Clinical Trials /

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

NCT03651128

Description:

This is a multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of bb2121 versus standard 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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety Study of bb2121 Versus Standard Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)
  • Official Title: A Phase 3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of bb2121 Versus Standard Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3)

Clinical Trial IDs

  • ORG STUDY ID: BB2121-MM-003
  • SECONDARY ID: U1111-1217-9988
  • SECONDARY ID: 2018-001023-38
  • NCT ID: NCT03651128

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
bb2121Arm A - Administration of bb2121
DaratumumabArm B- standard regimens as per Investigator's discretion
PomalidomideArm B- standard regimens as per Investigator's discretion
DexamethasoneArm B- standard regimens as per Investigator's discretion
BortezomibArm B- standard regimens as per Investigator's discretion
IxazomibArm B- standard regimens as per Investigator's discretion
LenalidomideArm B- standard regimens as per Investigator's discretion
CarfilzomibArm B- standard regimens as per Investigator's discretion
ElotuzumabArm B- standard regimens as per Investigator's discretion

Purpose

This is a multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of bb2121 versus standard 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.

Trial Arms

NameTypeDescriptionInterventions
Arm A - Administration of bb2121Experimentalbb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 450 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy
  • bb2121
Arm B- standard regimens as per Investigator's discretionExperimentalThe 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) OR Carfilzomib (CFZ) in combination with low-dose dexamethasone (Kd) OR Elotuzumab (ELO) in combination with POM and low-dose dexamethasone (EPd)
  • Daratumumab
  • Pomalidomide
  • Dexamethasone
  • Bortezomib
  • Ixazomib
  • Lenalidomide
  • Carfilzomib
  • Elotuzumab

Eligibility Criteria

        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 must understand and voluntarily sign an ICF prior to any study-related
             assessments/procedures being conducted.

          3. Subject is willing and able to adhere to the study visit schedule and other protocol
             requirements within this protocol and for a subject randomized to Treatment Arm A,
             subject agrees to continued follow-up for up to 15 years as mandated by the regulatory
             guidelines for gene therapy trials.

          4. 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

          5. Subject has received at least 2 but no greater than 4 prior MM regimens.

          6. Subject has received prior treatment with DARA, a proteasome inhibitor- and an
             immunomodulatory compound-containing regimen for at least 2 consecutive cycles.

          7. 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.

          8. Subject achieved a response (minimal response [MR] or better) to at least 1 prior
             treatment regimen.

          9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

         10. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior
             treatments, excluding alopecia and Grade 2 peripheral neuropathy.

         11. Adequate vascular access for leukapheresis

         12. Females of childbearing potential (FCBP) must:

             a. Have negative pregnancy test(s) as verified by the Investigator. This applies even
             if the subject practices true abstinence from heterosexual contact.

             b. Either practice true abstinence from heterosexual contact or agree to use, and be
             able to comply with, effective measures of contraception without interruption.

             c. Agree to abstain from breastfeeding during study participation. d. Refrain from
             tissue donation including egg cell donation or any other tissue/blood/organ donations.

         13. Male subjects must:

             a. Practice true abstinence or agree to use a condom during sexual contact with a
             pregnant female or a female of childbearing potential while participating in the
             study, during dose interruptions, even if he has undergone a successful vasectomy.

             b. Refrain from tissue donation including sperm or any other tissue/blood/organ
             donations.

         14. Only subjects that would be considered for any of the 5 proposed standard regimens
             (DPd, DVd, IRd, Kd, or EPd), as judged by the investigator, should be included in the
             study.

        Exclusion Criteria:

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

          1. Subject has any significant medical condition, laboratory abnormality, or psychiatric
             illness that would prevent the subject from participating in the study.

          2. Subject has any condition including the presence of laboratory abnormalities, which
             places the subject at unacceptable risk if he/she were to participate in the study.

          3. Subject has any condition that confounds the ability to interpret data from the study.

          4. Subject has nonsecretory multiple myeloma (MM).

          5. Subject has any of the following laboratory abnormalities:

             a. Absolute neutrophil count (ANC) < 1,000/μL b. 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) c. Hemoglobin
             < 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this
             level) d. Serum creatinine clearance (CrCl) < 45 mL/min e. Corrected serum calcium >
             13.5 mg/dL (> 3.4 mmol/L) f. Serum aspartate aminotransferase (AST) or alanine
             aminotransferase (ALT) > 2.5 × upper limit of normal (ULN) g. Serum total bilirubin >
             1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome h.
             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)

          6. Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on
             room air.

          7. Subject has prior history of malignancies, other than MM, unless the subject has been
             free of the disease for ≥ 5 years • Basal cell carcinoma of the skinSquamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  nodes, metastasis [TNM] clinical staging system) or prostate cancer that can be
                  treated with curative intent

          8. Subject has active or history of plasma cell leukemia, Waldenstrom's
             macroglobulinemia, POEMS syndrome or amyloidosis.

          9. Subject with known central nervous system (CNS) involvement with myeloma.

         10. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular
             coagulation.

         11. Subject has known chronic obstructive pulmonary disease (COPD) with a forced
             expiratory volume in 1 second (FEV1) 50% of predicted normal.

         12. Subject has a history or presence of clinically relevant CNS pathology such as
             epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS
             bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease,
             organic brain syndrome, or psychosis.

         13. 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, IRd, Kd or EPdas bridging as per Investigator's
             discretion if randomized to Treatment Arm A.

         14. 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, IRd,
             Kd, or EPd as per Investigator's discretion.

         15. Subject was treated with DARA in combination with BTZ with or without dexamethasone
             (DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd
             as bridging therapy but may receive DPd, IRd, Kd, or EPd as bridging as per
             Investigator's discretion if randomized to Treatment Arm A.

         16. 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, IRd,
             Kd, or EPd as per Investigator's discretion.

         17. Subject was treated with IXA in combination with LEN with or without dexamethasone
             (IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd
             as bridging therapy but may receive DPd, DVd, Kd, or EPd as bridging as per
             Investigator's discretion if randomized to Treatment Arm A.

         18. 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, DVd,
             Kd, or EPd as per Investigator's discretion.

         19. 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.

         20. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks prior
             to randomization.

         21. Subject has received any of the following within the last 14 days prior to
             randomization:

             a. Plasmapheresis b. Major surgery (as defined by the Investigator) c. Radiation
             therapy other than local therapy for myeloma-associated bone lesions d. Use of any
             investigational agents and systemic anti-myeloma drug therapy

         22. Echocardiogram (ECHO) or multigated acquisition (MUGA) with left ventricular ejection
             fraction (LVEF) < 45%.

         23. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic
             steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are
             allowed.

         24. Subject is positive for human immunodeficiency virus (HIV-1 and HIV-2), chronic or
             active hepatitis B or active hepatitis A or C.

         25. 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.

         26. 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.

         27. Hypersensitivity to DARA, thalidomide, lenalidomide, POM, BTZ, IXA, CFZ, ELO or
             dexamathasone. This includes rash ≥ Grade 3 during prior thalidomide, POM or
             lenalidomide therapy.

         28. 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, CFZ, ELO or
             dexamethasone.

         29. Subject is a female who is pregnant, nursing, or breastfeeding

         30. 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, or has acute diffuse infiltrative pulmonary and
        pericardial disease, subject cannot receive DVd as bridging therapy if randomized to
        Treatment Arm A or cannot receive DVd if randomized to Treatment Arm B.

        31. Subject was treated with K±d as part of their most recent anti-myeloma treatment
        regimen, cannot receive Kd if randomized to Treatment Arm B but may receive DPd, DVd, IRd
        or EPd as per Investigator's discretion.

        32. Subject was treated with EP±d as part of their most recent anti-myeloma treatment
        regimen, cannot receive EPd if randomized to Treatment Arm B but may receive DPd, DVd, Kd
        or IRd as per Investigator's discretion.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free Survival (PFS)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Time from randomization to time of death due to any cause
Measure:Event-free Survival (EFS)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description: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
Measure:Overall Response Rate (ORR)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
Measure:Minimal Residual Disease (MRD)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description: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)
Measure:Complete Response (CR) Rate
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
Measure:Duration of Response (DOR)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Time from first documentation of response (PR or better) to first documentation of disease progression or death from any cause, whichever occurs first
Measure:Time to Response (TTR)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:TTR is calculated as the time from randomization to the initial documented response (PR or better) based on IMWG guideline for responders
Measure:Adverse Events (AEs)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Number of participants with adverse events
Measure:Pharmacokinetics- Cmax
Time Frame:Minimum 5 years after bb2121 infusion
Safety Issue:
Description:Maximum peak in bb2121 chimeric antigen receptor (CAR) T cells
Measure:Pharmacokinetics- tmax
Time Frame:Minimum 5 years after bb2121 infusion
Safety Issue:
Description:Time to peak of bb2121 CAR T cells
Measure:Pharmacokinetics- AUC
Time Frame:Minimum 5 years after bb2121 infusion
Safety Issue:
Description:Area under the curve of CAR T cells
Measure:Pharmacokinetics- t-last
Time Frame:Minimum 5 years after bb2121 infusion
Safety Issue:
Description:Time to last measurable CAR T cells
Measure:Pharmacokinetics- AUC0-28days
Time Frame:Minimum 5 years after bb2121 infusion
Safety Issue:
Description:Area under the curve of CAR T cells from time zero to Day 28
Measure: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
Safety Issue:
Description:Questionnaire will be used as a measure of health-related quality of life
Measure: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
Safety Issue:
Description: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
Measure:Subject-reported outcomes as measured by European Quality of Life Multiple Myeloma Module (EORTC-QLQ-MY20)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality
Measure:Time to next antimyeloma treatment
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Time from randomization to first day when subject receives another anti-myeloma treatment
Measure:Progression-free survival after next line therapy (PFS2)
Time Frame:Minimum of 5 years from randomization
Safety Issue:
Description:Time from randomization to second objective disease progression or death from any cause, whichever is first

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Multiple Myeloma
  • bb2121
  • Relapsed and Refractory Multiple Myeloma
  • High Risk Multiple Myeloma

Last Updated

March 13, 2020