A phase I pharmacokinetic and pharmacodynamic study of AMG 479, a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R), in advanced solid tumors

Abstract

3002 Background: Increased IGF-1 signaling mediates tumor proliferation, reduces apoptosis, and correlates with higher incidence and progression of common cancers. AMG 479, a fully human monoclonal antibody against IGF-1R, exhibited broad antitumor activity in xenograft models, both as a monotherapy and with chemotherapy. Methods: Patients (pts) entered escalating dose cohorts of AMG 479 (from 1 to 20 mg/kg administered intravenously [IV] every two weeks [Q2W]). Study objectives were to determine safety, maximum tolerated dose (MTD), pharmacokinetic (PK) parameters, pharmacodynamic (PD) parameters of tumor glucose metabolism (FDG PET/CT), human anti- AMG 479 antibody formation, IGF-1R occupancy in neutrophils, and tumor response (CT RECIST, and PET/CT criteria). Results: Sixteen pts with advanced malignancies were treated with doses from 1 to 20 mg/kg. The median number of cycles was 3 (range 1 to 16). Grade 3 thrombocytopenia was considered dose limiting in 1 pt at 20 mg/kg. Other grade 3/4 non-hematologic toxicities were observed in 2 pts; no hyperglycemia greater than grade 2 was observed. Anti-AMG 479 antibodies, but not neutralizing antibodies, were detected in 1 pt. One pt had an infusion reaction (grade 2 chills/rigors resolving in 15 minutes) but could be retreated following premedication. AMG 479 exhibited dose-linear PK in the dose range from 1 to 20 mg/kg, reaching steady state after 3 doses; mean terminal t1/2 ranged from 7 to 11 days; mean serum clearance ranged from 9 to 14 mL/day/kg; Css exceeded IC90 measured in preclinical models. PD results indicated a trend to dose-proportional occupancy of IGF-1R in neutrophils and increased levels of serum IGF-1 and IGF-BP3 (40% and 20% on day 3, respectively). By CT RECIST criteria, 1 pt with a neuroendocrine tumor had a confirmed partial response and 5 pts had durable stable disease. By FDG-PET/CT criteria, 1 pt with breast cancer had a mixed response. Conclusions: AMG 479 appears to be well tolerated at doses up to 20 mg/kg IV Q2W; dose escalation is complete. AMG 479 administration resulted in PK values adequate for activity in preclinical models, saturable binding of IGF-1R in neutrophils, and preliminary anti-tumor activity. [Table: see text]