GOG 0233/ACRIN 6671 UPDATE & CHALLENGES UTILITY OF PET/CT & USPIO MRI IN DETECTION OF LYMPHADENOPATHY IN LOCOREGINALLY ADVANCED CERVIX CANCER ACRIN 2008 FALL MEETING ACRIN GYNECOLOGY COMMITTEE

Evidence of disease outside of the pelvis or abdominal nodal region amenable to biopsy or sampling (i.e. intrahepatic, pulmonary, or thoracic or supraclavicular lymphadenopathy on PET/CT) No evidence of disease outside of the pelvis or abdominal nodal region amenable to biopsy or sampling (i.e. intrahepatic, pulmonary, or thoracic or supraclavicular lymphadenopathy on PET/CT) Pre-operative USPIO MRI (One MRIs will be performed hours after injection of COMBIDEX) and PET/CT Scan of the abdomen and pelvis and chest PET/CT Scan of the abdomen and pelvis and chest Locoregionally advanced, histologically confirmed invasive cervical cancer ( Stages IB2, IIA ≥4cm, Stages IIB-IVA) SCHEMA Advanced Lymph adenopathy not amenable to surgery

Evidence of disease outside of the pelvis or abdominal nodal region on PET/CT No evidence of disease outside of the pelvis or abdominal nodal region on PET/CT Extra-peritoneal or laparoscopic abdominal & pelvic lymph node sampling Chemo-Radiation Therapy to start within four weeks of enrollment into the study Lymphadenectomy abandoned, Chemotherapy Protocol for Advanced /Recurrent Disease Bx ( + ) Biopsy of metastatic disease outside of the pelvis or abdominal nodal region by FNA, core biopsy, or surgical biopsy Bx ( -) Advanced Lymph adenopathy not amenable to surgery

OBJECTIVES PRIMARY  Accuracy of CT/PET to detect abdominal lymph node metastasis  Accuracy of USPIO MRI to detect abdominal lymph node metastasis

EXTRA-PERITONEAL/LAPAROSCOPIC LYMPHADENECTOMY  Separate regional lymphadenectomy  Rt. & Lt. Obturator  Rt. & Lt. External Iliac  Rt. & Lt. Common Iliac  Para-caval & Lt. Para-aortic  Independent confirmation of ± disease/region  Intra-operative frozen section/biopsy for grossly positive LNs  Lymphadenectomy for negative LNs

SAMPLE SIZE AND INTERIM ANALYSIS  Sample size: 325 patients in 36 months

CENTRAL READER STUDY AT ACRIN/Reader’s Institution  7 Readers for PET/CT & 7 Readers for USPIO MRI  60 positive and 60 negative patients  Blinded independent review  Initial PET review followed by PET/CT  Initial USPIO insensitive review followed by USPIO MRI

IMAGE QUALITY REVIEW According to Protocol  First 3 MRI cases from each participating center will be reviewed  Random sample of MRI cases to be reviewed  The same QA for PET/CT at the headquarter

PROTOCOL CHANGE PRE & POST COMBIDEX MRI  Study Population (N=40)  Pre Combidex injection MRI  Day of PET/CT  Post Combidex MRI  24 – 36 hours  Separate analysis during central reader study

HISTORY  Initial CTEP approval: April 2007  Activation date: September 2007  Amendment # 4 approval: September 2008  Accrued patients: N = 20

STUDY CHALLENGES  Administrative  Site issues  20 sites have shown interest  11 IRB approved  7 sites “ready” to accrue  4 sites have accrued (N = 20)  Oklahoma: 17 patients accrued  MSH in NY: 1 patient accrued  Providence, RI: 1 patient accrued  Brown: 1 patient accrued

SITES OPENED TRIAL  UCLA: July 2008 (Oct 2008)  Transportation, Uninsured patients, PET/CT approval  Montefiore Medical Center: March 2008  Received ECLS certification Sept  Brown University Jan (Sept. 2008)  Did not have access to Combidex

STUDY CHALLENGES  Administrative  Site issues  20 sites have shown interest  18 or 11 IRB approved  7 sites “ready” to accrue  4 sites have accrued  Imaging issues

IMAGING ISSUES QA: First 3 cases & Random  COMBIDEX MRI  T2*  Use of Glucagon  Coverage  PET/CT  Use of separate PET & CT machines  Lack of contrast

IMAGING ISSUES QA: First 3 cases & Random  COMBIDEX MRI  T2*  Use of Glucagon  Coverage  PET/CT  Use of separate PET & CT machines  Lack of contrast

LESSONS LEARNED  We are doing an efficacy study  Any deviation from standard require close monitoring  Evaluation of innovation  Any deviation from surgical guidelines  Establish a true date for trial opening at a site

STUDY OPPORTUNITIES  First ACRIN study involving an IND agent  First ACRIN study involving FDA  First ACRIN study requiring SAE reporting  First ACRIN /GOG full cooperative study

ACRIN / RTOG Concept: ACRIN / RTOG Concept: Pre-treatment tumor parameters and intra- therapy tumor response as measured by FDG- PET/CT and DCE-MRI  Evaluates 2 functional imaging methods (targeting metabolism and perfusion) for characterizing primary tumor regarding susceptibility to RT  Intra-therapy FDG-PET/CT or DCE-MRI at 3 weeks predicts patient-specific response to treatment, as indicated by 3-month post-treatment FDG-PET/CT  Perfusion parameters determined by DCE-MRI can be used as biomarkers for response to anti- angiogenic chemotherapy

STUDY RESPONSIBILITIES ACRINGOG Registration+ Data Collection & Management & Analysis ++ Data Management Training ++ Imaging Training + Pathology+

STUDY RESPONSIBILITIES ACRINGOG AE reporting + Imaging Adverse Event Collection+ Surgery Adverse Event Collection+ Publication++

INSTITUTIONAL MRI TRAINING  Site MRI PIs invited  One day course at ACRIN headquarter  MH, MG, MA presentations  Review of cases on individual workstations  Test cases on workstations

LYMPH NODE SAMPLING  Lymph nodes < 1cm to be bisected from its hilum  Lymph nodes > 1cm to be sliced in 5 mm sections from the periphery   Size of the largest focus of cancer in a lymph node for each region (mm)   Short axis of the largest positive lymph node (mm)  The 120 cases for central reader study will be reviewed for pathology in a central review

SUBMISSION TO FDA/CTEP  March 2006: Submission to FDA/CTEP  April 2006: Response from FDA/CTEP  June 2006: Response to FDA/CTEP  Last correspondence: August awaiting final approval

PROTOCOL CHANGE  Addition of USPIO insensitive MRI review  Termination of Combidex injection  Anaphylaxis, systolic blood pressure <80 mmHg, O 2 saturation lower than 80%  Evidence of hypersensitivity defined as generalized rash, urticaria, or pruritis  Central review is allowed at the reader’s institution

IMAGE QUALITY REVIEW  First 3 MRI cases from each participating center will be reviewed by Dr Harisinghani (MGH)  Random sample of MRI cases to be reviewed by MA and JB  The same QA for PET/CT at the headquarter

COMBIDEX & FDA SUBMISSION  The FDA stated that it was willing to work with Advanced Magnetics on how to address the issues raised in the approvable letter.

HISTORY  2003 – 2004 GOG approved PET study became ACRIN approved ACRIN 6671 USPIO MRI and PET/CT  Dec 2004 GOG organizes final protocol development and submission to CTEP

COMBIDEX & FDA SUBMISSION  March 24, 2005: Advanced Magnetics, Inc. announced today that the Company received an approvable letter from (FDA) regarding Combidex, FDA requested additional data to demonstrate the efficacy of Combidex. The FDA suggested that the data be limited to a well defined population of specific cancer types.

OBJECTIVES SECONDARY (IMAGING)  Accuracy of PET/CT to detect pelvic and abdomen & pelvic combined LNM  Accuracy of USPIO MRI to detect pelvic and abdomen & pelvic combined LNM

OBJECTIVES SECONDARY (IMAGING)  To compare the accuracy of PET/CT and USPIO MRI for abdomen, pelvic, A&P combined LNM  To determine the added value of PET/CT to PET alone  To determine the added value of USPIO MRI to USPIO insensitive MRI

OBJECTIVES SECONDARY (NON-IMAGING)  To determine complications associated with laparoscopic or extra-peritoneal lymphadenectomy including delay or interruption of treatment  To determine the adverse effects of USPIO

HISTORY  2003 – 2004 GOG approved PET study became ACRIN approved ACRIN 6671 USPIO MRI and PET/CT  Dec 2004 GOG organizes final development and submission to CTEP  June 2005 GOG asked ACRIN to take over FDA and CTEP submission

SUBGROUP OF ENTIRE COHORT

LITERATURE REVIEW PET & CERVIX CANCER  PET meta-analysis (15 published series) p  Pelvic LNs  Sensitivity: 79% (95% CI 65%-90%)  Specificity: 99% (95% CI 96%-99%)  Para-aortic LNs  Sensitivity: 84% (95% CI 68%-94%)  Specificity: 95% (95% CI 89%-98%)  PET/CT: Pelvis & Para-aortic (N=47) pp  Sensitivity: 73%  Specificity: 97% P Havrilesky LJ, Gynecol Oncol 2005 pp Radiology 2006 pp Sironi S, Radiology 2006

LITERATURE REVIEW MRI COMBIDEX & CERVIX CANCER  Prostate cancer (N=80) P  Pelvic LN  Sensitivity: 100%  Specificity: 96%  Gynecology cancer: Pelvis & Para- aortic (N=44) pp  Sensitivity: 95%  Specificity: 91% P Harisinghani MG, N Engl J Med 2003 pp Journal of Clinical Oncology, 2005 pp Rockall AG, Journal of Clinical Oncology, 2005

STUDY RESPONSIBILITIES ACRINGOG Registration+ Data Collection & Management & Analysis + Pathology+ AE reporting + Imaging Training +

STUDY RESPONSIBILITIES ACRINGOG Data Management Training + Imaging Adverse Event Collection+ Surgery Adverse Event Collection+ Publication++

PATIENT ACCRUAL N = 21  Study opened: Sept  First patient accrued at Oklahoma Univ.  Oklahoma: 17 patients accrued  MSH in NY: 2 patients accrued  Brown: 1 patient accrued

SAMPLE SIZE AND INTERIM ANALYSIS  Sample size: 325 patients in 36 months  Interim analysis  30 positive cases & 30 negative cases  At 20 th month  AMAG agrees to “Go ahead” with Sensitivity > 60%

RATIONAL FOR A CLINICAL TRIAL  Limited data for PET/CT For Para-aortic LNs  Almost no data for Combidex MRI for Para- aortic LNs  Published Study Methodology  Single center  Node/node correlation