Open Label Study of the Anti Insulin-like Growth Factor 1 Receptor (IGF-1R) Monoclonal Antibody, AVE1642, as Single Agent (Dose Escalation, Part 1) and in Combination With Velcade® (Combination, Part 2) in Patients With Recurrent, Refractory Multiple Myeloma (MM)

Primary Objectives:

Study Part 1: Determine the selected dose of AVE1642 administered every 3 weeks based on pharmacokinetic (PK) (Clearance of AVE1642), pharmacodynamic (PD) (insulin-like growth factor 1 [IGF-1] serum level) parameters, and eventual dose limiting toxicities (DLTs) in patients with recurrent, refractory multiple myeloma (MM).

Study Part 2: Assess the safety of the combination of the selected dose of AVE1642 with the recommended dose of Velcade®.

Secondary Objectives :

Study Part 1:

• To assess the safety profile: type, incidence and intensity of drug related adverse events (AEs)
• To assess the biological activity of AVE1642 (saturation of the receptors and down-regulation) on malignant plasma cells and on peripheral blood mononuclear cells (PBMC) and granulocytes
• To assess the biological activity of AVE1642 on the signalization pathway of the IGF-1 system (phosphorylated akt [pAkt], phosphorylated erk [pErk]) on malignant plasma cells when technically possible
• To define PK profile of AVE1642, and its PD effects on serum IGF 1, GF 2 and IGFBP-3
• To assess clinical efficacy (complete response [CR], partial response [PR], minimal response [MR] and stabilization) based on the European group for Blood and Marrow Transplantation (EBMT) criteria, when possible
• To assess potential immunogenicity by detection of human antihumanized antibodies (HAHA) anti-AVE1642

Study Part 2:

• To detect any PK or PD interaction between AVE1642 and Velcade®
• To assess clinical efficacy (CR, PR, MR, no change [NC]) according to EBMT criteria when appropriate
• To assess biological activity of AVE1642 in combination with Velcade® on malignant plasma cells collected from bone marrow aspirates: saturation and down-regulation of the insulin-like growth factor 1 receptor (IGF-1R) and activity on the signalization pathway of the IGF-1 system (pAkt, pErk) when feasible
• To detect immunogenicity reaction (HAHA)
• To characterize PK and PD profile of a low dose (0.5 mg/kg) of AVE1642 expected to be non biologically active