Abstract B121: Phase I study of MK-0646, a humanized monoclonal antibody against IGF-1R in combination with gemcitabine or gemcitabine + erlotinib (E) for advanced previously untreated pancreatic cancer

Abstract

Abstract Background: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/Akt signaling. Collectively, these pathways are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. IGF-1R + EGFR antagonists result in synergistic anti-tumor activity in preclinical pancreatic cancer models. Methods: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0–1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Arm A: G 1000 mg/m2 over 100 min, weekly × 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly × 4; Arm B: same schedule of G and MK-0646 as Arm A + E 100 mg daily. Cycles were repeated every 4 weeks. Radiologic responses measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival (PFS), response rate, toxicity and overall survival. Results: 22 pts enrolled, 15 males, 2 priorWhipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1–8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Two dose limiting toxicities observed in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Best radiologic responses: 6 PR (including 1 hepatic CR), 7 PD, 3 SD, 4 too early, 1 not evaluated, 1 not treated. PFS range in weeks for evaluable patients (n=12) was (4, 36+). Conclusion: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B121.