Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

Abstract

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]