A phase I study of q3W R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer

Abstract

3590 Background: Insulin-like growth factor receptor (IGF-1R) is a tyrosine kinase cell surface receptor overexpressed in cancer cells which mediates the mitogenic and anti-apoptotic actions of IGF, playing a key role in malignant transformation. The safety and pharmacokinetics of 3-weekly administration of R1507, a human monoclonal antibody selective for IGF-1R, were explored in this phase I dose escalation study in patients with advanced solid tumors or lymphomas. Materials and Methods: Multiple ascending doses of R1507 were administered as a 1 hour infusion every 3 weeks until the development of dose-limiting toxicity (DLT) or progressive disease. Inclusion criteria: ECOG PS 0–1, adequate hematologic, hepatic, and renal function, CD4 count >200/μl. Exclusion criteria: infection, immunosuppressive agents, diabetes mellitus, uncontrolled systemic disease, NYHA III/IV CHF. DLT defined as ≥ grade 2 hypersensitivity reaction; ≥ grade 3 non-hematologic toxicity; ≥ grade 2 cardiac toxicity; ≥ grade 3 hematologic toxicity = 7 days, or dose delay > 1 week due to toxicity. Blood samples were collected following 1st dose for non compartmental PK analysis and for future analysis of IGF-1R levels. Results: 21 patients (pts) (M:F 14:7) were enrolled in 1 of 4 dose levels (dose range 1–16 mg/kg). Mean pt age 57 yrs (range: 30–81), mean prior treatments 4.6 (range: 1–9). Mean treatment cycles 2.6 (range: 1- 6). Six pts remain on study. Adverse events (AE) included infection (6 pts), fatigue (4); rash, fever, arthralgia, cough, diarrhoea, abdominal and back pain (3 each). No DLT or serious AEs attributed to study drug were reported. Activity: 10 pts showed stable disease (median 33 days). PK: Clearance (CL) decreased from 812 mL/Day (Coefficient of Variation [CV] =19.9%) in the 1 mg/kg group to 418 mL/Day (CV=46.7%) in the 16 mg/kg group; Volume of distribution was in the range of 4.4 - 5.4 L (CV=10.9–34.8%). T1/2 increased from 4 to 9 days. Conclusions: Treatment with R1507 is tolerable at the dose of 16mg/kg q3W. Treatment-related toxicities are mild and clinically manageable. Decrease in CL across doses levels suggests a saturable elimination pathway. T1/2 value of ∼8 days supports a weekly dosing for future trials. [Table: see text]