Phase I Study of AVE1642 Anti IGF-1R Monoclonal Antibody in Patients with Advanced Multiple Myeloma.

Abstract Rationale: CD221 (IGF-1R) is aberrantly expressed in multiple myeloma (MM) and is associated with disease severity (Bataille et al, Haematologica2005;90:706). IGF-1R is thus an attractive therapeutic target in patients with advanced disease. Patients and methods: We have conducted an open-label dose escalation phase I study of AVE1642, anti IGF-1R monoclonal antibody, in patients with advanced MM. The primary objective was to determine the selected dose of AVE1642 administered every 3 weeks (q3w) based on pharmacokinetic (PK), pharmacodynamic (PD) parameters and dose limiting toxicities. The secondary objectives were to assess the safety profile, the biological activity (saturation of receptors) on peripheral granulocytes, the potential immunogenicity and preliminary clinical activity of AVE1642. Results: 14 patients have been treated with AVE1642 as IV infusion administered q3w (day 1 = day 22) at 3 different dose levels: 3 (n = 4), 6 (n = 6) and 12 mg/kg (n = 4). A median number of 2 infusions (1–8) were administered. AVE1642 was well tolerated, except reversible grade 3 hyperglycemia observed in 2 diabetic patients. No hypersensitivity during infusion was reported. No human antibody anti AVE1642 was detected. One patient with Bence-Jones MM experienced a decrease in proteinuria and relief of bone pain. Based on PK/PD results, the dose of 12 mg/kg of AVE1642 has been selected for further clinical evaluation in MM patients. Based on the in vitro synergistic activity of AVE1642 + bortezomib (Descamps et al, ASH2006, 845a), we have started a combination trial of AVE1642, 12 mg/kg q3w + bortezomib (1.3 mg/m2 at d1, d4, d8 and d11 q3w) in patients with advanced MM.