD IT IS THIRD INTRATUMORAL DOSE. NARROWS STUDIES ONCOLYTIC VIRUSES, THERE HAVE BEEN ADULT STUDIES SHOWING INTRATUMORAL SAFETY AT 1716 WITH SINGLE AND MULTIPLE DOSING, UP TO DOSE OF 10 THE 7TH. ADULT STUDIES WITH OTHER HERPES SIMPLEX VIRUSES GIVEN INTRAVASCULARLY PUBLISHED, SAFETY I DIDN'T MENTION THOSE BUT THEY INCLUDE THE NB 1020 GIVEN UP TO WEEKLY TIMES FOUR, 10 TO THE 8TH IRP 450 ONGOING TRIAL WITH DR. TANAVE AS GENERAL THEY REACHED UP TO 10 TO THE 9TH INTERHEPATIC ARTERY. WE FEEL PRE-CLINICAL INTRAVENOUS STUDIES SHOW SAFETY AND EFFICACY AND JUSTIFY ADDRESSING ISSUES WE HAVE HAD WITH OUR PEDIATRIC/YOUNG ADULT PHASE 1 STUDY SHOWN SAFETY TO DATE AT THE DOSES BUT FEW HINTS OF EFFICACY AND POOR IVYLIKELY DUE TO HE METASTATIC DISEASE AND MORE SYSTEMIC THERAPY. SO I WANT TO ACKNOWLEDGE THE FOLKS THAT FUNNED THIS STUDY, WE FUNED FROM THE FDA ORPHAN DRUG PROGRAM AND INTRATUMORAL PROGRAM AN WORKING WITH BUNCH BIOLOGICS AND PRIVATE FOUNDATION BY PARTS OF CHILDREN WITH CANCER CALLED SOLVING KIDS CANCER THAT HELPED FIRST COUPLE OF PATIENTS. BE HAPPY TO ANSWER ANY QUESTIONS. >> THANK YOU VERY MUCH, TIM. MANY OF THESE INDIVIDUALS WITH MUSCULOSKELETAL TUMORS OCCUR IN THE LIMB, WHERE INFUSIONAL THERAPIES ARE SOMETIMES USED, WE THOUGHTN'T DOING A ARM WITH AN INFUSIONAL THERAPY INTO A SPECIFIC LIMB? >> THAT'S AN INTERESTING IDEA. CERTAINLY PEOPLE HAVE BEEN TRYING NOW WITH CHEMOTHERAPY AN TNF ALPHA AND OTHER AGENTS. I HAVE NOT HAD CLINICAL EXPERIENCE WITH THAT AND THAT'S CONTROVERSY WITH CHEMOTHER P AND LIMB PROFUSION WITH WITH OSTEOSARCOMA, THERE'S INCREASEED INCIDENT OF TUMOR NECROSESSION WHEN THAT'S DONE BUT NOT AN IMPROVEMENT IN SURVIVAL SO THE GENERAL FEELING WAS SURGERY IS GOOD FOR LOCAL CONTROL BUT SYSTEMIC THERAPY IS NEEDED TO ADDRESS META STAT TIC DISEASE AN OVERALL SURVIVAL. LIMB PROFUSION, THE METASTATIC THOUGH RECUR IN THE IMAGING THE METASTATIC DISEASE IS MOST COMMONLY IN THE LUNG SO WOULDN'T ADDRESS THAT ISSUE EITHER. >> I WAS TRYING TO SAY HAVE YOU SHOW A RESPONSE, BECAUSE RIGHT NOW, ANY RESPONSE YOU CAN SHOW WITH 1716 WOULD BE A GREAT POSITIVE.ó– THAT WAS A POINT OF THAT COMMENT. >> DO YOU HAVE COMMENTS? >> GREAT STUDY. SORRY MY VOICE IS MISSING IN ACTION. ONE QUESTION I HAD IS THERE IS A IDEA CONCEPT MOST VIRUS ARE REALLY WORKING THROUGH AS IMMUNOTHERAPIES INCLUDING T VAX EXPERIMENT PUSHING THE IDEA THIS IS REALLY AN IMMUNOTHERAPEUTIC APPROACH. FROM THE STUDY DO YOU HAVE ANY SCIENTIFIC CORRELATION RELATED TO IMMUNE RESPONSE AGAINST TOW MORE YOU INJECTION WITH VIRUS OR ARE YOU PLANNING THAT IN THE FUTURE? >> WE HAVE NOT BUILT ANY OF THOSE BIOLOGIC STUDIES INTO CLINICAL TRIALS. WE HAVE STUDYING THE A LOT IN THE MOUSE AS MOST PEOPLE HAVE. IN FACT IF IF YOU'RE THIS Q&A BECK CITY NEXT WEEK, M.D. Ph.D. STUDENT HAS A TALK MONDAY AFTERNOON. MOUSE REASON DOE MYOSARCOMAS AND IMMUNE RESPONSE, A LARGE PART OF THE EFFECTS IS ANTITUMOR IMMUNITY. I THINK WE ARE NOT ALLOWED ELI ETHICALLY BIOPSY TUMOR POST INJECTION IN CHILDREN UNLESS IT HAS PROSPECT OF BENEFIT OR OVERSIMPLIFICATION OFETHICS BUT MORE DIFFICULT SO WE WOULD BE LIMITED TO LOOKING AT SERUM CYTOKINES OR CHEMOKINES. WHEN THE STUDY WAS OPEN THAT WASSEN ON THE RADAR AND WE HAVEN'T THOUGHT ABOUT AMENDENING THAT REGARD YET BUT IT MIGHT BE AN INTERESTING THING TO DO. WE'RE MORE CONSENTED ABOUT AT THIS POINT ACCRUAL AND EVEN BEING ABLE TO FINISH THE STUDY. >> YOU ALSO WERE SHOWING IN YOUR INITIAL SLIDE THE SENECA VALLEY AND THE CYCLOPHOSPHAMIDE DO YOU SEE BEING USEFUL TO YOUR STUDIES AS WELL IN T FUTURE? >> I THINK SO. I MEAN BASED ON YOUR DATA IN THE PAST AN ANIMAL MODELS THAT'S A POTENTIAL. RIGHT NOW WE THINK THAT IN OUR MOUSE SARCOMA MODELS, AGAIN, PRELIMINARY DATA, IT'S NOT AS MUCH THE IMMUNE RESPONSE TO -- THAT UP TO GET RID OF TO ALLOW VIRUS REPLICATION WHICH IS WHAT THAT CYCLOPHOSPHAMIDE IS DOING BUT THE IMMUNE RESPONSE AGAINST TUMORS, VERY IMPORTANT. SO THERE IS A RISK THOUGH YOU MAY GET BETTER REPLY CASE, YOU MAY WORST ANTITUMOR RESPONSE. >> THANK YOU. ANY OTHER COMMENTS? ANY COMMENTS FROM OTHERS ON THE PHONE? FROM PUBLIC? TIM, THANK YOU VERY MUCH FOR PRESENTING US THIS DATA AND THIS PROPOSAL TODAY. GOOD LUCK ON THE FUTURE STUDIES IN THIS AREA. >> THANK YOU, THANKS FOR HAVING US. >> WE ARE NOW GOING TO TAKE A LUNCH BREAK AND WE'RE GOING TO RECONVENE SHORTLY AT 12:45 TO TRY TO START THIS AFTERNOON'S MEETING AND TRY TO FINISH AHEAD OF TIME THIS AFTERNOON. THANK YOU, EVERYONE. >> SHE OBTAINED HER DOCTORATE DEGREE FROM THE UNIVERSITY OF (INDISCERNIBLE) FOLLOWED BY INTERNSHIP AT -- A P DOCTORAL FELLOWSHIP IN NEUROLOGY IN CONCORDIA UNIVERSITY AND CHEMISTRY AT YALE UNIVERSITY. SHE'S CARPALIA CERTAINIATE PROFESSOR OF -- CURRENTLY PROFESSOR OF CELL BIOLOGY AN CELL GENETHER P ACCEPTOR UNIVERSITY OF MEDICINE DENTISTRY NEW JERSEY. DURING THE PAST DECADE SHE BUILT EXTENSIVE EXPERTISE IN CLASSIFICATION OF NOVEL THERAPEUTICS TO CAP VAN'S DISEASE. DR. LEONE AND HER TEAM DID LONG TERM FOLLOW-UP FOR GENE THERAPY FOR CANAVAN DISEASE AND DETAILED THE FIRST CLINICAL -- VIRAL VECTORS IN THE HUMAN BRAIN AS PART OF AN INTERNATIONAL PHASE 1, 2 CLINICAL TRIAL WITH A MINIMUM OF FIVE YEAR FOLLOW-UP ON EACH PATIENT. THANK YOU FOR BEING HERE TO TALK TO US TODAY. >> THANK YOU. GOOD AFTERNOON. THANK YOU SO MUCH. THE RAC COMMITTEE TO INVITE ME HERE TO PRESENT TO RECAP THE LAST MORE THAN A DECADE OF WORK USING AAV IN THE BRAIN. THIS IS IN FACT WAS REVIEW, YOU CAN SEE THE FIRST RAC REVIEW MARCH OF 2000, KNOWLY 14 YEARS AGO. AND THIS PROTOCOL WAS ACTUALLY THE FIRST REPRESENTED THE FIRST CLINICAL USER IN THE HUMAN BRAIN, THE FIRST IND APPROVED FOR APPLICATION OF VIRAL VECTORS FOR NEUROLOGICAL NEUROGENETIC DISORDER. IN THIS CASE CANAVAN DISEASE. WHAT WE AIM TO DO IN THIS STUDY WAS TO OVEREXPRESS HUMAN (INDISCERNIBLE) ENZYME IN THE BRAIN OF AFFECTED CANAVAN PATIENTS. CANAVAN WITHIN GENETICS DI SORD, AUTOSOMEAL RECESSIVE DISEASE DISORDER CHARACTERIZED BY MUTATION IN THE GENE THAT RESULT IN LOSS OF FUNCTION, REDUCED FUNCTION OF (INDISCERNIBLE). THE RESULT IS ACCUMULATION OF N ACETYL AS AS PAR AT A TIME IN THE BRAIN, 98% SYNTHESIZED IN THE BRAINI TO THE BLOOD AND URINE. ONE DIAGNOSTIC MODEL TO CANAVAN DISEASE ARE IN FACT PRESENCE OF HIGH NAA EXTREMELY HIGH NAA IN THE URINE. ANOTHER OPTION FOR THE MUTATION IS KNOWN IN FACT GENETIC TESTING WHEN WE STARTED THIS WORK, MOST PATIENTS WE SAW THE FIRST PATIENT, WAS ASHKINAZE JEWISH ANCESTRY. THESE DAYS WITHIN THE LAST SAY SEVEN YEARS MAJORITY OF CASES DO NOT HAVE THIS COMMON MUTATION BUT INSTEAD RARE MUTATIONS OF WHICH MANY WE HAVE IDENTIFIED DURING THE STUDY, DURING THE GENE THERAPY STUDY. SO OVEREXPRESSION OF (INAUDIBLE) IN THE BRAIN IN SELECTED AREA WAS THE IDEA OF THIS GENE THERAPY STUDY WAS APPROVED IN PHASE 1 STUDY, FIRST APPLICATION OF NAD IN THE HUMAN BRAIN, A LOT OF TENSION VERY MUCH SCRUTINIZED, WELL REMEMBER WHAT HAPPENED IN 1999, THE RAC REVIEW WAS POSITIVE AT THAT TIME, THE FDA AGENT EXTREMELY PRODUCTIVE AND CONSTRUCTIVE RELATIONSHIP. THIS PROTOCOL WAS APPROVED APRIL 2001 IN THE FIRST PATIENT TO RECEIVE THE VIRAL VECTOR WAS IN FACT IN JUNE. CANAVAN DISEASE IS 99% OF THE PATIENTS THAT WE'RE GOING TO CALL AFFECTD BY TYPICAL FORM OF THE DISEASE. ARE AFFECTED BY THIS -- VERY LITTLE MYELIN BEING DEVELOPED, SO VERY SEVERE. VERY PROGRESSIVE AND UNIFORMLY FATAL, A MONOGENIC DISEASE, PATHOLOGY IS JUST UNIQUELY REPRESENTEDDED IN BRAIN ONLY THE BRAN IS AFFECTED IN THE DISEASE SO GENE THERAPY AT THIS TIME, THE IDEAL METHODOLOGY TO OVEREXPRESS A GENE, A HUMAN GENE TESTS THE SAFETY OF VIRAL VECTOR OF A BRAIN IN THE PATIENT AND THIS WAS THAT YOU SEE IN THE SURGICAL SECTION WITH -- IMAGINE TWO YEARS AND FIVE YEARS AT 6.9 YEARS OF AGE, THE FIRST PATIENT TO RECEIVE AAV 2 OVEREXPRESSING (INAUDIBLE). IN TERMS OF PHENOTYPE VERY CLEAR, PATIENTS ARE MACRO CEPHALIC, (INDISCERNIBLE) DISEASE AND P DO NOT SHOW ANY FORMATION SO THE MACRO RECEIVELY, THE FLOPPYNESS, THE VERY SLOW DEVELOPMENT USUALLY CARRIES ON URINE ANALYSIS AND P THAT'S HOW MAJORITY OF PATIENTS ARE DIAGNOSED THESE DAYS. EXTREMELY SEVERE AND LIFE EXPECTANCY USED TO BE 3 TO 5 YEARS, 18 YEARS AGO WHEN I STARTED WORKING WITH THIS DISEASE AT YALE UNIVERSITY. IN TERMS OF NEUROPATHOLOGY CHARACTERISTIC OF THIS DISEASE IS SPONGE FORM GENERATION OF THE BRAIN WITH BRAIN ATROPHY AND THIS MYELINATION. THE CLINICAL PHASES WERE DESCRIBED IN THE HUMAN GENE THERAPY ARTICLE HERE IN 2002, WHEN THE FIRST COHORT OF PATIENT ALREADY HAS RECEIVED 900 BILLION VIRAL PARTICLE EXPRESSED IN HUMAN HYDROXYLACE. WE DEFINE SAFETY END POINTS DURING THE PRE-CLINICAL PHASE. WE HAD TO JUST STUDY THE PATIENT AT LEAST TWICE, SOME OF THE PATIENTS MANY STUDIES ON NMR SPECTROSCOPY ENABLE TO ASSESS QUANTITATIVELY, NOT INVASIVELY, THE PRESENCE OF NAA AND SELECTED VOXELS IN THE BRAIN WHICH SHOWS SINGLE VOXEL SPECTROSCOPY RUNNING STUDIES SINCE SINCE LAST SENRY ON THIS WITH HOSPITAL PHILADELPHIA GROUP, LEADING THE GROUP THERE. MAGNETIC RESIDENCE STATUS AND DIFFUSION SENSE IMAGING, USING TO QUANTIFY EFFECT OF THERAPIES THAT WERE GOING GROSS MANY FOR FUNCTION MEASURE–f7#iz NEURODEVELOPMENTAL TESTS AND MANY ALSO DEVELOP ONE SPECIFIC EVALUATION WEIGH TEST FOR THIS PROTOCOL L. WE DID RUN SOME METABOLITE LEVEL QUANTIFICATION IN BLOOD, URINE, AND ONLY IN PATIENTS IMPLANTED WITH RESERVOIR WILL COLLECT CSS TO LOOK AT NAA AN METABOLITES IN CSF. WE DIP DO ANY LUMBAR PUNCTURE IN THE REST OF THE PATIENTS. WE ACTUALLY CONSIDERED UNETHICAL BY OUR IRB AT THAT TIME. SO WE PROCEED WITH THIS WITHEDLYING THEN THE SECOND PHASE WAS THE SURGICAL PHASE AND AFTER THE DELIVERY THERE WERE FOLLOW-UPS WITH #, 3, 6, 9, 12, 18, 24 MONTHS. THIS WAS THE PROTOCOL AS IT WAS APPROVED, AND WE'RE FOLLOWING UP PATIENTS IN -- AS OF THIS YEAR. 14 YEARS AFTER BEGINNING THE STUDY. THE DIAGRAM WHICH WAS ALSO PUBLISHED IN HOW MANY GENE THERAPY CLINICAL PROTOCOL SHOW EXACTLY WHAT WE WERE AIMING FOR, FRONTAL, PARIETAL, OCCIPITAL AREAS IN WHICH EACH AREA WOULD HAVE RECEIVED 150 BILLION GENOMIC PARTICLES OF AAV. DURING THIS WORK, DURING THE LAST DECADE, WE IDENTIFY MANY NOVEL MUTATIONS AN DELETIONS UNDER DIFFICULT TO IDENTIFY AN MISSENSE AND OTHER MUTATIONS THESE ARE TWO HARLS BUT WE HAVE SO SO FAR IN OUR DATABASE 35 NOVEL MUTATIONS. AND WITH WITH THIS WORK, IN ORDER TO LOOK AT BIOMARKERS OF DISEASE PROGRESSION AND POSSIBLY DISEASE REGRESSION IN THE BRAIN, WE ALSO IDENTIFY WHAT UNIQUE GROUP OF PATIENTS, PATIENTS WITH WITH NO RESIDUAL ACTIVITY OF HYDROXYLACE TO SISTERS WHO ARE MILDLY AFFECTED SO MILDLY THAT ONE SISTER HAD NO ISSUES WHATSOEVER AND ONE, THE YOUNGER HAS COME EEG ABNORMALITY, SO FAIRLY NORMAL. SO WE'RE STUDYING THIS MUTATION, WE PUBLISH SOME WORK ON THIS MUTATION BECAUSE WE WOULD LIKE TO DETERMINE HOW PATIENTS CAN DEVELOP MYELIN WITHOUT OXIDASE IN THE BRAIN. ANOTHER GROUP HERE IN LONG/LAND PUBLISH ON A PATIENT HOMOZYGOUS, ONE OF THE MUTATIONS THE TWO SISTERS WERE HETEROZYGOUS FOR THIS UNIQUE MUTATION WITH ADD SO QUITE ACTIVE GIRL ALSO WITH NEURODEGENERATIVE ACTIVITY AND MYELINATED BRAIN. AND VERY FUNCTIONAL. IN THE LAST TEN YEARS CHILDREN HOSPITAL PHILADELPHIA CONDUCTED HUNDREDS OF STUDIES IN THESE PATIENTS. AND SOME OF THE PATIENTS WHERE -- WERE ENLISTED AND ENROLLED, ALL THESE PATIENTS IN FACT PUBLISHED IN THIS PAPER, SIGN A CONCEPT TO ENROLL IN SURGICAL FACE OF PROCEDURE BUT ONLY A FEW ABLE L IN TERMS OF VECTOR LIMITATION IN TERMS OF ELIGIBLE CRITERIA TO BE PART OF THE SURGICAL PHASE THE MOST PERFORM ISSUE HERE WAS SMALL STUDY PHASE 1 STUDY, WE KNEW LITTLE ABOUT THE DISEASE AND FUNDING RECEIVED BY NINDS ENABLE US TO CHECK CRUCIAL NATURAL HISTORY DATA THAT GAVE IN SOME OF THE WORK IN FACT AS IN P PUBLICATION STILL BECAUSE THE LAST DECADE SO MANY THINGS HAPPEN SPECIFICALLY NMR ANALYSIS, THE EXISTENCE NOW OF THE DIFFUSION SENSOR IMAGING HIGHLY QUANTITATIVE TO ASSESS MYELINATION IS ONE OF THE TECHNIQUES THAT WE'RE USING NOW TO ASSESS MYELINATION AND ENHANCE IMPROVEMENT FOLLOWING THERAPY. SO IN HERE, PATIENTS WE JUST HAVE,çLOOKED AT MODELS USING A LINEAR MIX EFFECT MODEL. NORMAL PROGRESSION OF THE DISEASE IN BRAIN MASS. WE HAVE SEEN THE MRI BUT BEFORE OF COURSE THERE IS A LOSS IN BRAIN MASS, SINGLE L PATIENT LINES AND THE SAME MODEL WAS USED THIS GROUP OF PATIENT WAS WHERE NORMAL PATIENT WOULD BE MANY TERMS OF 4 SIX MILLIMOLAR IN THE BRAIN AND WHERE THE ACTUAL POPULATION OF PATIENTS WOULD GO, WOULD BE IN TERMS OF N AA IN THE PERIVENTRICULAR REGION DURING DEVELOPMENT. THE GENE THERAPY MOVED FORWARD QUITE QUICKLY, WE STARTED WITH OUR CDNA OF COURSE WITH OUR SUBLYZER AND ANNOUNCER AND BGA POLYA NAC PROMOTER WAS USED IN THOSE DAYS. AND PROMOTE WAS THE PROMOTER THAT WE KNEW THE MOST IN TERMS OF LONG TERMK PRESENTATION, PROMOTOR OF CHOICE AT THE TIME, WE AIM TO EXPRESS IN THE NEURONS WHERE NAA SYNTHESIZE SO THAT WE CAN REDUCE THE SOURCE. NORMALLY (INDISCERNIBLE) IS ENDOGENOUSLY IN MEMBRANE BOUND OLIGODENDROCYTES SO THIS IS WHAT WE COULD DO IN 2000, THIS IS THE APPROVAL RECEIVED AND INITIALLY WE HAD YOU MAY REMEMBER, IN THE OLD DAYS WE USED TO USE WILD TYPE ADENOVIRUS BUS THE FIRST PRODUCTION OF CLINICAL VECTOR WAS USING TRIPLE PLASMIDS, TRANSFECTING KIDNEY CELLS AND PURIFYING IT AND LATER ON JOHN (INAUDIBLE) 1998 DEVELOP HUMAN EMBRYONIC KIDNEY CELLS WITH ADENOVIRUS 51A GENE INSERTED JUST USE AAV CAPSID AS WELL AS TRANSGENE FOR THE TRANSFECTION SO TWO MODELS APPROVED BY FDA. SHARED WITH THE WORLD, SEVERAL P PUBLICATIONS, CHARACTERIZATION OF OUR PRODUCT. WE HAD TO DEMONSTRATE FEWER STERILE MICROPLASM, VINTAGE VIRUSES BUT ALSO HAD POTENCY. AND IN TERMS OF -- IN TERMS OF THIS STUDY, WE HAD TO EVER SINGLE BATCH OF CLINICAL GRADE AAV WE HAD TO HAVE 90% OR MORE FULL VARIANTS WITH OUR TRANSGENE. ANYTHING THAT HAS URNL HERE STAIN SHOWS IN FACT EMPTY CAPSID. SO FULL LENGTH CHARACTERIZATION, TOOK A WHILE TO PRODUCE A SUFFICIENT AM OF VECTOR FOR THESE PATIENTS BUT SO WE'RE DESCRIBEING WHAT WE HAVE DONE. ON THE END POINT FOR SAFETY AND OF COURSE TO EFFICACY, WE'RE AIMING TO DELIVERING ALPHA VECTOR AND ALPHA TRANSGENE TO REDUCE NAA LEVELS IN THE BRAIN OF THESE PATIENTS. MAGNETIC RESONANCE WILL SEE DATA SERUM ANALYSIS AND ALL THE DATA, MOST DATA I'M PRESENTING TODAY HAS BEEN PUBLISHED THE FIRST PATIENT THAT RECEIVE IS DIRECTOR OF A STROKE CENTER, CAPITAL HEALTH. DR. JOHNSON, DR. MCFEE, THE GREATEST CLINICAL COORDINATORS THAT WORK MANUFACTURING OF THE CLINICAL VECTOR. WE HAD THREE FADESES OF THE STUDIES. IN 2001 THE VECTOR WAS PRODUCING A NEW UNIVERSITY OF OAKLAND UNDER DIRECTION OF DR. USING, OTHER TWO VECTORS CLINICAL VECTORS WERE PRODUCED UNDER DIRECTION OF DR. SOMALSKI. GLP NOW GMP GENE THERAPY CENTER. WE AIM TO INJECT THE SAME AMOUNT OF GENOMIC PARTICLES. THE FINAL PRODUCT MAYBE LESS OR MORE CONCENTRATED SO$l„ WE'RE JUST THIS BY INCREASING REDUCING THE FLOW RATE, AND PATIENTS ALSO ADMINISTER IV MANIT OBJECTIONL WHICH DEMONSTRATEED TO HAVE -- DELIVER BETTER DISTRIBUTION OF THE VECTOR. FIRST TWO, DR. FREEZE REPORTED THE FIRSTLY PATIENTS. DR. FILLY 7 MORE PATIENTS AND DURING THIS TWO COHORT OF PATIENTS WE CONDITION USE STEREO TACTIC SURGERY, WE USE IT IN THE THIRD COHORT OF PATIENTS WITH DR. BOWMAN AT COOPER HOSPITAL. TRY TO BRING YOU BECOME TO THE DEMOGRAPHICS, THE FIRST COHORT OF PATIENTS WAS SCRUTINIZED BY THE FDA AND SELECTED. YOU CAN SEE THE FIRST PATIENT, SECOND PATIENT, THIRD PATIENT AFFECTED FROM 6.9 YEARS TO FIVE AND FOUR. THIS IS 2001, YOU CAN SEE THE INITIAL GROUP OF PATIENTS HAD TYPICAL JEWISH MUTATION AND WE ALSO HAVE DEMOGRAPHIC OF YOU CAN TREATED GROUP OF PATIENTS OF COURSE WAS USED AS A DATA COLLECT WAS USED TO DEVELOP OUR MIX MODEL ANALYSIS. IT WAS ALSO PUBLISHED. SERIOUS ADVERSE EVENT. WE ACTUALLY HAD VERY LITTLE ADVERSE EVENT, I WAS THERE, THE TEAM WAS THERE, WE WERE THERE, WE WERE THERE WHEN PATIENTS WERE DISCHARGE FOUR DAYS THE FIRST PATIENT HAD MILD FEVER AFTER DUE TO THAT SHE STAYED A FEW MORE DAYS IN HOSPITAL AND UNDER OUR GRADING WAS CONSIDERED A SERIES OF ADVERSE EVENTS WE REPORTED,ING THE PATIENT WAS DISCHARGED, EVERYTHING WAS FINE, ALSO TO BE CONSIDERED IN THE DISEASE JUST A TYPICAL FEVER OF UNKNOWN ORIGIN THAT JUST OCCURS VERY EARLY ON IN LIFE. KNOB ABNORMAL TO DEVELOP FEVERFUL WHAT WAS CONCERNING IS THE 13 PATIENT RECEIVE COOPER HOSPITAL, THE VECTOR WAS DISCHARGED FOUR DAYS LATER AND STILL WHEN HE LOST CONSCIOUSNESS, HE WAS RUSHED TO THE ER, JUST ADJACENT TO THE HOSPITAL. AND THE CAT SCAN WAS NORMAL. CSF WAS LUMBAR PUNCTURE WAS COMPLETELY NORMAL, CHEMISTRY WERE NORMAL. SO THE -- KEPT MAKING ISSUE ABOUT LACK OF CONSCIOUSNESS AND BEING FAMILIAR WITH THE PATIENT'S (INDISCERNIBLE) THERE WAS LACK OF CONSCIOUSNESS. SO WHAT TO DO NEXT? WE FORCED BASICALLY MRU WITH CONTRAST. AND AT THAT TIME, ONLY AT THAT TIME NOT WITH A CITY SCAN THAT WAS HIGHER THAN ABNORMAL IN THESE PATIENTS WE WERE ABLE TO IDENTIFY A TINY ABSESS THAT WAS FORMED IN THE RIGHT OCCIPITAL BURR HOLE, ABOUT TWO MILLIMETER. IT TOOK ABOUT LESS THAN AN HOUR TO PREPARE PATIENTS TO THE OR WITH NO OTHER CLINICAL SYMPTOM, JUST LOSS OF CONSCIOUSNESS, NO FEVER, NO CSF, AND WAS REMOVED BY DR. DURING THE BY MIDNIGHT AT THAT TIME. WE SAVED THE PATIENT LIFE BECAUSE IT WOULD OF COURSE DEVELOP MENINGITIS AND WITH THAT POSSIBLY IRREVERABLE EFFECTS FROM IT BUT YOU WILL SAY THEY WILL STRENGTHEN IMMEDIATELY WITH ANTIBIOTIC AND PATHOLOGY WAS DONE, SERIOUS ADVERSE EVENT WAS REPORTED TO THE RAC OF COURSE WITHIN HOURS. TO THE FDA AND IRB. HERE IS THE PATIENT. ONE YEAR AFTER THE GENE THERAPY, HE JUST TURNED 10 AND IMAGES RELEASED BY THE PARENTS. LOCKING AT NAA CHANGE MS. THE STUDY, WHAT WE HAVE IDENTIFIED THE PATIENTS TREATED. THE BLUE LINE SHOWS THE AVERAGE EFFECT OF ALL PATIENTS AFTER TREATMENT. THIS POINT IS ACTUALLY THE TREATMENT. THIS SHADED AREA IS WHERE NORMAL PATIENTS WOULD BE SO THE CONCENTRATION IN THE BRAIN. THE FRONTAL PERIVENTRICULAR AN OCCIPITAL WERE TREATED. BASAL GANGLIA WAS FAR AWAY FROM INJECTION AND WAS USED AS A CONTROL AREA. THIS FIRST PART PUBLISHED INCLUDES ALL PATIENTS. AS YOU CAN SEE, JUST A MAJOR EFFECT OF AGE, DURING ENROLLMENT WAITING FOR PROCEDURE, THERE WAS A GREAT DEAL OF DROP OF NAA. HOWEVER, IF IF WE REMOVE THE OLDER PATIENTS. AVERAGE PATIENTS OF 3.5 YEARS, WE HAVE WE HAVE DROP IN FRONTAL AND PERIVENTRICULAR AREA, QUITE SIGNIFICANT. IN THE SUPPLEMENTAL DATA OF THE ARTICLE YOU CAN SEE MANY OTHER METABOLITES. SOMETHING WE WERE LOOKING AT CHOLINE, WE COULD SPECTATE LATE THE BASAL GANGLIA WERE UNDERGOING ATROPHY BECAUSE OF THE DISEASE. RATHER THAN TREATMENT. THAT'S SPECULATION WITH JUST NO OTHER PATIENT, NEVER DONE POSTMORTEM STUDY TO IDENTIFY THE PRESENCE OF THE TRANSGENE IN THE BASAL GANGLIA. ANOTHER WAY TO REPRESENT THE DATA IS TO LOOK AT THE SLOPE POST TREATMENT INDIVIDUAL DIFFERENCES IN EACH AREA. SO HERE MOST PERIVENTRICULAR SLOPE IN TERMS OF BRAIN MASS, WE HAVE IN FACT DETERMINED THAT THE PARIETAL AREA, WHICH IS THE ONE WE ARE ABLE EFFECTIVE OVEREXPRESSION SIGNIFICANTLY SLOW DOWN THE PROGRESSION OF BRAIN ATROPHY. T 1 VALUES ARE JUST -- THE THE STUDY SHOWED -- IN THE SLEEP IN THE AREA OF THE O CORPUS CALLOSUM WHERE OLIGODENDROCYTES ARE AND THEY MIGRATE THE FIRST WITH YEARS OF LIFE TO CORTEX. IN FACT, THIS T 1 SLOPE AS RESPONSE POST TREATMENT CHANGES IN SLOPE HIGHLY ELEVATED IN PATIENTS. IN THE SCIENCE OF MEDICINE ALSO, WE SHOWED PATIENTS ARE TREATED, THESE A REPRESENTATIVE MRI AND TO ENSURE THAT WE WERE ABLE TO SUBSIDIZE SAMPLES AND BRAIN ATROPHY IN PATIENTS THAT RECEIVE TREATMENT. NEARLY TWO YEARS. WHILE WE WERE NOT ABLE TO DO SO IN A PATIENT THAT WAS 47, FOUR YEARS OLD NEARLY. SO THAT OBVIOUSLY SUBJECTING THE EARLIEST INTERVENTION IS BETTER FOR BENEFIT OF THE STUDIES. IN THOSE DAYS CONVENTIONAL MRI STUDIES WILL SHOW YOU WOULD BE ABLE TO SEE T-32 WEIGHED IMAGE WHITE MATTER IN THE FRONTAL AREA BEFORE AN AFTER, ONLY DURING THE LAST GROUP OF PARENTS, THIS WAS NOT PART -- PATIENTS, THIS WAS NOT PART OF STUDY BUT WOULD BE PART OF ANOTHER PUBLICATION WE'RE WORKING ON WITH DTI. DIFFUSION SENSOR IMAGING IS ONE OF THE TECHNIQUES THAT UNFORTUNATELY IS NOT PAID BY INSURANCE, THESE DAYS ANYWAY IS WE WERE DOING A CLINICAL TRIAL. AND SHOULD BE, COULD BE, HIGHLY QUANTITATIVE OF COURSE WHAT DIFFUSION TENSOR IMAGING EMPHASIZE IS BILATERAL MOVEMENT OF WATER MOLECULES. THAT OCCURS ONLY IN MYELINATED FIBERSFUL EVERYTHING ELSE OF COURSE GOES IN ALL DIRECTIONS. SO THIS IS TELLING US AND HAS TOLD US LAST PATIENT ACTUALLY THE ONE PATIENT THAT HAD THE OCCIPITAL ABSESS HERE, SHOW IMPROVE DTI VERY EXPERIMENTAL END POINT WE HAVE. PROFILE IN PATIENTS, JUST NOTHING MUCH REMARKABLE EXCEPT PATIENT AGE IN WHICH WE SAW A RESPONSE IN NEUTRALIZING ANTIBODIES AFTER THE TREATMENT BUT THEN OF COURSE WE DIDN'T HAVE ANY ENROLLMENT CRITERIA SELECTED FOR B NEGATIVE OR POSITIVE FOR ARCAV ANTIBODIES. WE DIDN'T INCLUDE THAT. BUT IN THE END THE PATIENTS I SHOWED YOU MRI THE ONE THAT DIDN'T DEVELOP HYDROCEPHALUS RESPONDED IT WELL SO PRESENT OF NEUTRALIZING ANTIBODY DIDN'T MAKE A DIFFERENCE IN TERMS OF EXPRESSION OF THE TRANSGENE IN THE BRAIN. AND THIS PATIENT, PATIENT H WE ALSO SAW ELEVATION OF SOME OF THE CYTOKINES, THIS WORK WAS PUBLISHED EXCEPT FOR,L 4. SPECIFICALLY IL-5 AND IL-10 JUST RAISE A FEW MONTHS AFTER THE GENE DELIVERY WHILE 2, 8 AND 12 AND FACTOR RESPONDING IMMEDIATELY. AND THE REASON POSSIBLY WAS THAT THE SAME PATIENT WAS OPPOSED TO ADENOVIRUS THAT'S HOW WE FACTOR JUST DETERMINE LOOKING AT ADENOVIRUS ANTIBODY IN SERA OF THIS PATIENT. IF YOU REMEMBER THE FIRST GROUP OF PATIENT WAS PRE-IMPLANTED WITH A RESERVOIR AND WE LOOK AT CSF TITER FOR ARCAV NEUTRALIZING ANTIBODY, IT WAS PRETTY MUCH NEGATIVE. THE DIFFERENCE IN THE LIFE OF PATIENTS WE USE A ROUGH MOTOR FUNCTION MEASURE TEST AND ONE OF THE MANY, AND IN THIS LINE ANY SINGLE POINT ABOVE THIS LINE SHOWS A RESPONSE TO THE THERAPY VERSUS NON-RESPONSE. THE RED DOTS ARE THE OLDER PATIENTS, THE PATIENT IS THE ONE THAT WE DIDN'T HAVE FOLLOW-UP AFTER THE GENE THERAPY. IN TERMS OF STUDY WHAT WE KNOW IS THAT THE GREATEST RESULT WE HAD JUST Z AS A NORMATIVE VALUE IN THESE PATIENT IS THAT THERE ARE FOUR DIMENSIONS FOR GROSS MOTOR FUNCTION MEASURE, ONE IS GROSS FINE MOTOR VISUAL RECEPTIVE AND EXPRESSIVE. THIS IS THE AGE THAT IS ASSIGNED TO PATIENTS. WITHIN THIS COHORT THE COHORTS WE HAVE STUDIED. THERE IS A POST TREATMENT AFFECT IN LINE ENROLLING AT 18 MONTHS, WHICH FADES AWAY WITH TIME. INSTEAD IN TERMS OF ALERTNESS WHICH WAS DETERMINED WITH A SPECIFIC CLINICAL EXAM WE HAVE AN EFFECT OF 60 MONTHS. THIS IS ALSO PUBLISHED, THERE WAS A POST TREATMENT EFFECT PEDIATRIC EVALUATION INDEX, A QUANTITATIVE ASSESSMENT FOR COGNITIVE FUNCTION AND DEVELOPMENT AND MOST OF THE PATIENTS WERE ABOVE ABOVE THE MEAN SO IT RESPONDED TO THE PROCEDURE. IN TERMS OF SEIZURES, MOST OF THE PATIENTS HAD SEIZURES PRIOR TO GENE THERAPY PROCEDURE AND THERE WAS A POST TREATMENT AFFECT WHICH MEANS REDUCING SEIZURE EVENTS AT 60 MONTHS. IN TERMS OF SURVIVAL, THE YOUNGEST JUST TURNED EIGHT, SHE RECEIVED GENE THERAPY 3.7 MONTHS, THE OLDEST WAS NEARLY 7 YEARS OLD, IS GOING TO BE 19 YEARS OLD IN AUGUST. ALL ALIVE AND WELL AND LIVING WITH THEIR FAMILIES. WHAT HAVE WE LEARNED FROM THIS? THE FIRST APPLICATION, THOSE WE COULD USE IS ONE-THIRD LESS THAN IT WAS ONE USE IN THE PRIMATE STUDIES ASSESSED FOR PRE-CLINICAL L -- GATHER FOR PRE-CLINICAL PORTION OF THE IND PROTOCOL. IT WAS VERY WELL TOLERATED. WE CAN SAY THERE WAS DECREASE IN ELEVATED AA, THERE WAS A CLINICAL -- IN PATIENTS ESPECIAut THE YOUNGEST ONE, SLOW TO PROGRESSION BRAIN ATROPHY, THERE WAS A LOW LEVEL OF NEW RESPONSE -- IMMUNE RESPONSE SPECIFICALLY PATIENTS THAT TURN HAVE ANTIBODIES FOR A ACTIONV AND EARLY INTERVENTION WOULD BE RECOMMENDED. THANK YOU TO MANY, MANY TIMES TO THE PEOPLE THAT HAVE ENABLED THIS WORK AND THE INSTITUTE THAT GIVE US THE ABILITY TO COLLECT ALL THIS DATA THROUGHOUT THE YEARS. THESE ARE PEOPLE I WOULD LIKE TO THANK, VERY SPECIAL THANKS THE LAST MOMENT WHICH MEANS TWO MONTHS AGO. VERY MANY THANKS TO THE FOUNDATION THAT HELPED US TO DO THIS WORK AND JOANNENA (INDISCERNIBLE) CHRISTINE AND A VERY SPECIAL FAMILY, THE SILVER RALPH LUIS AND CATHY SILVER IN CHICAGO. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU VERY MUCH. QUESTIONS? >> NICE STUDY. I NOTICE YOU SERIOUS ADVERSE EVENTS YOU HAD TOOL, HEMORRHAGE AS SUBARACNAL HEMORRHAGES, ARE THOSE ALL ATTRIBUTED TO THE SURGICAL PROCEDURE? >> YES. >> HOW LONG DO THEY TAKE TO CLEAR OUT? >> GOOD QUESTION. THEY CLEAR OUT QUICKLY. HOWEVER, IF YOU NOTICE SOME PATIENTS IMPROVE IN TERMS OF ROLLING THEY WERE NOT ABLE TO ENROLL AFTER THE GENE THERAPY. SO WHAT WE WERE ABLE TO SEE IS THAT PATIENTS THAT HAD THIS SUBARACNOID EVENT, MORE LIKELY TO HAVE OTHER EVENTS LATER ON WHEN THE (INAUDIBLE) IS FAR BECAUSE WE CAN QUANTIFY IN THE MRI. AS YOU KNOW, THE STAINING JUST REMAINS FOR OVER 12 MONTHS IN MRI. THE REASON WHY THIS WAS AN ISSUE BY P SUPERVISORS STATING THAT MAY HAVE UNDERGONE CHILD ABUSE BECAUSE OF IT. WE LINK TO SUBARACNOID PROCEDURE AND IT WAS QUITE THEIR HE WANT. WE LOOK AT THE REST OF THE PATIENTS CAREFULLY BECAUSE OF COURSE THERE IS (INAUDIBLE) IN OUR CAVE, AND OFFICE INFORMAL SO MANY RADIOLOGISTS DO WORK, YOU NEED TO PAY ATTENTION TO THE DIFFERENCE IN HIGHLY ABNORMAL BRAIN OF THESE PATIENTS. >> DR. LEONE, WHERE ARE YOU GOING WITH THE PROGRAM NOW? >> >> VERY GOOD QUESTION. WE CONTINUE TO WORK ON CANAVAN DISEASE AND I DIDN'T EMPHASIZE NAA, IT'S THE SECOND MOST ABUNDANT METABOLITE IN THE BRAIN WHICH REALLY ROLL STILL IS UNKNOWN. WE HAVE BEEN EXPLORING AND TRYING TO OUR REQUEST TO THE ROLE OF NAA WHICH IS ACTUALLY LINKED TO ALL NEURODEGENERATIVE DISEASE IN THE OPPOSITE WAY BECAUSE ALL ANNUITY GENRETIVE DISEASE HAVE A DROP IN NAA. WHERE ARE WE GOING WITH IT, DEVELOP A MATTER TO POTENTIAL LET REDIMER AND THAT'S BIOGENE THERAPY WITH CANAVAN DISEASE WE HAVE NOW A ANIMAL MODEL THAT WE'RE FULLY CHARACTERIZED AND WE HAVE IDENTIFIED MAJOR METABOLIC DEFICIT IN THE BRAIN, BUZZ GENE THERAPY RIGHT NOW, WE FEEL WE HAVE TOO HIGH A RISK AND WE'RE NOT THERE TO JUST GLOBALLY DELIVER THE GENE IN EVERY SINGLE OLIGODENDROCYTE OF THE BRAIN AND AN ISSUE WITH TIMING. WE'RE DEVELOPING A METABOLIC THERAPY IN FACT ADMINISTER ORALLY ALSO COULD BE IN UTERO AND TO PRE-MILK AND SO FORTH. SO WE'RE ALSO WORKING WITH A COMPANY ON STEM CELLS BECAUSE WE'RE SEEING AN AFFECT OF STEM CELL ENGRAFTMENT AND MYELINATION. THERE'S MUCH MORE POTENT IN MICE RA THAN ASYMPTOMATIC SO WE'RE WORKING ON ALL THIS. IN TERMS OF GENE THERAPY FOR CANAVAN DISEASE THIS IS WHAT WE HAVE, ALL THE FORMATION WE NEED TO TURN HOPEFULLY IN THE NEXT FIVE YEARS. CANAVAN DISEASE FROM TERMINAL DISEASE AND DISEASE. >> THANK YOU VERY MUCH. ANY COMMENTS? Q. QUICK QUESTION ABOUT YOU LOOKED AT EFFECT OF YOUR THERAPY AT MANY REGIONS OF THE BRAIN. DO YOU GET AHEAD OF TIME WHICH REGION THEY ARE SUPPOSED TO BE LOOKING FOR OR WHOLE SKIN AND SEE WHAT SIGNAL SHOWS UP? Q. SO WHEN WE LOOK AT MRI WE LOOK GLOBALLY AT AREAS, CONVENTIONAL MRI BUT THAT'S NOT WHAT WE FOCUS ON, T 1 SPECIFIC BRAIN AREAS, WITH SPECTROSCOPY WE RUN TWO MODES. TWO SINGLE VOXEL WHICH WOULD BE SELECTED AREA OF THE BRAIN FRONTAL BILATERAL PARIETAL AND ON SIP TALL AND ALSO USE A MULTI-HAVE BEEN SELL ANALYSIS. MULTI-VOXEL ANALYSIS IS NOT QUANTITATIVE SO TELL US FOR INSTANCE, THERE IS LACTATE, DECREASE IN LACTATE AND ANOTHER MARKER OF PROGRESSION. IN MANY NEURODEGENERATIVE DISEASES, IN SPECTROSCOPY USUALLY MEANS SOME MAJOR METABOLIC PROBLEM. SO IN TERMS OF WE'RE LOOKING AT THAT TIME WHOLE BRAIN. IN TERM OF METABOLITES WE'RE FOCUSING THESE SICK AREAS THAT WE AIM, THAT WE INJECT THE VECTOR TO BECAUSE THERE WAS A SAFETY STUDY LOCALIZED, WE DIDN'T AIM JUST INJECT GLOBALLY BUT WE HAVE SUBSCORES, OTHER STUDIESES, OF COURSE QUANTITATION THAT WE HAVE CHECKED DURING THE YEAR SO MANY GIGABYTES. >> DON. >> FEW COMMENTS, FIRST CONGRATULATIONS ON A LOT OF WORK OVER A LOT OF TIME AND STICKING WITH IT. SO ONE QUESTION I GUESS I HAVE, THE VECTOR AND TECHNOLOGY YOU USE IS NOW 10, 12 YEARS OLD, IS THERING TO TO YOU OR SOMEONE ELSE TRYING TO MAKE A MORE ACTIVE VECTOR, STRONGER PROMOTER CODON OPTIMIZE CDNA? DO YOU THINK THIS APPROACH CAN BE TUNED AND REACH MORE POTENCY OR DO YOU THINK THE IDEA OF INJECTING A FEW REGIONS JUST WON'T GET A GLOBAL ENOUGH EFFECT? >> PURE SPECULATION. FOR INSTANCE, TOMORROW HAVE DR. SOMALSKI GROUP. DEVELOP THIS VECTOR 89, 2.5 THAT COULD BE DELIVERED TO THE SYSTEM AND AFFECT -- DISTRIBUTE EFFECTIVELY IN THE BRAIN WITH PRIMATES STUDIES, COLLECTED SO OBVIOUSLY THE FIELD IS MOVING FORWARD. MOVING FORWARD QUICKLY. AND I'M HOPING THAT THIS WILL CON. BUT FROM WHAT I HAVE SEEN AND THE PATIENT THAT WAS FOR INSTANCE A ROLE 3.5 MONTHS WE DID SEE THE TOP IN NAA. THE DROP IN NAA DIDN'T DELIVER THE ACTUAL COGNITIVE DEVELOPMENT THAT I WOULD HAVE EXPECTED SO IT IS A POSSIBILITY. TO USE SOMETHING TO GLOBALLY EXPRESS THE VECTOR THAT EXPRESSES IN ORDER TO MAKE A DIFFERENCE BUT MY FIRST WORRY IS TIMING. IT TAKES TIME TO ENROLL PATIENTS, CHARACTERIZE THEM, TO IDENTIFY ALL THE WITH GENE THERAPY NOT GENE THERAPY AT THE -- IN CLINICAL PHASE 1 AND 2. I'M AFRAID THAT WE MAY NOT BE IN TIME TO MAKE A DIFFERENCE. DEFINITELY GO WITH A NOVEL GENE THERAPY METHOD BUT AT THIS TIME I'M WORKING ON IT, FOCUSING ON ORAL ADMINISTRATION. >> MY OTHER QUESTION WE HAVE BEEN SEEING RON CRYSTAL FREQUENT REPORTS ABOUT MRI ABNORMALITIES, T-1 DIFFUSION ABNORMALITIES THAT PERSISTED, SLOWLY GOING AWAY. DID YOU LOOK FOR AND SEE ANYTHING WITH YOUR INJECTION? I HAVE BEEN TRYING TO UNDERSTAND, IS IT A REACTION TO THE VIRUS OR INJECTION. HAVE YOU SEEN THE KINDS OF MRI ABNORMALITIES DESCRIBED IN >> I'M A MEMBER OF THE DATA SAFETY MONITORING COMMITTEE. DR. CRYSTAL, SO, YES. NO, NOT WITH THIS AAV, WE HAVE NEVER SEEN ANY T-1 T-2 ABNORMALITY. NO, ABSOLUTELY NOT, NOT ONE. >> I WANT TO CONGRATULATE YOU FOR THE WONDERFUL STUDY AND ENDURANCE. YOU MENTIONED (INAUDIBLE) >> IF YOU COULD SPEAK INTO THE MICROPHONE. >> GIVEN THE SUCCESS THAT THE (INDISCERNIBLE) CROWMATIC LEUKODYSTROPHY, CAN ONE EXPECT THIS TO BE SOMEWHAT SUCCESSFUL? >> WITH THE LEUKODYSTROPHY IS A VERY DIFFERENT DISEASE, I HAVEN'T WORKED WITH A YOU CAN STRAIT REDUCTION MODEL AND PUBLISH A SMALL GROUP OF PATIENTS SO I WISH GREAT LUCK TODAY TO THE ITALIAN TEAM. IN TERMS OF CANAVAN DISEASE AND MODEL ITSELF A. WE HAVE BEEN WORKING FIRST WITH THE AAV STUDY I DEVELOP THE FIRST AAV CLINICAL VECTOR FOR THE FIRST TIME WITH THIS GROUP OF AMAZING COLLABORATORS FOR THE FIRST TIME, I KNEW WHAT IT TOOK TO THE CLINIC. WE IDENTIFIED A COMPANY THAT ALREADY HAD FDA APPROVAL, FIRST WAS SHARON THAT HAD EMBRYONIC STEM CELL APPROVED FOR SPINAL CORD INJURY. AND WORK WITH WITH THOSE CELLS. IN THE ANIMAL MODEL AND THE LOOK AT THE EFFECT AND WE HAVEN PUB PUBLISHED THE REPORT AND EVENTUALLY DISCONTINUE THE WORK. SO NOW I'M USING CELLS PROVIDED BY STEM CELL INC. AND THOSE WITH -- WE SEE AMAZING RESULTS FROM THE IMPLEMENTING THE ANIMAL MODEL. >> I WAS TALKING BONE MARROW TRANSPLANTATION. >> BONE MARROW TRANSPLANTATION. >> YES. >> THE BONE MARROW TRANSPLANTATION CARRIES A LOT OF PROBLEMS. THERE IS ONLY ONE PATIENT THAT UNDERWENT TRANSPLANTATION AND DIED A MONTH AFTER DUE TO COMPLICATION OF IMMUNOSUPPRESSIVE THERAPY. I DON'T KNOW ANY OTHER PATIENTS THAT HAVE ENROLLED. ALL I KNOW I ACTUALLY NEVER MET THE PATIENT. >> THANKS. >> SO I HAVE A QUESTION. WHY DO YOU THINK THE GENE TRANSFER IS NOT RESULTING IN MORE MYELINATION? IS IT A QUESTION OF THE TIMING OF DELIVERY OR IS THERE SOMETHING ELSE INVOLVED IN THE MEK ANYMORE? >> PURE SPECULATION COULD BE TIMING, IT COULD BE WHERE THE ACTUAL GENE IS EXPRESSED, COULD BE BOTH. IT COULD BE THE LOCATION WHERE THE ACTUAL GENE WAS EXPRESSED, WE DIDN'T TARGET -- THE PROBLEM WITH CANAVAN DISEASE IS LOOKING AT DTI OF CELLS THAT ARE MYELINATEING AND JUST LOOKING IN THE CORPUS CALLOSUM TRY TO MIGRATE AND DON'T. ANYTIME MILD PHENOTYPE THE CELLS SLOWLY STEADILY DEVELOP AND THEN YOU SEE THE RAMIFICATION OF BEAUTIFUL FIBERS SO SOME OF THE TREATMENT THAT WE'RE USING SO POSSIBLY ALL OF THE ABOVE, THAT'S I THINK TIMING DEFINITELY APPROXIMATE ISSUE. AND LOCALIZATION OF THE GENE EXPRESSION AND POTENCY OF THE VECTOR. >> WOULD YOU CONSIDER NEONATAL GENE THERAPY WITH SEROTYPE LIKE AV-9 THAT CAN GO EVERYWHERE IN THE CNS? >> I WOULD POSSIBLY CONSIDER THAT AND THAT'S A POSSIBILITY, GENE THERAPY BRAIN SURGERY IS ASSOCIATED, MAY BE ASSOCIATED WITH HUGE DEAL OF RISK. WE SAW THOSE WITH THE CHILD THAT HAD BEEN ABSCESS SO IF WE COULD DELIVER THE SAME BENEFIT WITH ORAL MEDICATION, THAT COULD JUST BE ALSO ADMINISTERED TO THE MOTHER WHILE PREGNANT BECAUSE WE HAVE MANY FAMILIES THAT FOR INSTANCE ARE PROLIFE AND KNOW THEY'RE GOING TO HAVE A CHILD WITH CANAVAN DISEASE DURING PREGNANCY SO AS EARLY AS POSSIBLE PERHAPS WE'LL BE ABLE TO MAKE A DIFFERENCE. BUT JUST MY QUESTION IS REALLY TO BE ABLE TO CURE THE DISEASE, SO I AM CONVINCED TO BE ABLE TO REACH THE AIM SOONER OR LATER. >> THANK YOU. >> YOU'RE WELCOME. >> THANK YOU VERY MUCH. LET'S MOVE TO THE NEXT TOPIC ON THE AGENT TA, A IT IS CUSHION OF GENE TRANSFER PROTOCOL 1304-1226. A PHASE 1 STUDY OF GCC ENCODING REPLICATING RECOMBINANT ADENOVIRUS VACCINE IN STAGE 1 AND 2 CANCER PATIENTS. PRESENTING FOR US TODAY IS THE PI WHO IS TAKAMI IS A TOE, DIRECTOR OF METASTATIC PROGRAM AT THE DEPARTMENT OF ONCOLOGY AT THOMAS JEFFERSON UNIVERSITY HOSPITAL IN PHILADELPHIA. DR. SATO, IF YOU COULD INTRODUCE YOUR COLLEAGUES HERE WITH YOU. >> I'LL INTRODUCE DR. DR. (INDISCERNIBLE) FIRST, HE INVENTED THE TECHNOLOGY. I RESPECT HIM A ROT. IF YOU HAVE A DEEP QUESTION, I'M GOING TO ASK HIM TO ANSWER THAT QUESTION. THEN I WILL INTRODUCE DR. SNEEK FROM THE Ph.D. STUDENT AND HE GROWN UP A LOT AND NOW A KEY MEMBER OF THE DCCA PROGRAM. AND BASICALLY SUCH QUESTION, I WILL ASK HIM TO ANSWER. AND THEN I WILL ASK HIM TO START EXPLAINING BASICS OF THIS APPROACH FIRST. >> >> THE FOCUS OF OUR WORK IS (INAUDIBLE) CANCER T FOURTH MOST COMMON CAUSE OF CANCER AND SECOND MOST FREQUENT CAUSE OF CANCER RELATED DEATH IN THE UNITED STATES. ANNUALLY PRODUCES ABOUT 500,000 DEATHS WORLDWIDE. STAGING IN CASH FLOW RECTAL CANCER GREATLY IMPACTS DISEASE PROGNOSIS. WHERE PATIENTS WITH EARLY STAGE DISEASE THOSE FREE OF METASTASIS AND LYMPH NODES HAVE A POSITIVE PROGRESS NOISE. STAGE 3 PATIENTS POSSESS METASTASIS IN LYMPH NODES AND STAGE 4 PATIENTS POSSESS DISEASE SPREAD IN DISTANCE ORGANS. THOUGH THE EARLY STAGE PATIENTS ARE FREE OF DISEASE AND LYMPH NODES, THEY'RE ASSOCIATED WITH HIGH RISK OF DISEASE RECURRENCE. HERE IS RECURRENCE IN STAGE 1, 2, 3 PATIENTS. AND IN FACT STAGE 2 PATIENTS EXPERIENCE ABOUT 30% DISEASE RECURRENCE. THIS IS IMPORTANT BECAUSE THE PREVALENCE OF EARLY STAGE DISEASE IS INCREASING IN CASH FLOW RECTAL CANCER. IN 1995, ABOUT 55 PERCENT OF PATIENTS WERE DIAGNOSED WITH STAGE 4 AND A THIRD WITH STAGE 3 LEAVING ONLY A RELATIVELY SMALL PROPORTION OF PATIENTS WITH EARLY STAGE DISEASE. TODAY THAT'S GROWN TO INCLUDE ABOUT 40% OF PATIENTS. THIS TREND IS EXPECTED TO CONTINUE TO INCREASE IN THE COMING YEARS WITH IMPROVED COLON KAREN DIAGNOSTICS. THOSE THESE ARE ASSOCIATED WITH OR HAVE A HIGH RECURRENCE RATE, SURGERY IS THE ONLY TREATMENT EMPLOYED FOR THEM. ADJUVANT CHEMOTHERAPY AND TARGETED THERAPY SUCH AS ANTIBODIES ARE UTILIZED IN ADVANCE STAGE BUS NOT SHOWN TO BENEFIT EARLY STAGE PATIENTS. DEVELOPMENT OF NEW THERAPIES FOR THESE PATIENTS. THE FOCUS OF OUR WORK IS IMMUNOTHERAPY. RECENT META ANALYSIS OF VACCINES IN COLORECTAL CANCER PATIENTS HAVE SHOWN PATIENTS WITH EARLY STAGE DISEASE AND SUSPECTED MINIMAL RESIDUAL DISEASE HAD IMPROVEDDED OVERALL SURVIVAL AND DISEASE FREE SURVIVAL WHEN TREATED WITH NEWSPAPER THERAPIES COMPARED TO PATIENTS THAT WERE NOT. THE TREATMENTS WERE LARGELY UNEFFECTIVE IN LATER STAGE PATIENTS. ANOTHER IMPORTANT ASPECT OF THIS META ANALYSIS WAS IN THE NEARLY 2100 PATIENTS INVOLVED IN THE ANALYSIS, THERE WERE NO SERIOUS ADVERSE EVENTS WITH ANY OF THE TREATMENT. HERE IS A SMALL SUMLY OF ENCAPSULATING MOST ANTIGENS TARGETED IN COLORECTAL CANCER. HOWEVER, WE BELIEVE THESE ANTIGENS MAYBE SUBOPTIMAL BECAUSE THEY ARE EITHER NOT TUMOR SPECIFIC OR NOT PHYSICIANLY IMMUNOGENIC FOR NCI MANY NOT UNIVERSEALLY SHARED AMONG PATIENTS. ONE CATEGORY LARGELY UNEXPLORED IS INTESTINAL DIFFERENTIATION. THESE ARE ACTUALLY THE MOST INTERESTING TO US. WE'RE INTERESTED IN THEM BECAUSE OF A PHENOMENON KNOWN AS IMMUNE COMPARTMENTALIZATION. WHERE THE IMMUNE SYSTEM IS COMPARTMENTALIZED TO THE SUBCOMPARTMENT SHOWN HERE TWO EXAMPLES THE SYSTEMIC COMPARTMENT AND MUCOSAL COMPARTMENT. THE IMPORTANT ASPECT OF COMPARTMENTALIZATION IS IMMUNE RESPONSE IS GENERATED IN SYSTEMIC COMPARTMENT, DO NOT EXTENT TO MUCOSAL. I JUST WANT TO SHOW AN EXAMPLE OF THESE DATA. THIS WAS GENERATED BY JAY (INDISCERNIBLE) SYSTEMIC COMPARTMENT PRODUCED SYSTEMIC IMMUNE RESPONSES IN THE SLEEP BUT NO IMMUNE RESPONSES IN THE INTESTIN. THIS WAS A VIRAL CHALLENGE MODEL SHOWING THE MICE SYSTEMIC IMMUNIZED IN SYSTEME IMMUNE COMPARTMENT WHERE WERE FROM INTERRECTAL CHALLENGE WITH VIRUS. THE MECHANISMS ARE WELL DEFINED. FOR IMMUNE COMPARTMENTALIZATION. I HAD A SLIDE AT THE END VERY COMPLICATED, MANY INTERESTED IN SEEING THAT. IMMUNE COMPARTMENTALIZATION. TARGET INTESTINAL DIFFERENTIATION ANTIGEN. WE ENVISION AD MN STERLING VACCINE IN THE SYSTEMIC IMMUNE COMPARTMENT, ACQUIRED BY IMMUNE CELLS. IMMUNE RESPONSE IS GENERATED IN THE IMMUNE COMPARTMENT HERE IN THE SPLEEN. TARGET COLON CANCER METASTASIS SPREAD INTO THE IMMUNE COMPARTMENT, FREQUENTLY THE LIVER AND LUNGS ARE COMMON PLACE FOR COLOW RECTAL CANCER SPREAD. THIS IS EXCLUDEED FROM TRAVELING TO THE MUCOSA TO INTESTINES AND NOT CAUSE DISEASE SO HE CAN SEE THIS SCENARIO WORKING WELL IN COMBINATION WITH SURGERY TO REMOVE A PRIMARY TUMOR AND IMMUNOTHERAPY TO TREAT METASTASIS. THE ANTIGEN WE ARE INTERESTED IN IS CALLED GAY LITTLE CYCLASE C. GCC. EXPREACTED IN THE INTERINTESTINAL EPITHELIUM SEEN BY NORTHERN BLOT. THE SELECTIVE EXPRESSION GUANYLYL CYCLASE, TO DEVELOP A GCC DIAGNOSTIC, THIS IS REPRESENTATIVE DATA SHOWING EGG PRESENTATION AND COLON AND PRIMARY COLON CANCER BUT ABSENT IN OTHER LYMPH NODE LIVER AND LUNG. HOWEVER THOSE TISSUES CONTAINING COLON CANCER METASTASIS POSSESS GREAT DEAL OF PROTEIN. SO THE APPROACH WE ARE TALKING WE DEVELOPED A REPLIATION DEFICIENT ADENOVIRUS. EXPRESSING GCC ADMINISTERING INTRAMUSCULARLY GCC PROTEIN, ACQUIRED BY IMMUNE CELLS. THE VIRAL VECTOR IN THIS SCENARIO IS NOT ONLY TRANSDUCTION MECHANISM BUT BIOCOMPORTMENTS -- BIOCOMPONENTS PLAY AN IMPORTANT ROLE, THEY PROVIDE DANGER SIGNALS. THIS HELPS PRODUCE ROBUST T-CELL RESPONSE TO GCC, SELECTIVE TARGET AND KILL CANCER METASTASIS AS WELL AS ANTIBODY RESPONSE BY B CELLS THAT CAN PARTICIPATE. I WANT TO SUMMARIZE PRE-CLINICAL DATA. IMMUNIZATION OF MICE WITH GCC AD THOUGH VIRUS PRODUCE ANTIBODY RESPONSES AND T-CELL RESPONSES GCC COMPARED TO A CONTROL IMMUNIZATION. PROTECTION OF THE MICE LUNG CANCER METASTASIS, PET CT IMAGE ING AND BY STAINING. SPOTS QUANTIFIED HERE TUMOR:La– BURDEN. VACCINE ALSO HE CAN EXTENDED SURVIVAL OF MICE WITH THESE METASTASIS. WE ALSO LOOKED AT HOW PERSISTENT THE IMMUNE RESPONSES GCC, IF WE IMMUNIZE MICE, WAITED ON AVERAGE 100 DAYS, IN THESE EXPERIENCES THAT THEY HAD ENDURING T-CELL RESPONSES TO GCC, NOT SHOWN HERE ANTIBODY RESPONSE. IF WE CHALLENGE THE MICE AFTER THIS LONG INCUBATION PERIOD 100 DAYS THEY WERE PROTECTED AGAINST LUNG METASTASIS OF COLORECTAL CANCER QUANTIFIED BY TUMOR BURDEN PEN AND BY SURVIVAL. IN PREPARATION FOR THE TRIAL WE CONDUCTED A LARGE GLP STUDY WITH CRO. WE LOOK AT NEWSPAPER GENICITY OF SAFETY AT VECTOR AND TWO DIFFERENT DOSE LEVELS. CONSISTENT WITH OUR PREVIOUS DATA WE FOUND THE IMMUNE RESPONSES DOSE DEPENDENT AND DETECTABLE OUT AT 90 DAYS FOLLOWING IMMUNIZATION. VERY IMPORTANT TO MEDIATE PROTECTIVE EFFECT THAT WE SEE AGAINST TUMOR CHALLENGE. WHEN -- I'M SUMMARIZING SOME OF THE DATA QUICKLY HERE. VECTOR INSECTION SITE DRAINING LYMPH NODE TO LESSER EXTENT LIVER AND SPLEEN AND ALSO IN BONE MARROW. THIS IS QUANTIFIED -- QUANTIFIED MEDIATED COPY NUMBER OR PERCENT OF TISSUES WITH GREATER THAN 10,000 COPIES. AND FINALLY, WE LOOKED AT SAFETY AND JUST HERE ARE A CATEGORY OF MEASURES THAT WE CONDUCTED. WE OBSERVED NO DIFFERENCES IN ANY OF THESE MEASURES. THIS IS REPRESENTATIVE BODY WEIGHT HERE. IN CONCLUSION TO PRE-CLINICAL STUDIES, GCC TARGETED ADENOVIRAL VACCINE, DISTRIBUTES PRIMARILY TO INJECTION SITE, CREATING LYMPH NODE AND BONE MARROW. THE VECTOR EXPRESSION IS IMPORTANT TO HELP PRODUCE PERSISTENT IMMUNE RESPONSES TO GCC ANTIBODY AND T-CELL RESPONSES. THAT'S TUMOR IMMUNITY. AS FAR AS 100 DAYS AFTER IMMUNIZATION. THE VACCINE IS WELL TOLERATED IN ALL OF OUR MODELS, NOT PRODUCED AUTOIMMUNITY OR ANY OTHER TOXICITY. I'LL HAND OFF TO DO SATO FOR OUR TRIAL DESIN. >> I'LL EXPLAIN THE CLINICAL TRIAL PORTION OF THIS PROJECT. MY NAME IS TAKAMI SATO, MEDICAL ONCOLOGIST AND CO-DIRECTOR FOR THE CANCER IMMUNOLOGY PROGRAM CANCER CENTER. I HAVE BEEN INVOLVED IN DEVELOPMENT OF THE (INDISCERNIBLE) VACCINE FOR THE LAST 20 YEARS AND ALSO TREATMENT TRIAL USING THE VIRUS VECTOR BASED CANCER ANTIGEN. IN THIS CLINICAL TRIAL, THIS IS A PHASE 1 STUDY GCC REPLICATION TO RECENT HUMAN TYPE 5 RECOMBINANT ADENOVIRUS, VACCINE AND HUMAN GCC PA DAY. PA DRAW IS HELPER T-CELL TO IMMUNE RESPONSE AGAINST GCC. IN STAGE 1 AND STAGE 2 COLON CANCER PATIENTS. STUDY POPULATION AS I MENTION STAGE 1, STAGE 2 THOUGH METASTASIS IS NEGATIVE IN COLON CANCER PATIENT, DISCREPANCY OR DISPARITY MEDICAL AND CAUCASIAN POPULATION HAS BEEN DEPORTED, TEST A COHORT FOR THIS STUDY SEPARATELY ANALYZED, INVESTIGATED AND EACH CASE, EACH COHORT IS 22 PATIENT. >> IMPINGES THE VACCINE CONCEPT IS ADENOVIRUS VECTOR. CONTAINING TRUNCATING HUMAN GCC CONSTRUCT. WE ARE CD THE B CELL AND T-CELL IMMUNITY RESPONSE. AFTER INVESTIGATING PREVIOUS STUDY, ALSO BASED ON ANIMAL MODEL, PARTICLES FOR THIS STUDY WHICH HAD BEEN DEPORTED INDUCE IMMUNE REACTION AGAINST HAS ANTIVIRUS IMMUNITY. WE ALSO DECIDE TO CHOOSE BASED ON WHAT'S DR. SNEEK REPORTED. STUDY OBJECTIVE IS TO DETERMINE SAFETY AN (INAUDIBLE) TOXICITY OF 85 HDD COLON CANCER VACCINE. PRIMARY OBJECTIVE IS DETERMINE WHETHER GCC VACCINE INDUCE ANTIBODY RESPONSE TO GCC AT ONE MONTH FOLLOWING VACCINATION. , SECOND OBJECTIVE T-CELL RESPONSE TO GCC PROTEIN AT ONE MONTH FOLLOWING VACCINATION. WE ALSO INVESTIGATE ANTIBODY AN T-CELL RESPONSE TO GCC. THAT PERSISTS AT THREE MONTHS AND SIX MONTHS FOLLOWING VACCINATION. INVESTIGATE WHETHER MEMORY IS GOING TO BE DEVELOPED AFTER VACCINE ADMINISTRATION. SECONDARY ONTIVE NUMBER 3, RELATIVELY (INAUDIBLE) WE TRY TO INVESTIGATE THE RELATIONSHIP OF ANTIBODY AND T-CELL RESPONSE TO THE FOLLOWING FACTORS. NUMBER 1, WE WENTS TO INVESTIGATE WHETHER EXISTING -- EXISTENCE OF GCC MESSAGE LYMPH NODES ACCORDING TO DEVELOPMENT OF IMMUNE RESPONSE OR NOT. DIFFERENT RATIO BASED ON CAUCASIAN AND (INDISCERNIBLE). WE ALSO MEASURE (INAUDIBLE) TO SEW WHETHER THIS VACCINE IS NOT FROM MOTORING PROGRESSION, ALSO MACK SURE POTENTIALLY BENEFICIAL. INCLUSION, EXCLUSION CRITERIA IS LISTED HERE, MAJOR INCLUSION CRITERIA IS BLACK AND WHITE PATIENT. STAGE 1 OR STAGE 2 COLON CANCER BUT THERE'S NO INVOLVEMENT AND THE PATIENT HAVE TO SHOWN IMMUNE EXE TENSE TO A COMMON ANTIGEN AND LYMPH NODE MUST BE AVAILABLE FOR QUANTIFICATION OF METASTASIS MEASURED BY PCR. WE INCLUDE THE PATIENT WHO HAS A MUCH MORE 20 MONTHS -- SURGERY, TIME OF ENTRY PATIENT SHOULD HAVE ANY CLINICALTHER -- EVIDENCE OF METASTASIS. WE EXCLUDE THE PATIENT WITH VECTOR CANCER BECAUSE THEY HAVE DIFFERENT TYPE OF CLINICAL FOLLOW-UP AND POTENTIAL CLINICAL TREATMENT. SO WE ALSO EXCLUDE MEDICAL IMPROVEMENT INFLAMMATORY BOWEL DISEASE BASED ON IMMUNE REACTION AGAINS DISEASE (INAUDIBLE). IMMUNOTHERAPY EXPERIMENT APPROACH WILL BE EXCLUDED FROM A STUDY. THIS IS THOUGH THE STUDY. BASICALLY WHAT ONE WEEK PRIOR WE SEE A PATIENT AND EXPAND THE STUDY TO THE THE PATIENT BY THE PI OR CO-INVESTIGATORS. OTHER IMMUNE REACTION TO COMMON ANTIGENS SUCH AS (INDISCERNIBLE) WILL BE TESTED HERE. PATIENT WHO HAS AT LEAST ONE RESPONSE TO THE COMMON ANTIGEN IS INVOLVED. BASELINE IMMUNOLOGICAL (INAUDIBLE). AFTER PATIENT MEET CRITERIA IT WOULD BE INJECTED ON DAY 1 TO THE MUSCLE PARTICLE. TOXICITY ASSESSMENT WILL BE DONE ON DAY OF -- AND BASICALLY DAY 8 THE PATIENT VISIT CLINICAL GAME. DAY 30, DAY 90, 180, TOXICITY ASSESSMENT IMMUNOLOGICAL ASSESS MENT. STUDY EPIPOINT INCLUDE THE SAFETY BY CT 4.0. QUESTIONNAIRE NUMBER 3 DIAGNOSTIC CRITERIA FOR THE FUNCTION OF GI. DISORDER THE TO MONITOR ANY KIND OF GI TOXICITY (INAUDIBLE). IMMUNORESPONSE MEASURED BY ANTIBODY RESPONSE, BEELISA, VIOLATED, READY FOR THE STUDY. USAGE. WE ALSO MADE T-CELL RESPONSE BY ASSAY AND THEN PA DAY AND VIROVECTOR RESPONSE IS GOING TO BE USED AS A BASELINE SPECIFIC RESPONSE. ALSO WE HAVE TO MEASURE SURVIVAL, IT'S MEASURED FROM TIME OF (INAUDIBLE) AS WELL AS TIME OF THE INJECTION OF THE CANCER VACCINE. (INAUDIBLE) IS MADE BASED ON TWO APPROACHES CURRENT ESTIMATE NUMBER OF PATIENTS WHO NEED TO BE STUDIED HERE, TWO STAGE DESIGN TO ESTIMATE A COHORT SIZE. WE USE A (INAUDIBLE) 10% AND P-1 IS 40%. AND WITH 90 POWER PA TEN POWER AND 2.5% TYPE 1 WE TITRATE IT COHORT SITE AS 22. HOWEVER, TO MONITOR THE TOXICITY AND POTENTIAL EF EFFICACY ON THE CONTINUOUS BASIS, WE INSTALLED (INAUDIBLE) CONTINUE MONITORING VESSEL. THIS (INAUDIBLE) TOXICITY SAFETY CONTINUOUSLY EVALUATING THE PATIENT TO CONCLUDE TOXICITY ISSUE. SO WE TITRATE THIS TABLE BASED ON THE TOXICITY OF GREATER THAN 10% NOT ACCEPTABLE AND EXTRA SERIES AND 10% IS NOT ACCEPTABLE EITHER. OR LOWER IS NOT ACCEPTABLE SO TO CONTINUOUSLY MONITOR ALL+v0y PATIENTS WE PUT THE OLD PATIENT INTO THIS BAYESIAN MONITORING UP TO 22 PATIENTS, MIX RACE. EXPAND STUDY TWO COHORT AND WHAT EACH COHORT HAS 22 PATIENTS. THIS IS AN EXAMPLE OF THE BASE YEN TABLE. WE DEFINE -- BAYESIAN TABLE. WE DEFINE TOXICITY AS GRAY 3 DEFINED BY (INDISCERNIBLE) 1.0. ANY TIME DURING SICK MONTHS PERIOD. AND THEN TOXICITY 10% IS NOT OR GREATER IS NOT ACCEPTABLE. FOR EXAMPLE, IF WE WERE GOING TO -- IF TWO PATIENT DEVELOP GRAY 3 OR 4 TOXICITY, STUDIES ARE GOING TO BE STOPPED. ON THE OTHER HAND EACH PATIENT THAT HAS 23 PATIENTS, P IF TOXICITY NUMBER IS NOT FIVE, WE'RE GOING TO KEEP MOVING ON TO UP TO 44 PATIENT. IN WHICH 22 IS IN EACH COHORT. THIS SIMILAR TABLE FOR THE MINE GENICITY, ANALYSIS, ANTIBODY RESPONSE MEASURES BY ELISA WILL BE USED, PRIOR END POINT AND THIS IS FOR HUMAN ARCAG SPECIFIC -- RESPONSE WILL BE CONSIDERED, (INDISCERNIBLE) INCREASE AT ONE MONTH POST VACCINATION, COMPARED TO THE PRE-VACCINE BASELINE. AND THEN IN THIS TABLE WE TREAT TEN PATIENT, IF NOBODY IS SHOW ANY POSITIVE RESPONSE WE'RE GOING TO (INAUDIBLE) THE STUDY. ON THE OTHER HAND IF WE HAVE ONE RESPONSE WE'LL EXTEND IT TO 27 PATIENTS, IF WE DON'T SEE ANY OTHER RESPONSE WE'RE GOING TO (INAUDIBLE) THE STUDY. TWO PATIENT RESPONSES ARE NEEDED TO COMPLETE 44 PATIENTS. IN SUMMARY, THERE'S UNMEAT MEDICAL NEED TO PREVENT RECURRENCE BECAUSE THE KAREN PATIENT -- THIS PHASE 1 STUDY FOR STAGE 1 AND 2 NEGATIVE CANCER PATIENT, WE WILL BE INITIATED UPON REGULATORY APPROVAL THIS YEAR. THIS STUDY WE HAVE UTILIZED TO DESIGN FUTURE PHASE 2 OR PHASE 3 STUDY. THANK YOU VERY MUCH FOR YOUR ATTENTION. >> THANK YOU VERY MUCH. WHY DOPE WE START WITH REVIEWER DAVID ORNELLES. DAVID, WHY DON'T YOU START. AGAIN, IF YOU CAN GO THROUGH ALL YOUR POINTS INCLUDING ONES THAT HAVE BEEN SATISFIED BY THE INVESTIGATORS RESPONSES SO WE HAVE IT ON RECORD. >> I WOULD LIKE TO THANK YOU BOTH FOR A VERY CLEAR PROTOCOL, VERY CLEAR PRESENTATION, I APPRECIATE ALSO YOUR RESPONSES WERE CLEAR TO MY CONCERN, I ADDRESS ALL THESE I HAD TWO COMMENTS, FIVE POINTS ALL I WANT TO SPEAK TO. BUT THE PECULIAR NATURE OF REPLICATION VIRUSES COMING UP THAT'S A POINT I HAVEN'T WRITTEN ABOUT. BUT ALL THE POINTS I DISCUSS AND RAISED WERE WELL CONSIDERED. THE FIRST TWO COMMENTS THAT I REALLY MEANT SHARED WERE THE FACT THAT THE PERSISTENT ADENOVIRAL VECTORS AND ABILITY TO THE RAISE CD8 AND CD4 ANTIBODY AT CELLULAR RESPONSE REMAINS A HISTORY. SO THIS NEEDS TO BE CONSIDERED WITH STUDIES THAT GO FORWARD IN HUMANS AND THAT'S JUST A COMMENTARY AND WE APPRECIATE AND ACKNOWLEDGE THAT AND THE STUDY DESIGN WILL HELP. THIS IS RELATED TO THE FACT THAT ANOTHER STUDY WELL KNOWN STUDY, THE AD 5 STUDY USED FOR HIV HAVE RATHER UNEXPECTED OUTCOMES. SO THIS REQUIRED THAT ALL HUMAN STUDIES GOING FORWARD CONTINUE TO BE AWARE OF THE POSSIBILITY THAT THE RELATIONSHIP BETWEEN THESE ALLEGEDLY NON-REPLICATING VIRUSES AND HUMANS ARE NOT WELL UNDERSTOOD. SO WITNESS AGAIN, A STUDY OF THIS SORT DEMANDS WE CAN KEEP OUR EYES OPEN TO CONTINUE LEARNING. SO YOU ACKNOWLEDGE THAT, I APPRECIATE THAT. ALSO POINT OUT THE PARTICULAR STEPS I WAS REFERRING TO MAYBE UNIQUE TO AD 5 BUT WE NEED TO LEARN AND THIS PRESENTS AN OPPORTUNITY TO SEE MORE OF THAT. SO THE SPECIFIC COMMENTS I HAD WERE ALSO ADDRESSED, THE FIRST WAS THAT IT'S UNDERSTOOD THE REPLICATION DEFICIENT VIRUSES DON'T REPLICATE TYPICALLY, HOWEVER THE VIRUSES HAVE BEEN SHOWN TO REPLICATE OR AT LEAST REPLICATE THE DNA IN SYNCARP CELLS IN VITRO. SO THIS PRESENTS A UNIQUE OPPORTUNITY WHERE THE SPREAD OF THIS VIRAL VECTOR TO THETY SEMINATED CANCER CELLS MAY HAVE AN OPPORTUNITY TO REPLICATE. THAT'S NOTHING WE CAN DO, I CAN OFFER TO SUGGEST TO3xy TAKE ACTION OTHER THAN THE FACT THIS MAY OCCUR. IT MAYBE BENEFICIAL OR DELETERIOUS TO BE AWARE OF POTENTIAL IS WORTHWHILE. THERE'S NOTHING MORE TO DOTHAN BE AWARE OF IT. END INDICATE YOU'LL DO THAT. THE NEXT COMMENT I ASKED WHETHER THE EXPRESSION OF FRAGMENT OF DCC COULD HAVE A DOCUMENT INNOCENT EFFECT, IT'S 20% HOMOLOGOUS WITH OTHER GUANYLYL CYCLASE. I CERTAINLY ACCEPT THAT. THE OTHER CONCERN WAS IMMUNE RESPONSE COULD AFFECT FUNCTION OF ENDOGENOUS GUANYLYL CYCLASE IN THE GUT OR OTHER PLACES. AND THE EVIDENCE SUGGESTS THAT IT DOES, IN PARTICULAR THE ABILITY OF THIS PRODUCT TO PROTEIN TO ROLL OLIGOMER RISE IS NOT PRESENT SO LESS LIKELY TO HAVE A DOMINANT NEGATIVE EFFECT, THAT'S APPROPRIATE. I WAS CURIOUS AS TO THE PRE-CLINICAL MODEL OF THE MOUSE PROVIDES INADEQUATE OR ANY IMPACT IN THE CENTRAL NERVOUS SYSTEM OR ENTERIC NERVOUS SYSTEM AND STUDIES FORMED IN ANIMALS SUGGEST IT'S NOT -- SO I ACCEPT THAT CONCERN AS WELL. LASTLY I WAS MILDLY CONCERNED ABOUT HOW MANY SUBJECTS ARE EXPECTED TO HAVE -- YOU HAVE BEEN GIVEN A PREVIOUS ADENOVACCINE, EXCLUED POINTED OUT RATHER THOUGHTFUL CONSIDERATION, NOT LIKELY BUT THESE SHOULD BE EXCLUDED FOR THIS STUDY. ALL IN ALL I HAVE NO CONCERNS WITH ALL THE RESPONSES TO MY CONCERNS ARE VERY WELL MET. I HAVE NO OUTSTANDING CONCERN. ONE THING I WANT TO TALK ABOUT WHICH IS RISK BROUGHT UP HERE YOU POINT OUT IN THE APPENDIX, THE INABILITY TO GET RID OF REPLICATION COMPETENT ADENOVIRUS IN THE PRODUCTION. SO THE NUMBERS AS I SCANNED WITH 3 TIMES TEN TO THE 9 VIRAL PARTICLES, THIS MEANS LITTLE UNDER ONE AND 10 TO THE 9 INFECTIOUS PARTICLES PRESENT IN THAT. SO THIS STRIKES MESS NOT BEING A PARTICULAR CONCERN AS DESCRIBED IN YOUR UNDERSTANDING THE WORK WITH THE FDA TO CLEAR THIS UP GOING FORWARD. BUT I'M CURIOUS ANY TIME DURING THESE PROCEDURES DID YOUR FACILITY AT JEFFERSON PRODUCE REPLICATION INCOMPETENT VIRUS? IS THIS UNIQUE TO THIS VECTOR OR IS IT A COMMON ISSUE SHARED WITH THE SERVICE? IT Q. IT HAS ONLY -- WE USE A COMPARABLE HAVE BEENTOR BUT EXPRESS MOUSE GCC THAT WAS NOT RCA POSITIVE. INITIAL BATCHES RCA NEGATIVEX LARGE EXPANSION PAGES BUT TYPICALLY CAME UP POSITIVE, IT'S ISOLATED TO THIS VECTOR. THERE'S NOTHING REMARKABLE THAT MAKES IT DIFFERENT FROM THE OTHERS IS WE'RE NOT SURE WHAT'S GOING ON THERE. >> IT HAS HAPPENED TO US WITH OTHER VECTOR BUT THERE'S NOTHING UNIQUE ABOUT THE VIRUS THAT MAKES A DIFFERENCE THAN THE OTHERS. SO WE CAN'T FIGURE WHY IT'S OCCURRING. >> I HAVE NO COMMENT OTHER THAN ADENOSPECIES IS NOT PRESENT HERE HAS SOMETHING LIKE 19 OUT OF 22 IDENTICAL BASE EVEN COMBINATION COMBINATIONS eCO-LIE. THERE'S A UNIQUE SET OF NUCLEOTIDES THAT FAVOR RECOMBINATION. >> WE'RE NOT SURE, SOMETHING ABOUT GCC BIOLOGY. IT SHOULD BE INERT WHETHER IT'S DOING SOMETHING TO ENHANCE BUT WE DON'T KNOW. >> THANK YOU VERY MUCH. LET'S GO TO DR. PILEWSKI. >> IN OTHER VIRUSES IN THE BODY VERY INTERESTING COMMENT AND PROJECT THAT WE HAVE TO LOOK INTO. THE VIRUS IS DORMANT AND MAY NOT BE PRODUCING PROTEIN, IF THEY'RE PRODUCING PROTEIN BY THE IMMUNE SYSTEM, I DON'T KNOW YET. BUT THAT IS A VERY GOOD QUESTION. TO ADDRESS THE PROTENNIAL PROMOTION, (INDISCERNIBLE) STUDY PERIOD. I THINK UNLIKELY FOR THIS TYPE OF APPROACH BASED ON MANY OTHER VIRUS VACCINE BASE VACCINE TRIAL. >> DR. PILEWSKI. >> THANK YOU, ECHO DAVID'S COMMENTS, I THINK THE PROTOCOL IS WELL WRITTEN AND BASED ON SOME NICE RATIONAL WITH A NOVEL TARGET. MY COMMENTS BEFORE RELATIVELY STRAIGHT FORWARD. JUST RUN THROUGH THEM ONE BY ONE. CONSENT BY PRIMARY INVESTIGATOR OR SECONDARY INVESTIGATOR AND YOU CLARIFIED YOUR REVISION IS THE CONSENT FORM WILL BE ON PAIN P TRAINED BY A STUDY INVESTIGATOR OR CO-INVESTIGATOR AFTER A FACE TO FACE DISCUSSION. SECOND PERTAINS TO STUDY DESIGN, RATIONALE FOR ENROLLING PATIENTS BETWEEN TWO MONTHS AND TWO YEARS AFTER SURGICAL RESECTION GIVEN YOU HAVE THIS EXPLORETOR ANALYSIS OF WANTING TO LOOK FOR TIME TO RECURRENCE AL BE IT EXPLORE TORE AIM WOULD BE LIMITED. AND IN YOUR RESPONSE YOU ACKNOWLEDGE THAT WINDOW WHETHER SOMEBODY ENROLLED IN TWO MONTHS VERSUS 22 MONTHS MAY IMPACT TIME TO RECURRENCE, IMPACT THAT EXPLORATORY AIM BUT YOU NEED THAT WIDER RANGE IN ORDER TO ENROLL SUFFICIENT NUMBER OF PATIENTS. THAT SEEMS REASONABLE TO ME AS A RATIONALE WHY YOU WAN THAT BROAD RANGE. VACCINE DOSE WHY IT WAS SINGLE DOSE, WHY THE DOSE YOU CHOSE WITH WAS LIMITED TO THAT. YOU ADDRESSED THAT ON MURINE STUDIES WHERE YOU HAVE SHOWN YOU GET A NICE RESPONSE IN TERMS OF HUMORAL APPROXIMATE CELL MEDIATED IMMUNE RESPONSENESS VIRAL PARTICLES IN AMY REAP HOMOLOGUE VECTOR. AND IMAGE YOU HAVE CLINICAL RESPONSE IN THOSE ANIMALS AS WELL. IN YOUR RESPONSE YOU ADDRESS THAT&N– THAT DOSE WAS WHY YOU DON'T THINK A LOWER DOSE IS NECESSARY WOULDN'T ADVOCATE A LOWER DOSE, MY CONCERN DOSE WOULD NOT PERHAPS BE SUFFICIENT IN HUMANS BASED ON EXTRAPOLATION FROM MOUSE, I UNDERSTAND EXTRAPOLATION WAS FRAUGHT WITH DIFFICULTY, YOU HAVE TO START SOMEWHERE. IT DOESN'T MAKE SENSE TO USE THAT SINGLE DOSE OF 10 TO THE 11th VIRAL PARTICLES AND SEE WHAT YOUR IMMUNE RESPONSES HAVE ARE WITH YOUR DESIGN YOU'LL BE ABLE TO ASSESS FOR FUTILITY RELATIVELY EARLY AND POTENTIALLY MOVE TO HIGHER DOSE IF NECESSARY. SO I THOUGHT YOUR RESPONSE TO MY CONCERN WAS QUITE APPROPRIATE. NEXT WAS TOXICITY AND MONITORING TOXICITY, GIVEN THE THEORETICAL RATIONALE YOU HAVE THIS EPITOPE EXPRESSED IN NORMAL TEST EPITHELIUM AND ANY TO BE TESSIE RELATED TO THE GI TRACK, I RAISE THE QUESTION HOW TO MONITOR FOR THAT WITH CONCERN THAT IN ABSENCE OF A SYMPTOM QUESTIONNAIRE, ADDRESS GI ISSUES YOU MIGHT MISS TOXICITY. IOUS GUIDELINES FROM DIAGNOSTIC CRITERIA OR FUNCTIONAL GI DISORDERS, IN A BROAD SENSE HOW YOU'RE DOING WITH THE PROTOCOL. EXCLUSION CRITERIA AND RELATIONSHIP PRIOR CANCER VACCINE LITTLE PROTOCOL WHO EXCLUDE PATIENT WHOSE HAD PRIOR VACCINE AND YOU ADDRESSED THAT BY SAYING YOU'RE NOT GOING TO EXCLUDE PATIENTS WHO RECEIVED ANY SORT OF EXPERIMENTAL ADENOVIRUS VACCINE, THAT'S A UNUSUAL CIRCUMSTANCE BUT YOU HAVE ADDRESSED IT, YOU'RE NOT GOING TO EXCLUDE THOSE PATIENTS BUT WE'LL COLLECT THAT HISTORY. THE LAST ISSUES ARE RELATIVELY MINOR, ISSUES RELATED TO WORDING OF INFORMED CONSENT. I WAS CONCERNED ABOUT STATED AT THE FACT AND YOU REVISED THAT IN THE PROTOCOL. QUESTION ABOUT INDEMNIFICATION, SPONSORING INSTITUTIONS WAS GOING TO COVER MEDICAL COST THAT WERE NOT COVERED BY INSURANCE THIS IS NOT INDUSTRY SPONSORED TRIAL. I UNDERSTAND YOU'RE USING THE UNIVERSITY TEMPLATE FOR THAT, THAT MAKES SENSE TO ME. LASTLY INTELLECTUAL PROPERTY RIGHT AND HOW THAT'S CONDITION SAID TO PATIENTS AND CONSENT PROCESS. YOU MENTION STANDARD UNIVERSITY, LANGUAGE WILL BE EMPLOYED SO THAT THE PATIENTS ARE CLEAR WHERE THAT ISSUE LIES. SO YOU ADDRESSED ALL THE CONCERNS RAISED THOUGHTFULLY AND VERY SATISFYING. >> ANY OUTSTANDING CONCERN? >> NO. >> OKAY. I WAS THE THIRD REVIEWERS SO LET ME GO THROUGH SOME OF MY POINTS. SO FIRST ISSUE SINCE THERE WAS THE SAME ANTIGEN IN THE INTESTIN ES, HOW DO WE KNOW THERE'S A CROSS COLITIS, YOU ADDRESS WHY IT'S A CONCERN AND MOVING FORWARD WITH THE STUDY IT'S JUST -- HUMANS WITH CURRENT ANTIGEN P AS TO WHAT WILL HAPPEN. SO ON -- IN A DIFFERENT QUESTION I ASK WHETHER HOW MANY BOWEL MOVEMENTS PATIENTS WERE HAVING AFTER COLECTOMY HAS INCLUSION EXCLUSION CRITERIA SINCE TOXICITY CRITERIA FOR ANY KYLE IS REALLY A DIARRHEA AND INTESTINAL PROBLEMS THAT YOU CAN MEASURE BY BOW WE WOULD MOVEMENTS SO THE TWO ARE RELATED. YOU NEED AN OUTCOME PARAMETER WHICH YOU CAN ACTUALLY TELL THERE'S NO INTESTINAL TOXICITY AND PROVE ANIMAL WORK PANS OUT IN MAN AND YOU ALSO DON'T WANT TO HAVE PEOPLE HAVING SUCH TERRIBLE DIARRHEA AFTER COLECTOMY THAT YOU WILL ENTER INTO THIS TRIAL AND HAVE A FALSE READ-OUT OF A TOXICITY THAT DIDN'T REALLY EXIST FROM YOUR VACCINE. SO I WILL ASK ONE MORE TIME, WILL YOU USE A NUMBER OF BOWEL MOVES AS A RULE OUT CRITERIA, ABOVE A CERTAIN NUMBER OF BOWEL MOVEMENTS NOT LET THEM ENTER A TRIAL BECAUSE THEY WOULD BE AT RISK OF FALSE READ OUT FOR YOUR TRIAL? >> WE NOT PLANNED ON USING THAT AS CRITERIA. BEDISCUSSED IT PRIOR TO PERMIT IT CAN RESPONSES. WE HAD AT THAT POINT DECIDED NOT TO INCLUDE IT BUT IT'S SOMETHING WE'RE DISCUSSING. >> HAVE SOMETHING THAT THROWS OUT YOUR AGENTS SIMPLY AND HAVE THAT BE ONE OF THE PROBLEMS. THAT YOU ENCOUNTERED DOWN THE LINE, YOU ENROLL 22 AN ANOTHER 22 PATIENTS, NOT MANY PATIENTS. EVERY SO OFTEN WE DO A COLECTOMY WHERE PATIENTS ARE TERRIBLE AFTERWARDS IN CONTROLLING DIARRHEA AND ALL KINDS OF AGENTS, TO SEE THAT PATIENT IN THE TRIAL AND CONFOUNDING YOUR RESULTS BUT AGAIN, IT'S YOUR TRIAL AND JUST A RECOMMENDATION. THERE IS ONE ISSUE I'M HAVING A LITTLE TROUBLE WITH. YOU DID A STUDY YOU LOOK AT 2600 LYMPH NODES. RNA LEVELS MANY THE LYMPH NODES, MEASURE OF CULT LYMPH NODE METASTASIS. YOU COLOR HI SHOW IF YOU FIND M RNA FOR GCC IN THESE LYMPH NODES, THE PATIENTS DO WORSE, YOU CAN SEGREGATE OUT A GROUP OF PATIENTS AT HIGH RISK FOR RECURRENCE, THAT'S WHY YOU USE IT AS CRITERIA FOR YOUR STUDY HERE SO IF SOMEONE HAD SUCH A POSITIVE ALMOST OF NODE IN YOUR CURRENT STUDY, WOULD YOU TELL THEM? CHOOSE ADJUVANT CHEMOTHERAPY CONFERS 14% SURVIVAL BENEFIT FOR PATIENT WHOSE ARE NODE POSITIVE, A PROVEN BENEFIT TO PEOPLE WHO HAVE UNKNOWN POSITIVE. YOUR ANSWER SINCE IT WASN'T AN FDA APPROVED TEST THAT YOU WERE NOT GOING TO TELL THEM BUT IF YOU PUBLISHED A PAPER DEMONSTRATING YOU CAN ASSAY FOR A WORSE OUTCOME, BY AN EXAM AND NOW YOU CAN USEL‡a„ IT FOR INCLUSION CRITERIA FOR ONE OF YOUR TESTS, WHY NOT TELL THESE PEOPLE BECAUSE IF THEY TRULY ARE AT HIGHER RISK IF THEY HAD A BIGGER PRIMARY TUMOR, IT MIGHT BE A KEY BUT IT'S A HUGE POLYP OR MA ANYTHING LANT POLYP, THEY ARE BORDERLINE WHETHER GETTING GCC LYMPH NODE, WHY SHOULDN'T THEY HAVE CHOICE TO CHOOSE ADJUVANT CHEMOTHERAPY FOR POTENTIAL BETTER OUTCOME? >> I'M SCOTT WALTMAN, I'M GOING TO ANSWER YOUR QUESTION, I'M THE ONE THAT -- THE ANSWER TO YOUR QUESTION. >> LET ME FINISH MY THOUGHT. >> PLEASE. >> YOU CAN STILL HAVE THAT PATIENT IN THE TRIAL LATER. NOTHING SAYS THAT PATIENT COULD BE IN THE TRIAL. Q. I TOTALLY AGREE, IT HAS NOTHING TO DO WHETHER THE PATIENT IS IN THE TRIAL OR NOT IN THE TRIAL. THAT'S NOT WHAT I'M WORRIED ABOUT. TWO POINTS. NOT A CRITERIA FOR INCLUSION OR EXCLUSION IN THIS TRIAL. WE WANT TO KNOW IF THERE IS A CORRELATION BETWEEN A OKAY COULD TUMOR BURDEN ACROSS THE REGIONAL LYMPH NODE NETWORK AND IMMUNOLOGICAL RESPONSES OF THE PATIENT. WHETHER THE PATIENT HAS A OKAY COULD METASTASIS DOESN'T FACTOR WHETHER THEY'RE ENROLLED IN THE STUDY OR NOT. SO I WERE THE MAKE SURE THAT PIECE IS CLEAR. IN TERMS OF WHY WE DOPE REPORT BACK TO THE PATIENT. WHEN WE STARTED THE STUDIES WE CONSULTED WITH THE NCI. THEY REQUESTED THAT BECAUSE THIS IS AN EMPERIMENTAL DISEASE, IN THE YET VALIDATED, WE NOT REPORT BACK THE DATA TO THE PATIENTS. WE HAVE CONTINUED IN THAT VEIN THROUGH THE SERIES OF STUDIES THAT WE HAVE DONE. WE ACTUALLY HAVE AN ACTIVE TRIAL GOING ON RIGHT NOW CORRELATING OKAY CULT TUMOR BURDEN IN LYMPH NODE AND RESPONSE THE CHEMOTHERAPY. BUT THE ANALYSIS HASN'T BEEN DONE YET. I DON'T KNOW, IT GETS BACK TO IF THIS IS EMPERIMENTAL. I DON'T KNOW IF RESPONSE TO CHEMOTHERAPY IS GOING TO CORRELATE WITH OKAY CULT TUMOR BURDEN FINAL THE LYMPH NODES SO UNTIL WE, AGAIN, ACCORDING TO THE NCI AND ADVICE WE HAVE GOTTEN, UNTIL THIS IS A VALIDATED AND PROVEN TECHNOLOGY, WE'RE NOT REPORTING RESULTS BACK TO THE PATIENT. AND I'M HAPPY TO DISCUSS WITH YOU BUT YOU DID 2600 LYMPH NODES. THE DATA IS CLEAR. TOTALLY AGREE WITH YOU. >> WHY ISN'T THAT VALIDATED AS A PROGNOSTIC TEST FOR USE CLINICALLY FIRST OF ALL? AND THEN THE SECOND PART IS IN THIS STUDY, YOU MIGHT SAY I WANT TO SEE HOW THEY RESPOND TO IMMUNOLOGICALLY TO THE GCC, DEPENDING WHETHER THEY OPPORTUNITILY MIGHT CARRY THE ANTIGEN IN THE LYMPH NODES. BUT THEN I WILL SAY TO YOU, WHY NOT AFTER YOU ASSAY FOR THAT, WHICH IS A MONTH, TELL THEM SO THEY CAN AFTERWARDS CHEMOTHERAPY. IF I SAW YOUR FIRST PEOPLE, I KNEW I HAD GCC IN MY LYMPH NODE AND NOW YOU HAVE THAT DATA I WOULD WANT CHEMOTHERAPY. AT LEAST UNTIL YOU PRO-IN A TRIAL CHEMOTHERAPY DOESN'T HELP THOSE PEOPLE. >> I TAKE YOUR POINT. LET ME OFFER A COMPROMISE. DEFINITELY ETHICS COMMITTEE AT JEFFERSON AND ASK THEM FOR GUIDANCE IN THIS. THIS IS EXACTLY WHAT WE DID WHEN WE DID THE FIRST STUDY TO THE ETHICS COMMITTEE. LET ME GO BACK, I TAKE WHAT YOU'RE SAYING VERY SERIOUSLY, FIND OUT WHAT YOUR ADVICE WAS IN THE SITUATION T. DATA IS CONSIDERABLE AT THIS POINT, YOU CAN'T ALERT PATIENTS TO THE RESULTS. I'M HAPPY TO DO THAT. >> NOT SAYING YOU HAVE TO IMMEDIATELY TELL THEM, YOU MIGHT -- THEY MAY NOT FIND OUT UNTIL LATER BUT NOT THE TELL THEM EVER, I JUST DONE FEEL IS -- AT LEAST FROM MY STANDPOINT. >> IT'S HEART WARMING TO ME YOU HAVE CONFIDENCE IN THE TECHNOLOGY THAT WE DEVELOP. >> USING MOLECULAR DATA TO DECIDE CHEMOTHERAPY IS NOT EXPERIMENTAL. FOR MELANOMA COLON CANCER, LARGE TUMOR, MORE INVASIVE TUMOR IS ADJUVANT CHEMOTHERAPY STAGE 2 DISEASE. STILL ARGUABLE BUT AS (INDISCERNIBLE) SAID WE'RE GOING TO BRING THIS BACK TO A COMMITTEE THAT'S STRONG ENOUGH TO SAY STANDARD OF CARE IS USING MOLECULAR STUDY DATA TO OFFER CHEMOTHERAPY. THAT IS EXPERIMENTAL. >> IN MANY DISEASES WE DO. B RAP MUTATION, ALLOWS FOR THERAPIES. >> >> BY USING MOLECULAR ANALYSIS. THAT COULD PREDICT PROGNOSIS. HOWEVER, WITH BETA YOU SHALL USE THAT MOLECULAR DATA TO OFFER CHEMOTHERAPY, I DON'T THINK THAT'S STANDARD PRACTICE. SO BUT WE'RE GOING TO BRING THIS ISSUEETHICSES COMMITTEE TO ANSWER YOUR QUESTION. ALSO -- IN TERMS OF DIARRHEA, THEN I THINK FORM SUGGESTION CAN INCLUDE SOME KIND OF EXCLUSION CRITERIA. PRE-EXISTING GRADE 2 OR 3, EXCLUDED. EVERY DAY SO THEREFORE WE ARE KIND OF CONFIDENT MANAGING DIARRHEA BUT IT'S VERY GOOD POINT IF DIARRHEA IS SIGNIFICANT FOR COULD OF LIFE FROM THE BEGINNING THAT MIGHT INTERFERE WITH ANALYSIS OF THIS SO I APPRECIATE YOUR COMMENT. >> I CONCUR WITH THAT. >> (INAUDIBLE) IF THE DATA SHOULD SUPPORT IT. >> ESSENTIALLY YOU'RE BIASING, YOU WOULD BE BIASING THE POPULATION IN OUR FAVOR. >> I TOLDLY AGREE WITH YOU. >> I'M BIASING STUDY FOR POSSIBILITY OF DISCOVERYING THE TRUTH AS IT EXISTS. THAT'S WHAT I WAS TRYING TO DO. LAST COMMENT WAS REALLY, THE ETHNICITY. SELECTION. I UNDERSTAND WHY THERE IS A I WAS PUSHING FOR WHY NOT EXPAND BEI DON'T KNOW AFRICAN AMERICANS AND WHITE POPULATION. I TAKE YOUR POINTS, RIOT NOW THIS IS A SMALL STUDY YOU'RE TRYING TO LOOK FOR TEST A PARTICULARz3 HYPOTHESIS THAT'S ETHNICALLY DRIVEN. BUT THEN WHEN YOU SAY BLACK WHAT DO YOU MEAN AND HOW YOU'RE GOING TO CHOOSE THE RIGHT POPULATION FOR YOUR HYPOTHESIS. >> TRICKY QUESTION. THE WAY WE HAVE DONE THIS IN THE PAST WITH AFRICAN AMERICAN VERSUS CAUCASIAN STUDIES, IT'S SELF-REPORTING RACE. SO ALL OUR TRIALS IN THE PAST SELF-REPORTING OF RACE. WE HAVEN'T DONE -- WE HAVEN'T GONE BEYOND SELF-REPORTING. SO AFRICAN AMERICAN AND CARIBBEAN AMERICAN WOULD BE THE SAME TO YOU FOR YOUR TRIAL. JUST GETTING CLARIFICATION. Q. QUESTION. LAST PART. WHEN YOU MEASURE RECURRENCE, YOU'RE CURRENTLY CHOOSING RECURRENCE FROM VACCINATION. IS THAT TRUE? IF YOU'RE THINKING -- REFERRING TO DISEASE FREE SURVIVAL. >> WE DO IT FROM THE TIME THEY WERE DIAGNOSED AND HAD SURGERY AND ALSO FROM THE TIME >> WANT TO BE HERE BOTH ARE DONE. >> ABSOLUTELY. Q. VERY GOOD. >> THERE'S HISTORICAL DATA FOR THE VACCINE -- SO WE CAN CAN'T PROVIDE ANYTHING ABOUT THAT WITH REGARD TO DATA BUT WE USE THE HISTORICAL DATA IN TERMS OF TIME TO PROGRESSION FROM THE SURGERY TO MAKE SURE THIS IS NOT PROMOTING ANYTHING. >> THOSE ARE REALLY MY ONLY REMAINING ISSUES. ANY OTHER COMMENTS FROM RAC MEMBERS, ANDREW? >> SPEAKING FROM A IMMUNOLODGEE PERSPECTIVE, I MENTION SOMETHING HERE WHICH IS GCC DID A PRETTY GOOD JOB EXPLAINING A NOVEL TUMOR ANTIGEN. I GET THAT. PRETTY GOOD JOB (INAUDIBLE) FOR PROGNOSIS. I GET THAT. WHAT EVIDENCE IS THERE THAT IMMUNE RESPONSE MEANS GCC IS PROTECTED? IT'S WHAT WOULD NORMALLY HAVE PROTECTIVE IMMUNE RESPONSES. IS THERE ANY EVIDENCE THAT THERE IS IMMUNE RESPONSE WITH GCC AND THAT IMMUNE RESPONSE IS HELPFUL TO DISEASE PROGREG, ET CETERA. >> IN PATIENTS THERE'S NOTHING KNOWN ABOUT GCC IMMUNOLOGY. WE HAVE IMMUNE RESPONSES IN PATIENTS DE NOVO AND OBVIOUSLY STUDY WITHIN THE VACCINE. IN MICE WE KNOW THAT THE VAX SCENE GENERATES IN NODES PROTECTIVE BUT BEYOND THAT WE DON'T KNOW ANYTHING ABOUT PARTICIPATE. >> I'M INTERESTED, WHAT YOU'RE CONDONED ABOUT? >> YOU'RE GOING TO BE EXPLORING BUT THERE ARE POSSIBLE MECHANISM S GCC CAN BE MET. THERE'S ALWAYS A CONCERN THAT GENERATING A RESPONSE CAN HAVE TARGETED AFFECTS. THIS COMMITTEE (INAUDIBLE). >> UNFORTUNATELY (INAUDIBLE) >> I'M SORRY. I'M SORRY. UNFORTUNATELY WE HAVE THE MOUSE MODEL. THE NEXT STEP UP IS DOING A PHASE 1 STUDY TO LEARN EXACTLY WHAT YOU'RE TRYING TO GET AT. HOPEFULLY MAN EQUALS MOUSE AND BEAUTIFUL, BUT YOU WON'T KNOW UNTIL YOU DO THE PHASE 1 STUDY. >> YOUR POINT IS VERY WELL TAKEN. >> OTHER ISSUES? >> I CONTINUE TO BE CURIOUS AND NOT UNTROUBLED BY THE SEPARATION TO BLACK AND WHITE COHORT GROUPS. I UNDERSTAND THE CLINICAL SIGNIFICANCE. BUT THE SELF-REPORTING HAS BEEN SUCH A ODD WAY TO THINK ABOUT. ARE YOU LOOKING FOR AFRICAN OR GIN IT'S HOW PEOPLE -- HOW PEOPLE DESCRIBE IS QUITE SUBJECTIVE. AND I'M USUALLY DOING SOME OTHER DATA POINTS THAT'S GOING TO VALIDATE THAT OR JUST A LITTLE OFF THE CUFF? HOW WOULD YOU USE THIS, YOU SPEAK VAGUELY ABOUT WANTING TO USE THIS LATER FOR CLINICAL INTERVENTION, NOT SURE HOW THAT WOULD HAPPEN. I'M CONCERNED ABOUT THIS PART OF THE IT. >> I APPRECIATE YOUR CONCERN AND I UNDERSTAND IT. I'M FAMILIAR WITH THE DATA THAT SAYS A PERSON COWHO COMES IN AND DESCRIBES THEMSELVES AS BLACK, COULD BE 90% GENETICALLY CAUCASIAN. I AM FAMILIAR WITH THAT. I WILL TELL YOU THAT FOR MUCH OF THE DATA THAT DEMONSTRATES A DISPARITY IN OUTCOMES BETWEEN THE BLACK AND WHITE POPULATION IN COLON CANCER THOSE PATIENTS ARE SELF-DESCRIBED BLACK AND WHITE. THOSE ARE THE POPULATIONS THAT -- I'M GOING AFTER THAT SPECIFIC DISPARITY. THOSE ARISE IN POPULATIONS SELF-DESCRIBED WHITE AND SELF-DESCRIBED BLACK. IN TERMS OF USING THIS VACCINE TO ADDRESS -- THE DISPARITIES IN OUTCOMES IN COLON CANCER IN THE BLACK AND WHITE POPULATION, IT BASED ON POPULATIONS DESCRIBE -- SELF-DESCRIBING. SO WE THINK IN THAT RESPECT IT'S APPROPRIATE. BUT P I ABSOLUTELY TAKE YOUR POINT. DOES THAT MAKE SENSE? Q. YEAH. >> I'LL GIVE YOU ONE -- >> WHAT COMES TO MIND IS BIVALENT. >> YES, YES, YES, YES. THE OTHER THING THAT'S INTERESTING, THE OTHER TIDBIT I'LL OFFER HERE IS WE DID A STUDY THIS GOES BACK TO OKAY CULT METASTASIS, THE GCC TEST LOOKING FOR OKAY CULT TUMOR CELL IN LYMPH NODES AND WE DID IT IN SELF-DESCRIBED BLACK POPULATION AND SELF-DESCRIBED WHITE POPULATION TO SEE IF THE ESTABLISHED DISPARITY IN OUTCOMES IN STAGE 1 AND 2 COLON CANCER, THERE'S A GOOD -- THERE'S A DISPARITY IN OUTCOMES WHERE THE BLACK POPULATION SELF-DESCRIBED BLACK POPULATION HAS WORSE OUTCOMES STAGE 1 AND 2 THAN CAUCASIAN. WE WENT IN THERE AND LOOKED SELF-DESCRIBED POPULATIONS, WE WENT IN THERE AND LOOKED AT OKAY CULT TUMOR BURDEN ACROSS THE REGIONAL LYMPH NODE NETWORK AND SURE ENOUGH, THE AFRICAN AMERICAN -- THE BLACK POPULATION , HAS A MUCH HIGHER OKAY CULT TUMOR BURDEN ACROSS THEIR REGIONAL LYMPH NODE NETWORK AT TIME OF PRESENTATION THAN THE SELF-DESCRIBED WHITE POPULATION. SO I'M TELLING YOU THIS TO ILLUSTRATE THAT WHILE I UNDERSTAND THE COMPLEXITY OF SELF-DESCRIPTION OF RACE, FOR THESE STUDIES–r IT'S ACTUALLY APPROPRIATE THOSE ARE -- THAT'S THE POPULATION AND THE DISPARITY WE'RE GOING AFTER. DOES THAT MAKE SENSE? >> ABSOLUTELY. >> THANK YOU. OTHER COMMENTS? ANY COMMENTS FROM PEOPLE ON THE PHONE? ANY PUBLIC COMMENTS? WE WILL TAKE A FIVE MINUTE BREAK AND THEN WE'LL READ BACK TO YOU FURTHER RECOMMENDATIONS. DR. SATO AND YOUR TEAM, I THANK YOU VERY MUCH FOR PRESENTING TO US TODAY A VERY CLEAR PROTOCOL. HERE IS A DRAFT LIST OF PENDING RECOMMENDATIONS. I WILL READ THEM. CLINICALLY, THOUGH THIS IS A REPLICATION DEFECTIVE VIRUS IT MAY REPLICATE AND THEREFORE PRUDENT TO EVALUATE SAMPLES COLLECTED FOR IMMUNOLOGIC STUDIES FOR THE ADENOVIRAL VECTOR OR GENE PRODUCTS. NUMBER 2, GCC IS EXPRESSED NORMAL BOWEL CELLS AND THEREFORE A POTENTIAL FOR GI TOXICITY. THIS MAYBE MANIFESTED AS RECURRENT LOOSE STOOL OR FREQUENT STOOLS, COLECTOMY IS RISK FOR FRIABLE STOOLS CONSIDERED EXCLUSION CRITERIA BASE PD ON FREQUENCY SO NOT TO CONFOUND ANALYSIS OF ADVERSE EFFECTS. YOU HAVE DONE A STUDY OF 257 PATIENTS WITH IN ZERO COLORECTAL CANCER. IN THESE PATIENTS NEARLY 2600 LYMPH NODES WERE ASSESSED FOR GCC mRNA EXPRESS. THE APPEARANCE OF GCC mRNA EXPRESSION WAS A SIGNIFICANT PREDICTOR OF RECURRENCE, ONE OF THE END POINTS OF THE CURRENT STUDY IS TO ASSAY LYMPH NODES COLLECTED AT COLECTOMY BY QUANTITATIVE RT PCR FOR GCC. DATA SUGGESTS IF IT IS FOUND TO BE HIGH, IT IS THE PATIENTS MAY HAVE MICROMETASTASIS. SUBJECTS MAY INTERESTED IN THIS INFORMATION BUT WE UNDERSTAND IT IS STILL IN AN EMPERIMENTAL MARKER AND THE DECISION TO DISCLOSE THIS INFORMATION TO THE SUBJECTS IS A DIFFICULT QUESTION SINCE SUBJECTS MAY MAKE DECISIONS BASED ON THIS INFORMATION AND IT IS NOT A VALIDATEDDED MARKER. YOUR INCLINATION IS NOT TO DISCLOSE THE DATA SINCE IT IS NOT A LICENSED FDA TEST, WE URGE YOU TO HAVE A DIALOGUE WITH YOUR INSTITUTIONAL REVIEW BOARD REGARDING WHETHER AND HOW THIS INFORMATION SHOULD BE SHARED. JUST TO PUSH THAT, IF THE DATA IS AS GOOD AS THAT PAPER YOU WROTE YOU SHOULD BE PUSHING FOR A VALIDATED ASSAY. AND THEN -- BECAUSE I THINK IT WOULD BE A HELP AND A PANEL OF THESE ASSAYS WILL HELP US DOWN THE LINE TO BE SMARTER ABOUT STAGING THESE PATIENTS. SO THE RECOMMENDATIONS ARE AS READ, ANY ADDITIONS OR CHANGES FROM ANY OF THE RAC MEMBERS? ANY ADDITIONS FROM PEOPLE ON THE PHONE? ANY COMMENTS BACK FROM THE INVESTIGATORS. (OFF MIC) WE VERY MUCH APPRECIATE THE THOUGHTFUL (INAUDIBLE). >> LET'S -- MOVE TOWARDS A VOTE. DR. KOCH. >> YES. >> ORNELLES, YES. >> (INAUDIBLE). (INAUDIBLE) YES. >> (INAUDIBLE). YES. >> HANG ON ONE SECOND. IF YOU SHALL TURN ON THE MICROPHONE, YES. >> CON, YES. FONG, YES. >> KNOB, YES. >> BADLY YES. >> CANON, YES. >> (INAUDIBLE), YES. >> WOOLEY YES. >> KNOB, YES. >> MS. MALLINO? >> MALLIN O, YES. >> THANK YOU VERY MUCH. >> THANK YOU. >> WE ARE WAY AHEAD OF SCHEDULE AND I -- IN ORDER THAT IF THERE WERE PEOPLE WATCHING THE WEBCAST WE DON'T GET SO FAR AHEAD THAT THEY MISS THE DISCUSSIONS. WE'RE GOING TO TAKE A FULL 15 MINUTE BREAK AND WE'LL RESTART AT -- YEAH, AT 3 O'CLOCK. >> WE'RE GOING TO MOVE TO THE LAST PROTOCOL IN THE CONSIDERATION THIS AFTERNOON. THIS IS A DISCUSSION OF HUMAN GENE TRANSFER PROTOCOL NUMBER 1304-1224, ENTITLED E-10A ADENOVERSE FOR THE RECOMMEND OF RECURRENT METASTATIC SQUAMOUS CELL CARCINOMA HEAD AND NECK. THE PRESENTER IS DR. GEORGE YOO, PROFESSOR AND CHIEF MEDICAL OFFICER OF CAMANOS CANCER CENTER AND MEDICINE. HE'S AN OLIGOOLOGIST AT WAYNE STATE UNIVERSITY IN DETROIT. DR. YOO, CAN CAN YOU INTRODUCE COLLABORATORS AND CO-PRESENTERS PLEASE. >> THE MEMBERS OF THE TEAM ARE DR. GEORGE THOMAS, DR. BOB JOYCE AND DR. NANCY STEWARD. FIRST I WANT TO THANK THE COMMITTEE FORGIVING US THE OPPORTUNITY TO PRESENT OUR PROTOCOL, ESPECIAL HI DR. STROME, KOCH AND DRESSER WHO GAVE A DETAILED REVIEW OF THE PROTOCOL. THE OTHER MEMBERS OF THE TEAM HAVE BEEN AVAILABLE TO ANSWER QUESTIONS THAT I CANNOT. I'M A CONSULTANT FOR MARSALA BIOTECH. SINCE 20 MINUTES ISN'T LONG ENOUGH TO PRESENT THE FULL PROTOCOL WHAT I HAVE DONE IS PROVIDED AN OUTLINE THAT FOCUSED IN FOUR AREAS, GIVING AN OVERVIEW OF UNDERSTANDING E-1A, PROVIDING A SUMMARY OF THE PROTOCOL, AND ALSO GOING OVER THE KEY POINTS OF THE TRIAL DESIGN AND REVIEWING SOME OF THE BIOLOGICAL ACTIVITY OF E-10A. SO ENDOSTATIN IS THE PROTEIN AND GENE WE STUDY. ENDOSTATIN BY ITS NAME INHIBITS ANGIOGENESIS BY AFFECTING THE ENDOTHELIAL CELL BY MOVEMENT AND MECHANISM AND IT CAUSES CELL CYCLE ALIST REST AND APOPTOSIS IN THE ENDOTHELIAL CELLS. E-10A IS WILD TYPE HUMAN ENDOSTATIN GENE INSERTED TO A NON-REPLY CATTING ADENOVIRUS. D THE A KNOW VIROHAS THE E-1A AND EP SECTION DELETED AND HAS A C AND B PROMOTER AND IL-2 SIGNAL TRANSDUCTION PEPTIDE TO GO TO EXTRA CELLULAR DOMAIN. ONE ADVANTAGE OF E-10A IS WHEN YOU INJECT IT INTERTUMORALLY IT WILL BE AROUND FIVE TO 7 DAY THES IN SERUM VERSUS IV ENDOSTATIN WITH A HALF LIFE OF TEN HOURS. THIS IS THE SUMMARY OF THE PROTOCOL. THE OBJECTIVE OF THE PROTOCOL IS TO DEMONSTRATE BENEFIT OF E-10A TREATING PATIENTS WITH RECURRENT UNRESECTABLE HEAD AND NECK CANCER IN COMBINATION WITH CHEMOTHERAPY T. PROPOSED TRIAL HAS 400 SUBJECTS T. TREATING GROUPS ARE TWO AND THE FIRST GROUP IS GOING TO BE E-10A WHICH IS THE INTERTUMORAL INJECTION OF E-10A AND CHEMOTHERAPY. THE SECOND GROUP IS CHEMOTHERAPY ALONE. RANDOMIZED ONE TO ONE RATIO SO THEY WILL BE 200 PATIENTS IN EACH ARM. E-10A WILL BE DELIVERED IN INTRATUMORAL INJECTION USING ONE TIMES TEN TO THE 12 VIRAL PARTICLES PER INJECTION. AND WILL BE INJECTED DAYS 1 AND 8 EVERY 21 DAYS. THE CHEMOTHERAPY TO USE IS A CHOICE OF EITHER USING 5 FU AN CISPLATIN 5 S YOU, CARBO PLATIN AND (INDISCERNIBLE) WERE TABSING AND ONE OF THE PLATINS WITH OR WITHOUT 5 FU. I'M GOING TO A LOT OF DETAIL HOW WE CAME TO THAT CONCLUSION OF USING CHEMOTHERAPY REGIMEN T. KEY POINTS TO GO OVER IN THE PRESENTATION IS PHASE 1 AND PHASE 2 JUSTIFICATION FOR THE PROPOSED PHASE 3 TRIAL. I'LL TALK ABOUT THE CLINICAL PRE-CLINICAL DATA THAT SUPPORTS THE SYNERGY BETWEEN E-10A AND CHEMOTHERAPY. ALSO GO OVER CLINICAL BEHAVIOR AND TREATMENT FOR RECURRENT METASTATIC HEAD AND NECK CANCER THAT LED US TO DEVELOP CHEMOTHERAPY FOR THAT THIS TRIAL. DETAIL ABOUT THE STATISTICAL DESIGN, AND COVER THE SAFETY PROFILE OF E-10A ANDŤqHd ADENOVIRUS VECTOR. THIS IS A SUMMARY SLIDE OF PHASE 1 TRIAL. THERE WERE 15 PARENTS ENROLLED IN THIS TRIAL. MOST WERE HEAD AND NECK. THERE'S ONE COLON, AND ONE CERVICAL CANCER. ALL THESE PATIENTS RECEIVE AN EJECTION OF E-10A ONCE A WEEK FOR TWO WEEKS. THERE IS FOUR DOSE GROUPS THAT ARE LISTED UP ON TOP OF DIFFERENT VIRAL PARTICLES. THIS OUTCOME OF THIS TRIAL SHOW E-10A WAS WELL TOLERATED, THERE WAS NO DOSE DEPENDENT TOXICITY AND NO SEVERE ADVERSE EVENTS. THERE WERE MINOR EVENTS RECORDED, THERE WERE ESSENTIALLY LOCAL L REACTION AND EJECTION SITE WHICH ARE LOCAL PAIN AND FEVER AND SWELLING. BESIDES THAT, THERE'S NO OTHER SEVERE OR ANY MINOR ADVERSE EVENTS REPORTED. S THAT SLIDE THAT SUMMARIZE FROM A LOT OF PHASE 2 TRIAL. THE PHASE 2 TRIAL WAS AN OPEN LABEL RANDOMIZED TRIAL WHICH LOOKED AT COMBINE E-10A WITH CHEMOTHERAPY, CHEMOTHERAPY WAS TAX OBJECTIONL AND CISPLATIN IN PATIENTS WITH HEAD AND NECK CANCER. PATIENTS WITH ADVANCED METASTATIC HEAD AND NECK CANCER, SOME CARCINOMAS WERE ALLOWED ON THIS TRIAL. THE TWO STUDY GROUPS WERE E-10A, PLUS CHEMOTHERAPY DESCRIBED THERE, CHEMOTHERAPY ALONE. IT WAS DELIVER INTERTUMORALLY. THE OUTCOME FOR THE TRIAL IS THE MEDIAN PROGRESSION FREE SURVIVAL WAS 6.9 IN HEMOGLUTE AND 3.9 IN CHEMO ONLY GROUP. SO 92% BENEFIT WHICH WAS STATISTICALLY SIGNIFICANT, THE MEDIAN SURVIVE, FOR CHEMOTHERAPY WAS 14.3 MONTHS IN THE HOMOTHERAPY ALONE GROUP. THAT SHOWED A 31% BENEFIT BUT NOT STATISTICALLY SIGNIFICANT. THIS LED US, I'LL GO OVER CAREFULLY IN A COUPLE OF SLIDES LATER TO STATISTICAL DESIGN FOR OUR TRIALS WHICH LED TO 400 PATIENTS, 200 PATIENTS IN EACH ARM. PRE-CLINICAL DATA WHICH SHOW THAT THERE WAS SYNERGY BETWEEN E-10A AND CHEMOTHERAPY. THE DIAGRAM ON THE LEFT IS A XENOGRAPHIC MOUSE MODEL USED IN HYPERPHARYNGEAL HUMAN CANCER CELLS AND YOU CAN SEE THAT THERE WAS 5 GROUPS TESTED, SALINE CONTROL, VECTOR ALONE, THE HEMOTHERAPY, THE E-10A ALONE AND E 10A PLUS CHEMOTHERAPYSIS PLATINUM. YOU CAN SEE THAT THE BLACK LINE SHOWS THAT THERE WAS A SIGNIFICANTLY SLOWER GROWTH OF TUMOR IN E 10A GROUP, COMBINED WITHSIS PLATINUM. THE NEXT DIAGRAM SHOW IT IS SAME DATA EXCEPT FOR THE FACT THIS ISN'T A BAR GRAPH, YOU CAN SEE THERE IS A STATISTICALLY SIGNIFICANT IMPROVEMENT IN TUMOR GROWTH WHEN E-10 ACTION WAS COMBINED WITH CISPLATIN. WE FOUND SIMILAR RESULTS OR OTHER SIMILAR RESULTS LOOKING AT ANOTHER LUNG CANCER MODEL AND SIMILAR, THEY WERE INJECTED WITH THE TUMOR: AND THEN TREATED WITH A FIVE GROUP AND YOU CAN SEE THE BLACK LINE HERE DEMONSTRATES THE COMBINATION OF E-10 A WITH HEMOTHERAPY SUPPRESSEDD THE GROWTH OF THE TUMOR. ANOTHER FINDING THAT WAS DISCOVERED WAS THAT WHEN OTHERS LOOKED AT THE LEVEL OF CONCENTRATION OFSIS PLATINUM IN THE TUMOR, AS WE EXPECT WHEN ALIEN WAS INJECTED, NO INJECTABLE TOSIS PLATINUM, WHEN CHEMOTHERAPYSIS PLATINUM WAS USE THERE HAD OOH'S A LEVEL OF PLATINUM DETECTED. AND WHEN YOU LOOK ATSIS PLATINUM PLUS E-10A THERE'S FIVE FOLD HIGHER INTRATUMORAL DOSE OF CHEMOTHERAPY. SO THERE WAS A PARADOXICAL DELIVERY OR INCREASED DELIVERY OF E-10A AND CHEMOTHERAPY INTO THE TUMOR ITSELF. SO BECAUSE OF PRE-CLINICAL DATA, IT LED US OR LED THE OTHER INVESTIGATORS TO GO AND LOOK AT E-10A USING CHEMOTHERAPY IN THE PHASE 1 AND PHASE 2 TRIAL WE DESCRIBED. SO WHAT I WANT TO DO IS GIVE A LITTLE BACKGROUND ABOUT RECURRENT HEAD AND NECK CANCER. IN GENERAL RECURRENT RESECTABLE METASTATIC HEAD AND NECK CANCER HAD POOR OUTCOME. MEDIAN SURVIVAL IS BETWEEN 5 AND 10 MONTHS. THERE WAS NO STANDARD CHEMOTHERAPY THAT IS USED IN THESE GROUP OF PATIENTS. THIS FRANK WARDEN AT UNIVERSITY OF MICHIGAN REVIEWED 14 TRIALS, RECENT TRIALS AND HE SHOWED THAT REALLY THE SURVIVAL ISN'T MUCH DIFFERENT IN THE CHEMOTHERAPY REGIMENS USED. ALSO HEAD AND NECK CANCER THERE REALLY IS NOT A TARGET IN HEAD AND NECK CANCER. THERE ISN'T A TARGET LIKE BREAST CANCER WHERE WE HAVE THE PRER HER 2 NEW AND WE CAN USE THERAPY GUIDE THERAPY. WE DON'T HAVE THE HEAD AND NECK CANCER. SO REAL iICLY WE'RE USING STANDARD CYTOTOXIC CHEMOTHERAPY TO TREAT RECURRENT HEAD AND NECK METASTATIC DISEASE. WE ALSO -- WHAT'S ALSO OCCURS IS VARIABILITY OF PATIENTS WHO DEVELOP RECURRENT METASTATIC DISEASE AND HOW MUCH CHEMOTHERAPY EXPOSURE THEY'LL HAVE, SOME ARE NEVER GOING TO HAVE CHEMOTHERAPY, FOR WHO COMES WITH NEWLY DIAGNOSED METASTASIS WHICH SUSPECT UNCOMMON, ONLY 5 TO 10% OF PATIENTS WILL NEVER RECEIVE CHEMOTHERAPY BUT NEED A SYSTEMIC THERAPY, NOT A LOCAL THERAPY. PATIENTS WILL HAVE RECURRENCE AFTER SURGERY RADIATION WILL NEVER HAVE SEEN CHEMOTHERAPY ALSO. SOME RECEIVE HEMOTHERAPY IN ADJUVANT SETTING FOR INDUCTION OR CHEMORADIATION. SOME PATIENTS MAY HAVE SEEN CHEMOTHERAPY FOR THEIR RECURRENT OR METASTATIC DISEASE, THAT THEY RARELY SEE AND BE TREATED SO THOUGH THERE'S A VARIABILITY IN THE AMOUNT OF CHEMOTHERAPY A PATIENT SEES IT'S TOP LINE HERE MEDIAN SURVIVAL IS POOR FOR THESE GROUP OF PATIENTS. THAT'S THE GROUP WE WANT TO SEE. WHAT WE ARE GOING TO DO IN TRIAL IS STRATIFY FOR THE AM THEY HAVE SEEN IN THE PAST. WHEN P YOU LOOK AT WHAT ARE TREATMENT GUIDELINES FOR RECURRENT UNRESECTABLE AND METASTATIC HEAD AND NECK CANCER, THERE ARE OPINIONS AND BIASES THERE. SO WE HAVE TO LOOK TO IS NCCN GUIDELINES AN MEDICAL ONCOLOGY EXPERTS. RECURRENT UNRESECTABLE DISEASE CAN BE TREATED WITH CHEMOTHERAPY AND REIRRADIATION IN CHEMOTHERAPY, THEY HAVE SEEN RADIATION BEFORE AND ANYONE WHO HAD THE METASTATIC DISEASE IS TREATED WITH SYSTEMIC THERAPY, NOT LOCAL THERAPY SO TREATED WITH CHEMOTHERAPY. THERE IS A QUESTION WHY ARE WE USING RADIATION. ONE ELIGIBILITY CRITERIA IS PATIENTS WHO AREN'T SUITABLE FOR SURGERY OR RADIATION WHICH INCLUDES RERADIATION ARE NOT ELIGIBLE FOR THIS TRIAL. SO IF REIRRADIATION IS CONSIDEREDDED FOR THIS -- FOR THE PATIENTS THEY'RE NOT ELIGIBLE FOR TRIAL. THE NCCN GUIDELINES DOES ALLOW RERADIATION AND CHEMOTHERAPY AS OPTION FOR RECURRENT DISEASE BUT QUOTING THEIR GUIDELINES FOR HIGHLY SELECTED GROUP OF PATIENTS TREATED IN CENTERS WHERE THERE'S HIGH-LEVEL EXPERTISE SOME THIS IS A SMALL GROUP OF PATIENTS TREATED WITH REREADIATION. SO THE NEXT THING THAT COMES UP IS WHAT KIND OF CHEMOTHERAPY DO YOU USE FOR PATIENTS WITH RECURRENT METASTATIC HEAD AND NECK CANCER, THERE'S DIFFERENT OPTIONS BUT WE AGAIN LOOK TO THE NPPN GUIDELINES AN COMBINATION CHEMOTHERAPY, THERE'S FOUR THEY LISTED FOR NON-NAY SEW PHARYNGEAL, 5 FUSIS PLATINUM, 5 FU CARBO P PLATINUM AND HEBOTUX. TERA TAXOL ORSIS P&A PLATIN AND CARBO PLATIN AND CISPLATIN AND HERBOTUX. PROTOCOL WE MIRRORED WHAT THE GUIDE INWILL ARE, THE ONLY CHANGE IS ALLOWING CARBO PLATINUM TO BE USED BECAUSE PATIENTS CANNOT TOLERATE HIGH DOSESIS PLATINUM AND WE'RE GOING TO ALLOW 5 FU IF INVESTIGATOR WANT TO BE ADDING TO THE TAXING SIS PLATINUM PROTOCOL SO WE'RE MIRRORING THE GUIDELINES FOR THE CHEMOTHERAPY REGIMEN. SO THERE IS NOT A STANDARD CHEMOTHERAPY REGIMEN, WHAT THE NCN GUIDELINES TALK ABOUT IN CHEMOTHERAPY SECTION IS CHOICE SHOULD BE INDIVIDUALIZED BASED ON PATIENT CHARACTERISTICS. SO THE CHOICE IS INDIVIDUALIZED FOR EACH PATIENT, PART OF THIS IS DUE TO THE FACT WHAT KIND OF CHEMOTHERAPY DID THEY RECEIVE BEFORE. IF THEY RECEIVE TAXING BEFORE, IT DOESN'T MAKE SENSE THAT THEY RECEIVE AGAIN BECAUSE THEY ALREADY FAILED ON THAT. WE HAVE GENERAL HEALTH AND COMORBIDITY OF THE PATIENT. IF THE PATIENT HAS RENAL DYSFUNCTIONSIS PLATINUM IS NOT THE CHOICE OF CHEMOTHERAPY THAT WE WANT TO USE. A LOT OF PATIENTS MAY NOT TOLERATE HIGH DOSE SIS PLATINUM REGIMEN. THAT'S WHY WE ALLOW IN THE INVESTIGATOR TO CHOOSE ONE OF THREE CHEMOTHERAPY STANDARDS. SO NOT CHOOSING ONE STANDARD BECAUSE THEY MAY NOT USE ONE STANDARD, ALLOWING ONE OF THREE STANDARDS ALLOWED IN FOR TREATING RECURRENT METASTATIC DISEASE. ALSO THE STATISTICAL DESIGN WE'LL STRATIFY THE CHEMOTHERAPY SO THE MEDICAL ON ONLY GIST HAS TO DECLARE WHICH CHEMOTHERAPY IS PLANNED AND IT WILL BE STRATIFIED AT ONE OF THREE GROUPS SO THE STATISTICAL DESIGN INCLUDES RANDOMIZATION STRATIFIED ORGANIZE TO THE ECOG PERFORMANCE STATUS, CHEMOTHERAPY REGIMENT, WHETHER THIS IS FIRST TIME RECURRENCE OR REFRACTORY DISEASE, PRESENCE AND ABSENCE OF METASTASIS. NOW WE FEEL IS CHILD IS POWERED TO ADEQUATELY DETECT A DIFFERENCE IN PHASE 2 TRIAL THOUGH THERE WAS A 36 -- 31% DIFFERENCE, IT PROBABLY WASN'T POWERED ENOUGH TO DETECT A DIFFERENCE. THE MEDIAN OVERALL SURVIVAL IN THE CONTROL ARM IS SIX MONTHS. HAZARD R OWE IS.71. RATIO OF.71. AND ONE SIDED SIGNIFICANCE LEVEL OF ALPHA OF.025, ASSUMING EXPONENTIAL SURVIVAL 400 SUBJECTS WILL HAVE TO BE ENROLLED IN THIS TRIAL, 200 ON EACH ARM. GOING TO CHANGE AND TALK ABOUT ADVERSE EVENT REPORTING. THESE TWO BARS WHERE THE ONLY SIGNIFICANT ADVERSE EVENTS WITH THE INJECTION OF THE PHASE 1 TRIAL ALONE SO YOU CAN SEE A SKIN REACTION WHICH INCLUDES A PAIN AND ERYTHEMA, ROUGHLY 6 TO 7% AND THERE WAS A FEVER REPORTED UP TO 20% OF PATIENTS REPORTED A FEVER WITH INJECTION. PHASE 2 TRIAL LOOKING AT THAT TIME'S TWO GROUPS AT PHASE 2 TRIAL, THAT WAS E-10A PLUS CHEMOTHERAPY AND CHEMOTHERAPY ALONE. THERE WERE ROUGHLY A 2% PATIENTS REPORTED A SKIN REACTION. NONE CHEMOTHERAPY ALOPE ARM. YOU LOOK WHAT'S REPORTED AT HIGHER RATE IN CHEMOTHERAPY ARM BUT FEVER AND NAUSEA. MOST WAS GRAY 1 AND GRAY 2, THERE WAS ONE GRAY 3 IN E-10A AND HEMOTHERBY. IF YOU LOOK AT THE -- AND CHEMOTHERAPY. IF YOU LOOK AT BOTH THE ARMS THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN ELEVATED LIVER ENZYMES IN THE TWO ARMS. THERE WAS A QUESTION BY ONE REVIEWER ABOUT LIVER TOXICITY, THE PRE-CLINICAL MODEL, NO TOXICITY, CHRONIC OR ACUTE, THERE WAS NO ABNORMAL HEPATIC FUNCTION AND NO LIVER HISTOLOGY NOTED IN THE PRE-CLINICAL ANIMAL TOXICITY MODELS. I REVIEWED PHASE 1 AND 2 TRIALS NO SIGNIFICANT ADDED TOXICITY BY LIVER E-10A AND IN THE PROPOSED TRIAL WE ARE GOING TO BE MEASURING LIVER FUNCTION AND TOXICITY STRICTLY BOTH IN THE TREATMENT PHASE AND FOLLOW-UP PHASE WE USE STANDARD ADVERSE REPORTING, SO WE FEEL THE LARGER GROUP OF PATIENTS IF THERE'S UNKNOWN TOXICITY THAT WE WILL BE ABLE TO DETECT IT. I ALSO WANT TO MENTION VECTOR SPREADING LOCAL LEVEL AND BLOOD LEVEL. WE LOOK AT THE TWO AREAS THAT WE LOOKED AT INJECTION SITE AND PHARYNX ITSELF, WE LOOK AT PCR TECHNIQUES, THERE WAS NO RESIDUAL VIRUS DETECTED IN THE INJECTION SITE BY USING SUAVE FOUR DAYS AFTER INJECTION THOUGH IT WAS DETECTED UP TO THREE DAYS AFTER INJECTION. IN THE PHARYNX NO DETECTION AFTER THREE DAYS. PLAID LEVELS WITH ANY VECTOR MEASURE, THERE WAS ABSORPTION IN THE BLOOD 4 TO 8 HOURS AFTER INTRATUMORAL INJECTION AND ABSORPTION AMOUNT WAS NOT RELATED TO THE DOSE. NO E 10A DETECTED IN 7 DAYS IN ALL SUBJECTS. THIS IS A MOUSE MODEL, THE MELANOMA MOUSE MODEL WHERE THE MICE WERE ALLOWED TO DEVELOP A TUMOR, THEN THE ADENOVIRUS AND ENDOSTATIN WAS INJECTED TO TUMOR AND COPY NUMBER IS TIMES TEN TO THE FOURTH WAS DETECTED WITH MEASURED ON THIS ACCESS, YOU CAN SEE AS EXPECTED YOU SEE A HIGH LEVEL OF ADENOVIRUS IN THE TUMOR ITSELF. THIS WAS NO DETECTABLE ADENOVIRUS AFTERWARDS. IT WAS DETECTABLE LEVELS IN THE BLOOD, IT DIDN'T SHOOT UP UNTIL LATER DAY 3, LOOK AT THE ORGANS THOUGH THERE'S LOW LEVEL DETECTION OF ADENOVIRUS IN ALL ORGANS THERE'S NO DETECTABLE LEVEL AFTER 11 DAYS. WE ALSO REVIEWED THE CLINICAL TRIALS THAT ACTUALLY HAD PUBLISHED DATA INTRATUMORAL INJECTIONS, THERE ARE ONLY 9 WHO HAVE PUBLISHED DATA, USING NON-REPLICATING ADD 5 VIRUS. THEY REPORTED 837 PATIENTS, THEY HAD SIX VECTORS AND NO PROMOTER AND NO TOXICITY RELATED TO ADD 5, THE ONLY ONE REPORTED WAS LOCAL INJECTION TOXICITY. BASED ON REVIEW OF THESE OTHER TRIALS USING NON-REPLICATING ADENOVIRUSES IN THE PROFILES WE OBSERVED IN THE TRIALS WE PRESENT THERE ARE NO SIGNIFICANT SAFETY ISSUES WITH THE INTERTUMORAL INJECTIONS OF E-10A. NEXT I'LL TALK THE BIOLOGIC ACTIVITY OF E-10A IN THE PHASE 2 TRIALS SIX CASES WERE LOOKED AT WERE THE TUMOR BIOPSIES BEFORE AND AFTER INJECTION OF E-10A AND ONE PROTEIN THAT WAS MEASURED WAS ENDOSTATIN EXPRESSION BEFORE TREATMENT, THIS IS A HISTOLOGICAL SECTION OF TUMOR. THERE'S NO ENDOSTATIN EXPRESSION USING IMMUNOHISTOCHEMISTRY TECHNIQUE. AFTER TREATMENT, THERE ARE BROWN AREAS, A LOT OF EXPRESSION CYTOSOLICLY AND EXTRA CELLULAR DOMAIN. THIS IS ANOTHER EXPERIMENT LOOKING AT CD34 EXPRESSION WHICH IS EXPRESSED IN THE ENDOTHELIAL CELLS AND OBSERVING MICROVESSEL DENSITY. IF YOU LOOK AT THE BEFORE AND AFTER, THE NUMBER OF BLOOD VESSELS IS LOWER, AFTER INJECTION BECAUSE OF THE ENDOSTAT IS INHIBITING BLOOD VESSEL FORMATION. THIS IS SHOWN BY LOOKING AT THE MICROVESSEL DENSITY, ROUGHLY 25 DOWN TO BELOW 20. ANOTHER MEASUREMENT IS WE CAN LOOK AT SERUM. THE REASON SERUM IS NICE THE LOOK AT BECAUSE IT'S SURROGATE END MARKER, NOT ALL PATIENTS CAN UNDERGO BIOPSY BEFORE AND AFTER TREATMENT, SO IF YOU LOOK AT THE ENDOSTATIN EXPRESSION IN THE SERUM BY ELISA, INVESTIGATORS DID IT AND BEFORE AND AFTER THE FIRST CYCLE AND BEFORE AND AFTER THE SECOND CYCLE, GET 20 PATIENTS. OBSERVATION IS IT INCREASED 20 HOURS POST TRANSFECTION -- INCREASED 8 TO 12 HOST POST INJECTION, PEAKED AT THREE TO FIVE DAYS POST INJECTION AND FOR MOST OF THE PATIENTS AT A TIME RETURNED TO BASELINE AFTER 14 DAYS. SOME PATIENTS REMAIN ELEVATED UP TO 28 DAYS, SIX PATIENTS ENDOSTATIN LEVEL REMAINED ELEVATED UP TO 28 DAYS. THIS SHOW IT IS ENDOSTATIN SERUM LEVELS OF 20 PATIENTS BEFORE AND AFTER TREATMENT. SO ENDOSTATIN LEVELS INCREASE. SO THIS IS THE SERUM ENDOSTATIN LEVEL IS SURROGATE BIOMARKER TO DETERMINE HOW MUCH EXPRESSION THERE WAS. BUT ALSO THERE WAS A QUESTION OUT THERE, IS SERUM ENDOSTATIN, COULD THAT HAVE A SYSTEMIC BENEFIT, THAT'S SOMETHING WE JUST DONE KNOW. I WANT TO THANK THE COMMITTEE FOR HEARING OUR PRESENTATION. I WANT TO THANK DR. KOCH FOR THEIR DE-- AND DR. STROME. THERE WAS CLARIFICATION IN THE APPLICATION AND CONCEPT THAT WE'RE GOING TO ADDRESS, I WILL LEAVE IT OPEN FOR DISCUSSION AND QUESTIONS. >> DR. KOCH. >> THANK YOU. THANKS FOR THE PRESENTATION, OVERALL WAS A WELL WRITTEN STRAIGHT FORWARD PROTOCOL. I WOULD GO OVER MY COMMENT AND HOW YOU ADDRESS THEM IN A LOT OF HER PRESENTATION TARGETED TOWARDS THINGS THAT WERE SAID SO MY FIRST CONCERN WAS THAT THERE WAS SOME CONFUSION AND INCONSISTENCIES THE NUMBER OF CYCLES AND YOU # AN ERROR AND YOU CORRECTED THAT AND THAT WOULD BE SIX CYCLES OF FOR A TOTAL OF 12 INJECTIONS. I ASKED FOR THE DATA ON -- IF YOU'RE GIVING 12 INJECTIONS, DOES THE EXPRESSION STAY CONSISTENT OR IS THERE TOLERANCE OVER TIME AND YOU PRESENTED THAT DATA IN YOUR SLIDES AND ANSWERED THAT IN DETAIL, BOTH PRIMARILY IN THE CLINICAL DATA WHERE MULTIPLE INJECTIONS HAVE BEEN GIVEN. I BROUGHT OUT THE LIVER TOXICITY SINCE I WOULD HAVE ASSUMED THAT'S WHERE THE ADENOVOICE WOULD GO. PRESENTED THE DATA QUITE NICELY AND YOU'RE OBVIOUSLY GOING TO DO LIVER FUNCTION TESTS, ET CETERA. I BROUGHT UP EXCLUSION RYE TIERIA FROM A CARDIOVASCULAR STAND POINT, THE IF THERE'S UNDERLYING CARDIOVASCULAR DISEASE YOU OBVIOUSLY DON'T WANT TO SHUT DOWN ANGIOGENESIS GOING ON IN THE HEART, YOU'RE GOING TO INCLUDE NOW ANGINA, MAYBE UNSTABLE ANGINA, NOT JUST PAST MI. I ASKED SPECIFICS HOW THE VIRUS IS STORED. AND YOU ANSWERED THAT QUITE NICELY. THAT'S ALL I HAD. >> ANY REMAINING ISSUES? >> NO, I DON'T HAVE ANY REMAINING ISSUES. >> THANK YOU. DR. STROME. >> A LITTLE LARYNGITIS, I APOLOGIZE FOR THAT. THANK YOU FOR THE PRESENTATION, IT WAS VERY WELL DONE. I DO HAVE SOME CONSIDERATIONS THAT WEREN'T ANSWERED. I THINK IT BEST TO GO THROUGH SOME OF THESE. FIRST WAS RADIATION CHEMOTHERAPY, YOU DID ADDRESS THAT TO A CERTAIN EXTENT THOUGH REIRRADIATION, I DIDN'T GET THAT WHEN I READ THE ORIGINAL PROTOCOL REAR RADIATION, EXCLUSION. BUT LATER ON YOU SUGGESTED SOME OF THE SITES THAT YOU HAVE MIGHT NOT HAVE INTENSITY MODULATED THERAPY FOR THOSE UNAWARE AND I CONSIDER THAT THE STANDARD OF CARE. WHY WOULD YOU HAVE A SITE INVOLVED IN THE TRIAL? THAT WASN'T OF THE STANDARD OF CARE? >> IT GETS RADIATION GOING TO BE STUDIED IN THIS TRIAL SO WHETHER IT HAS IMRT AVAILABLE -- >> THAT'S WHERE THE DIFFERENCE COMES. THERE IS SOME INCREDIBLE DATA THAT'S OUT NOW, THAT SUGGESTS THAT IT RELATES TO PATIENT INCLUSION AND EXCLUSION. IF YOU DON'T HAVE THE LATEST IN YOUR ABILITY TO TREAT THE PATIENT, AND GET RESULTS THAT ARE POTENTIALLY POSSIBLE TO GET, YOU LOOK AT ALL THE DATA, YOU MIGHT SAY THIS PATIENT IS A CANDIDATE FOR THIS THERAPY. WHERE IF YOU HAVE THE LATE eIN THANT TO MANAGE THE PATIENT -- ABILITY TO MANAGE THE PATIENT A DIFFERENT WAY, THAT PATIENT WILL HAVE THE OPPORTUNITY TO BENEFIT FROM THAT. AND THE REASON THAT I SAY THAT IS THERE'S A COUPLE OF THINGS THAT THAT I THINK ARE IMPORTANT. THE NEW GUIDELINES FOR RADIATION OF HEAD AND NECK CANCER PUBLISHED IN INTERNATIONAL JURY ROOM OF READIATION ONCOLOGY AND PHYSICS, IT WAS A CONSENSUS HOW PATIENTS SHOULD BE MANAGED. WHAT IT SAYS IS TREATMENT IS JUSTIFIED BECAUSE CLINICAL TRIALS HAVE SHOWN LOCAL TREATMENT IMPROVES OVERALL SURVIVAL. IT IS THE ONLY LOCAL TREATMENT OBVIOUS POTENTIALLY CURATIVE PET CP AND OTHER THINGS SCREENING. BUT FOR THE MOST PART AS I WENT THROUGH A LITTLE BIT OF THIS DATA, I WOULD SEE DISTINCTION TO WHAT HE SAID, ONLY A SELECT FEW PATIENTS ARE CANDIDATES FOR THIS TREATMENT, THE VAST MAJORITY. IF YOU DON'T HAVE THE ABILITY TO TREAT THAT WAY, THEN THE PATIENT SUSPECT GOING TO BE ABLE TO GET THE TREATMENT AND WON'T BE OFFERED THE TREATMENT. LET ME RUN THROUGH A FEW SAMPLES WITH YOU. HEAD AND NECK ONCOLOGY, 2012. WE'RE NOT TALKING HUTTICAL DATA. ADMITTEDLY THE NUMBER OF CASES IS SMALL BUT USE ONLY IMRT FOR RECURRENT HEAD AND NEBRASKA CANCERS THAT HAD PRIOR RADIATION THERAPY. THE MEDIAN OVERALL SURVIVAL WAS 35 MONTHS, THE RELAPSE-FREE SURVIVAL WAS 45 MONTHS AND 80% OF THOSE PATIENTS HAD NO EVIDENCE OF THE DISEASE IF WITH WE GO BACK AND LOOK WHERE IT STARTED THE CLASSIC PAPER IN MY MIND WAS FROM THE UNIVERSITY OF CHICAGO AND THAT WAS PUBLISHED IN '06. THE SAME (INAUDIBLE) DATA AND 115 PATIENTS WERE INVOLVED IN THAT TRIAL AND THE THREE YEAR SURVIVAL RATE USING STANDARD RAID CONGRATULATION THERAPY WAS 22%. WE'RE TALKING ABOUT SURVIVAL. I DIDN'T PARTICULARLY CARE FOR THAT TRIAL AT THE TIME BECAUSE I THOUGHT THAT THE MORBIDITY WAS TOO HIGH. THE THINGS HAVE IMPROVED IN THE LAST SEVEN YEARS. UNIVERSITY OF MICHIGAN, 54% HAD DAILY TREATMENTS, THERE ARE DIFFERENT TREATMENT PROTOCOLS AND 40% TWICE A DAY, RADIATION THERAPY A LOT IMRP RESULTS TWO YEAR OVERALL SURVIVAL 40%. FIVE YEAR, FIVE YOUR SURVIVAL. 22%. SO WHAT I'M TALKING ABOUT IS SITES THAT YOU PICK HAVE TO HAVE LATE TECHNOLOGY AVAILABLE SO PATIENTS CAN GET THE BEST CARE. WE'RE NOT TALKING ABOUT SMALL OBSCURE PLACES. OVERALL SURVIVAL ONE YEAR PUBLISHED IN 2009, 103 PATIENTS, ONE YEAR, OVERALL SURVIVAL, 64% TWO YEAR OVERALL SURVIVAL, 40%. LAST ONE THAT I'M QUOTE IS ONE THAT HAS REAL SIGNIFICANCE RELATIVE TO THE QUESTION OF SELECTIVITY AND THAT THIS IS SORT OF JUST A SMALL SELECT GROUP, THAT WOULD BE RESPONSIVE TO THIS. THE DATA, 35 PATIENTS WHAT'S INTERESTING HERE IS THEY TOOK ALL COMERS BUT THE ALL COMERS WITH WERE PATIENTS THAT THEY HAD SPECIFICALLY TREATED SO THEY KNEW THE PATIENTS FROM BEFORE, 35 PATIENTS, THEY TREATED THEM, GAVE THEM THE HIGHEST DOSE RADIATION THERAPY BECAUSE THEY'RE AGGRESSIVE IN TERMS OF RADIATION THERAPY AND FIBER. AND THEY LOOK AT THOSE THAT FAIL. THE ONLY INCLUSION CRITERIA WAS ONE AT IF THE FARBER, AND TWO, THAT THEY HAD RECURRENT LOCALLY RECURRENT DISEASE. IF YOU LOOK AT THAT DATA, THEIR TWO YEAR SURVIVAL IS 40% SO WE'RE BEGINNING TO GET A PATTERN HERE. AND THEIR ONE YEAR SURVIVAL, THIS IS OVERALL SURVIVAL, NO JUST RELAPSE FREE, THIS IS OVERALL SURVIVAL. 64% AND TWO YEARS SURVIVAL IS 40%. WHAT'S MOST SIGNIFICANT FOR ME, FOR THE MOST PART I'M CHEMOTHERAPY ANALYST, WHAT'S MOST SIGNIFICANT IS IF YOU LOOK AT THE PATIENTS ONE HUGE COMPLICATION REIRRADIATION OR THE FIRST IRRADIATION CHEMOTHERAPY TRIALS IS THE INABILITY TO SWALLOW. AT ONE YEAR, 78% WERE ABLE TO SEXUAL L LOW WITHOUT ANY EXTERM MEANS. THEY DIDN'T NEED PEGS. AND OF THOSE SURVIVING TWO YEARS, 89% WERE TUBE FREE SO WHAT'S HAPPENING WITH IMRP IS WHERE YOU SEE DECREASE COMPLICATIONS, INCREASE SURVIVAL. SO AGAIN I'M GO OVER IT. YOU HAVE TO HAVE IN MY OPINION SITES TO GIVE THE MOST SPECIFIC AND UP TO DATE OPPORTUNITY FOR THE PATIENTS TO BE CURED. IF YOU DON'T HAVE THOSE YOU ARE MORE THAN LIKELY NOT TO BE OFFERED THOSE. PATIENT ALSO GO INTO ANOTHER TRIAL. SO WHY COMPARE AN ARM HERE? I THINK YOU WANT TO COMPARE FOR A COUPLE OF REASONS. THERE HAVE BEEN TWO TRIALS BY RTOB, RADIATION THERAPY ONCOLOGY GROUP AND BOTH SUGGESTED REIRRADIATION PLUS CHEMOTHERAPY ARE SUPERIOR TO CHEMOTHERAPY ALONE. A PHASE 3 TRIAL WHERE THEY INTEND TO LOOK AT CHEMOTHERAPY AN RADIATION THERAPY, AND CHEMOTHERAPY ALONE, UNFORTUNATELY DIDN'T HAVE ENOUGH ACCRUAL. SO POTENTIAL IS HERE WITH PICKING THE PROPER SITES, TO MAKE A DIFFERENCE UNDERSTANDING WHAT THE DIFFERENCES ARE BETWEEN WHAT YOUR TRIAL WOULD BE AND WHAT THE STANDARD OF CARE WOULD BE, WHICH I BELIEVE IS CHEMORADIATION THERAPY. FOR THE VAST MAJORITY OF PATIENTS. SO I THINK THAT WHAT ABSOLUTELY HAS TO HAPPEN HERE, AS I SAID, YOU NEED TRIALS TO BE CARRIED OUT, BEST INSTITUTIONS WHERE THEY CAN GET THE BEST TREATMENT. THAT'S OFFERED FOR THOSE SMALL GROUP OF PATIENTS, THEN THOSE ARE THE ONLY ONES WILL BE CONSIDERED TO YOUR TRIAL. I'M REALLY WORRIED HOW THIS IS PRESENTED TO THE PATIENT. RELATIVE TO HOW TO PROCEED. THE OTHER CONSIDERATIONS WERE WE TALKED A LITTLE ABOUT SURVIVAL DATA AND YOU SAID YOU FELT OVERALL SURVIVAL DATA WAS ENCOURAGING BECAUSE IT WAS 18 MONTHS AND PATIENT POPULATION THAT'S BETTER THAN HISTORICAL DATA AND I THINK I'M CONCERNED THIS IS A PALLIATIVE EFFORT. WHEN YOU ADDRESS IT TO WHERE WE HAVE THE ABILITY TO GO I THINK YOU NEED TOwo#I BETWEEN BOTH IF YOU POSSIBLY CAN. SO THAT TALKS ABOUT THAT AREA. ONLY ONE CHEMOTHERAPY REGIMEN WAS USED IN PHASE 1 AND PHASE 2 TRIALS. YOU ONLY HAVE ANIMAL DATA, FORSIS PLATINUM. THAT'S WHERE ANIMAL DATA IS. YOU DON'T HAVE ANIMAL DATA FOR THE OTHERS. THE PROBLEM IS YOU HAVE A HOMOJEEPIOUS POPULATION AND THEY WERE RELATIVELY YOUNG. AND MY FRIEND IN CHINA, THERE'S LITTLE DRINKING IN HYPERBUT HEAD AND NECK DISEASE IN THE UNITED STATES IS A COMBINATION OF ALCOHOL AND SMOKING. AND ALCOHOL IN A GOOD PERCENTAGE OF THE PATIENTS LEADS TO LIVER DISEASE. SO WHAT YOU'RE DOING IS LOOKING AT A DIFFERENT PATIENT FACE, YOU'RE LOOKING AT PATIENTS WITH POTENTIALLY UNDERLYING LIVER DISEASE NOW THAT YOU DON'T HAVE DATA FOR AND YOU'RE GOING TO BE TREATING THEM WITHOUT A PRICE. SOME OF THESE OTHER DRUG -- WITH OTHER DRUGS. SOME OF THESE HAVE MORE LIVER TOXICITY. THE PROBLEM IS THAT WITH MORE LIVER TOXICITY AND ENDOSTATIN THEN YOU RUN THE RISKS THAT I MENTIONED WHICH ARE POTENTIALLY MORE LIVER DAMAGE AND OTHER CONSIDERATION THAT I HAD. AND I'M NOT ON THAT POINT YET. BUT WE WILL GET TO IT WHEN WE GET TO THE LIVER. SO THIS STUDY WILL BE LOOKING AT WHAT STAGE OF UNTREATED HEAD AND NECK -- WHAT I MEANT TO SAY WAS UNTREATED UNRESECTABLE SQUAMOUS CELL CANCER, SORRY ABOUT THAT. SEASON AMEN TO BELIEVE STANDARD THERAPY, THAT'S REIRRADIATION. PLUS CHEMOTHERAPY IN THESE PATIENTS TESTIMONY INCLUSION OF THOSE USING STANDARD THERAPY THAT COULD BE IN FAVOR OF PALLIATIVE CARE THOSE QUESTIONS RELATIVELY UP FRONT TO PROPERLY EXECUTED INFORMED CONCEPT, IF THE PATIENT DID SUCH I WOULD BE CONCERNED ABOUT RELIABILITY RELATIVE TO STUDY COMPLETION. SO STUDY LOOKS AT PATIENTS WITH STAGE 4B RECURRENT AND 4C CANCER, YOU SAY THE STANDARD THERAPY FOR THESE ACCORDING TO GUIDELINES IS CHEMOTHERAPY BUT AGAIN, I THINK I PRESENTED DATA THAT MAY STILL BE THE CASE. ADVANCED VERSUS NON-RESECONDABLE I USE INTERCHANGE BY ARE BIG DIFFERENCES. THIS AGAIN RELATES TO INCLUSION CRITERIA. YOU MAY DISAGREE WITH ME AN OLIGOONCOLOGIST BUT I DON'T THINK IN RECURRENT DISEASE 180-DEGREE ENCASEMENT OF CAROTID ARTERY MAKES A DISEASE UNRESECTED. ESPECIALLY IF THERE ARE DIFFERENT FORMS POST-OPERATIVE TREATMENT. SO INCLUSION CRITERIA FOR SURGERY, COMES DOWN TO ONE'S EXPERIENCE AND IT TENDS TON GREATER AT THE SITES THAT HAVE THE MOST EXPERIENCE AN OFTEN HAND IN HAND THE BEST VIDEO THERAPIST AND BEST ONCOLOGISTS. SO THE ONLY NON-TREATED GROUP I WOULD CONSIDER APPROPRIATE, STAGE #C IN THE TWO ARMS DESCRIBED. EVEN THEN YOU HAVE TO BE INCREDIBLY DILIGENT. I JUST SAW A PATIENT THREE YEARS OUT. I'LL SHARE T WITH YOU. HE PRESENTED WITH A LARGE TUMOR WHICH IS A T-3 THANK YOU SOMEWHERE BETWEEN 4 AND 6-CENTIMETERS AND HAD INITIALLY ONE TREATMENTED HE HAD BILATERAL ADENOPATHY AND ROUTINE CHEST FILM, WE'LL GET TO THAT, WAS NEGATIVE BUT WHEN HE WAS ADMITTED FOR WORKUP HE WAS FOUND TO HAVE A LESION IN HIS LUNG. ALL THAT UP ON PET SCAN. LOOK ON THE SURFACE, INITIATED THAT PATIENT IS GOING TO BE GIVEN POTENTIALLY AT THAT TIME (INAUDIBLE). IT TURNS OUT HE HAD A SINGLE ISOLATED SITE IN THE PERIPHERY, AND THAT WAS A DIFFERENT LESION. IN OTHER WORDS ADENOCARCINOMA VERSUS SQUAMOUS CELL CARCINOMA OF HEAD AND NECK. IF YOU AREN'T DILIGENT IN FOLLOWING THAT, THAT PATIENT COULD HAVE EASILY SLIPPED INTO THIS THERAPEUTIC TRIAL. HA THAT MAY NOT HAVE HAPPENED BUT IT COULD HAVE HAPPENED. IT AGAIN RELATES TO PATIENTS, HOW WORK UP IS GOING TO PROGRESS, WHERE IT HAPPEN, IS METASTATIC DISEASE THE ALONE AN INDICATION I SAID HERE MOSTLY MOST INSTANCES WOULD BE BUT THE MOST PART IT WOULD BE BUT THEN AGAIN SOME SAY ISOLATED METASTASIS IS A LOT DIFFERENT CAN RESPOND TO LOCAL RESECTION PARTICULARLY THE ONE IN THE LUNG AND THEN TO STANDARD OF CARE, PARTICULARLY THAT STANDARD OF CARE HAPPENS TO BE INVOLVED IN PATIENTS (INAUDIBLE) POSITIVE. SO I AGAIN, NUMBER 6 RECURRENT CANCER CONSIDER TRYING THOSE PATIENTS WHO FAIL CHEMO AN SURGERY OR COPY NATION THEREOF AND SECOND COURSE OF CHEMORADIATION AS THE NEXT BEST OPTION. THEN I SAID IT'S IMPORTANT THE KNOW LOCATIONS IN PRIMARY TUMORS IN THE REPORTED CHINA STUDY. AND THEY'RE EVENLY DISTRIBUTED BETWEEN ARMS. THEY'RE SIGNATURE CAP DIFFERENCES IN RESPONSIVITY TO CHEMOTHERAPY THAT RELATE TO SITE. THIS BECOMES MORE CRITICAL GIVEN MODEST DIFFERENCES IN RESPONSE BETWEEN THE ARMS. NUMBER 8, IS IT NECESSARY, IT IS NECESSARY TO KNOW HBV STATUS OF ALL PATIENTS. THE REASON FOR THATŤAD IS, WHAT YOU DON'T KNOW AND WHAT YOU DIDN'T KNOW IN YOUR DATA IS WHETHER OR NOT THE POSITIVE BENEFITS WHICH ARE WITH WITH HPV POSITIVITY IN (INAUDIBLE) BASICALLY, THESE PATIENTS HAVE A MUCH BETTER RESULT OF TREATMENT. WHAT WE DON'T KNOW IS IN PATIENTS WHO FAIL THAT TREATMENT, WOULD SIMILARLY HAVE BETTER RESULT WITH SUBSEQUENT THERAPY. AND WHAT WE NEED TO KNOW IS EXACTLY THAT. IF YOU'RE DOING THIS TRIAL YOU HAVE THE OPPORTUNITY IF YOU KNOW THE HPV STATUS TO SEE IF THOSE PATIENTS DO IN FACT RESPOND BEAR OR SUPPOSE THE OPPOSITE WOULD BE WORSE BUT I DON'T THINK IT WOULD BE WORSE, THE TREATMENT. AND WHY IS THAT IMPORTANT? BECAUSE WE DOPE HIT HOME RUNS WITH ANY OF THE STUFF THAT WE DO. WE HIT -- WE SIT SINGLES WITH WHAT I DO. AND LET'S JUST SAY FOR EXAMPLE, THAT HPV GROUP YOU ARE TREATING HAD A BETTER RESPONSE THAN THE REST OF THE GROUP YOU WERE TREATING, THAT WOULD BE A SIGNIFICANT CONTRIBUTION. IN MY OPINION, THAT'S WHY HPV STATUS IS IMPORTANT. AND WHY I THINK WHAT YOU QUOTED HERE WITH EXCEPTION OF CANCERS OF UNKNOWN PRIMARY T PANEL BELIEVES HPV STATUS SHOULDN'T BE ROUTINE CONSIDERATION TREATMENT SELECTION AT THIS TIME. I KNOW OF KNOW -- I CAN STATE -- I CAN GO THROUGH ALL THE MEETINGS, NO SUBSTANTIVE HEAD AND NECK PROGRAM DOESN'T TODAY ROUTINE HPV TESTING ON ALL THESE PATIENTS, BECAUSE WE'RE GOING IS DOE DEESCALATION FOR THOSE PATIENT BECAUSE THEY'RE SO SENSITIVE TO WHETHER WE DO IN TREATMENT TODAY. SO I THINK ALL THE PATIENTS NEED TO BE TREATED. YOU HAVE YOUR DATA IN CHINA BUT IT'S SUSPECT BECAUSE YOU DIDN'T HAVE HPV TREATMENT. YOU SAY WELL, IT PROBABLY DOESN'T MATTER BECAUSE WE ONLY TREATED PATIENTS THAT WERE ADVANCED BUT I POINTED OUT AS TO WHY IT COULD HAVE MEANING AND COULD HAVE MAJOR MEANING AND THAT MAJOR MEANING WAS POSITIVE, WHAT HAPPENS IS YOU HAVE UNKNOWN PATIENTS HPV POSITIVE THEY MIGHT HAVE HAD A BETTER RESPONSE THAN YOU WOULD HAVE SKEWED DATA. PRIMARY SITE EPISTAGE RANDOMIZATION, YOU DIDN'T THINK THAT WAS IMPORTANT. THE GUIDELINES THAT I SUGGESTED FIRST OFF RESTAGING WAS ESSENTIAL FOR TUMORS THAT FAIL AND I THINK IT'S ALWAYS VALUABLE TO LOOK AT PRIMARY STAGE AND RESTAGE BECAUSE I THINK IT CAN POTENTIALLY GIVE YOU SOME SUGGESTION AS TO WHAT YOU MIGHT EXPECT IN TERMS OF RESPONSE TO THERAPY YOU'RE GOING TO GET. IF YOU HAD A MUCH MORE ADVANCED STAGE THAN WHAT YOU HAD INITIALLY THAT'S A PROBLEM IT MAY PORTEND A RESPONSE. WHEREAS IF YOU HAD RECURRENT DISEASE, BUT IT WAS RELATIVELY LIMITED, THAT MIGHT SUGGEST BETTER RESPONSE. YOU CAN TEASE THESE OUT WHEN YOU LOOK. WHEN YOU HAVE THAT DATA AVAILABLE TO YOU. I THINK THAT'S BEST TO GIVE FAN JEER KAREN, WE WENT OVER THAT, A VASTIN, I BROUGHT THAT UP ONLY IN THAT -- THE MECHANISM DECREASING BLOOD SUPPLY TO TUMORS IS THE SAME. WHETHER BETTER FOR METASTATIC DISEASE BECAUSE P YOU TREAT RECOUP CANCER THAT DON'T HAVE METASTATIC DISEASE AND WHETHER USING AVASTIN CAN BE A BETTER CHOICE, I DON'T KNOW. AND I AGREE IT MAY NOT HAVE A PLACE IN THIS TRIAL BUT I CERTAINLY THINK IT HAS A PLACE IN INFORMED CONSENT. MAJOR INFORMED CONSENT. YOU MENTIONED ONE ANIMAL IN YOUR TRIAL, WE WHEN OVER THAT. SOME SENSITIZATION OF TUMOR CELLS, STATED (INAUDIBLE) FOR THAT. SO I THINK WE'RE PROGRESSING. I'M SORRY TO BELY BOAR THIS BUT THESE POINTS ARE SIGNIFICANT. THEN WE COME TO THE LIVER. I SAID I WOULDN'T GIVE)/P ABDOMINAL CT IF OSTEOBLAST WAS HE WILL VAILED YOUR BOND IS FOR CLINICAL PRACTICES GENERALLY DO BUT STRINGENCY IN THE TRIALS IS BEING DONE IN ORDER TO RULE OUT ANY RARE HEPATOCYTE THAT STRUCK ME RELATIVE HI ODD BECAUSE YOU'RE ONLY USING ROUTINE CHEST FILMS. TO LOOK FOR METASTATIC DISEASE. YOUR COMMENT WAS THAT (INAUDIBLE) RECOMMENDATIONS FROM NCCN GUIDELINES JUST IMAGING INCLUDING CHEST X-RAY CT IS CONSIDERED APPROPRIATE. BUT AT THE LAST MEETING WITHIN THE LAST SIX MONTHS OF THE PULMONOLOGY GROUP FOLLOWING PATIENTS WITH HEAD AND NECK CANCER, OR WITH FOR METASTASIS OR PRIMARY LUNG CANCER IN SMOKERS THAT HAVE BEEN SMOKERS FOR A LONG TIME, THEY CATEGORICALLY RECOMMEND LOWER EXPOSURE CT. ALL THE REST OF THE TRIALS COME OUT IN THE LAST TWO YEARS SAID NO BENEFIT TO CHEST X-RAYS AND THAT CT IS THE WAY TO GO, YOU'RE GOING TO PICK UP THAT STUFF. CT HAS TO USE -- I JUST DON'T SEE WHY YOU WOULDN'T DO THAT PARTICULARLY IF YOU'RE USING A CT TO LOOK FOR RELATIVELY LOW IMPACT DISEASE IN THE LIVER. IT JUST -- IT JUST DOESN'T COMPUTE. I WOULD SUGGEST CONSIDERING A RATIO IN ADDITION TO DETERMINING THE IS THE AT THIS. PATIENT SHOULD BE CAPABLE REPORTING DAILY WEIGHTS. THIS WAS STUFF THAT YOU HAD MENTIONED AND YOU APPRECIATED THAT COMMENT. THEN ONE OF THE THINGS THAT YOU SAID, AND CORRECT ME IF I'M WRONG, IF YOU FELT THAT SOME ADVERSE EVENTS WAS NOT RELATED TO ENDOSTATIN BUT MORE RELATED TO CHEMOTHERAPY REGIMEN, THAT SYSTEM OF THOSE MIGHT NOT BE REPORTED. THAT'S WHY I RAISE THE CONSIDERATION THAT I BELIEVE CANCER ELEVATION REQUIRES HOSPITALIZATION EVEN IF CONSIDERED POTENTIALLY RELATED TO CHEMOTHERAPY WHICH HAD BEEN REPORTED. YOU SAID THAT SITUATION WOULD BE REPORTED. BUT I THINK THIS OTHER IT SHOULD BE REPORTED IF YOU'RE GO TAG ERR ERR OPT SIDE OF THE REPORTING FEE RATHER THAN (INAUDIBLE). INFORMED CONSENT. MUST BE MADE CLEAR THE (INAUDIBLE) ADVERSE EVENTS ADVERSE SIDE EFFECTS TO SECONDARY TREATMENT, CHEMOTHERAPY RAID CRAIG THERAPY OR YOUR TREATMENT (INAUDIBLE). THIS WAS HUGE FOR ME. ABSOLUTELY HUGE. I WANT TO HEAR FROM OUR ONLY MORE EMPHASIS FOR THIS. I QUESTION THE CLINICAL TRIAL THAT HAS POTENTIAL TO BELIEVE BIAS. I FULLY UNDERSTAND THE SUPPLY PRODUCT AND FINANCIAL SUPPORT PERSONNEL, THOSE DOLLARS BE EXPENDED. THE THING IS THIS. IF ONE IS SALARIED SALARY AND THE MONEY GOES TO THE INSTITUTION AND DOESN'T ACCRUE TO THE INDIVIDUAL, THAT MIGHT BE ACCEPTABLE. BUT IF THAT PHYSICIAN IS INVOLVED PATIENT SELECTION DATA ENTRY AND DATA ACCRUAL, I FUNDAMENTALLY BELIEVE THAT THAT'S THE WRONG THING TO DO. I WOULD LIKE TO HEAR FROM THE -- FURTHER EMPHASIS ON THAT. (OFF MIC) >> ISN'T IT ON? THE RED LIGHT IS ON? RESEARCH IS WORK, IT'S IMPORTANT WORK AND PEOPLE SHOULD GET PAID FOR IT. SO HAVING SALARY PAID FOR BY SPONSOR IS STANDARD AN NORMAL. WHAT YOU'RE EXPRESSING CONCERN ABOUT IS CAPITATED PAYMENTS AS INCEPTIVES AND THAT IS GENERALLY SO FIRST SHOULD GET PAIDTOR WHATEVER HIS OR HER WORK IS. SOMETIMES WORK IN UPRIGHT PRACTICE SETTING HAS TO BE CAPITATED BECAUSE YOU RECRUIT TEN PATIENTS IT TAKES TEN TIMES A MUCH TIME AS ONE. SO REIMBURSEMENT TO PRACTITIONERS NOT ON SALARY WHO ARE ON FOE FOR SERVICE AND TAKE TIME OUT FROM THEIR PRACTICE TO RESEARCH, LOOKS LIKE CAPITATION. BUT IN AN ACADEMIC SETTING WHERE SOMEBODY IS ON SALARY, NOTHING IN MY VIEW IS INAPPROPRIATE ABOUT HAVING HIS OR HER SALARY BE PAID, SOME ESTIMATE HOW MUCH TIME HE OR SHE TAKES TO DO THE RESEARCH AND HAVING THAT PAID BY MONTH. >> THE QUESTION IS WHERE DO THE DOLLARS GO? IF THE DOLLARS GO TO THE PHYSICIAN, IF IT GOES TO THE SALARY PHYSICIAN IS SALARY. FROM MY PERSPECTIVE IF YOU'RE A SALARIED PHYSICIAN, I CAN TELL YOU WHEN I RAN A HUGE DEPARTMENT WE TOOK -- I WOULDN'T HAVE IT. I WOULDN'T ALLOW IT. IF THE INSTITUTION HAD SAID WE TAKING TIME FROM PRACTICE, TIME AWAY FROM PRACTICE, AND THE INSTITUTION HAS TO BE COMPENSATED, THAT'S A DIFFERENT ISSUE. BUT IF MONEY ACCRUES TO THE PHYSICIAN, LIKE TAKING MONEY FROM A DRUG COMPANY, IT SHOULDN'T HAPPEN. (OFF MIC) >> THERE ARE SOME ACADEMIC SETTINGS WHERE PHYSICIANS, YOU KNOW, THEY ARE NO MORE MONEY AND THERE'S AN ISSUE WITH THAT. >> MARSHALL. LET'S COME BACK TO THE OUTSTANDING ISSUES THAT YOU HAVE. >> THAT'S AN OUTSTANDING ISSUE. >> YEAH, YEAH, WE'LL COME THROUGH THE WHOLE LIST AND LET'S ARTICULATE WHAT IT IS THAT'S TROUBLING YOU ON THAT FRONT. LET'S START WITH IT -- THE FIRST ISSUE YOU HAD WHICH THE IMRT, STANDARD TREATMENT FOR RECURRENT HEAD AND P NECK CANCER. >> I THINK I HAVE TO AGREE WITH THE NCCN GUIDELINES REAL." RADIATION IS REFLECTIVE AND ALSO FOR A SELECT GROUP OF PATIENTS. I COME FROM A PRESTIGIOUS HEAD AND NECK CANCER AREA. WE HAVE IMRT. AND WE DO RADIATION. BUT IT HAS TO BE HIGHLY SELECT GROUP OF PATIENTS. IF A PATIENT RECURS THREE OR FOUR MONTHS AFTER THEIR RADIATION, IT DOESN'T MAKE SENSE TO DO IT AGAIN, MOST PATIENTS ARE GOING TO HAVE PERSISTENT TOXICITIES WITHIN A YEAR AFTER THEY GET THEIR RADIATION. SO IT DOESN'T MAKE SENSE TO USE SOMETHING THAT FAIL SOD RECENT RECENTLY. AND WE AGREE MORE WITH THE NCCN GUIDELINES, WE HAVE IMRT. WE DON'T BELIEVE IT IS STANDARD TO USE REIRRADIATION IN ALL PATIENTS. IN A SELECT GROUP IT MAKES SENSE TO USE THE THERAPY. I THINK DR. STROME MENTIONED THEY DID TRY TO DO A PHASE 3 TRIAL AND COULDN'T DO IT BECAUSE OF ACCRUAL PROBLEMS BECAUSE THERE'S BIAS OUT THERE YOU WILL NEVER GET ANYONE TO AGREE. THE TRIALS OUR SINGLE INSTITUTION TRIAL, REALLITY BASIS TO DRIVE A PHASE 3 TRIAL TO ANSWER THE QUESTION. BUT IT CAN'T BE ANSWERED. >> MARSHALL CLARIFY SOMETHING FOR ME. FIRST LINE RADIATION IS IMRT. AND INSTITUTIONS THAT HAVE IMRT. SO IF THEY RECUR AFTER RECENT IMRT ARE THEY GIVEN NEW IMRT? >> THAT'S WHAT HAPPENEDDED (INAUDIBLE). >> SPEAK INTO THE MICROPHONE. >> THAT IS WHAT THE FARBER TRIAL WAS. THEY FAILED AGGRESSIVE IMRT. THEY GOT MORE IMRT AND IT WAS BENEFIT IF I BELIEVE. >> I GAVE YOU NUMBERS. SO THAT'S BENEFICIAL. THE QUESTION IS THE PATIENT CAN'T UNDERSTAND THIS. WHAT WE KNOW IS THAT IF YOU GO TO A MEDICAL ONCOLOGIST, YOU'RE MORE THAN LIKELY TO GET MEDICAL TREATMENT. IF YOU GO TO A SURGEON YOU MAY JUST GET SURGICAL TREATMENT, RADIATION ONCOLOGIST YOU'RE LOOKLY TO GET RADIATION ONCOLOGY. SO THE KEY IS, THEN I SAID ONE THING WE DIDN'T GET TO WAS IN INFORMED CONSENT IT SHOULD BE STATED REIRRADIATION IS A POSSIBILITY WITH CURE. >> SO LET'S COME DOWN THE WHAT WE CAN AGREE ON BECAUSE OBVIOUSLY IT OAT A DISAGREEMENT IN TERMS OF PRACTICE. MARSHALL, YOU SAID YOU WOULD LIKE INSTITUTIONS OFFERING THIS TO HAVE CAPABILITY OF IMRT AND YOU WOULD LIKE TO HAVE IN THE CONCEPT FORM THAT REIRRADIATION IS AN OPTION FOR AS TREATMENT FOR POTENTIAL CURE. THOSE TWO -- SO LET ME ASK DR. YOO ABOUT THAT F. SOMETHING WAS IN OUTLYING REGIONAL HOSPITAL OUTSIDE DETROIT AND DIDN'T HAVE IMRT AN HAD A LESION THAT WAS CONSIDERING PATIENT WAS CONSIDERED FOR PLACEMENT INTO THIS TRIAL, WOULD THAT PATIENT BE BETTER SERVED BY BEING REFERRED TO YOUR CENTER FOR RERADIATION WITH IMRT? Q. THIS PATIENT FOLLOWING NCCN GUIDELINES AND TUMOR BOARD LICK NEW PATIENTS DO. NOT NEWLY DIAGNOSED NEW PATIENTS P AND THEY WOULD BE CONSIDERED FOR WHAT WAS THE BEST THERAPY. IF IT IS RERADIATION, THEY HAVE THE FAILURE MORE THAN TWO YEARS OUT, THAT IS CONSIDERED AN OPTION AS CHEMOTHERAPY. >> WITHIN THE CON FINES OF THIS TRIAL, IS THERE A MECHANISM WHEREBY THAT PATIENT MIGHT BE REFERRED TO YOU TO AN INSTITUTION THAT HAS IMRT FOR GOOD TREATMENT? I'M ASKING. IS THERE A MECHANISM WITHIN YOUR TRIALS NETWORK TO ALLOW THAT TO HAPPEN? >> I GUESS IF A PATIENT WAS ELIGIBLE FOR PATIENT RECURRED WITHIN -- >> IT -- AND A RELATED CENTER DOING THIS TRIAL BUT NOT AT YOUR CENTER. >> I MEAN OBVIOUSLY THERE'S REFERRAL PATTERNS THAT ARE KIND OF FIXED BUT YES, THEY WOULD -- THEY COULD BE REFERRED TO US FOR IMRT IF THAT WAS INDICATED. >> WITHIN THE TRIAL IS THERE A MECHANISM FOR THIS TO HAPPEN? >> I DON'T THINK WITHIN THE TRIAL ITSELF, I THINK SELECTION PROCESS IS IN PRE-SELECTION, IT'S REALLY AFTER PRESENTING IN TUMOR BOARD AND SELECTING THAT THE PATIENT IS BETTER FOR IMRT, WE IRRADIATION THEN THEY WOULD DO THAT, IF A PATIENT WAS SELECTED BETTER SUITED FOR CHEMOTHERAPY, THEN IT WOULD BE SELECTED WHETHER THEY GET STANDARD CHEMOTHERAPY OR THEY GET ENROLLED ON TO THIS TRIAL. >> BECAUSE I JUST WANT TO DISTILL THIS DOWN TO THINGS THAT WE CAN ACCOMPLISH. >> OKAY. >> WHAT MARSHALL IS WORRIED ABOUT, IF IMRT IS ACTUALLY A GOOD THERAPY FOR PEOPLE WHO HAVE ALREADY BEEN PREVIOUSLY RADIATED, AND A PATIENT IS ACTUALLY 30-MILES TO YOUR CENTER BEING CONSIDERED FOR YOUR YOUR TRIAL THAT PATIENT SHOULD BE TOLD IMRT IS A POSSIBILITY AND THAT SOMEHOW WITHIN THE SYSTEM THE PATIENT WILL BE REFERRED SINCE THEY -- A GOOD THERAPY MAY ONLY BE MILES AWAY FROM WHERE THEY ARE. RATHER THAN -- >> YES AND THE NEWLY THING I'M SAYING IS IT'S NOT IN THE PROTOCOL, IT WILL BE BEFORE THE PROTOCOL. IT WILL BE DONE WITH MULTIDISCIPLINARY APPROACH TO THE PATIENTS. >> ARE ANY SITES CONSIDEREDDED GOING TO BE OUTSIDE THE COUNTRY? BECAUSE IF THERE ARE THEN THE DISCUSSION IS TOTALLY DIFFERENT. THERE ARE MANY PLACES IN THE WORLD HEAD AND NECK CANCER HAPPENS WHERE THERE IS NOT GOOD RADIATION THERAPY. AND NOT EVEN IMRT, GOOD RADIATION THERAPY. IF THAT WERE THE CASE, THE DISCUSSIONS TOTALLY DIFFERENT BECAUSE IN THOSE COUNTRIES, STANDARD OF CARE IS NOT IMRT AND HOW DO YOU RECONCILE THAT WITHIN THE CONFINES OF THE TRIAL? >> TURN OFF -- TURN ON THE MIC. >> OKAY. I'M ANSWER THAT QUESTION WE'RE DOING A TRIAL IN CANADA WITH THE (INAUDIBLE) ARE APPROXIMATELY STATEMENT AS U.S. FOR TREATMENT. WE ARE CONSIDERING GOING TO WESTERN EUROPE AND WOULD CONSIDER STANDARD OF CARE IN WESTERN EUROPE TO ENSURE THE SAME AS U.S. AND CANADA. >> SO NO ASIAN SITES AT PRESENT ON YOUR LIST OF PRAISES. >> NO. >> THEN THE DISCUSSION WOULD BE VERY DIFFERENT. SO THEN HOW SHOULD WE MARSHALL MACK YOU HAPPY IN TERMS OF RECOMMENDATIONS TO THE GROUP TO THE IMRT? WHAT WOULD SATISFY YOU? >> YOU CAN TURN ON YOUR MICROPHONE. >> PATIENTS ALL PATIENTS AT BETY, THE FIRST THING, THINK TO HAVE IT. IF THEY DON'T HAVE IT ONE OF THOSE THINGS MENTIONED IN RESPONSE WAS -- IS THAT ALL SITES DON'T HAVE IMRT. AND THE SITES WOULD DETERMINE THERAPEUTIC REGIMEN. THAT'S IN RESPONSE, AM I CORRECT? THAT'S IN THE RESPONSE. >> WHAT IS IT PATIENTS REFERRED FROM AN OPINION IMRT INSTITUTION, BUZZ H MANY PEOPLE ARE TREATED AT SITES THAT DON'T HAVE IMRT. THEY ARE CARED FOR AND THE REALITY IS THAT THE DECISION VERSUS TO BE MADE AT THOSE SITES AS TO WHERE THE PATIENT -- WHAT WILL HAPPEN TO THE PATIENT NEXT. AN OPINION FROM A RADIATION ONCOLOGIST AT IMRT SITE BE SATISFACTORY TO YOU. >> THAT'S GOOD, I THINK YOU HAVE TO LOOK AT THE REALITIES. THERE CAN BE AIGRETTES HOSPITAL IN A COMMUNITY PEOPLE WON'T GO, FOR EXAMPLE IN CLEVELAND. THEN FIVE MILES IS THE CLEVELANDICALLY INCOME BUT THEY WANT THE STAY IN THE HOSPITAL IN THEIR LITTLE TOWN. THAT IS WHY I SAID, AND THEY LIKE THE DOCTORS LOCALLY AND THEIR INTERNISTS LOCALLY. IF THEY DOPE HAVE IT AND SOMEBODY SAYS WE HAVE THIS BUT WE CAN SEND YOU OA, MOST WILL SAY WE'LL STAY HERE, WHAT DO YOU HAVE TO OFFER ME? TO DENY THAT PATIENT A CHANCE AT A TRIAL THOUGH OF THIS SORT ONE BE RIGHT EITHER. I'M TRYING TO FIGURE OUT >> THAT'S RIGHT. IT WOULDN'T BE BUT THE LIKELIHOOD IS THEY'RE GOING TO HAVE MORE THAN LIKELY THEY'RE GOING TO GET THIS IN THE LOCAL COMMUNITY. THEY MAY NOT TRAVEL, BIG PERCENTAGE WON'T. SO THAT'S WHY I SAY THE TRIAL SHOULD BE RESTRICTED TO SITES WHERE THEY HAVE THE ABILITY TO DO THIS. MY PROBLEM WITH THAT, MARSHALL, HERE THEY ARE, THEY'RE ACCRUING 200 PATIENTS IN EACH ARM. IT'S A BIG TRIAL. THEY'RE ASKING A GOOD QUESTION. THEY HAVE DATA THAT SUPPORTS GOING FORWARD WITH A TRIAL TO ASK THIS QUESTION. AND THEN TO DENY THE PATIENTS WHO WON'T TRAVEL THE CHANCE TO ENTER A TRIAL, DOESN'T SEEM RIGHT EITHER. I'M TRYING TO FIGURE OUT HOW TO DO THIS IN WAY TO GO FORWARD WITH ASKING A GOOD QUESTION AND TAME MAKE SURE PATIENTS UNDERSTAND ADDITIONAL TREATMENT OPTION STANDARD OF CARE, THAT COULD PROVIDE FOR SMALL PERCENTAGE OF PEOPLE, A CURE. IN THIS CLINICAL SITUATION. SO I'M TRYING TO GET TO THAT POINT. LORI. >> IN TERMS OF THE CURE, IT HASN'T HAPPENED YET. SO THE LIKELIHOOD OF THAT BEING CURATIVE -- >> I'M TALKING ABOUT RERADIATION WITH IMRT. >> SMALL PERCENTAGE OF PEOPLE ARE CURED BY THAT RERADIATION. >> I DON'T KNOW, THAT'S PARTICULARLY SMALL, 22% IS A GOOD NUMBER AND THAT'S BEEN FIVE YEAR DATA. SO IT ISN'T LIKE WE'RE TALKING 5%, WE'RE TALKING 22%. >> TRYING TO MAKE SURE PATIENTS UNDERSTAND THAT NUMBER EXISTS FROM DATA. AND SO AGAIN, TRYING TO FIGURE OUT HOW TO GET TO THAT PIPE OF EDUCATING THE PATIENTS, WHILE AT THE SAME TIME, NOT TAKING PEOPLE THAT WON'T TRAVEL OFF TRIAL, NOT ENTERING THE TRIAL AND TRYING TO GET TO A POINT WHERE TRIAL, THIS TRIAL CAN HAPPEN AND AT THE SAME TIME MAKING SURE PATIENTS ARE EDUCATED ADS TO WHAT -- ALL THE ALTERNATIVES BECAUSE THAT'S PART OF THE COB SENTING PROCESS, THAT'S WHAT I'M TRYING TO GET TO, WHAT MAKES YOUP HAPPY THAT THAT COULD BE SATISFIED. SO IS IT SAYING IN THE CONCEPT FORM THERE IS A 20% POSSIBILITY RADIATION I MRT POTENTIALLY PROVIDE FIVE YEAR SURVIVAL? >> YOU KNOW WHAT IT IS TO GET CONSENT. YOU'RE SITTINGENING A HOSPITAL THAT DOESN'T HAVE THE ABILITY TO DO THE LATE eTECHNOLOGY. AND THERE MUST BE SOME IN THE TRIAL BECAUSE IT WAS MENTIONED. THE INTAKE PHYSICIAN IS THERE. THERE IS THE POSSIBILITY YOU CAN GO FOR MORE RAYIATION BUT YOU HAVE ALREADY HAD IT. MORE CHEMOTHERAPY AND YOU EAR SORT OF SICK FROM BOTH OF THEM. WE HAVE A KNEW TRIAL FOR YOU. JUST GREAT. >> LAURIE. >> CAN YOU OF THINGS TROUBLING ABOUT YOU HAVE CONVINCED ARE TROUBLING AND THE NEED TO CONSIDER AS YOU CRAFT WHAT WE'RE GOING TO SAY. SEEMS TO ME GENE TRANSFER TECHNOLOGY IS NOT LOW TECH, NOT FOR PEOPLE IN RURAL AREAS WHO DON'T HAVE ACCESS TO ADVANCE MEDICAL CARE BUT THE LOWER TECH ALTERNATIVE WE OTHER TALKING ABOUT NOW AS IT'S THE CASE, THAT'S COUNT COUNTER INTUITIVE TO ME. IT'S CAUTIOUSLY PROCEEDING BY ALLOWING THESE INTERVENTIONS ON PEOPLE WHO WERE DESPERATE WHO HAD NOTHING TO PROVE, WHOM CONVENTIONAL THERAPY DIDN'T WORK AND HIGHER RISK OF THIS FUNDAMENTALLY UNTESTED THEORETICAL APPROACH WAS WORTH IT BECAUSE THEY HAD NO ALTERNATIVE TO INCONVENTIONAL THERAPY. WHAT YOU POINTED OUT IS THEY DO HAVE ALTERNATIVES SO THE CATCHMENT GROUP HAS TO BE THE PEOPLE WHO STILL QUALIFY. NOT PEOPLE WHO JUST CAN'T DRIVE THAT FAR OR CAN'T GET THERE OR ARE POOR. THEN WE HAVE THIS OTHER THING GOING ON. WE CAN'T USE THEM IN THAT WAY. AS IF USING NAIVE POPULATIONS, IT RAISES FOR ME A FUNDAMENTAL PROBLEM WITH WITH THE STRUCTURE OF WHAT WE SAY WE'RE DOING AS WE'RE ADVANCING SLOWLY ON THE RAC. SO THAT'S ONE. THAT IS MY RESPONSE AND YOU CONVINCE MED DOING IT AT BIG MEDICAL CENTERS WITH PEOPLE WHO HAVE TRULY FAILED EVERY OTHER CHOICE AND TRIED EVERY OTHER CHOICE AND STILL NEED SOMETHING ELSE,'S WHEN THE THERAPY -- AND IF THERE SHOULD BE ENOUGH MEDICAL SENT -- ENOUGH MEDICAL SENORS THAT'S THE CASE BESIDES DANE FAR HERB WHERE THEY CAN DO RECRUITMENT. >> SO THE OTHER THING ABOUT -- >> THEY CAN HAVE IT AT WAYNE STATE. THAT'S THE KIND OF SETTING THAT I THINK WE OUGHT TO BE HAVING FOR THIS TYPE OF A TRIAL. THESE PEOPLE ARE DESPERATE. YOU HAVE TO SEW THEM. >> I THINK YOU PHRASED IT WHEN YOU WERE DESCRIBING THAT INFORMED CONSENT DISCUSSION. THAT WOULD BE A FRAMING DISCUSSION. IF THEY TAKE MONEY FOR IT PER CAPITA WHICH IS AN UNFORTUNATE PUN I THUG MY COLLEAGUES WOULD NOTICE FOR THIS CASE, THESE CASES YOU HAVE TO HAVE THAT ON THE CONCEPT FORM: AT THE LEAST. I'M WITH YOU, I THINK IT'S PROBLEMATIC WHENEVER TREATMENTS -- TREATING PHYSICIANS ARE PAID PER PATIENT IN THIS WAY THOUGH I UNDERSTAND MARKET JUSTIFICATION I THINK OTHER JUSTIFICATIONS NON-MARKET ONES THAT ARE MORE COMPELLING TO ME. IT NEEDS TO BE THERE IN THE CONSENT FORM YOU'RE GETTING PAID TO RECRUIT. (OFF MIC) >> MARSHALL, IF YOU WILL TURN ON YOUR MIC. >> IFFY SESSION INVOLVED IT WOULD BE INTAKE. IT WAS THERE TO OVERSEE THE PROJECT. PER P HAPPENS THEN FOR ME, I LOOK THINGS DOES IT PASS A SMELL TEST OR NOT, IT DOESN'T PASS MY SMELL TEST IFFY SESSION IS PAID WHEN IT DOCUMENTS TO INTAKE AND INTERPRETING DATA. IT MAYBE DONE BUT IT'S FUNDAMENTALLY WRONG. IF A PHYSICIAN. I THINK PEOPLE SHOULD GET PAID FOR WORK I THINK WHEN YOU'RE DOING EMPERIMENTAL RESEARCH, AND POTENTIALLY BIAS CAN ENTER INTO IT, I DON'T THINK THEY SHOULD BE ACCEPTING SALARY. WE NEVER DID, I WOULDN'T ALLOW IT -- (OFF MIC) >> NIH PAYS SALARIES FOR SO PEOPLE CAN DO WORK? >> VERY DIFFERENCE THING. THAT IS -- THAT'S DOING BASIC RESEARCH. THAT IS NOT TRANSLATIONAL AT THAT POINT IN TIME. THAT IS DOING FOR THE MOST Ö– PART BAYING IS RESEARCH AT LEAST THE ONES THAT I HAD SALARY SUPPORT AND THEY NEED THAT SALARY SUPPORT BECAUSE THEY ARE DOING CLINICAL WORK FOR SCIENCE, >> SALARIES ARE PAID FOR CLINICAL TRIALS ALSO. >> THE THEY ARE. THE QUESTION IS DO YOU AGREE WITH IT? I DONE. PEOPLE WHO DO THAT FOR NOTHING? SPEND 80 PEST OF THEIR TIME DOING CLINICAL TRIALS FOR NOTHING? >> NO, NOT 80%. (OFF MIC) >> THE PRINCIPLE IF YOU'RE DEALING WITH PATIENT CARE AND YOU DO INTAKE ON DATA ANALYSIS, THERE'S POTENTIAL FOR BIAS. >> I WOULD BE CONCERNED THAT IF A PHYSICIAN IS PAID PER PERSON IN THE TRIAL THEY WOULD AGGRESSIVELY RECRUIT PATIENT Z BECAUSE THE MORE THEY HAVE THE MORE MONEY IN THE POCKET. I WOULD BE CONCERNED ABOUT THAT. I WORK FOR UNIVERSITY, I'M SALARIED. WHEN I WRITE A P GRANT I PUT FROM 5 TO 30% OF MY EFFORTS ON THE GRANT, GRANT STATE GETS MONEY I DEN GET MORE IN MY POCKET BECAUSE I'M WORKING ON THAT RESEARCHOK„ AND BRIGHT STATE NEEDS TO BE COMPENSATED BUT I HAVE THE SAME CONCERNS YOU HAVE ABOUT PHYSICIANS WHO WOULD BE GETTING PAID PER PERSON. I THINK THEY WOULD POTENTIALLY GET AGGRESSIVE AND MAYBE RECRUIT PEOPLE WHO MIGHT BE BETTER OFF WITH ANOTHER TREATMENT OR ANOTHER TRIAL >> IF YOU'RE GETTING PAID TO RECRUIT TO THE TRIAL AND THE EXPECTATION IS TO RECRUIT 5, 10, 30 PATIENTS TO THE TRIAL, AND YOU RECRUIT ZERO TO THAT TRIAL YOU WON'T GET PAID ANY MORE. THE GRANT ISN'T RENEWED. SO PAYMENT HAS TO BE TO YOUR SUCCESS AND RECRUIT REALLY SUCK SETSFULLY. IT'S NOT THEY DON'T COUNT EACH AND SEND A CHECK FOR EACH ONE THOSE PRIVATE PRACTICE IS THE WAY IT WORKS. I DON'T UNDERSTAND WHAT WE'RE TALKING ABOUT HERE, STANDARD FOR PEOPLE TO GET PAID TO DO CLINICAL TRIALS, GETTING PAID DEPENDS RECRUITING SO THAT'S AN INCENTIVE, INVESTIGATORS HAVE INCENTIVE TO TRY TO ENCOURAGE PEOPLE TO JOIN TRIAL? SURE. IF THEY DIDN'T THEY WOULDN'T BE DOING THAT KIND OF WORK. >> MARSHALL TURN OFF WHERE ARE MIC A SECOND. LET ME IS -- IS THE PAYMENT SCHEME IN THIS TRIAL ANY DIFFERENT THAN ANY OTHER TRIAL? Q. NO, NO DIFFERENT. >> LET ME MAKE SURE EVERYONE UNDERSTANDS AROUND THE TABLE. WHETHER IT IS A COOPERATIVE GROUP STUDY, WHETHER RTOG, OR ANY OF THESE TRIALS GROUPS THAT ARE FUND BY THE NIH, PAYMENT IS PER CAPITA. EF TIME YOU ENTER SOMEBODY IN A TRIAL OF APPROXIMATE RTLG OR NSAPV TRIAL, THEY -- THE INSTITUTION IS PAID A FEE FOR THAT PISH AND MANY TIMES THAT GOES TO SALARY SUPPORT AS WELL AS DATA SUPPORT AND GROUP SUPPORT FOR THE GROUP ENROLLING PATIENT IN THE TRIAL. MANY OF -- ALMOST EF PHARMACEUTICAL TRIAL IS DONE THAT WAY SO THERE'S NOTHING DIFFERENT ABOUT WHAT THIS TRIAL IS. SO DOCTOR,WHEN YOU ENTER A PATIENT IN THIS TRIAL THIS IS NOT DOLLARS DIRECTLY TO YOUR POCKET, IT'S GOING TO SALARY SUPPORT. >> YEAH. THAT'S BECAUSE AGAIN IN ORDER FOR PEOPLE TO GO AND SPEND HALF THEIR TIME 80%, WHATEVER PERCENTAGE OF TIME THEY HAVE TO HAVE SALARY SUPPORT TO DO THE WORK. SO THERE IS NOTHING FUNDAMENTALLY DIFFERENT FROM THIS THAN IF YOU WERE ENTERING A PATIENT IN THE RTOG. >> HOOK VERY CLOSELY AT THE EFFORT, IS THERE ENOUGH RESOURCES PROVIDED FOR THE PHARMACEUTICAL ANY COMPANY TO OFFSET THE WORK THAT'S DONE. >> MOST INSTITUTIONS NOW WON'T LET YOU ENROLL -- PARTICIPATE IN THE TRIAL OF ANY SORT UNLESS THIS PER CAP P TA SCHEME IS SET UP IN THE WHOLE BUDGETING PROCESS IS DONE. >> EVERY TRIAL IS DIFFERENT BUT IT'S NOT USUALLY PER CAPITA, IT'S BASED ON PERCENT EFFORT. ESTIMATED ON PERCENT EFFORT UP OR DOWN IT CAN BE READJUSTED BY 80% EFFORT. >> WE'RE IN AGREEMENT ON THAT. IF THE MONEY DOESN'T GO DIRECTLY TO THE INVESTIGATOR, IT GOES TO SUPPORT THE SALARY THAT'S LOST BUT HIS SALARY DOESN'T CHANGE. THAT'S OKAY. >> I THINK THE OPERATIVE WORD IS INCREMENTALLY TO THE INVESTIGATOR. INVESTIGATOR REPLACEMENT FOR OTHER AS LONG AS NOT INCREMENTALLY (INAUDIBLE). >> EXACTLY RIGHT. IF MORE -- IF THE INVESTIGATOR AS WE JUST SAID IS GOING TO GET SALARY ABOVE AND BEYOND HI NORMAL SALARY, THAT'S PROBLEMATIC. >> SO MY QUESTION SO YOU, MARSHALL, IS THERE A REASON YOU BELIEVE THIS TRIAL WOULD BE DIFFERENT THAN ANY OTHER TRIAL BEING PROPOSED WHERE THE SAME REIMBURSEMENT SCHEME IS DONE? >> YEAH. WHEN WE'RE TALKING SMALLER HOSPITALS, THOSE PEOPLE THEY MAY BE -- THEY DON'T GET SALARIED FROM THE HOSPITAL. THEY'RE MAKING THEIR OWN MONEY. IF THEY DEBT MORE MONEY OVER AND ABOVE SALARY TO DO THIS BECAUSE GUYS WORK AND THEY CAN WORK MORE, I THINK IT'S A PROBLEM. >> IN OTHER WORDS, IF A PRIVATE PRACTITIONER WORKING IN ACADEMIC HOSPITAL WHO'S PART AND PARCEL OF THE TRIAL AND IS GETTING MORE MONEY THAN HE WOULD HAVE HAD FROM WHATEVER HIS YEARRY PATIENT CARE SALARY WITHDRAWAL WOULD BE. >> BUT THAT'S NOT -- THAT'S A DISCUSSION ABOUT THE TRIAL REIMBURSEMENT SET UP NATIONALLY MORE THAN ABOUT THIS TRIAL YOU'RE BRINGING UP. Q. IT IS. >> Ö OKAY. >> SO AGAIN, ONE OPTION IS TO JUST PUT ANYTIME THE CONSENT THAT REIMBURSEMENT IS PAID TO THE RECRUITING INSTITUTION FOR SUPPORT. BUT AGAIN, THIS IS NO DIFFERENT THAN ANY OTHER COOPERATIVE GROUP TRIAL WHERE SMALL HOSPITAL PARTICIPATE. AND YOU OPEN NSABB TRIAL AND A SMALL HOSPITAL PARTICIPATES, IT'S EXACTLY THE SAME MECHANISM. THE NIH IS THE ONE PAYING THAT EXTRA FEE. SO I JUST WONDER WHETHER WE SHOULD INDICT THIS TRIAL MORE THAN ANY OTHER TRIAL, WE REVIEW TODAY AND ANY OTHER DAY BECAUSE OF THAT BUT IF YOU THINK WE SHOULD P PUT IN THE CONSENT FORM BE GOOD WITH A CONSIDERING THAT, YEAH. YEAH. BECAUSE IT'S LIKE PAGE CHARGES FOR PUBLICATION. DISCLAIMER THAT IT IS ADVERTISING IF YOU CHARGE PEOPLE PAGE CHARGES. >> TO A DIFFERENT POINT. I THINK I REASONFULLY DISAGREE WITH MARSHALL AND LORI ON THIS ISSUE WHETHER A PATIENT WHO LIVES IN AT A DISTANCE FROM A MAYOR CENTER AND FOR WHATEVER REASONS IS UNABLE TO GET THIS ADDITIONAL THERAPY APPROACH WHETHER INAPPROPRIATE TO OFFER HIM OR HER THE TRIAL. IF PEOPLE'S CIRCUMSTANCES THROUGH NOBODY'S FAULT NOT THE INVESTIGATOR'S FAULT SOMEBODY LIVES FAR AWAY, AND NATURE OF THEIR SITUATION IS SUCH THAT THE ONLY WAY THEY CAN POSSIBLY GET SOMETHING THAT MIGHT BE HELPFUL FOR THEIR TEARER DISEASE IS JOIN A TRIALND IF THEY LIVE SOMEWHERE ELSE THEY HAVE MORE CHOICES, I DON'T KNOW THAT IT'S HELPFUL TO THAT PATIENT TO EXCLUDE HIM OR HER FROM TAKING ADVANTAGE OF THE ONE OPTION THEY MIGHT HAVE. OBVIOUSLY THEY SHOULD BE INFORMED THERE ARE OTHER STANDARDS THERAPIES OR TRADITIONAL APPROACHES TO THIS AND IF THEY CAN AVAIL OF THEMSELVES OF THAT SO MUCH THE BETTER. BUT TO PROHIBIT THEM FROM JOINING A TRIAL BECAUSE THEY HAVE FEWER OPTIONS IS TO REDUCE FEWER TO ZERO OPTIONS. >> IT'S THE PRESENTATION IN AN INSTITUTION DOESN'T HAVE THE WHEREWITHAL TO PROVIDE THAT SERVICE FUNDAMENTALLY BE DIFFERENT IS WHAT I BELIEVE THAN IF THEY HAD IT. IF THAT'S THE CASE, THEN THESE PATIENTS THEY DON'T UNDERSTAND ALL THIS. IT'S HOW IT'S PRESENTED IS THE WAY THAT IS GOING TO DETERMINE WHETHER OR NOT THEY ENTER THAT TRIAL. IF YOU DON'T HAVE SOMETHING, AND YOU WANT TO MAINTAIN THAT PATIENT, IT'S JUST A LITTLE NUANCES THAT MAKE THE DIFFERENCE. SO IF A PATIENT FUNDAMENTALLY DECLINES RADIATION, THEY HATE IT, SOME PEOPLE DO, OBVIOUSLY THEY'RE IN THE TRIAL. BUT IT'S THE PRESENTATION PIECE THAT I FIND TO BE CRITICAL. AND I FUND MENTALLY BELIEVE IF YOU DON'T HAVE SOMETHING TO OFFER, THE PRESENTATION IS POTENTIALLY GOING TO BE DIFFERENT IN A SIGNIFICANT PERCENTAGE OF CASES. >> YEAH. PREGNANT IS EVERYTHING BUT THAT CAN BE DISTORTED AND PRESENTED IN AN UNFAIR WAY AT THE ACADEMIC CENTER ALSO. SO THAT'S A HAZARD AND COON SENT FORS ARE ONE WAY TO AT LEAST MAKE SURE THE PATIENT GETS BALANCED INFORMATION. BUT IF I'M IN A RURAL AREA WITH A PATIENT WHO IS ONLY PRACTICAL OPTION IS TO JOIN A TRIAL, IT SEEMS TO ME THERE ARE WAYS OF PRESENTING THAT TO A PATIENT THAT'S HONEST AN BALANCED AND SAYING IF YOU LIVE SOMEWHERE ELSE YOU MIGHT HAVE TWO OPTIONS HERE. GIVEN YOUR SITUATION YOU ONLY HAVE ONE, BUT I THINK SOMETHING YOU OUGHT TO CONSIDER LET ME HELP YOU THINK THIS THROUGH. I DON'T THINK -- IT CAN BE DONE IN A BAD WAY BUT IT COULD BE IN A HONEST WAY THAT ALLOWS THE PATIENT TO CHOOSE. I DON'T THINK IT'S -- (INAUDIBLE) (OFF MIC) >> PLEASE MICROPHONE. >> 100-MILE AWAY YOU CAN BE CURED. THE TREATMENT I'M OFFERING YOU WILL ADD FOUR MONTH TO YOUR LIFE AND YOU'RE GOING TO DIE. WHAT ARE YOU GOING TO CHOOSE? DO YOU THINK IT WILL BE PRESENTED THAT WAY? >> IT'S PRESENTED IN A DISHONEST WAY THAT'S A PROBLEM BUT IT'S A PROBLEM IN ANY CENTER. (OFF MIC) >> TURN THESE OFF PLEASE. SO I THINK THE WAY IN THE CONSENT UNDER ALTERNATIVE TREATMENT THERE IS SHOULD BE A CLEAR STATEMENT ANOTHER WAY YOUR DISEASE COULD BE TREATED IS BY IMRT, IT MAY NOT BE AVAILABLE AT YOUR LOCAL INSTITUTION, OTHER INSTITUTIONS MAY HAVE IT YOU MAY WANT TO CONSIDER THIS, AND THEN YOU'VE INFORMED THEM OF IT THAT OF ITS EXISTENCE AND THAT IT'S THE BURDEN IS ON THEM TO SEEK OUT THE NEAREST SENT THEIR MIGHT HAVE IT. >> I JUST NEED TO -- IS IT A STARK -- IF THAT'S THE CASE THAT SHOULD BE SOMEWHERE ON THE CONSENT FORM. HERE IS THE DATA. THIS IS THE MOST IMPORTANT, RIGHT? >> TURN ON YOUR MICROPHONE. PLEASE. >> WHAT SPEAKS TO THAT I SUGGESTED THEY FOLLOW THE PATIENTS FOR FIVE YEARS. ON THE CHANCE THERE IS GOING TO BE A LONG TERM SURVIVAL. THE ANSWER THAT CAME BACK WAS, THE MEDIAN SURVIVAL IS I FORGET WHAT IT IS, THEY SAID BUT IT WASN'T LONG. AND THAT WHATEVER SHORT DURATION THEY FOLLOW THE PATIENTS TWO YEARS OR A YEAR WAS ADEQUATE. AND SO YEAH, THAT'S IT. THERE HAVE BEEN TO THIS POINT IN TIME THERE'S BEEN NO CURES WITH THIS ENTITY. IF SOMEBODY HAD BAD METASTATIC DISEASE AND YOU CAN GIVE THEM FOUR MONTHS LONGER THAN WHAT THEY WOULD HAVE HAD, THEY WANT TO GO THROUGH IT, GREAT. THAT'S WHERE I THINK THE TRIAL SHOULD BE. IT SHOULD BE FOR PATIENTS THAT HAVE FAILED REAR RADIATION, PLUS MINUS CHEMOTHERAPY. WHICH IS SECOND LINE. AND I THINK IT SHOULD BE FOR PATIENTS WITH DOCK THEMENTED MULTIPLE WHICH MEANS MORE THAN ONE, CHEST METASTASIS. WITHOUT ANY TREATMENT. THAT MAYBE TOUGH ON RECRUEL -- ACCRUAL. BUT THAT IS LIFE. THERE WILL BE DATA. IT ISN'T MAGIC TO GET 200 PEOPLE IN THE TRIAL. WHAT'S MAGIC IS TO GET THE RIGHT PEOPLE IN THE TRIAL. >> YOU BROUGHT UP A POINT HAVING ONLY ANIMAL DATA FORSIS PLATINUM PLUS VIRUS. SO WHAT IS YOUR RECOMMENDATION THERE? >> THAT IS ONE MORE TO ENDURE. >> I WANT TO MAKE SURE ALL YOUR POINTS ARE ON PAPER. >> THAT'S THE POINT. IF YOU WERE TO TO THIS THE WAY I THINK -- AND SOME OF THE POINTS THAT WERE RAISED ARE TRUE, IF YOU HAVEN'T RESPONDED TO THE FIRST CHEMOTHERAPEUTIC AGENT, YOU PROBABLY CHAT ANOTHER BUT THE8 WITH RIDIATION THERAPY ALONE. AND THAT WOULD DEPEND NOT ERB BUT TOW MORE BOARD SOME THE REAL FUNDAMENTAL ISSUE IS, SHOULD THOUGH PATIENTS BE ENTERED OR JUST USE PATIENTS THAT HAD A DIFFERENT CHEMOTHERAPEUTIC AGENT. AND SELECT THOSE PATIENTS THAT WERE THE PATIENTS TREATED WHERE THEY WERE IN CHINA. IN OTHER WORDS LIMITED TO PATIENTS THAT HAVE HAD A DIFFERENT CHEMOTHERAPY AS INITIAL THERAPY. AS PART OF INITIAL THERAPY PROTOCOL. AND THOSE PATIENTS THAT FAIL THEN THEY CAN HAVE THESIS PLATINUM AND THAT TRIAL IS DONE. YOU BROUGHT UP THE LIVER THING YOURSELF. SYSTEM OF THESE OTHER AGENTS ARE MORE TOXIC TO THE LIVER. WE ARE NOT DEALING WITH THE POPULATION IN THIS COUNTRY WILL HAVE NORMAL LIVER TO START OUT WITH WITH FOR THE MOST PART. WHICH IS NOT WHAT WE SEE HERE IS ALCOHOL AND SMOKING RELATED AND THEY COME IN WITH LIVER DISEASE TO START. SO THE PREFERENCE IS TO STICK TO WHAT WAS DONE BEFORE AND LET 'CRUEL FALL WHERE IT MAY. THAT DATA EXISTS. MORE ARE TREATED WITH HERBOTUP AND RAID AGO THERAPY. >> THE NCNN GUIDELINES ALLOWS ALL THOSE OTHER REGIMENS. IF SOMEBODY WAS NOT ON TRIAL THEY WOULD GET THOSE OTHER REGIMENS. >> BUT THIS IS A TRIAL. AND IT'S A NEW APPLICATION. IT'S AN APPLICATION (INAUDIBLE). IF YOU WERE TO SAY WE'RE GOING TO DO PHASE 1 TRIAL APPROXIMATE COMPARE ONE DRUG AND ANOTHER DRUG WITH VECTOR, GREAT. BUT WE AREN'T THERE ANY MORE. WE'RE NOW PHASE 3 TRIAL. AND PHASE 3 TRIAL AT LEAST HOW I KNOW IS CONTINUATION ON (INAUDIBLE). SO WOULD PHASE 1, 2 DATA WITH THOSE REGIMENSING TO MAKE YOU HAPPY? OKAY. DR. DRESSER, GO WITH YOUR REVIEW. >> I'M NOT FINISHED. >> I'M SO SORRY. >> WE HAVEN'T RESOLVED THE ISSUE OF CHEST CT AS THE PRIMARY MODAL ITY. THE DATA IS ALL VERY REAL. IT'S -- >> THANK YOU, I'LL BE VERY SIMPLE. I ASKED ABOUT THE FACT THAT THIS TRIAL WILL GIVE PEOPLE DIFFERENT CHEMOTHERAPY AGENTS THAN THE EARLIER TRIALS DID. WHETHER THERE MIGHT BE DIFFERENT INTERACTIONS AND P I THINK YOU ADDRESSED THAT. THEN A NUMBER OF COMMENTS OPT CONSENT FORM TO CHANGE REFERENCES TO THERAPY, TREATMENT TO TERMS LICK INVESTIGATIONAL DRUGS THAT WOULD NOT IMPLY PROVEN THERAPY AND YOU AGREED TO DO THAT. THE FORM SHOULD IT WILL SUBJECTS THAT THE PREVIOUS TRIALS INVOLVE PEOPLE WITH DIFFERENCE CHEMOTHERAPY AGENTS THAN SUBJECTS IN THIS TRIAL AND THAT COULD MEAN DIFFERENCE SIDE EFFECTS, ADDITIONAL SIDE EFFECTS AND YOU AGREED TO DO THAT. YOU SAID THERE WOULD BE NO BENEFIT TO SUBJECTS FOR PARTICIPATION AND I SAID IF THERE'S NO POSSIBLE BENEFIT THIS SHOULDN'T BE A PHASE 3 TRIAL. SO I WAS ACTUALLY SAYING YOU WERE BEING TOO CAUTIOUS. SO THERE IS POTENTIAL FOR BENEFIT AND YOU AGREED TO THAT AND THAT WAS ALL THAT I ADDRESSED. I THINK WHAT YOU AND TEAM ARE HEARING FROM THE COMMITTEE REALLY IS THIS. IN PHASE 3 TRIAL YOU'RE TRYING TO ESTABLISH A NEW STANDARD OF CARE. AND IN ORDER TO DO THAT, YOU HAVE THE HAD BEEN SURE THE DATA SUPPORTS DOING A BIG TRIAL THAT YOU GUYS ARE GOING TO INVEST IN AND AT THE END OF THE TRIAL THAT WHAT WE DON'T END UP WITH IS SOMEBODY CRITIC SAYING YOU DENT COMPARE TO CURRENT STANDARD OF CARE APPROXIMATE THEREFORE WE DON'T BELIEVE YOU AND WE'RE NOT GOING TO USE YOUR THERAPY ANYWAY. THEREFORE IT'S WASTED TIME, AND RISK FOR SUBJECTS THAT ENTERED THIS TRIAL. AND I THINK THE BIGGEST WORRIESES BEING VOICED HERE IS THAT IF REPEAT IMRT REALLY IS A STANDARD OF CARE, IT NEEDS TO BE SOMEWHERE IN THE PROTOCOL AND STRESSED AND ESPECIALLY IF IT CAN BE A POTENTIALLY CURATIVE STANDARD OF CARE. THE OTHER PART OF GREAT CONCERN TO PEOPLE AROUND THE TABLE ARE IF YOU DID A PHASE 1, 2 TRIAL COMBINING A CHEMOTHERAPY WITH YOUR AGENT AND PROPOSING TO DO A PHASE 3 TRIAL, COMBINING WITH OTHER IRK AGENTS YOU HAVE NOT TESTED IN PHASE 1, 2 SETTING, THAT RAISES RED FLAGS. WITH FOLKS AROUND THE TABLE. I AM LESS CONCERNED ABOUT CAPITATION PAYMENTS, SIMPLY BECAUSE THAT IS A SCHEME USED BY NIH, BY ROUTINELY BY PHARMA AND IT'S JUST HOW THE INSTITUTION, DISPERSE IT AND HOW IT WILL BE ACKNOWLEDGED TO THE SUBJECT ENTERING THE TRIAL SO THEY UNDERSTAND THERE IS PAYMENT EXCHANGED BUT MOST SAVVY SUBJECTS WILL KNOW THAT, THAT TRIALS HAVE TO BE -- TIME HAS TO BE PAID FOR AND INSTITUTIONAL RESOURCES HAVE TO BE SUPPORTED.KwG SO IF YOU WANT TO RESPOND TO SOME OF THESE OTHER CRITICISMS RIGHT NOW BEFORE WE FIND -- TRY TO FINALIZE A -- ADDITIONAL RECOMMENDATIONS, FOR YOUR GROUP, I WOULD LIKE TO HEAR FROM YOU GROUP RIGHT NOW BEFORE WE FINISH WRITING. >> THE FIRST COMMENT IS REIRRADIATION. I PUT UP THERE WHAT THE COMMENT IS FOR N CCN GUIDELINES. I THINK THERE IS MANY EXPERTS IN HEAD AND NECK CANCER WHO WILL ARGUE WHAT IF WE IRRADIATION Z AS STANDARD OF DARE WHEN YOU HAVE SINGLE INSTITUTION DATA THAT IS PROMISING THE MOST IMPORTANT THING TO DO IS TAKE IT TO A PHASE 3 TRIAL TO SEE IF IT HOLES TRUE IN A MULTI-INSTITUTIONAL RANDOMIZED SETTING AND THE DATA IS NOT OUT THERE. SO TO SAY CONSENT OR TELL PATIENT THEY HAVE A CURATIVE OPTION WHEN IT HASN'T BEEN TESTED I THINK IS DIFFICULT IN MY MIND. THE QUESTION ABOUT CHEMOTHERAPY IS A GOOD QUESTION BUT THIS IS A DIFFERENCE TRIAL DESIGN. I AGREE. SIMILAR TO WHAT'S GOING OUT THERE WHERE YOU CAN TAKE WITH TARGETED THERAPY, YOU CAN TAKE ONE GROUP OF PATIENTS AND DO A GROUP THERAPY ON MASTER PROTOCOL. THIS IS THE SAME THING WHERE YOU TAKE A GROUP OF PATIENTS WHERE POOR PROGRESS MOSES APPROXIMATE USE ACCEPTABLE CHEMOTHERAPY REGIMENS. BECAUSE WHAT WE'RE TESTING IS WE'RE NOT TESTING E 10A A A TARGETED AGENT TO WORK WITH CHEMOTHERAPY, WE'RE TESTING THE ANTI-ANGIOGENESIS PROPERTY OF TE 10A WITH STANDARD CYTOTOXIC THERAPY IN WHAT IS CONSIDERED STANDARD CHEMOTHERAPY. SO I WOULD ADDRESS THOSE TWO QUESTIONS IN THAT WAY AND THAT I KNOW THERE'S A STRONG ARGUMENT MADE THAT REIRRADIATION IS SORT OF CURATIVE. BUT IN WHAT SETTING, IN A SINGLE INSTITUTION SETTING, NOT RANDOMIZED CONTROLLED MULTI-INSTITUTIONAL SETTING. AND REITERATE THIS IS A LITTLE DIFFERENT DESIGN AND WE KNOW THIS. BUT WE ALSO KNOW THAT WE HAVE A HETERO JEEPIOUS POPULATION WITH DIFFERENCE CHEMOTHERAPIES THEY HAVE SEEN THAT WE'RE GOING TO PUT IN A DIFFERENT TRIAL DESEEN FOR STANDARD OF CARE PLUS ANTI-ANGIOGENESIS. >> LET ME RESPOND AND THEN TAKE A BREAK AN COME UP WITH RECOMMENDATIONS FOR YOU. I HAD A TEACHER WHO SAID THE BEST TRIALS, CLINICAL TRIALS YOU CAN DO ARE THE ONES THAT THE GUY AT THE MORGUE TELL YOU IS POSITIVE. SO IF YOU TELL ME THAT THE AVERAGE SURVIVAL OF PATIENT IN THIS POPULATION IS 4 TO 8 MONTHS AND SINGLE INSTITUTIONS REPORTING FIVE YEARS SURVIVALS, BE IT 20% OR WHATEVER THE NUMBER IS. IT SAYS IT HAS TO BE SOMETHING TO THOSE PATIENTS. IT AGREE IT WOULD BE BETTER IN A MULTI-INSTITUTIONAL SETTING WHERE IT'S VERIFIED BUT IF RESPONSE REALLY FROM THE GROUP IS FROM YOUR GROUP IS THAT BEONLY NEED TO FOLLOW THESE PATIENTS TWO YEARS BECAUSE NOBODY SURVIVES MORE THAN THAT, AND THERE ARE INSTITUTIONAL SERIES THAT HAVE FIVE YEAR SURVIVAL, WHATEVER THAT TREATMENT IS, YOU HAVE TO ACKNOWLEDGE THAT IT COULD BE A -- >> >> WE HAVE THAT DATA WITH SURGERY, IF WE'RE ABLE TO OPERATE ON PATIENT WHOSE HAVE RECURRENT DISEASE, WE HAVE UP TO 30 TO 40% SURVIVAL ALSO BUT IF THEY WERE THE PATIENTS INCLUDED ON THIS TRIAL, THEIR INSTITUTIONAL BIAS WHERE RANDOMIZED CONTROL TRIAL GETS RID OF THAT SO NOT SAYING THEY HAVE THE DATA BUT UNTIL YOU RAISE IT TO WHAT THE GOLD STANDARD IS OR YOU HAVE TO UNDERSTAND, WE DOPE KNOW WHAT THESE PATIENTS, THEYSOR OF SURLILY RESECONDABLE BUT WENTEN RADIATION. I CAN'T ANSWER THAT QUESTION. >> THEN COMING TO THE COMBINATION THERAPIES. YOU'RE RIGHT. WHAT YOU'RE TESTING IS TRYING TO DO AN ANTI-ANGIOGENIC THERAPY BUT WITH NEW DRUGS YOU DON'T COMPLETELY KNOW WHAT THE TO BE CITYSISTIES WILL BE. ON THE OTHER SIDE YOU DONE KNOW THE REGIMEN YOU'RE GOING TO GIVE IN TERMS OF CHEMOTHERAPY SIGH LISTEN YOUR VECTOR. AND ACTUALLY DELIVER NO VIABLE VECTOR OR NO ACCESSIBLE GENE THAT'S YOUR TARGET BECAUSE YOU HAVE NO DATA ON THOSE COMBINATIONS SO YOU MIGHT ACTUALLY BE SABATOGING YOUR LARGE TRIAL BY INCLUDING NEW REGIMENS THAT WILL TURN OFF YOUR E-10A AND SO AGAIN, YOU COULD SEE MANY DIFFERENT WAYS OF LOOK AT THAT. AND TO GO INTO A PHASE 3 CLINICAL TRIAL AND NOT HAVE ANY PHASE 1, 2 DATA JUST IS ALSO A LITTLE WORRYSOME. SO AGAIN THAT'S WHY THERE'S BEEN SUCH DISCUSSION. NOW YOU KNOW THAT. SO LET'S TAKE A FIVE MINUTE BREAK WHILE WE CRAFT A DRAFT SET OF RECOMMENDATIONS AND THEN WE'LL GO THROUGH THEM.O—y &. >> ANY ADDITIONAL COMMENTS FOR PEOPLE ON PHONE. ANY PUBLIC COMMENTS? SPLIT LET ME READ YOU THESE DRAFT RECOMMENDATIONS FROM -- SO LET ME READ YOU THESE DRAFT REPRESENTATIONS FROM THE RAC. GIVEN THE MORE FAVORABLE PROGNOSIS WITH POSITIVE HPV STATUS THE TRIAL SHOULD DETERMINE STATUS AS THIS INFORM IT IS THE RESULTS THE LACK OF DATA ON HPV STATUS AN PROVEIUS TRIALS MEANS DATA HOW IT PERFORMS IN HPV POSITIVE CANCERS VERSUS NEGATIVE CANCERS IS OF YET UNKNOWN. THE TRIAL USES MULTIPLE CHEMOTHERAPY AGENTS BUT THE ONLY ANIMAL AND CLINICAL DATA IS WITH SIS PLATINUM, RECONSIDER WHETHER THE PHASE 3 TRIAL SHOULD ONLY ENROLL THOSE WHO HAD PREVIOUS NON-SIS PLATINUM BASED REGIMENTS AND IT SHOULD BE PARALLEL TO THE DESIGN OF THE PREVIOUS TRIALS OR CONSIDER GATHERING ADDITIONAL DATA IN PATIENTS USING THE OTHER COMBINATIONS, A PHASE 2, 3 TRIAL, BEFORE COMMITTING TO PHASE 3 TRIAL WITH MULTIPLE CHEMOTHERAPY AGENTS THE TRIAL PROPOSES A CHEST X-RAY TO EVALUATE LUNG METASTASIS. NEW DATA INDICATE ASKER MANY SENSITIVE TEST IS LOW DOSE CT, WHICH LIKELY HAS GREATER SENSITIVITY WITH SOME INCREASE IN RADIATION. INFORMATION TO BE GAINED FROM A CT SCAN LIKELY OUTWEIGHS THE RISK OF RADIATION IN THIS POPULATION PEER K WHETHER THE INFORMATION TO BE GATHERED WILL BE IMPORTANT FOR DETERMINING APPROPRIATE THERAPIES FOR THE PATIENT. AND FOR YOUR EFFICACY ANALYSIS. ETHICAL. PATIENT POPULATION ELIGIBLE FOR THIS TRIAL IS THAT ARE THOSE PATIENT WHOSE ARE HAVE RECURRENT OR METASTATIC DISEASE NOT ELIGIBLE FOR SURGERY OR RADIATION. THE STANDARD OF CARE HAS EVOLVED WITH RERADIATION, AS ON OPTION FOR A NUMBER OF PATIENTS RECUR AFTER RADIATION AND CHEMOTHERAPY. HOWEVER, SOME SITES FOR THIS TRIAL WILL NOT HAVE IMRT AND THERE'S RISK PATIENT BE REFERRED TO THIS TRIAL BECAUSE THEY'RE AT A SITE THAT DOES NOT HAVE IMRT AS AN OPTION. AVAILABILITY TO BE DISCUSSED AND INFORMED CONSENT, DATA ON EFFICACY AND ALTERNATIVE CLINICAL -- AT THE CLINICAL ALTERNATIVE SITES, PROVIDE CURATIVE THERAPIES SHOULD BE STATED. CHEMOTHERAPY IN THIS POPULATION IS NOT CURATIVE. IT SHOULD INFORM SUBJECTS THAT PHYSICIANS WILL BE REIMBURSED FOR SUBJECT ENROLLED CH AVASTIN IS USED THIS HEAD AND NECK CANCER AS ANTI-ANGIOGENIC AGENT AND SHOWN TO SENSITIZE TUMORS TO SIS PLATINUM, THIS APPROACH SHOULD BE DISCUSSED IN THE INFORMED CONSENT. >> NOT SURE WHAT'S ACCURATE YOUR MEN ABOUT PHYSICIANS PAID FOR PATIENTS ENROLLED. SOME INSTITUTIONS IT'S NOT QUITE THAT ALGORITHMIC, SO IS IT YOUR PHYSICIAN WILL BE PAID BUT THAT'S -- >> HOW ABOUT INSTITUTIONAL REIMBURSED >> PHYSICIAN WILL BE REIMBURSED. I JUST PIPE OUT, I THINK IT IS APPROPRIATE FOR PATIENTS TO KNOW DOCTORS ARE PAID FOR DOING RESEARCH STUDIES BUT THERE'S NOTHING DIFFERENT IN THE CONSENT FORMS THE MAKE IT A STANDARD FOR WHOLE RESEARCH PROJECTS. I WOULD HATE THE FLAG THIS ONE AS IF THERE'S SOMETHING UNUSUAL GOING ON THAT THE DOCTORS WERE SHOCKED TO FIND OUT THE DOCTORS ARE GETTING PAID THE DO RESEARCH. >> I DON'T THINK THIS TRIAL IS DIFFERENCE THAN ANY OTHER TRIALS WE CONSIDERED. SO EITHER WE >> THAT SHOULD BE SOMETHING TO RECOMMEND ON ALL THE TRIALS. >> I'M RELATIVELY NEW SO THERE'S A CERTAIN THING WE SHALL SAY SHOULD BE STANDARD. THERE SHOULD BE ONE. WE'RE GOOD PUTTING IN LANGUAGE ABOUT HOW IT'S NOT A BENEFIT IN ONE AN TWO AN SHOULD BE A BENEFIT IN PHASE 3. IT'S OKAY FOR THE STANDARD. THE FACT WE HAVEN DONE IT BEFORE DOESN'T P MEAN WE CAN -- >> IS THERE A MECHANISM TO MAKE SURE THIS HAPPENS ON ALL TRIALS? ALL THE PHARMACEUTICAL TRIALS THAT WE DO AN MOST NIH RELATED TRIALS THAT WE DO HAVE SIMILAR MECHANISM. I AGREE WITH YOU. HAVING THE PATIENT UNDERSTAND THAT WOULD BE A GOOD THING. >> IT'S NOT A RAC FUNCTION TO MAKE GENERAL RULES FOR GENERAL RESEARCH CONSENT FORMS THERE'S NO EXPERTISE ON THIS COMMITTEE ABOUT THAT, I AGREE IT OUGHT TO BE IN ALL CONSENT FORMS. MAKE A MESSAGE JACQUELINE SENDS TO HER SUPERIORS THAT THIS SHOULD BE PART OF THE BASIC TEMPLATE OF NIH SPONSORED RESEARCH OR SOMETHING LIKE THAT. I DON'T THINK WE SHOULD ADD TO EVERY LETTER AT THIS TEMPLATE. OR GENERAL RAKE STATEMENT. I DON'T THINK THAT'S OUR FUNCTION. >> ARE YOU MOVING WE REMOVE THIS FROM HERE? >> FIRST WE DON'T WRITE CONSENT FORMS AN IRBs WILL DO WHAT THEY WANT TO DO. SO THE WAY I MIGHT PUT IT, THERE WAS A DISCUSSION, THE COMMITTEE WAS IN FAVOR OF AND INVESTIGATORS COMPENSATION BEING DISCLOSED IN THIS STUDY AS IN ALL STUDIES SO IRB CAN NOTE FDA OR WHOEVER READS THESE MINUTES WILL SEE THAT WE MADE THAT POINT BUT I DONE WANT TO EVERY POINT FORWARD FOR US TO COMMIT OURSELVES THE STICKING IT INTO EVERY APPROVAL LETTER. >> THAT'S WHY I WAS ASKING WHETHER THERE WAS A GENERAL PLACE TO MAKE A RECOMMENDATION WHERE -- I WOULD MAKE IT AS A RECOMMENDATION PROTOCOL, I WOULD MYSELF PUT ANYTIME THE MINUTES OF THE MEETING. DO WE HAVE A SEPARATE SAYING THE COMMITTEE DISCUSSED THE DESIRABILITY OF -- IT COULD BE IT IS NOT OFFENSIVE TO THESE INVESTIGATORS NOTHING WRONG WITH INCLUDENING THEIR LETTER, THERE WAS DISCUSSION ABOUT DESIRABILITY OF HAVINGRYTOR COMPENSATION BE PART OF ALL CONSENT FORMS INCLUDING THIS ONE. >> THERE'S NOTHING WRONG WITH WITH MAYBEING A RECOMMENDATION THAN HAVING THIS IN THIS. YOU HAVE TO START SOMEWHERE. SO IF WE DECIDED FROM HERE IN IT'S IMPORTANT WE CAP SAY BECAUSE YOU HAVEN'T DONE IT BEFORE WE SHOULDN'T START DOING IT. >> YOU DONE WANT TO IT FOR EVERYONE FROM HERE ON? >> POSSIBLY. UNLESS THERE'S -- THE OTHER QUESTION ON THE IMRT ARE WE RECOMMENDING A STATEMENT PUT IN THE CONCEPT FORM? THEY'RE A ACTUALLY IN WRITING WHERE A PERSON CAN READ IT. CAN YOU READ THAT? >> WE WILL POLISH THAT. THE AVAILABILITY OF BIOMARKERS SHOULD BE DISCUSSEDDED IN INFORMED DO CONSENT. DATA ON EFFICACY AND ALTERNATIVE CLINICAL SITES MAYBE ABLE TO PROVIDE POTENTIALLY CURATIVE THERAPIES SHOULD BE DISCUSSED. >> SHOULD BE DISCUSSED BUT DOES THAT MEAN -- PUT IN WRITING. >> IN THAT ALTERNATIVE CLINICAL SITES PROVIDE POTENTIALLY CURATIVE THERAPIES I WERE SETTED IN THAT CONSENT. >> INSERT. BECAUSE IF YOU SAY DISCUSS, THEN THEY MAY OR MY NOT BRING IT UP. BUT IF WE SHOULD RECOMMEND IT IN WRITING WHERE THE PATIENT CAN READ IT. >> ON THE FINANCIAL BENEFIT TO THE INVESTIGATOR, MY OWN IRB REQUIRES THAT IN ALL FORMS, I THINK THAT'S SOMETHING PROBABLY WAYNE STATE REQUIRES MOST INSTITUTIONS DO REQUIRE IT. I THINK WE'RE REI WERE EVENTUALING THE WHEEL HERE. >> ANY OTHER -- ANY CHANGES? ANY ADDITIONS? >> WHAT'S NOW THE FINAL THING ON THAT FINANCIAL -- WHAT ARE WE GOING TO DO? ARE WE GOING TO PUT IT IN OR NOT AS A RECOMMENDATION? >> YOU HAVE IT IN YOUR INFORMED CONCEPT ALREADY? Q. YES. (OFF MIC) >> I WANT IT TO BE A LITTLE MORE RESTRICTIVE IF THERE WAS GOING TO BE DOLLARS IN THERE. MY POINT, IF MONEY GOES TO THE INSTITUTION FOR TIME SPENT BY SALARIED PHYSICIAN, THAT'S OKAY. IF THE MONEY GOES TO THE PHYSICIAN, OVER AND ABOVE, NOT OKAY BY ME. I HAVE TAKEN UP ENOUGH TIME. >> I AGREE WITH THAT. FOR ME IT'S A TROUBLING INSTITUTION WIDE PRACTICE THAT'S GOTTEN OUT OF HAND. THIS MAY NOT BEEN EXAMPLE OF OUT OF HAND BUT T CLEARLY IT IS TROUBLING. >> PATIENTS ARE INFORMED PHYSICIANS ARE BEING PAID PER CAPITAL P TA? IS IT WORDED THAT WAY? HOW IS IT WORDD? (OFF MIC) >> ANY OTHER ADDITIONS? MCMIC >> ABOUT THIS WHY THIS SHOULD BE CALLED A PHASE 2 CLINICAL TRIAL, NOT A PHASE 3, CHANGE IN PROTOCOL. >> >> DID I READ YOUR THING WRONG? >> IS THAT ONE -- ALL RIGHT. >> IT'S WHAT BROUGHT UP THAT A PHASE 2 TRIAL THESE OTHER AGENTS SHOULD BE CONSIDERED, I THINK YOU PUT THAT IN THERE. >> PHASE 2 RUN IN TRIAL, FROM THIS WOULD BE A REASONABLE THING. FOR NO OTHER REASON YOUR VECTOR EBB PRESSES THOSE COMBINATIONS. ANY OTHER ADDITIONS OR CHANGE? SO LET'S PUT IT TO A VOTE. DR. KOCH. >> KOCH, YES. >> (INAUDIBLE). YES. >> I'M GOING TO ABSTAIN. >> (INAUDIBLE), YES. >> CHIOCCA, YES. >> ORNELLES, YES. >> PILEWSKI, YES. >> KOHN, YES. >> FONG, YES. >> (INAUDIBLE), YES. >> CHIOCCA, YES. >> BADLY, YES. >> CANON, YES. >> ABSTAIN. STROME. >> (INAUDIBLE). YES. >> WOOLEY YES. >> DRESSER YES. >> MS. MALLINO? >> MALLINO, YES. >> THANK YOU VERY MUCH, THANK YOU DR. YOO AND YOUR TEAM. >> THANK YOU VERY MUCH. I WOULD LIKE TO NOW INTRODUCE DR. AMY PATTERSON WHO IS ASSOCIATE DIRECTOR FOR SCIENCE POLICY AT NIH WHO IS HERE WE'RE GOING TO MOVE FROM OUR AGENDA TOMORROW MORNING A PREGNANT CERTIFICATE SO WE'LL DO THAT RIGHT NOW. >> THANK YOU, MR. CHAIRMAN, THANK YOU, JACKIE. THANK YOU, MEMBERS TO HAVE RAC FOR HAVING ME. MANY OF U YOU KNOW, THIS OOH'S A BITTERSWEET MOMENT EVERY JUNE WHEN WE RECOGNIZE THE SERVICE OF RAC MEMBERS WHO COMPLETED THEIR TERM OF SERVICE. THIS IS ONE OF THOSE OCCASIONS. OVER THE PAST SEVERAL YEARS THIS ENTIRE COMMITTEE HAS ADVISED THE NIH ON SCIENCE, SAFETY AND ETHICS ISSUES AS WELL AS CLINICAL APPLICATIONS OF RECOMBINANT DNA RESEARCH. IN DOINGw3 IT'S FAIR TO SAY YOU PROVIDED A VERY CRITICALLY IMPORTANT SERVICE, IN FACT A UNIQUE SERVICE. THIS IS AN OPEN TRANSPARENT FORUM. THAT HAS NO PARALLEL IN THIS COUNTRY OR ELSEWHERE. IT PROVIDES A SERVICE NOT ONLY TO THE AGENCY, TO THE SCIENTIFIC COMMUNITY, BUT THE PUBLIC AT LARGE. THE INDIVIDUAL EXPERTISE YOU BRING WHERE FROM WALKS OF LIFE BRING VERY IMPORTANT PERSPECTIVE TO THE PROTOCOLS THAT ARE BROUGHT BEFORE YOU, THE BIOSAFETY ISSUES THAT ARE BROUGHT BEFORE YOU. AND IT'S YOUR WORK, YOUR INSIGHT THAT PROVIDE THE RAC WITH ITS BROAD NATIONALLY AND INTERNATIONALLY REASONED POINTS OF VIEW. FOR THOSE MEMBERS LEAVING SERVICE TODAY BUT ALSO FOR ALL THE MEMBERS IN GENERAL, WE HOPE THAT AS YOU GO FORWARD AND CONTINUE TO SERVE SCIENCE AND THE PUBLIC YOU'LL LOOK BACK ON YOUR TIME, YOUR DAYS HERE SPENT WITH US REVIEWING PROTOCOLS, PROVIDING FINDINGS AND RECOMMENDATIONS, AS AN EXPERIENCE THAT WAS REWARDING. YOU ARE ACTUALLY ON THE FOREFRONT ON DEVELOPMENTS OF A FASCINATING REALM OF SCIENCE AND YOU HAVE HAD THE OPPORTUNITY TO CONTRIBUTE TO THAT SCIENCE IN A VERY PRACTICAL WAY, YOU CONTRIBUTE TO SOCIETY IN BY VIRTUE OF CONTRIBUTING AGAIN TO WHAT IS A FAIRLY UNIQUE FORUM THAT OPERATES PRE-COMPETITIVE SPACE OPEN AND TRANSPARENT. I AM NOT WHICH OF ANY OTHER COMPARABLE FORUM FOR THE DISCUSSION OF IN PHASE 1, PHASE 2, PHASE 3 PROTOCOLS. IN THIS MULTI-DISCIPLINARY OPEN WAY. EFFORTS AND INSIGHTS YOU BRING TO BARE ON THIS TASK TO INFORM GENE TRANSFER RESEARCH, AND HAVE GONE VERY FAR TO PROMOTING SCIENTIFIC PROGRESS. AS WELL AS ENHANCING MEASURES TO ENSURE SAFETY AND OVERSIGHT OF RESEARCH PARTICIPANTS. I THINK BACK SEVERAL YEARS WHEN I WAS IN JACKIE'S SEAT EARLIER DAYS OF THE RAC. HOW THE FIELD MATURED OVER THE YEARS. THE COMMENTS AND ROLES OF THE RAC HAVE LIKEWISE MATURED OVER THE YEARS AND TAKEN ON NEW SHAPES. TO MATCH DEVELOPMENTS IN THE FIELD AND WE CAN LOOK FORWARD TO SIMILAR CHANGES IN THE FUTURE. NOW, AS YOU KNOW AT NIH GREAT WORK NEVER GOES UNRECOGNIZED SO FOR THOSE DEPARTING MEMBERS, YOU ARE JOINING AN ILLUSTRIOUS GROUP RAC ALUMNI, DON'T BE SURPRISE LIKE ALL GROUPS YOU GET CALLED ON TO COME BACK AN HELP THE TEAM. WE ARE NOTORIOUS FOR CALLING ON MEMBERS WHO HAVE ONCE BEEN ON RAC SERVICE WE CONSIDER YOU ALWAYS ON RAC SERVICE, THOUGH YOU'RE INITIALLY LEAVING THE COMMITTEE TODAY WE CAN CALL ON YOU IN AD HOC CAPACITY AND TAX YOUR EXPERTISE. SO NOW I WILL LIKE TO OFFER A MODEST TOKEN OF APPRECIATION, ALSO A PHOTO TOE ON OPPORTUNITY HERE WITH THE FLAGS, I WOULD LIKE TO ASK CHAIRMAN AND JACKIE TO COME UP, AND I'M GOING TO ACKNOWLEDGE, IT'S WORTH PAUSING A MOMENT IN ACKNOWLEDGE. IN FOR EACH MEMBER DEPARTING THE COMMITTEE TO ACKNOWLEDGE THEIR POSITIONS AND THEIR SPECIFIC CONTRIBUTIONS TO THE WORK OF THIS GROUP. SO FIRST CALL DR. ANDREW BADLY, DIRECTOR OR THE NIH IMMUNOLOGY LAB AND ASSOCIATE DIRECTOR OF RESEARCH RESOURCES AN PROFESSOR OF MEDICINE, DIVISION OF INFECTIOUS DISEASES AT THE MAYO CLINIC. DR. BODILY SERVED ON THE RAC SINCE 2010. IN ADDITION TO HIS CONTRIBUTIONS OF REVIEW NUMBER OF PROTOCOLS, HE SERVED ON GENE TRANSFER SAFETY ADVISORY BOARD. EVERYONE KNOWS INFECTIOUS DISEASE EXPERTISE HAS BEEN INVALUABLE IN THOSE DISCUSSIONS OF BIOCONTAINMENT, NOVEL INFECTIOUS AGENERALS INCLUDING THE NOTABLE RECENT AMENDMENT TO THE NIH GUIDELINES TO ADDRESS RESEARCH WITH HIGH H 5N 1. SO WITHOUT FURTHER ADIEU, (OFF MIC) >> NEXT UP TO BAT IS DR. ANTONIO CHIOCCA DEPARTMENT OF NEUROSURGERY AND CO-DIRECTOR OF INSTITUTE FOR THE NEUROSCIENCES AT THE BRIGHAM AND WOMEN'S IN BOSTON. AS WELL AS SURGICAL DIRECTOR NEUROONCOLOGY DANE FANNER. HE SERVED1 ON RAC SINCE 2010 AND SURGICAL EXPERTISE AN EXPERIENCE AS INVESTIGATOR HAVE BEEN INVALUABLE TO THE COMMITTEE. REVIEWS NOVEL PROTOCOLS FOR PEDIATRIC NEUROLOGICAL DISORDERS AN SAFETY DATA FOR ONGOING PROTOCOL. HE TOO IS AN ACTIVE MEMBER WHICH SERVES AS CRITICAL ONGOING OVER SIGHT ACTIVITY FOR EVALUATING EMERGING SAFETY DATA. NEXT DEPARTING MEMBERS MS. MALLINO, I UNDERSTAND SHE IS TORCHING IN. ARE YOU THERE? MY UNDERSTANDING IS SHE GOT HER TOKEN OF APPRECIATION DELIVERED BY FEDEX TODAY AND WE'LL JUST ACKNOWLEDGE THAT SHE JOINED THE RAC IN 2009 AFTER A FULL CAREER IN LOCAL GOVERNMENT INCLUDING MAYOR OF UNIVERSITY PARK HERE IN MARYLAND, HAVING SERVED AS PUBLIC REPRESENTATIVE ON UNIVERSITY OF MARYLAND IDC. SO SHE CAME WELLmZ' SERVE ON THIS COMMITTEE. WE UNDERSTAND THE BECOMING A RAC MEMBER IS A CHALLENGING EXPERIENCE ESPECIALLY NON-SCIENCE MEMBERS AS IT'S AKIN TO LEARNING SOMEWHAT OF A FOREIGN LANGUAGE AND BECOMING FLUENT IN A SHORT AMOUNT OF TIME. SHE CERTAINLY FOUND HER VOICE AN BROUGHT TO THE DISCUSSIONS PERSPECTIVE THAT WAS CRITICAL TO HAVE AT THE TABLE. SHE CONTINUED TO DO THIS AFTER RELOCATING TO MONTANA HAVING TO NEGOTIATE THE CONFERENCE, NEW TRAVEL POLICY THAT LED TO MEETINGS WAS LIKELY EQUAL THE MEETING TIME AND WE O GRATEFUL FOR HER CONTRIBUTIONS AN DEDICATION. NEXT LIKE TO CALL DR. SUSAN ROSS. DR. ROSS IS PROFESSOR DEPARTMENT OF MICROBIOLOGY AT UPENN. SHE SERVED ON THE RAC SINCE 2009 AND IN ADDITION TO MUMMOUS REVIEWS SHE WAS AN ORGANIZER OF THE DECEMBER 2010 INTERNATIONAL CONFERENCE ON RETROVIRAL VECTORS AN LONG TERM GENE COLLECTION. IN ADDITION SHE'S A VERY ACTIVE MEMBER OF THE BIOSAFETY WORKING GROUP WHICH DURING HER SERVICE AMENDED THE NIH GUIDELINES TO EXPAND THE SCOPE OF SEMINOLE CHANGE IN THE GUIDELINES, FIRST MAJOR ALTERATION OF ITS SCOPE SINCE THEY WERE FIRST WRITTEN AND ISSUED IN 1976. SO IT WAS EXPANDED TO COVER SYNTHETIC NUCLEIC ACIDS, CERTAIN EMPERIMENTS DEVELOPED IN NEW HOST VECTOR SYSTEM. UPDATED A I APPENDIX B OF THE NIH GUIDELINE WHICH -- IS IN FACT THE STARTING POINT FOR ALL RISK ASSESSMENTS, UPDATED THE BIOSAFETY CONTAINMENT THE ADDRESS EXPERIMENTS TO DEVELOP THE SO CALLED GAIN OF FUNCTION EMPERIMENTS TO DEVELOP MAMMALIAN FORM OF HIGH PATH H 5N 1 AND FINALLY DEVELOPED A PROPOSAL TO STREAMLINE REVIEW GENE TRANSFER PROTOCOL. SO WE'RE VERY INDEBTED TO SUSAN FOR HER WILLINGNESS TO GIVE SO GENEROUSLY OF HER TIME AND HER EXPERTISE. LAST BUT CERTAINLY NOT LEAST, LIKE TO RECOGNIZE YOUR CHAIR DR. FONG, IN CHAIR SURGERY MEMORIAL SLOAN-KETTERING, DR. FONG JOINED THE RAC IN 2009 AND HE TOOK OVER AS CHAIR OF THE COMMITTEE IN 2011. HE HAS SKILLFULLY LED THIS GROUP THANK YOU NUMEROUS REVIEWS APPROXIMATE NEW ACTIVITIES SUCH AS EXPERIENCE ALLOWING REAL TIME COMMENTS THROUGH THE WEB. HIS LAST WORD ON PROTOCOL, ALWAYS PROVIDE INVESTIGATORS WITH NEW WAY TO THINK ABOUT HOW THEY APPROACH THEIR WORK. IN SPITE OF HIS DEMANDING SCHEDULE HE NOT ONLY LED THE RAC MEETINGS BUT CHAIR AD NUMBER INCLUDING THE DECEMBER 2011 MEETING ON RNAi OLIGOS AND THE JUNE 2012 MEETING ON RARE DISEASES AN FUTURE LEADERS OF GENE THERAPY. HIS SPARE TIME, HE HAS LED THE GENE TRANSFER SAFETY ASSESSMENT BOARD PROVIDING BOTH NIH AND FDA WITH NOW WAYS TO THINK ABOUT AND ANALYZE DATA UNDER REVIEW. WE ARE GRATEFUL TO DO FONG FOR HIS LEADERSHIP AN FORTITUDE IN LEADING THE RAC. WE HAVE CERTIFICATE TO GIVE YOU. WE ALSO HAVE A TOKEN, I HOPE YOU HAVE BEEN LIFTING WEIGHTS. THESE ARE BOOKENDS FOR YOU ONCE ONE SIDE HAS YOUR NAY, THE OTHER SIDE HAS THE NIH EMBLEM, BUT A MODEST TOKEN AN APPRECIATION FOR YOUR SERVICE. >> I WILL HAVE TO TAKE UP READING. >> THANK YOU. FINALLY WE'RE VERY PLEASED TO ANNOUNCE DR. DON KOHN PROFESSOR PIOLOGY IMMUNOLOGY AN MOLECULAR GENETIC AT PEDIATRICS AT THE SCHOOL OF MEDICINE, HAS ACCEPTED POSITION OF CHAIR OF THE RAC. A GREAT DEAL OF CONFIDENCE AND TRUST THAT WE TURN TO HIM FOR LEADERSHIP OF THE RAC. DR. KOHN, WOULD YOU LIKE TO SAY A FEW WORDS? >> JUST IT'S VERY CHALLENGING SHOES TO FILL. >> THANK YOU EACH AND EVERY ONE, WE'RE VERY GRATEFUL FOR WHERE YOUR SERVICE,S IN A TIME OF TRANSITION IN THE FIELD OF GENE THERAPY LOOKING AT NEW VECTOR SYSTEMS, REPLICATION COMPETENT VECTOR SYSTEMS, THIS IS ALSO A TIME WHEN THE ROLE OF THE RAC IS BEING EXAMINED. AND I THINK YOUR THOUGHTS ON HOW TO MAKE THE RAC MOST RELEVANT TO SCIENCE AND TO ENSURE AS A PUBLIC SERVICE, TO COMMUNITY AND PATIENTS AND TO THE PUBLIC IS VERY IMPORTANT TO US. SO WE LOOK FORWARD TO WORKING WITH YOU. THANK YOU. [APPLAUSE] >> WITH THAT I CALL A CLOSE TO THE FIRST DAY OF THE 134th MEETING. THANK YOU.