Background: IGF-1R activation results in the phosphorylation of IRS-1 and the PI3-Kinase/Akt, mTOR and S6 kinase pathways in pancreatic cancer. Monoclonal antibody MK-0646 blocks IGF-1-receptor interaction, internalizes and degrades IGF-1R. Receptor cross-talk between IGF-1R and EGFR and IGF-1R-induced PI3-kinase mediates resistance to anti-EGFR agents. Prior phase I established the maximal tolerated dose of MK-0646 as 10 mg/kg with G and 5 mg/kg with G+E. Methods: Patients (pts) with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Phase II study has 3 arms and uses adaptive randomized design with progression-free survival (PFS) as primary endpoint: Arm A (G + MK-0646), Arm B (G + E + MK-0646) and Arm C (G + E). G was administered as 1,000 mg/m² over 100 min, weekly x 3, MK-0646 weekly x 4 and E 100 mg daily. Cycles repeated q 4 weeks. On progression, arm C pts crossed over to arm B. Secondary endpoints: overall survival (OS), response rate and toxicity. Results: 58 pts enrolled (53 evaluable), 34 males, 3 prior Whipple, 48 PS 1, 5 PS 0. Median of 2 cycles administered (range 1, 12+). Accrual: Arm A= 20, B=23, C=10 pts. Median follow up A=48, B=30, C=26 weeks. Grade 3-4 toxic events/ arm: neutropenia 9/A, 26/B, 1/C; platelets 5/A, 10/B; anemia 2/B; AST 3/B,3/C; hyponatremia 1/A, 5/B; hyperglycemia 3/A, 3/B; dehydration 1/B; thrombus 2/B and infection 2/B. Partial responses: 20% Arm A, 25% Arm B, 10% Arm C. Median PFS Arm A=17 weeks (CI:7,34), Arm B=8 weeks (8,18), Arm C= 8 weeks (3,22); PFS was significant in favor of arm A (p=0.0425). OS arm A=48 wks (14,82), B=30 wks (18,56), C=26 wks (8,40). No significant difference noted in OS in the 3 arms (p=0.4) in this cross-over study. Sustained responses (> 8 weeks) occurred in arms A and B only; greater proportion of arm A pts survived >40 weeks (p=0.04). Conclusions: MK-0646 is tolerable in combination with G; toxicities were higher with G+ E+ MK-0646. Sustained PRs, limited toxicity and encouraging survival were noted with G+ MK-0646 (arm A) in this preliminary analysis.