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Background of Pancreatic Cancer & NCIC CTG PA.3 Study Design

Background of Pancreatic Cancer & NCIC CTG PA.3 Study Design . Malcolm Moore, MD Professor of Medicine and Pharmacology Princess Margaret Hospital Chair, NCIC Clinical Trials Group — GI Committee. Pancreatic Cancer. US and Canada Approximately 35,400 new cases in 2005

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Background of Pancreatic Cancer & NCIC CTG PA.3 Study Design

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  1. Background of Pancreatic Cancer & NCIC CTG PA.3 Study Design Malcolm Moore, MD Professor of Medicine and Pharmacology Princess Margaret HospitalChair, NCIC Clinical Trials Group—GI Committee

  2. Pancreatic Cancer • US and Canada • Approximately 35,400 new cases in 2005 • Approximately 35,000 deaths in 2005 • 4th-leading cause of cancer-related deaths • Most patients are diagnosed with advanced disease • 5-year survival < 4%

  3. GemcitabineRegistration Study in Pancreatic Cancer † Composite of measurements of pain (analgesic consumption and pain intensity),Karnofsky performance status, and weight Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML,et al. J Clin Oncol. 1997;15:2403-2413

  4. Pancreatic Cancer 2005 • Limited treatment options • Gemcitabine is the only FDA-approved treatment • Attempts to improve outcome in advanced disease have been unsuccessful • Unmet medical need remains

  5. Study NCIC CTG PA.3 A Randomized, Placebo-Controlled Study of OSI-774 (Tarceva) Plus Gemcitabinein Patients with Locally Advanced, Unresectable or Metastatic Pancreatic Cancer

  6. Study NCIC CTG PA.3 • International study led by the NationalCancer Institute of Canada Clinical Trials Group (NCIC CTG) • Principal Investigator: Malcolm J. Moore, MD • NCIC CTG Physician Coordinator: Wendy Parulekar, MD • Co-sponsored by OSI Pharmaceuticals • Physicians and patients blinded to treatment assignment

  7. Study ConductRole of NCIC CTG • NCIC CTG • Served as overall study-coordinating center • Developed protocol, amendments, and CRFs • Provided medical monitoring and data management across all countries • Managed and monitored Canadian sites • Oversight provided by NCIC DSMC • Maintained clinical database blinded to treatment assignment • Performed statistical analyses after database lock and unblinding 08-08-05 Backup Catergories/Study Concuct.ppt

  8. Study ConductRole of OSI Pharmaceuticals • OSI Pharmaceuticals • Provided study drug and financial support • Recruited and managed CROs for non-Canadian sites • No access to clinical database prior to database lock and unblinding • Performed the statistical analyses for regulatory filing 08-08-05 Backup Catergories/Study Concuct.ppt

  9. Key Eligibility Criteria • Unresectable, locally advanced or metastatic adenocarcinoma of the pancreas • Measurable or nonmeasurable disease • ECOG performance status 0 to 2 • Prior radiotherapy for local disease allowed • No prior chemotherapy, except for 5-FU or gemcitabine as a radiosensitizer Note: EGFR-positive status not required

  10. Study Schema RANDOM I ZE Gemcitabine 1,000 mg/m2 IV + Tarceva daily PO Stratified by • Center • ECOG PS (0/1 vs 2) • Stage of disease(locally advanced vs distant metastases) 1:1 Gemcitabine 1,000 mg/m2 IV + Placebo daily PO Gemcitabine 1,000 mg/m2 IV Cycle 1: Days 1, 8, 15, 22, 29, 36, 43 of an 8-week cycle Cycle2 onward: Days 1, 8, 15 of a 4-week cycle

  11. Study Endpoints • Primary endpoint • Overall survival • Key secondary endpoints • Progression-free survival • Response rate • Quality of life (selected countries) • Assess tumor EGFR status with outcomes • Safety

  12. Statistical Considerations and Sample Size • Hazard ratio (HR): Relative risk of death for patients on Tarceva + gemcitabine, compared to those receiving placebo + gemcitabine • Study sample size based on an 80% power to detect hazard ratio of 0.75 (a 33% increase in survival) with a 5% level of significance • Minimum of 381 deaths required for an event-driven analysis • Sample size initially: 800 patients with accrual over9 months; minimum follow-up of 2.8 months • Modification of sample size to 450 during the study • Extension of follow-up to 18 months • No change in number of deaths for event-driven analysis

  13. Tarceva Dosage • Initial patients randomized at 100 mg • Plan for interim blinded safety analyses • Three safety analyses conducted after 8, 16, 50 patients entered at 100 mg • No safety concerns • Continued accrual worldwide at 100 mg • Entered patients at Canadian centers at 150 mg • Interim safety analysis at 150 mg (n = 16) • Over 85% of planned accrual achieved • Continued accrual at 100 mg to sample size of 450

  14. Study Timelines • 29 Nov 2001—First patient randomized • 31 Jan 2003—Last patient randomized (N = 569) • 13 Jan 2004—381st death in the 100 mg cohort documented in the NCIC CTG database • Final data cleaning initiated • 444 events occurred prior to 15 Jan 2004 • 17 Sep 2004 • Database locked and unblinded

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