ClinicalTrials.gov identifier: NCT

Transcription

1 ClinicalTrials.gov identifier: NCT RANDOMIZED PHASE 2 EVALUATION OF BEVACIZUMAB VERSUS BEVACIZUMAB/FOSBRETABULIN IN RECURRENT OVARIAN, TUBAL OR PERITONEAL CARCINOMA: A NRG ONCOLOGY AND GOG STUDY Bradley J. Monk, MD 1, Michael Sill, PhD 2, Joan L. Walker, MD 3, Paul A. DiSilvestro, MD 4, Greg Sutton MD 5, Krishnansu S. Tewari, MD 6, Eduardo R. Pajon, MD 7, Lainie P. Martin, MD8, Jeanne M. Schilder, MD 9, Robert L. Coleman, MD 10, Jai Balkissoon, MD 11, Carol Aghajanian, MD University of Arizona Cancer, Phoenix, AZ; 2. Gynecologic Oncology Group, NRG Oncology, Buffalo, NY; 3. University of Oklahoma Health Sciences Center, Oklahoma City, OK; 4. Women & Infants Hospital, Providence, RI; 5. Washington University School of Medicine, St. Louis, MO; 6. University of California, Irvine, Orange, CA; 7. Colorado Cancer Research Program CCOP, Denver, CO; 8. Fox Chase Cancer Center, Philadelphia, PA; 9. Indiana University Medical Center, Indianapolis, IN; 10. M.D. Anderson Cancer Center, Houston, TX; 11. Oxigene Inc., San Francisco, CA; 12. Memorial Sloan-Kettering Cancer Center, New York, NY

2 Relevant Faculty Disclosure X No, nothing to disclose Yes, please specify: Company Name Expenses Consulting/ Advisory Board Funded Research Royalties/ Patent Stock Options Ownership/ Equity Position Employee Other (please specify) Oxigene x x Genentech/Roche x x x Amgen x GlaxoSmithKline x x x

3 Proportion Surviving/Progression-Free Single Agent Bevacizumab is Active in Recurrent Ovarian Cancer Phase 2 trial of 62 patients Measurable disease 1 or 2 one prior cytotoxic regimens 21 % objective response rate 40.3% survived progression free for at least 6 months Median progression-free survival (PFS) = 4.7 months Median overall survival (OS) = 7 months No bowel perforations Activity not related to platinum sensitivity, age, number of prior regimens, or performance status Surv/PFS CensoredFailedTotal PFS Survival Months on Study Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: GOG Protocol 170D Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. J Clin Oncol Nov 20;25(33):

4 Vascular Disrupting Agents (VDAs): Target Established Tumor Vasculature Anti-angiogenesis agents target the migration, growth, and differentiation of new tumor associated endothelial cells Tumor blood flow before VDA* VDAs collapse and occlude established tumor blood vessels Blood flow reduction leads to tumor necrosis Unlikely to cause resistant mutations Broad combination potential: chemo and anti-angiogenic drugs Tumor blood flow after VDA* * Dynamic Contrast Enhanced - Magnetic Resonance Imaging (DCE-MRI) using the paramagnetic contrast agent gadopentetate dimeglumine (Gd-DTPA)

5 Fosbretabulin Fosbretabulin is a watersoluble prodrug of ciscombretastatin A4 (cis-ca4) Combretastatin A4 (CA4) is a natural product isolated from the African bush willow (Combretum caffrum)

6 Fosbretabulin: Mechanism-of-Action Potent and reversible tubulin depolymerizing agent Selectively targets immature endothelial cells typically seen in solid tumors Lack smooth muscle and pericytes, rely more on tubulin to maintain the flat shape of vessel wall Tubulin inhibition rounds up affected endothelial cells, obstructing blood vessel lumen Blockage at any point in a vessel segment will shut off blood flow upstream and downstream Leads to rapid cell death and necrosis

7 Phase Ib Fosbretabulin + Bevacizumab (Sustained Tumor Blood-Flow Inhibition ) Fosbretabulin Bevacizumab + Fosbretabulin DCE-MRI parameter changes Nathan PD et al Clin Cancer Res Jun 15;18(12):

8 Study Objectives- GOG 186i 1 2 Primary objective: To assess whether the addition of fosbretabulin to bevacizumab prolongs the duration of Progression Free Survival (PFS) Secondary objectives: To compare response rates and overall survival To evaluate adverse events in each arm

9 Key Subject Eligibility Criteria-GOG 186i Persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma Measurable or detectable disease 1 3 prior chemo regimens with no more than 1 non-platinum, non-taxane regimen PS of 0 2 if 1 prior regimen PS of 0 1 if 2 3 prior regimens Prior bevacizumab front-line allowed Acceptable organ function PS = Performance status

10 Phase II Study Design-GOG 186i Target n=103 Enrolled n=107 1:1 randomization Bevacizumab 15 mg/kg IV q3 weeks* (n=54) Bevacizumab 15 mg/kg + fosbretabulin 60 mg/m 2 IV q3 weeks* (n=53) *Treatment continued until disease progression or adverse events prohibited further therapy

11 Subject Stratification-GOG 186i Platinum-free interval PFI 182 days, 182 PFI 365 days or PFI > 365 Measurable disease status Prior use of bevacizumab therapy

12 Statistical Considerations-GOG 186i Superiority trial = 37.5% reduction in hazard rate considered important 1 Primary endpoint assessment 2 Secondary endpoints assessments Disease progression or death Cox proportional hazards according to stratification 82 events to achieve an 80% power with an alpha of 0.1 Objective tumor response ITT Objective tumor response among measurable disease by RECIST 1.1 Overall survival Adverse events by CTCAE v 4.0 PFS = Progression-Free Survival; CTCAE = Common Terminology Criteria for Adverse Events; RECIST = Response Evaluation Criteria in Solid Tumors; CA-125 = cancer antigen 125 test

13 Patient Demographics-1 Characteristic Category Bevacizumab Bevacizumab + fosbretabulin N % n % Age group Total >= Ethnicity Non-Hispanic Performance status Hispanic/Unknow n/unsp

14 Patient Demographics-2 Characteristic Category Bevacizumab Bevacizumab + fosbretabulin N % n % Cell type Serous Endometrioid Mixed Epithelial Adenocarcinoma No. of prior regimens Clear Cell Mucinous Prior Regimen Prior Regimens Prior Regimens

15 Patient Demographics-3 Bevacizumab + Bevacizumab Characteristic Category fosbretabulin N % n % Prior bevacizumab No Yes Measurable disease No Platinum sensitive Yes Platinum resistant Platinum sensitive Platinum sensitive >12 M

16 Patient Treatment Summary-GOG 186i Regimen Number entered Never treated Ineligible Toxicity evaluable 1 Bevacizumab Bevacizumab+fosbretabulin Total Patients who are Toxicity Evaluable excluded patients who had no adverse event data submitted or were ineligible

17 % of subjects Number of Cycles-GOG 186i Bevacizumab Median bevacizumab = 7 cycles Median bevacizumab + fosbretabulin = 6 cycles Bevacizumab + fosbretabulin Number of cycles

18 Proportion progression-free Progression-free Survival Analysis by Intention to Treat : Bev 2: Bev+Fos Events Total Median (mo) Months on Study Treatment comparison HR* 90% CI 1-sided P value Exp to ref [0.47, 1.00] *Hazard Ratios of the experimental level to the reference level of the treatment comparison were stratified by measurable disease status (Yes/No), prior bevacizumab use (Yes/No), and platinum sensitivity (>12 months/ 12 months) using a Cox proportional hazards model; Bev = bevacizumab; Bev+fos = bevacizumab+fosbretabulin

19 Proportion progression-free Progression-free Survival by Treatment Among platinum resistant subjects : Bev 2: Bev+Fos Events Total Median (mo) Months on Study Treatment comparison HR* Log-rank P value Exp to ref *Hazard Ratio of the experimental level to the reference level of the treatment comparison were stratified by measurable disease status (Yes/No) and prior bevacizumab use (Yes/No), using a Cox proportional hazards model. The C.I. is questionable and therefore not available, which may be due to the small number of patients within some strata; Bev = bevacizumab; Bev+fos = bevacizumab+fosbretabulin

20 Proportion progression-free Progression-free Survival by Treatment Among platinum sensitive subjects PFI >6M : Bev 2: Bev+Fos Events Total Median (mo) Months on Study Treatment comparison HR* 90% CI Log-rank P value Exp to ref 0.67 [0.43, 1.03] *Hazard Ratio of the experimental level to the reference level of the treatment comparison were stratified by measurable disease status (Yes/No), prior bevacizumab use (Yes/No), and platinum sensitivity (>12 months/ 12 months) using a Cox proportional hazards model; Bev = bevacizumab; Bev+fos = bevacizumab+fosbretabulin

21 Status and Response Rate-GOG 186i Characteristic Category Bevacizumab Bevacizumab + fosbretabulin N % n % Response Partial response Stable disease Increasing disease Indeterminate Non-measurable Pending Alive/cause of death Alive w/o progression Alive with progression Dead from disease Dead, neither Rx nor disease Dead, undetermined cause Total The relative probability of responding on the Bev+Fost arm to the Bev Only arm is 1.27 (among measurable disease patients). The odds ratio for responding on the Bev+Fost arm to the Bev Only arm is 1.41 (90% CI 0.58 ~3.47). Measurable disease ORR: Bevacizumab = 28.2% (90% CI 16.7 ~ 42.3%) among 39 patients Bevacizumab + fosbretabulin = 35.7% (90% CI 23.5 ~ 49.5%) among 42 patients Total

22 Proportion alive Overall Survival by Intention to Treat 1.0 1: Bev 2: Bev+Fos Events Total Median (mo) Months on Study Treatment comparison HR* 90% CI 2-sided P value Exp to ref 1.03 [0.56, 1.89] 0.94 *Hazard Ratios of the experimental level to the reference level of the treatment comparison were stratified by measurable disease status (Yes/No), prior bevacizumab use (Yes/No), and platinum sensitivity (>12 months/ 12 months) using a Cox proportional hazards model; Bev = bevacizumab; Bev+fos = bevacizumab+fosbretabulin

23 Reasons for Coming Off Study % of subjects that came off study On study/unspecified Disease progression Refusal Adverse events Other reason Bevacizumab Bevacizumab + fosbretabulin

24 Summary of Adverse Events System organ class Bevacizumab only (# of events) Bevacizumab + fosbretabulin (# of events) Grade Blood/Lymphatics Gastrointestinal Infections Investigations Metabolism/nutrition Musculoskeletal Nervous system Renal/urinary Resp/thoracic/mediastinal Vascular disorders

25 Phase II Safety Summary The proportion of grade 3 hypertension in the reference arm was 19.6% (10) vs 32.7% (17) in the combination arm. There were no grade 5 treatment related adverse events reported One grade 4 AE occurred in each treatment arm Bevacizumab One metabolism/nutrition related AE Bevacizumab + fosbretabulin One hypertension AE One bowel perforation in the bevacizumab arm All adverse events were manageable *AE adverse event

26 Overall Outcomes and Conclusions- PFS GOG 186i Median 4.8 months with bevacizumab vs. 7.3 months with combination The observed PFS HR was (90% 2-sided C.I. was 0.47 ~ 1.00) ORR (measurable): The proportion responding to bevacizumab was 28.2% of 39 patients The proportion responding to combination therapy was 35.7% of 42 patients The odds ratio for responding to the combination arm relative to the reference arm was 1.41 (90% CI 0.58 ~ 3.47) Conclusions: Based on the results of this study the combination regimen warrants further evaluation in ovarian cancer Fosbretabulin may increase the frequency of hypertension OS data are currently immature The OS HR was 1.03 (90% C.I ~ 1.89)

27 Acknowledgements Patients, Families and: Duke University Medical Center Women's Cancer Center of Nevada Northeast Georgia Medical Center University of Oklahoma Health Sciences Center Cedars-Sinai Medical Center University of Chicago University of Iowa Hospitals and Clinics John Muir Medical Center-Concord Campus Indiana University Hospital/Melvin and Bren Simon Cancer Center Women and Infants Hospital UC San Diego Moores Cancer Center Maine Medical Center-Bramhall Campus Providence Saint Joseph Medical Center Hartford Hospital Sudarshan K Sharma MD Limted-Gynecologic Oncology Sinai Hospital of Baltimore Cleveland Clinic Cancer Center/Fairview Hospital Northeast Georgia Medical Center Hillcrest Hospital Cancer Center Saint Joseph's Hospital and Medical Center Washington University School of Medicine Delaware/Christiana Care CCOP Saint Vincent Oncology Center Beebe Medical Center Mercy Hospital Miami Virginia Commonwealth University University of Massachusetts Memorial Health Care Saint Vincent Hospital Fox Chase Cancer Center Penrose-Saint Francis Healthcare Greenville Health System Cancer Institute CCOP Presbyterian - Saint Lukes Medical Center - Health One Exempla Lutheran Medical Center