SWOG S0727: A randomized phase II trial of combination gemcitabine plus erlotinib plus IMC-A12 (cixutumumab) versus gemcitabine plus erlotinib as first-line treatment in patients (pts) with metastatic pancreatic cancer.

Abstract

TPS223 Background: A multitargeted approach in treating pancreatic cancer is rationalized by the multiple genetic abnormalities in this disease. In addition, evidence so far indicates that a single targeted treatment is unlikely to be effective. Insulin-like growth factor-1 receptor (IGF-1R) overexpression is observed and implicated in proliferation, survival, angiogenesis, and invasion. There is preclinical evidence of a cross talk between epidermal growth factor receptor (EGFR) and IGF-1R signaling pathways that may explain the acquired resistance to anti-EGFR drugs. SWOG reported a phase I evaluation of the combination of gemcitabine (1,000 mg/m2 i.v. days 1, 8, 15), erlotinib (100 mg po daily), and cixutumumab (6 mg/kg iv days 1, 8, 15, 22) of each 28-day cycle in chemonaive pts with metastatic pancreatic cancer. Ten pts were enrolled and assessed for toxicity. There was no apparent worsening of gemcitabine or erlotinib related toxicities by the addition of cixutumumab (Philip et al., GI Symposium 2010). Methods: The recommended phase II dose of cixutumumab 6 mg/kg/week in combination with standard dose and schedule of gemcitabine and erlotinib carried forward to the randomized phase II portion of the study, which has enrolled 38 pts to date. The primary endpoint for the phase II portion of this trial is progression-free survival (PFS). Pts are randomized to either Arm 1 (erlotinib + gemcitabine + cixutumumab) or Arm 2 (erlotinib + gemcitabine). Major inclusion criteria include metastatic disease, PS of 0-1, measurable or evaluable disease, and no prior gemcitabine. Major exclusions are AST/ALT > 2.5 × ULN, abnormal bilirubin, ANC < 1,500, or platelet < 100,000. Based on a type 1 error of 10% and 90% power and approximately 1.5 years of accrual and 1 year of follow-up, a planned sample size of 106 pts would be needed to detect an improvement in PFS from 2-3.3 months. Once 50% of the expected events in the control arm have occurred, an interim analysis of the primary endpoint will be performed with the intent of testing the alternative hypothesis (e.g., terminate early if a 1.65 hazard ratio is deemed highly unlikely [p< 0.005]). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Bristol-Myers Squibb, Curis, Nektar Therapeutics, OSI, Roche, sanofi-aventis OXiGENE Amgen, Bayer, Onyx, Roche, sanofi-aventis Bristol-Myers Squibb, Chugai Pharma, Genentech, Genvec, GlaxoSmithKline, ImClone Systems, Novartis, OSI, sanofi-aventis