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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
Janssen, LP
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Description
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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.

Condition or disease Intervention/treatment Phase
Non-Hodgkin's Lymphoma Hodgkin Lymphoma Multiple Myeloma Biological: Nivolumab Biological: Ipilimumab Biological: Lirilumab Biological: Daratumumab Drug: Pomalidomide Drug: Dexamethasone Phase 1 Phase 2

Detailed Description:
NOTE: Currently, this study is only open to nivolumab+daratumumab vs daratumumab monotherapy in multiple myeloma patients.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 316 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multiple Phase 1/2 Cohorts of Nivolumab Monotherapy or Nivolumab Combination Regimens Across Relapsed/Refractory Hematologic Malignancies
Actual Study Start Date : August 2, 2012
Actual Primary Completion Date : September 25, 2020
Estimated Study Completion Date : December 22, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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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:
  • Yervoy
  • BMS-734016
  • 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 Name: 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 Name: Darzalex

Drug: Pomalidomide
Administered PO
Other Name: Pomalyst

Drug: Dexamethasone
Administered PO and by IV infusion
Other Name: 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 Name: Darzalex


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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 ]
  5. Number of Participants That Experienced Drug-related Grade 3-4 AEs in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  6. Number of Participants That Experienced Drug-related Grade 3-4 SAEs in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  7. Number of Participants That Experience Drug-related Grade 3-4 SAEs in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  8. Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Hematology [ Time Frame: approximately up to 4 years ]
  9. Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Liver [ Time Frame: approximately up to 4 years ]
  10. Number of Participants With Clinical Laboratory Abnormalities by Worst Toxicity Grade in the Nivolumab + Daratumumab Cohort - Thyroid [ Time Frame: approximately up to 4 years ]

Secondary Outcome Measures :
  1. 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


  2. 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.

  3. 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


  4. 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


  5. 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.

  6. 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)

  7. 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

  8. 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

  9. 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).


  10. 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

  11. Objective Response Rate in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  12. Duration of Response in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  13. Progression Free Survival in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
  14. Cmax in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
    Maximum observed serum concentration

  15. Tmax in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
    Time of maximum observed serum concentration

  16. Cmin in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
    Serum concentration achieved at the end of dosing interval (trough concentration)

  17. 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

  18. AUC (TAU) in the Nivolumab + Daratumumab Cohort [ Time Frame: approximately up to 4 years ]
    Area under the concentration-time curve in one dosing interval

  19. 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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01592370


Locations
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Sponsors and Collaborators
Bristol-Myers Squibb
Janssen, LP
Investigators
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Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:
Study Protocol  [PDF] April 23, 2019
Statistical Analysis Plan  [PDF] September 8, 2021

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01592370    
Other Study ID Numbers: CA209-039
2018-001030-17 ( EudraCT Number )
First Posted: May 7, 2012    Key Record Dates
Results First Posted: February 17, 2022
Last Update Posted: September 13, 2023
Last Verified: September 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
 Hemorrhagic Disorders
Dexamethasone
Nivolumab
Ipilimumab
Daratumumab
Pomalidomide
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists