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An Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma and in Subjects With High-Risk Multiple Myeloma (KarMMa-2)

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ClinicalTrials.gov Identifier: NCT03601078
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : July 24, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE July 17, 2018
First Posted Date  ICMJE July 26, 2018
Last Update Posted Date July 24, 2019
Actual Study Start Date  ICMJE December 13, 2018
Estimated Primary Completion Date March 12, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • Overall response rate (ORR)- Cohort 1 [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an independent response committee (IRC)
  • Complete response (CR) rate - Cohort 2a , b and c [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved CR or stringent CR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
Original Primary Outcome Measures  ICMJE
 (submitted: July 17, 2018)
  • Overall response rate (ORR)- Cohort 1 [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an independent response committee (IRC)
  • Complete response (CR) rate - Cohort 2 [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
Change History Complete list of historical versions of study NCT03601078 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • Complete response (CR) rate - Cohort 1 [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
  • Overall response rate (ORR) - Cohort 2a, b and c [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
  • Time to response (TTR) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to first documentation of response (PR or greater)
  • Duration of response (DoR) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first documentation of response (PR or greater) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first
  • Progression-free survival (PFS) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to first documentation of PD, or death due to any cause, whichever occurs first
  • Time to progression (TTP) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to first documentation of PD
  • Overall survival (OS) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to time of death due to any cause
  • Adverse Events (AEs) [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Type, frequency, seriousness and severity of adverse events (AEs), adverse events of special interest (AESIs) (including cytokine release syndrome, neurotoxicity and infection), and relationship of AE to study drug.
  • Pharmacokinetics - Cmax [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Maximum expansion of 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 - tlast [ 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
  • Immunogenicity [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Development of an anti-CAR antibody response
  • Minimal Residual Disease (MRD) negative rate [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Proportion of subjects that are MRD negative
  • Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30) [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Questionnaire will be used as a measure of health-related quality of life
  • Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire [ Time Frame: Minimum 5 years after bb2121 infusion ]
    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 EORTC-QLQ-MY20 [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality
  • Very good partial response (VGPR) rate - Cohort 2c [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved VGPR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
Original Secondary Outcome Measures  ICMJE
 (submitted: July 17, 2018)
  • Complete response (CR) rate - Cohort 1 [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
  • Overall response rate (ORR) - Cohort 2 [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC
  • Time to response (TTR) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to first documentation of response (PR or greater)
  • Duration of response (DoR) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first documentation of response (PR or greater) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first
  • Progression-free survival (PFS) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to first documentation of PD, or death due to any cause, whichever occurs first
  • Time to progression (TTP) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to first documentation of PD
  • Overall survival (OS) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Time from first bb2121 infusion to time of death due to any cause
  • Adverse Events (AEs) [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Type, frequency, seriousness and severity of adverse events (AEs), adverse events of special interest (AESIs) (including cytokine release syndrome, neurotoxicity and infection), and relationship of AE to study drug.
  • Pharmacokinetics - Cmax [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Maximum expansion of 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 - tlast [ 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
  • Immunogenicity [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Development of an anti-CAR antibody response
  • Minimal Residual Disease (MRD) [ Time Frame: Minimum of 2 years after bb2121 infusion ]
    Proportion of MRD evaluable subjects that are MRD negative
  • Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30) [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Questionnaire will be used as a measure of health-related quality of life
  • Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire [ Time Frame: Minimum 5 years after bb2121 infusion ]
    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 EORTC-QLQ-MY20 [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma and in Subjects With High-Risk Multiple Myeloma
Official Title  ICMJE A Phase 2, Multicohort, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma and in Subjects With Clinical High-Risk Multiple Myeloma (KarMMa-2)
Brief Summary This study is a multi-cohort, open-label, multicenter Phase 2 study to evaluate the efficacy and safety of bb2121 in subjects with relapsed and refractory MM (Cohort 1), in subjects with MM having progressed within one 18 months of initial treatment including autologous stem cell transplantation (ASCT) (Cohort 2a), and without ASCT (Cohort 2b) or, in subjects with inadequate response post ASCT during initial treatment (Cohort 2c) Approximately 181 subjects will be enrolled into one of two cohorts. Cohort 1 will enroll approximately 73 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens. Cohort 2a will enroll approximately 39 MM subjects, with 1 prior anti-myeloma therapy including ASCT and with early relapse. Cohort 2b will enroll approximately 39 MM subjects with 1 prior anti-myeloma therapy not including ASCT and with early relapse. Cohort 2c will enroll approximately 30 MM subjects with inadequate response to ASCT during their initial anti-myeloma therapy. The cohorts will start in parallel and independently.
Detailed Description Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured for cohorts 1, 2a and 2b only.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE Biological: bb2121
bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA CAR lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR)
Study Arms  ICMJE Experimental: bb2121 in relapsed and refractory multiple myeloma patients
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
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: February 7, 2019)
181
Original Estimated Enrollment  ICMJE
 (submitted: July 17, 2018)
122
Estimated Study Completion Date  ICMJE March 12, 2025
Estimated Primary Completion Date March 12, 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 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 and abnormal serum immunoglobulin kappa lambda free light chain ratio
  3. Subjects with one of the following cohort specific requirements:

    Cohort 1 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens:

    • Subject must have received at least 3 prior anti-myeloma treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
    • Subject must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen
    • Subject must have received prior treatment with a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody
    • Subject has evidence of PD on or within 60 days of the most recent prior treatment regimen
    • Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen

    Cohort 2 subjects with 1 prior anti-myeloma treatment regimen:

    • Subject must have received only 1 prior anti-myeloma treatment regimen. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen
    • Subject must have the following HR factors:

      - R-ISS stage III AND

    • Early relapse defined as:

    Cohort 2a: PD < 18 months since date of start of initial therapy. Initial therapy must contain induction, ASCT (single or tandem) and lenalidomide containing maintenance.

    Cohort 2b: PD < 18 months since date of start or initial therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone Cohort 2c: Subject must have received minimum 3 cycles of induction therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone. Subjects must have had ASCT (single or tandem AND < VGPR (excluding PD) at first assessment between 70 to 110 days after last ASCT, with initial therapy without consolidation and maintenance.

  4. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  5. Subject must have recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy

Exclusion Criteria:

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

  1. Subject used any investigational agents within 14 days of leukapheresis
  2. Subject received any of the following within the last 14 days of leukapheresis:

    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 systemic anti-myeloma drug therapy
  3. Subject with known central nervous system involvement with myeloma
  4. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation
  5. History or presence of clinically relevant central nervous system (CNS) pathology
  6. Subject with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, or clinically significant amyloidosis
  7. Inadequate organ function Subject with 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 starting study treatment
  8. Ongoing treatment with chronic immunosuppressants
  9. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy
  10. Subject has received ASCT within 12 weeks prior to leukapheresis
  11. Subject has history of primary immunodeficiency
  12. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C
  13. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment
  14. Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years
  15. Pregnant or lactating women
  16. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab
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,   France,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03601078
Other Study ID Numbers  ICMJE BB2121-MM-002
U1111-1216-4209 ( Other Identifier: WHO )
2018-000264-28 ( 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: Lars Sternas, MD, PhD 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