Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Efficacy and Safety Study of bb2121 Versus Standard Triplet Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03651128
Recruitment Status : Recruiting
First Posted : August 29, 2018
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE August 16, 2018
First Posted Date  ICMJE August 29, 2018
Last Update Posted Date July 18, 2019
Actual Study Start Date  ICMJE October 12, 2018
Estimated Primary Completion Date June 23, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 27, 2018)
Progression-free Survival (PFS) [ Time Frame: Minimum of 5 years from randomization ]
Time from randomization to the first documentation of progressive disease based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma assessed by an independent response committee (IRC) or death due to any cause, whichever occurs first.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03651128 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2018)
  • Overall Survival (OS) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to time of death due to any cause
  • Event-free Survival (EFS) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to the first documentation of progressive disease, first day when subject receives another anti-myeloma treatment or death due to any cause, whichever occurs first
  • Overall Response Rate (ORR) [ Time Frame: Minimum of 5 years from randomization ]
    Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
  • Minimal Residual Disease (MRD) [ Time Frame: Minimum of 5 years from randomization ]
    Percentage of MRD evaluable subjects that are MRD negative (defined at a minimum of 1 in 10^5 nucleated cells) using flow cytometry (EuroFlow) and next generation sequencing (NGS)
  • Complete Response (CR) Rate [ Time Frame: Minimum of 5 years from randomization ]
    Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
  • Duration of Response (DOR) [ Time Frame: Minimum of 5 years from randomization ]
    Time from first documentation of response (PR or better) to first documentation of disease progression or death from any cause, whichever occurs first
  • Time to Response (TTR) [ Time Frame: Minimum of 5 years from randomization ]
    TTR is calculated as the time from randomization to the initial documented response (PR or better) based on IMWG guideline for responders
  • Adverse Events (AEs) [ Time Frame: Minimum of 5 years from randomization ]
    Number of participants with adverse events
  • Pharmacokinetics- Cmax [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Maximum peak in bb2121 chimeric antigen receptor (CAR) T cells
  • Pharmacokinetics- tmax [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Time to peak of bb2121 CAR T cells
  • Pharmacokinetics- AUC [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Area under the curve of CAR T cells
  • Pharmacokinetics- t-last [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Time to last measurable CAR T cells
  • Pharmacokinetics- AUC0-28days [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Area under the curve of CAR T cells from time zero to Day 28
  • Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30) [ Time Frame: Minimum of 5 years from randomization ]
    Questionnaire will be used as a measure of health-related quality of life
  • Subject-reported outcomes as measured by EuroQoL Group European Quality of Life-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) Health Questionnaire [ Time Frame: Minimum of 5 years from randomization ]
    Is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal
  • Subject-reported outcomes as measured by European Quality of Life Multiple Myeloma Module (EORTC-QLQ-MY20) [ Time Frame: Minimum of 5 years from randomization ]
    Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality
  • Time to next antimyeloma treatment [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to first day when subject receives another anti-myeloma treatment
  • Progression-free survival after next line therapy (PFS2) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to second objective disease progression or death from any cause, whichever is first
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Study of bb2121 Versus Standard Triplet Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)
Official Title  ICMJE A Phase 3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of bb2121 Versus Standard Triplet Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3)
Brief Summary

This is a multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of bb2121 versus standard triplet regimens in subjects with relapsed and refractory multiple myeloma (RRMM).

The study is anticipated to randomize approximately 381 subjects with RRMM. Approximately 254 subjects will be randomized to Treatment Arm A and approximately 127 subjects will be randomized to Treatment Arm B.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Biological: bb2121
    bb2121
  • Drug: Daratumumab
    Daratumumab
  • Drug: Pomalidomide
    Pomalidomide
  • Drug: Dexamethasone
    Dexamethasone
  • Drug: Bortezomib
    Bortezomib
  • Drug: Ixazomib
    Ixazomib
  • Drug: Lenalidomide
    Lenalidomide
Study Arms  ICMJE
  • Experimental: Arm A - Administration of bb2121
    bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 450 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy
    Intervention: Biological: bb2121
  • Experimental: Arm B- standard regimens as per Investigator's discretion

    The participants will receive one of following regimens dependent on the subject's most recent anti-myeloma treatment regimen:

    Daratumumab (DARA) in combination with pomalidomide (POM) and low-dose dexamethasone (dex) (DPd) OR DARA in combination with bortezomib (BTZ) and low-dose dex (DVd) OR Ixazomib (IXA) in combination with lenalidomide (LEN) and low-dose dex (IRd)

    Interventions:
    • Drug: Daratumumab
    • Drug: Pomalidomide
    • Drug: Dexamethasone
    • Drug: Bortezomib
    • Drug: Ixazomib
    • Drug: Lenalidomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 27, 2018)
381
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 23, 2025
Estimated Primary Completion Date June 23, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

  1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
  2. Subject has documented diagnosis of MM and measurable disease, defined as:

    • M-protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours and/or
    • Light chain MM without measurable disease in the serum or urine: Serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio
  3. Subject has received at least 2 but no greater than 4 prior MM regimens.
  4. Subject has received prior treatment with DARA, a proteasome inhibitor- and an immunomodulatory compound-containing regimen for at least 2 consecutive cycles.
  5. Subject must be refractory to the last treatment regimen. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose of any drug within the regimen) of completing treatment with the last anti-myeloma regimen before study entry.
  6. Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen.
  7. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  8. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 peripheral neuropathy.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

  1. Subject has nonsecretory multiple myeloma (MM).
  2. Subject has any of the following laboratory abnormalities:

    1. Absolute neutrophil count (ANC) < 1,000/μL
    2. Platelet count: < 75,000/μL in subjects in whom < 50% of bone marrow nucleated cells are plasma cells and platelet count < 50,000/μL in subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells (it is not permissible to transfuse a subject to reach this level)
    3. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this level)
    4. Serum creatinine clearance (CrCl) < 45 mL/min
    5. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
    6. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)
    7. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome
    8. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) > 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors)
  3. Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on room air.
  4. Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years
  5. Subject has active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome or amyloidosis.
  6. Subject with known central nervous system (CNS) involvement with myeloma.
  7. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation.
  8. Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal.
  9. Subject has a history or presence of clinically relevant CNS pathology.
  10. Subject was treated with DARA in combination with POM with or without dex (DP±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DPd as bridging therapy but may receive DVd or IRd as bridging as per Investigator's discretion if randomized to Treatment Arm A.
  11. Subject was treated with DP±d as part of their most recent anti-myeloma treatment regimen, cannot receive DPd if randomized to Treatment Arm B but may receive DVd or IRd as per Investigator's discretion.
  12. Subject was treated with DARA in combination with BTZ with or without dex (DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd as bridging therapy but may receive DPd or IRd as bridging as per Investigator's discretion if randomized to Treatment Arm A.
  13. Subject was treated with DV±d as part of their most recent anti-myeloma treatment regimen, cannot receive DVd if randomized to Treatment Arm B but may receive DPd or IRd as per Investigator's discretion.
  14. Subject was treated with IXA in combination with LEN with or without dex (IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd as bridging therapy but may receive DPd or DVd as bridging as per Investigator's discretion if randomized to Treatment Arm A.
  15. Subject was treated with IR±d as part of their most recent anti-myeloma treatment regimen, cannot receive IRd if randomized to Treatment Arm B but may receive DPd or DVd as per Investigator's discretion.
  16. Previous history of an allogeneic hematopoietic stem cell transplantation, treatment with any gene therapy-based therapeutic for cancer, investigational cellular therapy for cancer or BCMA targeted therapy.
  17. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks prior to randomization.
  18. Subject has received any of the following within the last 14 days prior to randomization:

    1. Plasmapheresis
    2. Major surgery (as defined by the Investigator)
    3. Radiation therapy other than local therapy for myeloma-associated bone lesions
    4. Use of any investigational agents and systemic anti-myeloma drug therapy
  19. Echocardiogram (ECHO) or multigated acquisition (MUGA) with left ventricular ejection fraction (LVEF) < 45%.

21. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C.

22. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring IV antimicrobials for management.

23. Subject has a history of class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to randomization.

24. Hypersensitivity to DARA, thalidomide, lenalidomide, POM, BTZ, IXA or dex. This includes rash ≥ Grade 3 during prior thalidomide, POM or lenalidomide therapy.

25. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab or hypersensitivity to the excipients contained in the formulation of DARA, POM, LEN, IXA, BTZ or dex.

26. Subject is a female who is pregnant, nursing, or breastfeeding 27. For a subject randomized to Treatment Arm B and will be on a POM- or LEN-containing regimen; unable or unwilling to undergo protocol required thromboembolism prophylaxis.

28 Subject is intolerant to bortezomib, subject cannot receive DVd as bridging therapy if randomized.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com
Listed Location Countries  ICMJE Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03651128
Other Study ID Numbers  ICMJE BB2121-MM-003
U1111-1217-9988 ( Registry Identifier: WHO )
2018-001023-38 ( EudraCT Number )
Has Data Monitoring Committee Yes
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  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Steven Novick, MD Celgene
PRS Account Celgene
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP