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)

• ClinicalTrials.gov Identifier: NCT03601078
• Recruitment Status: Recruiting
• First Posted: July 26, 2018
• Last Update Posted: April 27, 2023
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: July 17, 2018
• First Posted Date: July 26, 2018
• Last Update Posted Date: April 27, 2023
• Actual Study Start Date: December 13, 2018
• Estimated Primary Completion Date: December 18, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 16, 2022)

• Overall response rate (ORR)- Cohort 1 [ Time Frame: Up to approximately 5 years ]
  Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator
• Complete response (CR) rate - Cohort 2a , b, c and Cohort 3 [ Time Frame: Up to approximately 5 years ]
  Percentage of subjects who achieved CR or stringent CR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator

Original Primary Outcome Measures (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

Current Secondary Outcome Measures (submitted: November 21, 2022)

• Complete response (CR) rate - Cohort 1 [ Time Frame: Up to approximately 5 years ]
  Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator
• Overall response rate (ORR) - Cohort 2a, b, c and Cohort 3 [ Time Frame: Up to approximately 5 years ]
  Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator
• Very good partial response (VGPR) rate - Cohort 2c [ Time Frame: Up to approximately 5 years ]
  Percentage of subjects who achieved VGPR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator
• Time to response (TTR) [ Time Frame: Up to approximately 5 years ]
  Time from first bb2121 infusion to first documentation of response (PR or greater) [Cohorts 1 and 2]; time from first dose of lenalidomide pre-leukapheresis to first documentation of response [Cohort 3 only]
• Duration of response (DoR) [ Time Frame: Up to approximately 5 years ]
  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: Up to approximately 5 years ]
  Time from first bb2121 infusion to first documentation of PD, or death due to any cause, whichever occurs first (Cohorts 1 and 2); time from first dose of lenalidomide pre-leukapheresis to first documentation of PD, or death due to any cause, whichever occurs first (Cohort 3 only)
• Time to progression (TTP) [ Time Frame: Up to approximately 5 years ]
  Time from first bb2121 infusion to first documentation of PD (Cohorts 1 and 2); time from first dose of lenalidomide pre-leukapheresis to first documentation of PD (Cohort 3 only)
• Overall survival (OS) [ Time Frame: Up to approximately 5 years ]
  Time from first bb2121 infusion to time of death due to any cause (Cohorts 1 and 2); time from first dose of lenalidomide pre-leukapheresis to time of death due to any cause (Cohort 3 only)
• Adverse Events (AEs) [ Time Frame: Up to approximately 5 years ]
  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.
• Percentage of participants who received lenalidomide maintenance for the first 3 cycles following bb2121 infusion with at least 75% dose compliance - Cohort 3 [ Time Frame: Up to 3 months ]
• 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
• 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

Original Secondary Outcome Measures (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: 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: A Phase 2, Multi-cohort, 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 18 months of initial treatment including autologous stem cell transplantation (ASCT) (Cohort 2a), or without ASCT (Cohort 2b) or, in subjects with inadequate response post ASCT during initial treatment (Cohort 2c). Approximately 235 subjects will be enrolled into one of three cohorts. Cohort 1 will enroll approximately 97 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. Cohort 3 will enroll approximately 30 newly diagnosed multiple myeloma (NDMM) participants with suboptimal response to ASCT.
• 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• 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)
  Other Name: BMS-986395
• Drug: Lenalomide
  Specified dose on specified days
  Other Name: Revlimid®

Study Arms

• 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
• Experimental: BB2121 with lenalidomide maintenance in newly diagnosed multiple myeloma
  Interventions:

  • Biological: bb2121
  • Drug: Lenalomide
• Experimental: BB2121 in clinical high-risk multiple myeloma patients
  Intervention: Biological: bb2121

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 16, 2022): 235
• Original Estimated Enrollment (submitted: July 17, 2018): 122
• Estimated Study Completion Date: December 30, 2030
• Estimated Primary Completion Date: December 18, 2023 (Final data collection date for primary outcome measure)

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. For Cohorts 1 and 2 only, participant 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:
   • 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.

   Cohort 3 participants with newly diagnosed MM (NDMM) who received only induction and ASCT, without subsequent consolidation or maintenance Cohort 3

   • Must have received 4 to 6 cycles of induction therapy which must contain at minimum, a proteasome inhibitor and an immunomodulatory agent and must have had single ASCT within 6 months prior to consent
   • Must have achieved documented PR or VGPR at first post-ASCT assessment approximately 100 days after ASCT and this response must be maintained at screening
   • Per Investigator's assessment, subject must be a candidate for single-agent lenalidomide 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 prior to leukapheresis or, for Cohort 3, within 14 days prior to consent

2. Subject received any of the following within the last 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent:

   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
17. Prior history of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 6 months prior to consent (For Cohort 3)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: BMS Study Connect Contact Center www.BMSStudyConnect.com; 855-907-3286; Clinical.Trials@bms.com

Contact: First line of the email MUST contain the NCT# and Site #.

• Listed Location Countries: France, Germany, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03601078
• Other Study ID Numbers: 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: Not Provided
• Current Responsible Party: Celgene
• Original Responsible Party: Same as current
• Current Study Sponsor: Celgene
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Celgene
• Verification Date: April 2023