Study of Natalizumab in Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The primary objectives of the study are to evaluate the safety profile and the anti-tumor activity of 2 dose levels of natalizumab in participants with relapsed or refractory multiple myeloma. Secondary objectives are to assess the pharmacokinetic (PK) profile of natalizumab in this study population and to assess peripheral blood mononuclear cell (PBMC) saturation of very late antigen-4 (VLA-4, an α4-integrin) and evaluate possible correlations with clinical activity.

Detailed Description
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Despite no protocol-defined study stopping criteria being met, the sponsor decided to terminate enrollment after the phase 1 portion was complete and to not move into the phase 2 portion of the study. This decision was made due to difficulty enrolling participants and was not due to any safety concerns.

Official Title
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A Phase 1/2, Two-Arm, Dose-Finding Study of Natalizumab for the Treatment of Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: BG00002 (natalizumab)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Relapsed or refractory multiple myeloma that was treated with or was considered inappropriate for treatment with bortezomib and an IMiD® drug (including an analogue). Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. Corrected calcium <10.6 mg/dL. Key Exclusion Criteria: Candidates for stem cell transplantation willing to undergo transplantation. (Subjects who are candidates for stem cell transplantation, but are not willing to undergo transplant will be eligible for the study.) Autologous stem cell transplantation <3 months post-transplant. Prior allogeneic stem cell transplantation. Nonsecretory myeloma. Plasma cell leukemia (>2000/µL circulating plasma cells by standard cell counting differential), hyperleukocytosis (white blood cells >100,000/µL), clinical evidence of hyperviscosity syndrome, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS), or primary systemic amyloidosis. Subjects who cannot undergo a brain magnetic resonance imaging (MRI) study. Clinically significant (as determined by the Investigator) 12 lead electrocardiogram (ECG) abnormalities, including QTc prolongation (>450 ms in males, >470 ms in females). NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Natalizumab 300 mg<br>Intravenous (IV) infusions of natalizumab 300 mg once every 28 days for 6 months. | Drug: BG00002 (natalizumab)<br> <br> * Other names: Tysabri;|
| Experimental: Natalizumab 450 mg<br>Intravenous (IV) infusions of natalizumab 450 mg once every 28 days for 6 months. | Drug: BG00002 (natalizumab)<br> <br> * Other names: Tysabri;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLTs = any ≥grade 3 toxicity related to treatment; treatment delays of ≥7 days due to any toxicity related to treatment, with the exception of hepatic transaminases; or alanine and/or aspartate aminotransferase (ALT and/or AST) >3*upper limit of normal (ULN) with either a total bilirubin >2*ULN or an international normalized ratio (INR) >1.5 related to treatment, or with the appearance of worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia. | Day 1 up to Day 28 | 
| Objective Response Rate (ORR) | Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). | Day 1 up to Month 6 | 
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant administered medicinal (investigational) product and that does not necessarily have a causal relationship with this product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. See the adverse events section of the record for more details. | Day 1 up to Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Participants Who Achieve A Complete Response | Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). Complete Response (CR): negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas , and ≤ 5% plasma cells in the bone marrow. Stringent CR (sCR): CR as defined above, and normal free light chain (FLC) ratio, and absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence, based on a κ/λ ratio of > 4:1 or < 1:2 performed on a minimum of 100 plasma cells. | Day 1 up to Month 6 | 
| Kaplan-Meier Estimates for Duration Of Response For Participants With A Response | Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). Kaplan-Meier methods were used to estimate the median duration of response and associated 95% confidence intervals. | Day 1 up to Month 6 | 
| Pharmacokinetic (PK) Profile Of Natalizumab | PK modeling, either compartmental or noncompartmental-based, was used to describe serum concentrations. Standard PK parameters estimated include: area-under-the-concentration-time curve (AUC), maximum-observed concentration (Cmax), time-to-reach maximum concentration (Tmax), total body clearance (Cl), volume of distribution (Vd), and elimination half-life (t1/2). | Cycles 1 and 6: Day 1 (before infusion and 0.25, 2, 6 and 24 hours after infusion), Days 8, 15, 22. Cycles 2-5: Day 1 (before infusion and 0.25 hour after infusion) | 
| Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) |  | Cycle 1: Day 1 (1 hour before infusion and 1 and 24 hours after infusion), Days 8, 15, 22. Cycles 2-5: 1 hour before and 1 hour after infusion). Cycle 6: Day 1 (1 hour before infusion and 1 hour after infusion), Days 8, 15, 22. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed or refractory Multiple Myeloma