An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients With Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine the side effects of treatment of the combination of nivolumab and daratumumab in participants with relapsed/refractory multiple myeloma.

Detailed Description
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NOTE: Currently, this study is only open to nivolumab+daratumumab vs daratumumab monotherapy in multiple myeloma patients.

Official Title
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Multiple Phase 1/2 Cohorts of Nivolumab Monotherapy or Nivolumab Combination Regimens Across Relapsed/Refractory Hematologic Malignancies

Conditions
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Non-Hodgkin's Lymphoma, Hodgkin Lymphoma, Multiple Myeloma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab
* Biological: Lirilumab
* Biological: Daratumumab
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Have received at least 3 prior lines of therapy, including a proteasome inhibitor [PI] and an immunomodulatory agent [IMiD] OR have disease that is double refractory to a PI and IMiD More than 12 weeks post-transplant of your own blood forming stem cells (autologous transplant) Have detectable disease measured by a specific protein in your blood and/or urine Must consent to bone marrow aspirate or biopsy. Exclusion Criteria: Solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia, or monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), primary amyloidosis, Waldenstrom's macroglobulinemia, POEMS syndrome or active plasma cell leukemia Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti CTLA 4, or anti-CD38 antibody, or allogeneic stem cell transplantation Seropositive for human immunodeficiency virus (HIV), Hepatitis B surface antigen or Hepatitis C antibody positive (except if HCV-RNA negative), or history of active chronic hepatitis B or C History of central nervous system involvement or symptoms suggestive of central nervous system involvement by multiple myeloma Other protocol defined inclusion/exclusion criteria could 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab monotherapy (Dose Escalation)<br>Nivolumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort | Biological: Nivolumab<br>* Administered by intravenous (IV) infusion<br>* Other names: Opdivo;|
| Experimental: Nivolumab + Ipilimumab<br>Nivolumab and Ipilimumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort | Biological: Nivolumab<br>* Administered by intravenous (IV) infusion<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Administered by IV infusion<br>* Other names: MDX010;|
| Experimental: Nivolumab + Lirilumab<br>Non-randomized Nivolumab: 3 mg/kg given every 2 weeks Lirilumab: 3 mg/kg given every 4 weeks Enrollment is closed for this cohort | Biological: Nivolumab<br>* Administered by intravenous (IV) infusion<br>* Other names: Opdivo;Biological: Lirilumab<br>* Administered by IV infusion<br>* Other names: BMS-986015;|
| Experimental: Nivo + Dara + Pom + Dexa vs. Nivo + Dara<br>Randomized Nivolumab: Cycle 1: 240 mg Day 15 Cycle 2-6: 240 mg Days 1, 15 Cycle 7 & beyond: 480 mg Day 1 Daratumumab: Cycle 1-2: 16 mg/kg Days 1, 8, 15, 22 Cycle 3-6: 16 mg/kg Days 1, 15 Cycle 7 & beyond: 16 mg/kg Day 1 Pomalidomide: 4 mg po (by mouth) daily on Days 1 - 21 of each 28-day cycle Dexamethasone: Weeks without daratumumab dosing: 40 mg po daily (Days 1, 8, 15, 22) of each 28-day cycle for participants ≤ 75 years old 20 mg po daily (Days 1, 8, 15, 22) of each 28-day cycle for participants > 75 years old Weeks with daratumumab dosing: 20 mg iv before the daratumumab infusion and 20 mg po after the daratumumab infusion in participants ≤ 75 years old 16 mg iv before the daratumumab infusion and 4 mg po after the daratumumab infusion in participants > 75 years old Enrollment is closed for this cohort | Biological: Nivolumab<br>* Administered by intravenous (IV) infusion<br>* Other names: Opdivo;Biological: Daratumumab<br>* Administered by IV infusion<br>* Other names: Darzalex;Drug: Pomalidomide<br>* Administered PO<br>* Other names: Pomalyst;Drug: Dexamethasone<br>* Administered PO and by IV infusion<br>* Other names: Intensol;|
| Experimental: Daratumumab vs. Nivolumab + Daratumumab<br>Randomized Nivolumab: Cycle 1: 240 mg Day 15 Cycle 2 & beyond: 480 mg Day 1 Daratumumab: Cycle 1-2: 16 mg/kg Days 1, 8, 15, 22 Cycle 3-6: 16 mg/kg Days 1, 15 Cycle 7 & beyond: 16 mg/kg Day 1 | Biological: Nivolumab<br>* Administered by intravenous (IV) infusion<br>* Other names: Opdivo;Biological: Daratumumab<br>* Administered by IV infusion<br>* Other names: Darzalex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced Drug Related Grade 3-4 AEs | Number and percent of participants that experienced drug related Grade 3-4 AEs occurring up to 100 days after the last dose of study drug. | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Number of Participants That Experienced Drug Related Grade 3-4 SAEs | Number and percent of participants that experienced drug related Grade 3-4 SAEs occurring up to 100 days after the last dose of study drug. | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade - Liver | Number and percent of participants that experienced drug related Grade 3-4 AEs occurring up to 100 days after the last dose of study drug. | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade - Thyroid |  | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Number of Participants That Experienced Drug-related Grade 3-4 AEs in the Nivolumab + Daratumumab Cohort |  | approximately up to 4 years | 
| Number of Participants That Experienced Drug-related Grade 3-4 SAEs in the Nivolumab + Daratumumab Cohort |  | approximately up to 4 years | 
| Number of Participants That Experience Drug-related Grade 3-4 SAEs in the Nivolumab + Daratumumab Cohort |  | approximately up to 4 years | 
| Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Hematology |  | approximately up to 4 years | 
| Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Liver |  | approximately up to 4 years | 
| Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Thyroid |  | approximately up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | the best response designation over the study as a whole, recorded between the date of first dose and the last efficacy assessment prior to subsequent therapy. Measured in Complete Response and Partial Response | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Best Overall Response - Multiple Myeloma Group | the best response designation over the study as a whole, recorded between the date of first dose and the last efficacy assessment prior to subsequent therapy. | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Duration of Response | the best response designation over the study as a whole, recorded between the date of first dose and the last efficacy assessment prior to subsequent therapy. Measured in Complete Remission and Partial Remission | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to approximately 37 months Nivo Liri: approximately up to 4 years 1 month | 
| Duration of Response - Multiple Myeloma Group | the best response designation over the study as a whole, recorded between the date of first dose and the last efficacy assessment prior to subsequent therapy. Measured in Complete Response and Partial Response | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to 5 months Nivo Liri: approximately up to 4 years 1 month | 
| Progression Free Survival | Progression free survival (PFS) is defined as the time between date of randomization and date of progression or death, whichever occurs first. Participants who died without a reported prior progression were considered to have progressed on the date of their death. Subjects who did not progress or die were censored on the date of their last efficacy assessment. | From date of randomization to date of progression or death, whichever occurs first (up to approximately 24 months) | 
| Progression Free Survival Rate | The percentage of participants remaining progression free at the specified timepoints (up to 48 Months) | From randomization to the specified timepoints (up to 48 months) | 
| Overall Survival | The percentage of participants remaining alive. Median values are computed using Kaplan-Meier method | Nivo Mono: approximately up to 6 years and 9 months Nivo Ipi: approximately up to3 years Nivo Liri: approximately up to 4 years 1 month | 
| Number of Participants With PD-L1 Expression | Number of Participants with PD-L1 expression in the following categories baseline PD-L1 expression ≥ 1% baseline PD-L1 expression < 1% without PD-L1 quantifiable at baseline | At baseline (prior to start of study treatment) | 
| Percentage Change From Baseline in the Modified Severity Weighted Assessment Tool (mSWAT) Score | mSWAT is a scoring technique involving the direct assessment of the percentage of body-surface-area (BSA) affected by skin lesions. There are 12 body regions (each one assigned a different percentage of BSA). For each body region, the assigned BSA percentage is multiplied by a factor weighing the type and severity of lesion observed (patch= x1, plaque = x2, tumor= x4). The sum of the individual body region sub-scores is then summed to generate the final mSWAT score, which ranges from 0 (best outcome) to 400 (worst outcome). | From baseline (last measurement before start of study treatment) to last available measurement after start of study treatment (88 weeks for Nivo mono, 93 weeks for nivo+ipi, 25 weeks for nivo+liri) | 
| Time to MRD Negativity Status in the Nivolumab + Daratumumab Cohort | Time to MRD Negativity status in specific NGS and NGF sensitivity levels | approximately up to 4 years | 
| Objective Response Rate in the Nivolumab + Daratumumab Cohort |  | approximately up to 4 years | 
| Duration of Response in the Nivolumab + Daratumumab Cohort |  | approximately up to 4 years | 
| Progression Free Survival in the Nivolumab + Daratumumab Cohort |  | approximately up to 4 years | 
| Cmax in the Nivolumab + Daratumumab Cohort | Maximum observed serum concentration | approximately up to 4 years | 
| Tmax in the Nivolumab + Daratumumab Cohort | Time of maximum observed serum concentration | approximately up to 4 years | 
| Cmin in the Nivolumab + Daratumumab Cohort | Serum concentration achieved at the end of dosing interval (trough concentration) | approximately up to 4 years | 
| AUC (0-T) in the Nivolumab + Daratumumab Cohort | Area under the plasma concentration-time curve from time zero to the last time of the last quantifiable concentration | approximately up to 4 years | 
| AUC (TAU) in the Nivolumab + Daratumumab Cohort | Area under the concentration-time curve in one dosing interval | approximately up to 4 years | 
| End of Infusion Nivolumab Concentration Levels in the Nivolumab + Daratumumab Cohort | Serum concentration achieved at the end of study drug infusion | Measurements collected at cycles 1, 2, 3, 5, 7, and 11; each cycle is 28 days |