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

• ClinicalTrials.gov Identifier: NCT01592370
• Recruitment Status: Active, not recruiting
• First Posted: May 7, 2012
• Results First Posted: February 17, 2022
• Last Update Posted: September 13, 2023
• Sponsor: Bristol-Myers Squibb
• Collaborator: Janssen, LP
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: May 3, 2012
• First Posted Date: May 7, 2012
• Results First Submitted Date: September 24, 2021
• Results First Posted Date: February 17, 2022
• Last Update Posted Date: September 13, 2023
• Actual Study Start Date: August 2, 2012
• Actual Primary Completion Date: September 25, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2022)

• Number of Participants That Experienced Drug Related Grade 3-4 AEs [ Time Frame: 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 and percent of participants that experienced drug related Grade 3-4 AEs occurring up to 100 days after the last dose of study drug.
• Number of Participants That Experienced Drug Related Grade 3-4 SAEs [ Time Frame: 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 and percent of participants that experienced drug related Grade 3-4 SAEs occurring up to 100 days after the last dose of study drug.
• Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade - Liver [ Time Frame: 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 and percent of participants that experienced drug related Grade 3-4 AEs occurring up to 100 days after the last dose of study drug.
• Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade - Thyroid [ Time Frame: 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 [ Time Frame: approximately up to 4 years ]
• Number of Participants That Experienced Drug-related Grade 3-4 SAEs in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
• Number of Participants That Experience Drug-related Grade 3-4 SAEs in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
• Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Hematology [ Time Frame: approximately up to 4 years ]
• Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Liver [ Time Frame: approximately up to 4 years ]
• Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Thyroid [ Time Frame: approximately up to 4 years ]

Original Primary Outcome Measures (submitted: May 4, 2012)

Safety and tolerability of BMS-936558 as measured by the occurrence of AEs, SAEs, deaths, hematologic laboratory abnormalities, serum chemistry laboratory abnormalities, and changes in blood pressure and heart rate measurements [ Time Frame: Up to 100 days after the last treatment (expected to be no more than 225 weeks) ]

• AEs = adverse events
• SAEs = serious adverse events

Current Secondary Outcome Measures (submitted: January 27, 2022)

• Best Overall Response [ Time Frame: 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 ]
  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
• Best Overall Response - Multiple Myeloma Group [ Time Frame: 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 ]
  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.
• Duration of Response [ Time Frame: 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 ]
  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
• Duration of Response - Multiple Myeloma Group [ Time Frame: 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 ]
  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
• Progression Free Survival [ Time Frame: From date of randomization to date of progression or death, whichever occurs first (up to approximately 24 months) ]
  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.
• Progression Free Survival Rate [ Time Frame: From randomization to the specified timepoints (up to 48 months) ]
  The percentage of participants remaining progression free at the specified timepoints (up to 48 Months)
• Overall Survival [ Time Frame: 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 ]
  The percentage of participants remaining alive. Median values are computed using Kaplan-Meier method
• Number of Participants With PD-L1 Expression [ Time Frame: At baseline (prior to start of study treatment) ]
  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
• Percentage Change From Baseline in the Modified Severity Weighted Assessment Tool (mSWAT) Score [ Time Frame: 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) ]
  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).
• Time to MRD Negativity Status in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  Time to MRD Negativity status in specific NGS and NGF sensitivity levels
• Objective Response Rate in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
• Duration of Response in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
• Progression Free Survival in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
• Cmax in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  Maximum observed serum concentration
• Tmax in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  Time of maximum observed serum concentration
• Cmin in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  Serum concentration achieved at the end of dosing interval (trough concentration)
• AUC (0-T) in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  Area under the plasma concentration-time curve from time zero to the last time of the last quantifiable concentration
• AUC (TAU) in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  Area under the concentration-time curve in one dosing interval
• End of Infusion Nivolumab Concentration Levels in the Nivolumab + Daratumumab Cohort [ Time Frame: Measurements collected at cycles 1, 2, 3, 5, 7, and 11; each cycle is 28 days ]
  Serum concentration achieved at the end of study drug infusion

Original Secondary Outcome Measures (submitted: May 4, 2012)

• Maximum observed serum concentration (Cmax) of BMS-936558 [ Time Frame: 7 time points up to 20 weeks ]
• Serum concentration achieved at the end of dosing interval (trough concentration) [Cmin] of BMS-936558 [ Time Frame: 7 time points up to 20 weeks ]
• Time of maximum observed serum concentration (Tmax) of BMS-936558 [ Time Frame: 7 time points up to 20 weeks ]
• Area under the plasma concentration-time curve from time zero to the last time of the last quantifiable concentration [AUC(0-T)] of BMS-936558 [ Time Frame: 7 time points up to 20 weeks ]
• Antitumor Activity of BMS-936558 as measured by Best Overall Response (BOR) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ]
  BOR is defined as the best response designation over the study as a whole, recorded between the date of first dose and the last tumor assessment prior to subsequent therapy
• Antitumor Activity of BMS-936558 as measured by Objective Response Rate (ORR) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ]
  ORR is defined as the proportion of subjects whose BOR is either partial response (PR) or complete response (CR) divided by the number of treated subjects (or response-evaluable subjects)
• Antitumor Activity of BMS-936558 as measured by duration of Objective Response [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ]
  The duration of response is defined as the time when the measurement criteria are first met for PR or CR (whichever is reported first) until the date of documented disease progression or death. For subjects who neither progress nor die, the duration of response will be censored at the date of their last disease assessment
• Antitumor Activity of BMS-936558 as measured by Progression Free Survival Rate (PFSR) [ Time Frame: Baseline (within 28 days of treatment), Week 4, Week 8, Week 16, Week 24, and every 16 weeks thereafter until confirmed disease progression assessed up to Week 156 ]
  The PFSR is defined as the probability of a subject remaining progression free or surviving to time t, where t = 8, 16 and 24 weeks. Progression free survival (PFS) is defined as the time between date of first dose of study therapy and date of progression or death, whichever occurs first
• Immunogenicity of BMS-936558 as measured by the frequency of subjects with an increase in anti-drug antibody levels from baseline [ Time Frame: Baseline (within 28 days of treatment), week 4, week 6, week 12, week 20, and at follow-up (35 ± 7 days after last treatment and 90-120 days since last treatment) ]
• PD-L1 expression levels [ Time Frame: Baseline (within 28 days of treatment) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients With Multiple Myeloma
• Official Title: Multiple Phase 1/2 Cohorts of Nivolumab Monotherapy or Nivolumab Combination Regimens Across Relapsed/Refractory Hematologic Malignancies
• Brief Summary: 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: NOTE: Currently, this study is only open to nivolumab+daratumumab vs daratumumab monotherapy in multiple myeloma patients.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Non-Hodgkin's Lymphoma
• Hodgkin Lymphoma
• Multiple Myeloma

Intervention

• Biological: Nivolumab
  Administered by intravenous (IV) infusion
  Other Names:

  • BMS-936558
  • Opdivo
• Biological: Ipilimumab
  Administered by IV infusion
  Other Names:

  • Yervoy
  • BMS-734016
  • MDX010
• Biological: Lirilumab
  Administered by IV infusion
  Other Name: BMS-986015
• Biological: Daratumumab
  Administered by IV infusion
  Other Name: Darzalex
• Drug: Pomalidomide
  Administered PO
  Other Name: Pomalyst
• Drug: Dexamethasone
  Administered PO and by IV infusion
  Other Name: Intensol

Study Arms

• Experimental: Nivolumab monotherapy (Dose Escalation)

  Nivolumab solution intravenously as specified

  Non-randomized

  Enrollment is closed for this cohort

  Intervention: Biological: Nivolumab
• Experimental: Nivolumab + Ipilimumab

  Nivolumab and Ipilimumab solution intravenously as specified

  Non-randomized

  Enrollment is closed for this cohort

  Interventions:

  • Biological: Nivolumab
  • Biological: Ipilimumab
• 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

  Interventions:

  • Biological: Nivolumab
  • Biological: Lirilumab
• 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

  Interventions:

  • Biological: Nivolumab
  • Biological: Daratumumab
  • Drug: Pomalidomide
  • Drug: Dexamethasone
• 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

  Interventions:

  • Biological: Nivolumab
  • Biological: Daratumumab

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 27, 2022): 316
• Original Estimated Enrollment (submitted: May 4, 2012): 110
• Estimated Study Completion Date: December 22, 2023
• Actual Primary Completion Date: September 25, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Greece, Italy, Poland, United States

Administrative Information

• NCT Number: NCT01592370
• Other Study ID Numbers: CA209-039; 2018-001030-17 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Janssen, LP

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: September 2023