A Phase 1/2, Multi-center, Open-label, Dose-escalation Study of Elotuzumab(Humanized Anti-CS1 Monoclonal IgG1 Antibody) and Bortezomib in Subjects With Multiple Myeloma Following One to Three Prior Therapies.

Study Overview
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Brief Summary
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This Phase 1/2, multi-center, open-label, multiple-dose, dose escalation study will evaluate the combination of elotuzumab and bortezomib in subjects with MM following 1 to 3 prior therapies. For the Phase 1 portion, elotuzumab will be administered by intravenous (IV) infusion at up to 4 dose levels ranging from 2.5 mg/kg to 20.0 mg/kg within 30 minutes following the administration of bortezomib at 1.3 mg/m^2 IV bolus. Bortezomib will be given in 21 day cycles (twice weekly for 2 weeks on Days 1, 4, 8, and 11 followed by a 10-day rest period). Elotuzumab will be administered as a separate infusion within 30 minutes following bortezomib administration on the same days as the first and last dose of each bortezomib cycle (i.e., Days 1 and 11).

Detailed Description
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The phase 2 portion of this study was not initiated because a decision was made to conduct a phase 2 randomized clinical trial.

Official Title
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A Phase 1/2, Multi-center, Open-label, Dose-escalation Study of Elotuzumab(Humanized Anti-CS1 Monoclonal IgG1 Antibody) and Bortezomib in Subjects With Multiple Myeloma Following One to Three Prior Therapies.

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Elotuzumab (HuLuc63)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males or females, age 18 years or older. Diagnosis of MM and documentation of 1 to 3 prior therapies. M-protein spike (complete immunoglobulin molecule) of >= 1g/dL in serum and/or >= 0.5 g excreted in a 24-hour urine collection sample. Light chain only disease is not an inclusion criteria. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. No prior bortezomib treatment OR responsive (PR or better) to prior bortezomib treatment for a minimum of 3 months OR responsive to prior bortezomib treatment at the time of going to another treatment or ceasing treatment. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <=3 x upper limit of normal (ULN). Total bilirubin <=2 x ULN. Serum creatinine <=2.0 mg/dL (unless related to MM, then <=3.0 mg/dL). Must have adequate bone marrow function defined as: Absolute neutrophil count >1,000 cells/mm3 (1.0 x 10^9 cells/L) without growth factor support for 7 days; Platelets >=75,000 cells/mm3 (75 x 10^9 cells/L) without transfusion within 72 hours of screening; Hemoglobin >=8 g/dL without red blood cell transfusion within 2 weeks of screening; Serum calcium (corrected for albumin) level at or below ULN range (treatment of hypercalcemia is allowed and subject may enroll if hypercalcemia returns to normal with standard treatment); additional screening time may be allowed for confirmation - consult with sponsor's medical monitor. Use of appropriate contraception where applicable. Negative urine pregnancy test where applicable. Must have 2-dimensional echocardiogram indicating left ventricular ejection fraction (LVEF) >=45% within 30 days prior to the first dose of elotuzumab. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations). Exclusion Criteria Life expectancy of less than 3 months. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years. Uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary,(including acute diffuse infiltrative pulmonary and pericardial disease), hepatic, and renal diseases unless renal insufficiency is felt to be secondary to MM. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia. Prior treatment with bortezomib in 3 months prior to the first dose. Thalidomide, lenalidomide cytotoxic chemotherapy, or corticosteroids (except prior to infusion of first dose of study drug as prophylaxis for infusion reactions) within 2 weeks of the first dose of elotuzumab. Prior therapy with anti-CD56+ therapeutics. Radiotherapy within 2 weeks prior to the first dose of elotuzumab. Investigational drug within 3 weeks or 3x the half-life of the investigational drug (whichever is longer ) of the first dose of elotuzumab. Prior peripheral stem cell transplant within 12 weeks of the first dose of elotuzumab. Nitrogen mustard agents, melphalan, or monoclonal antibodies within 6 weeks of the first dose of elotuzumab. Neuropathy >=Grade 2 (NCI CTCAE v3.0). Current orthostatic hypotension. Known active infections requiring antibiotic, antiviral, or antifungal therapy. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation. Any condition that in the investigator's opinion makes the subject unsuitable for study participation. Hypersensitivity to recombinant proteins or excipients in elotuzumab or bortezomib.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>2.5 mg/kg | Drug: Elotuzumab (HuLuc63)<br>* Cohort 1 - 2.5 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 2 - 5.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 3 - 10.0 mg/kg elotuzumab IV withbortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; and Cohort 4 - 20.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8.<br>* Other names: Elotuzumab;|
| Experimental: Cohort 2<br>5.0 mg/kg | Drug: Elotuzumab (HuLuc63)<br>* Cohort 1 - 2.5 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 2 - 5.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 3 - 10.0 mg/kg elotuzumab IV withbortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; and Cohort 4 - 20.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8.<br>* Other names: Elotuzumab;|
| Experimental: Cohort 3<br>10.0 mg/kg | Drug: Elotuzumab (HuLuc63)<br>* Cohort 1 - 2.5 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 2 - 5.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 3 - 10.0 mg/kg elotuzumab IV withbortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; and Cohort 4 - 20.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8.<br>* Other names: Elotuzumab;|
| Experimental: Cohort 4<br>20.0 mg/kg | Drug: Elotuzumab (HuLuc63)<br>* Cohort 1 - 2.5 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 2 - 5.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; Cohort 3 - 10.0 mg/kg elotuzumab IV withbortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8; and Cohort 4 - 20.0 mg/kg elotuzumab IV with bortezomib on Days 1 & 11, with only Bortezomib IV on Days 4 & 8.<br>* Other names: Elotuzumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify the maximum tolerated dose of elotuzumab in combination with bortezomib (phase 1). | The highest dose level of elotuzumab at which <= 1 dose-limiting toxicity occurs in 6 subjects | First cycle of treatment. | 
| Evaluate the efficacy of elotuzumab in combination with bortezomib (phase 2). | Objective response rate (complete and partial response) according to European Group for Blood and Marrow Transplantation (EBMT) criteria | Screening to the 30 day follow up visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of elotuzumab in combination with bortezomib (phase 1). | Objective response rate according to EBMT criteria, duration of response, time to progression, and progression-free survival | Screening to the 30 day follow up visit. | 
| Evaluate the safety of elotuzumab in combination with bortezomib (phase 1 and 2). | Frequency, severity, and relationship of adverse events and serious adverse events with the combination of elotuzumab and bortezomib | Screening to the 30 day follow up visit. | 
| Evaluate the pharmacokinetic parameters of elotuzumab in combination with bortezomib (phase 1 and 2) | Pharmacokinetic profile | Screening to the 30 day follow up visit. | 
| Evaluate the immunogenicity of elotuzumab in combination with bortezomib (phase 1 and 2). | Incidence of elotuzumab-specific antidrug antibodies | Screening to the 30 day follow up visit. | 
| Evaluate the pharmacodynamics of elotuzumab in combination with bortezomib (phase 1 and 2). | Changes in pharmacodynamic endpoints as they relate to dose, response, and toxicity of elotuzumab in combination with bortezomib | Screening to the 30 day follow up visit. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Patients After One to three Prior Therapies