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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma; Hodgkin Lymphoma; Non-Hodgkin's Lymphoma
• Intervention / Treatment: Biological: Nivolumab; Biological: Ipilimumab; Biological: Lirilumab; Biological: Daratumumab; Drug: Pomalidomide; Drug: Dexamethasone

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 316
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Local Institution - 0045
  • Sint-Niklaas, Belgium, 9100
    • Local Institution - 0047
  • Yvoir, Belgium, B-5530
    • Local Institution
• France
  • Nantes Cedex 1, France, 44000
    • Local Institution - 0044
  • Vienne
    • Poitiers, Vienne, France, 86021
      • Local Institution - 0043
• Greece
  • Athens, Greece, 11528
    • Local Institution - 0039
• Italy
  • Bologna, Italy, 40138
    • Local Institution
• Poland
  • Chorzow, Poland, 41-500
    • Local Institution
  • Poznan, Poland, 61-848
    • Local Institution - 0040
  • Warszawa, Poland, 02-776
    • Local Institution - 0049
  • Wroclaw, Poland, 50-367
    • Local Institution - 0042
• United States
  • California
    • Clovis, California, United States, 93611
      • Local Institution - 0035
    • Los Angeles, California, United States, 90095
      • Division Of Hematology & Oncology Ctr. For Health Sciences
    • Los Angeles, California, United States, 90095
      • Local Institution - 0012
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Local Institution - 0017
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Florida
    • Orlando, Florida, United States, 32804
      • Local Institution - 0023
  • Illinois
    • Skokie, Illinois, United States, 60077
      • Local Institution - 0037
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Local Institution - 0019
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Local Institution - 0018
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • The Sidney Kimmel Comprehensive Cancer Center
    • Baltimore, Maryland, United States, 21231
      • Local Institution - 0003
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0009
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 0015
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Ann Arbor, Michigan, United States, 48109
      • Local Institution - 0011
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Rochester, Minnesota, United States, 55905
      • Local Institution - 0002
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Local Institution - 0033
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center
    • Hackensack, New Jersey, United States, 07601
      • Local Institution - 0014
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Local Institution - 0001
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Local Institution - 0028
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU Center for Hematologic Malignancies
    • Portland, Oregon, United States, 97239
      • Local Institution - 0006
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Local Institution - 0007
    • Philadelphia, Pennsylvania, United States, 19111
      • Local Institution - 0004
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute At The Univ. Of Utah
    • Salt Lake City, Utah, United States, 84112
      • Local Institution - 0005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab monotherapy (Dose Escalation); Nivolumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort	Biological: Nivolumab; Administered by intravenous (IV) infusion; Other Names: BMS-936558; Opdivo
Experimental: Nivolumab + Ipilimumab; Nivolumab and Ipilimumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort	Biological: Nivolumab; Administered by intravenous (IV) infusion; Other Names: BMS-936558; Opdivo; Biological: Ipilimumab; Administered by IV infusion; Other Names: BMS-734016; Yervoy; MDX010
Experimental: Nivolumab + Lirilumab; 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; Administered by intravenous (IV) infusion; Other Names: BMS-936558; Opdivo; Biological: Lirilumab; Administered by IV infusion; Other Names: BMS-986015
Experimental: Nivo + Dara + Pom + Dexa vs. Nivo + Dara; 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; Administered by intravenous (IV) infusion; Other Names: BMS-936558; Opdivo; Biological: Daratumumab; Administered by IV infusion; Other Names: Darzalex; Drug: Pomalidomide; Administered PO; Other Names: Pomalyst; Drug: Dexamethasone; Administered PO and by IV infusion; Other Names: Intensol
Experimental: Daratumumab vs. Nivolumab + Daratumumab; 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; Administered by intravenous (IV) infusion; Other Names: BMS-936558; Opdivo; Biological: Daratumumab; Administered by IV infusion; Other Names: Darzalex

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Janssen, LP
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, Millenson MM, Cohen AD, Schuster SJ, Lebovic D, Dhodapkar M, Avigan D, Chapuy B, Ligon AH, Freeman GJ, Rodig SJ, Cattry D, Zhu L, Grosso JF, Bradley Garelik MB, Shipp MA, Borrello I, Timmerman J. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016 Aug 10;34(23):2698-704. doi: 10.1200/JCO.2015.65.9789. Epub 2016 Jun 6.
• Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015 Jan 22;372(4):311-9. doi: 10.1056/NEJMoa1411087. Epub 2014 Dec 6.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2012
• Primary Completion (Actual): September 25, 2020
• Study Completion (Estimated): December 22, 2023

Study Registration Dates

• First Submitted: May 3, 2012
• First Submitted That Met QC Criteria: May 4, 2012
• First Posted (Estimated): May 7, 2012

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immune Checkpoint Inhibitors; Dexamethasone; Pomalidomide; Nivolumab; Daratumumab; Ipilimumab
• Other Study ID Numbers: CA209-039; 2018-001030-17 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No