Study of AVE1642 Anti-IGF1R Monoclonal Antibody in Patients With Advanced Multiple Myeloma

Study Overview
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Brief Summary
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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

Official Title
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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)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: AVE1642
* Drug: Velcade


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multiple myeloma confirmed by bone marrow aspirate or biopsy Patient had to have relapsed and/or refractory multiple myeloma after at least 1 standard therapy, and have demonstrated disease progression Previous exposure to Velcade was allowed, provided no DLTs of Grade 3 or above had been observed during previous treatment (for Part 2 of the study only) Exclusion Criteria: Prior therapy with any IGF-1 system targeting compound History of allogenic stem cell transplantation in case of concomitant immunosuppressive therapy within 6 months before study entry. Patients having undergone autologous stem cell transplantation(s) may have been included in the study History of organ transplant and any patient receiving long term systemic immunosuppressive therapy The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVE1642/ AVE1642 with Velcade<br> | Drug: AVE1642<br>* For Part 1, AVE1642 was administered on Day 1 and then every three weeks intra-venously with the dose escalation step starting at 3 mg/kg/infusion with a classical dose escalation schema of 3+3. For Part 2, AVE1642 was administered at doses ranging from 0.5 mg/kg to 12 mg/kg<br>Drug: Velcade<br>* For Part 2 ONLY, fixed dose of 1.3 mg/m² administered on Days 1, 4, 8, and 11.<br>* Other names: Bortezomib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| definition of the Selected Dose (SD) | Selected Dose will be based on the AVE1642 clearance /IGF-1 plateaus and on safety (less than 33% of pts with dose limiting toxicity (DLT)when administered as single agent in a first part of the study. The safety and pharmacokinetics of the regimen in combination with bortezomib will be assessed in the second part of the study | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the efficacy (complete, partial, minimal responses and stabilizations) | According to the European Group for Blood and Marrow Transplantation (EBMT) criteria when appropriate (e.g. baseline M Protein, % Plasma Cells in Bone Marrow,skeletal disease status and at least one evaluable post-baseline assessment) | 2 years | 
| Pharmacokinetic drug interaction between AVE1642 and Velcade (part 2) |  | Day 22 |