An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients With Multiple Myeloma
- Conditions
- Non-Hodgkin's LymphomaMultiple MyelomaHodgkin Lymphoma
- Interventions
- Biological: NivolumabBiological: IpilimumabBiological: LirilumabBiological: Daratumumab
- Registration Number
- NCT01592370
- Lead Sponsor
- Bristol-Myers Squibb
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 316
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Nivolumab + Ipilimumab Nivolumab Nivolumab and Ipilimumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort Nivolumab + Ipilimumab Ipilimumab Nivolumab and Ipilimumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort Nivolumab + Lirilumab 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 Nivolumab monotherapy (Dose Escalation) Nivolumab Nivolumab solution intravenously as specified Non-randomized Enrollment is closed for this cohort Nivolumab + Lirilumab Nivolumab Non-randomized Nivolumab: 3 mg/kg given every 2 weeks Lirilumab: 3 mg/kg given every 4 weeks Enrollment is closed for this cohort Daratumumab vs. Nivolumab + Daratumumab 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 Nivo + Dara + Pom + Dexa vs. Nivo + Dara Nivolumab 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 Daratumumab vs. Nivolumab + Daratumumab Nivolumab 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 Nivo + Dara + Pom + Dexa vs. Nivo + Dara Daratumumab 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 Nivo + Dara + Pom + Dexa vs. Nivo + Dara Pomalidomide 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 Nivo + Dara + Pom + Dexa vs. Nivo + Dara Dexamethasone 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
- Primary Outcome Measures
Name Time Method Number of Participants That Experienced Drug Related Grade 3-4 SAEs 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 That Experienced Drug-related Grade 3-4 AEs in the Nivolumab + Daratumumab Cohort approximately up to 4 years 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 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 - Liver 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 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
Name Time Method Best Overall 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 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 ResponseProgression Free Survival Rate 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)
Progression Free Survival in the Nivolumab + Daratumumab Cohort approximately up to 4 years Tmax in the Nivolumab + Daratumumab Cohort approximately up to 4 years Time of maximum observed serum concentration
Best Overall Response - Multiple Myeloma Group 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.
AUC (0-T) in the Nivolumab + Daratumumab Cohort 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 approximately up to 4 years Area under the concentration-time curve in one dosing interval
Duration of Response 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 RemissionDuration of Response - Multiple Myeloma Group 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 ResponseOverall Survival 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 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 baselineDuration of Response in the Nivolumab + Daratumumab Cohort approximately up to 4 years Cmax in the Nivolumab + Daratumumab Cohort approximately up to 4 years Maximum observed serum concentration
End of Infusion Nivolumab Concentration Levels in the Nivolumab + Daratumumab Cohort 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
Time to MRD Negativity Status in the Nivolumab + Daratumumab Cohort 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 approximately up to 4 years Cmin in the Nivolumab + Daratumumab Cohort approximately up to 4 years Serum concentration achieved at the end of dosing interval (trough concentration)
Progression Free Survival 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.
Percentage Change From Baseline in the Modified Severity Weighted Assessment Tool (mSWAT) Score 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).
Trial Locations
- Locations (41)
Local Institution - 0007
🇺🇸Philadelphia, Pennsylvania, United States
Division Of Hematology & Oncology Ctr. For Health Sciences
🇺🇸Los Angeles, California, United States
Local Institution - 0043
🇫🇷Poitiers, Vienne, France
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Local Institution - 0009
🇺🇸Boston, Massachusetts, United States
Local Institution - 0012
🇺🇸Los Angeles, California, United States
Local Institution - 0035
🇺🇸Clovis, California, United States
Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
The Sidney Kimmel Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
Local Institution - 0028
🇺🇸Columbus, Ohio, United States
Local Institution - 0015
🇺🇸Boston, Massachusetts, United States
Local Institution
🇵🇱Chorzow, Poland
Local Institution - 0047
🇧🇪Sint-Niklaas, Belgium
Local Institution - 0049
🇵🇱Warszawa, Poland
John Theurer Cancer Center
🇺🇸Hackensack, New Jersey, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Local Institution - 0042
🇵🇱Wroclaw, Poland
Local Institution - 0001
🇺🇸New York, New York, United States
Local Institution - 0044
🇫🇷Nantes Cedex 1, France
Local Institution - 0004
🇺🇸Philadelphia, Pennsylvania, United States
Local Institution - 0045
🇧🇪Gent, Belgium
Local Institution - 0039
🇬🇷Athens, Greece
Local Institution - 0019
🇺🇸Indianapolis, Indiana, United States
Huntsman Cancer Institute At The Univ. Of Utah
🇺🇸Salt Lake City, Utah, United States
Local Institution - 0005
🇺🇸Salt Lake City, Utah, United States
Local Institution - 0018
🇺🇸Westwood, Kansas, United States
Local Institution - 0006
🇺🇸Portland, Oregon, United States
OHSU Center for Hematologic Malignancies
🇺🇸Portland, Oregon, United States
Local Institution - 0002
🇺🇸Rochester, Minnesota, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Local Institution - 0033
🇺🇸Omaha, Nebraska, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Local Institution - 0017
🇺🇸Aurora, Colorado, United States
Local Institution - 0037
🇺🇸Skokie, Illinois, United States
Local Institution - 0003
🇺🇸Baltimore, Maryland, United States
Local Institution - 0014
🇺🇸Hackensack, New Jersey, United States
Local Institution - 0040
🇵🇱Poznan, Poland
Local Institution - 0023
🇺🇸Orlando, Florida, United States
University Of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Local Institution - 013
🇺🇸New Haven, Connecticut, United States
Local Institution - 0011
🇺🇸Ann Arbor, Michigan, United States