Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for ganitumab (GAN, AMG 479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC).

4049 Background: GAN is an investigational, fully human monoclonal antibody against IGF1R. In a phase II study, 125 patients (pts) with mPC were randomized 1:1:1 to GAN +G, placebo (P) +G, or conatumumab + G. Addition of GAN (12 mg/kg IV, Q2W) to G (1,000 mg/m2) showed evidence of improved OS and PFS (Kindler, JCO 2010:28 abstr 4035). An E-R analysis was done to inform P3 dose selection for GAN. Methods: GAN PK was estimated via a population PK model. An E-R analysis was performed with pts from the GAN+G and P+G arms (~40 pts/arm). The effect of estimated steady-state area under the curve (AUCss) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS-AUCss and PFS-AUCss associations were assessed by multivariate analysis. Exposure-safety data were analyzed with descriptive statistics and linear regression. P3 doses for GAN were explored with Monte Carlo simulations using population PK and parametric survival models. Results: There was a positive as...