A phase IB study of AMG 479, a type 1 insulin-like growth factor receptor (IGF1R) antibody, in combination with panitumumab (P) or gemcitabine (G).

3583 Background: IGF1R signaling plays a key role in oncogenesis and protects some tumors from anti-cancer agents. AMG 479 is a fully human monoclonal antibody (IgG1) against IGF1R. It has exhibited single-agent activity in early clinical studies and additive effects with other therapies in preclinical models.,This phase 1b, open-label study of AMG 479 in combination with either P or G evaluates safety, pharmacokinetics, and the maximum tolerated dose of AMG 479 for each regimen. Patients (pts) with advanced solid tumors, ECOG 0-2, and without prior G (in G arm only) received P (6 mg/kg IV day 1 Q2 weeks) or G (1000 mg/m IV day 1, 8, and 15, Q4 weeks) in combination with AMG 479 in sequential dose escalating cohorts (6 or 12 mg/kg IV Q2 weeks) using a 3+3+3 design. Assessments included dose-limiting toxicities (DLT) during the first 21 days and WHO tumor response (Q8 wks).,As of 11/13/07, 18 pts were enrolled (arm P/G, n = 10/8); median age 57; 94% had prior chemo. In arm P (6 or 12 mg/kg AMG 479, n = 6/4) there was 1 DLT in the 6 mg/kg cohort (Grade 3 hyperglycemia). In arm G (6 mg/kg AMG 479, n = 8) there was 1 DLT (Grade 4 neutropenia). Treatment-emergent adverse events (AE) of any grade with n >2 Additional treatment-related Grade 3/4 AEs (P,G): AST/ALT (0,13%); hyperglycemia (10,0%). Clearance of AMG 479 in arm P and G was 12.0 ± 4.2 and 11.4 ± 4.9 mL/day/kg, respectively, similar to the Ph 1 monotherapy study (10.5 ± 4.1, n = 23). A partial response was observed on arm P (AMG 479 12 mg/kg) in a colon cancer patient (KRAS wild-type) who previously progressed on cetuximab. Stable disease as best response was noted in an additional 5 of 6 evaluable pts on arm P, and in 4 of 5 on arm G.,AMG 479 (12 mg/kg) appeared tolerable when combined with P and showed activity in refractory disease. AMG 479 (6 mg/kg) appeared tolerable when combined with G; accrual to the 12 mg/kg cohort is complete. Serum biomarker (IGF-1 and IGF binding protein 3) and tumor analyses (PIK3CA & RAS mutation) will be presented. [Table: see text] [Table: see text].