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Chemotherapy for pancreatic cancer

A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: A preliminary analysis of CALGB 80303.

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Chemotherapy for pancreatic cancer

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  1. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: A preliminary analysis of CALGB 80303 Hedy Lee Kindler, Donna Niedzwiecki, Donna Hollis, Ebele Oraefo, Deborah Schrag, Herbert Hurwitz, Howard McLeod, Mary Mulcahy, Richard Schilsky, and Richard Goldberg for the Cancer and Leukemia Group B

  2. Chemotherapy for pancreatic cancer • Gemcitabine • Cornerstone of treatment • Response rates 5-10% • Median survival 5-6 months • Many gemcitabine doublets • ‘Promising activity’ in phase II studies • No survival benefit in phase III trials • Phase III trial: Gemcitabine + erlotinib • Modest improvement in overall survival

  3. Vascular endothelial growth factor:A key role in pancreatic cancer biology • VEGF • Over-expressed in PC • Inhibition of VEGF • Suppresses PC growth in preclinical models • High VEGF expression • Correlates with advanced stage and decreased survival

  4. Gemcitabine + bevacizumab in advanced pancreatic cancer • Bevacizumab • Monoclonal antibody to VEGF • Phase II trial: Gemcitabine + bevacizumab1 • 52 patients with stage IV PC • Partial response rate: 21% • Median survival: 8.8 months • 1-year survival: 29% 1Kindler et al, JCO 23: 8033-8040, 2005

  5. CALGB 80303 Trial design R A N D O M I Z E Gemcitabine Bevacizumab Advanced pancreatic cancer N=590 Gemcitabine Placebo • Stratification: • Performance status: 0/1 vs. 2 • Extent of disease: metastatic vs. locally advanced • Prior radiation: yes/no

  6. Statistics • 90% power to detect a 35% increase in median overall survival from 6.0 to 8.1 months (2 sided logrank  =0.05) • Toxicity monitoring for bleeding, proteinuria, HTN, and thrombosis • Five planned interim analyses for the primary endpoint of overall survival (3 during accrual, 2 during follow-up)

  7. CALGB 80303: Endpoints Primary Endpoint: • Overall survival Secondary Endpoints: • Objective response rate • Duration of response • Progression-free survival • Toxicity

  8. Three companion studies to CALGB 80303 Clinical Economics/Quality of Life Presented at ASCO 2007: • Oral Session: Patient and Survivor Care Abstract #9008  • D. Romanus, et al: Does health-related quality of life improve for pts who respond to chemotherapy? Analysis of pts with advanced pancreas cancer receiving gemcitabine on CALGB study 80303 • Poster discussion: Upper GI Cancer Abstract #4524 • D. Schrag, et al: A patterns-of-care study of post-progression treatment among patients with advanced pancreas cancer after gemcitabine therapy on CALGB study 80303 Angiogenesis biomarker study Pharmacogenomic predictors of outcome • Will be reported at a later date

  9. Eligibility-1 • Histologically/cytologically confirmed unresectable pancreatic adenocarcinoma • No prior chemotherapy for metastatic disease • > 4 weeks from adjuvant chemo or radiation • No prior gemcitabine, bevacizumab, or other VEGF inhibitor • ECOG PS 0-2 • Adequate hematologic, hepatic, renal function, <1+ proteinuria

  10. Eligibility-2 • No documented invasion of adjacent organs • No recent invasive surgical procedures • Surgery >28 days, FNA >7 days • No significant bleeding episodes in prior 6 months, no esophageal varices • Anticoagulants permitted, on a stable therapeutic dose • No clinically significant cardiovascular disease • Written informed consent

  11. CALGB 80303: Treatment R A N D O M I Z A T I O N Gemcitabine 1000 mg/m2 D 1, 8, 15 Bevacizumab 10 mg/kg D 1, 15 Gemcitabine1000 mg/m²D 1, 8, 15 Placebo D 1, 15 1 cycle = 28 days CT scans: obtained every 2 cycles

  12. CALGB 80303: Trial progress Activated: June 30, 2004 Enrollment completed: April 14, 2006 Final accrual: 602 patients Contributors: CALGB, ECOG, CTSU Study unblinded: June 26, 2006 Current analysis database frozen: May 7, 2007 Number of events (deaths) observed: 500 (>100% of the total expected deaths at planned final analysis)

  13. Release of study data on CALGB 80303 • Based on a protocol-specified interim analysis, with 64% of information on overall survival, the CALGB Data Safety Monitoring Board released study data in June 2006 because a futility boundary was crossed • The DSMB felt that it was unlikely that there would be significant differences in overall survival between treatment arms with further follow-up • All patients on treatment were unblinded and notified of these results • Patients thought to benefit from bevacizumab could continue it with informed consent

  14. Patient characteristics

  15. CALGB 80303: Dose Delivery

  16. CALGB 80303: Grade ¾ toxicity

  17. CALGB 80303: Objective Response

  18. CALGB 80303: Survival

  19. CALGB 80303: Progression-Free Survival by Treatment Arm Bevacizumab 4.9 mo Placebo 4.7 mo HR = 1.00 P = 0.99 HR=1.00 p=0.99

  20. CALGB 80303: Overall Survival by Treatment Arm Bevacizumab 5.8 moPlacebo 6.1 mo HR = 1.03 P = 0.78

  21. CALGB 80303: Overall Survival by Disease Stage Metastatic 5.7 mo Locally advanced 9.9 mo HR = 1.4 P = 0.009

  22. CALGB 80303: Overall Survival by Performance Status PS 0: 8.0 mo PS 1: 4.8 mo PS 2: 2.8 mo P = 0.0001 p=0.0001

  23. Patient characteristics in phase II and III trials of gemcitabine + bevacizumab

  24. CALGB 80303: Conclusions • The addition of bevacizumab to gemcitabine does not improve survival in patients with advanced pancreatic cancer • The distribution of patients with good prognostic factors likely accounts for differences between CALGB 80303 and the prior phase II trial, and confirms the need for randomized trials in this disease • It is anticipated that the companion studies of angiogenesis biomarkers, pharmacogenomics, and clinical economics/quality of life will provide additional insights into the biology and clinical management of advanced pancreatic cancer

  25. Acknowledgments • The patients who participated in this study • CALGB Statistical Center and Central Office: • Donna Niedzwiecki, Donna Hollis, Ebele Oraefo, Susan Sutherland, Sarah Duggan • National Cancer Institute: • Margaret Mooney, Helen Chen • Genentech: • Eric Hedrick, Robert Mass • The many CALGB, ECOG, and CTSU investigators, nurses, and data managers who enrolled and took care of the patients on this trial

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