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

Study Overview
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Brief Summary
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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
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Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured for cohorts 1, 2a and 2b only.

Official Title
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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)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: bb2121
* Drug: Lenalomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study: Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF) 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 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 Subject must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 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: Subject used any investigational agents within 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent Subject received any of the following within the last 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent: Plasmapheresis Major surgery (as defined by the investigator) Radiation therapy other than local therapy for myeloma associated bone lesions Use of any systemic anti-myeloma drug therapy Subject with known central nervous system involvement with myeloma Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation History or presence of clinically relevant central nervous system (CNS) pathology Subject with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, or clinically significant amyloidosis 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 Ongoing treatment with chronic immunosuppressants 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 Subject has received ASCT within 12 weeks prior to leukapheresis Subject has history of primary immunodeficiency Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C Subject has uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years Pregnant or lactating women Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab Prior history of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 6 months prior to consent (For Cohort 3)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BB2121 in relapsed and refractory multiple myeloma patients<br>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 | Biological: bb2121<br>* 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)<br>* Other names: BMS-986395;|
| Experimental: BB2121 with lenalidomide maintenance in newly diagnosed multiple myeloma<br> | Biological: bb2121<br>* 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)<br>* Other names: BMS-986395;Drug: Lenalomide<br>* Specified dose on specified days<br>* Other names: Revlimid®;|
| Experimental: BB2121 in clinical high-risk multiple myeloma patients<br> | Biological: bb2121<br>* 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)<br>* Other names: BMS-986395;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate - Cohort 1 | Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator | Up to approximately 5 years | 
| Overall response rate (ORR) - Cohort 2a, b, c and Cohort 3 | Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator | Up to approximately 5 years | 
| Very good partial response (VGPR) rate - Cohort 2c | Percentage of subjects who achieved VGPR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator | Up to approximately 5 years | 
| Time to response (TTR) | 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] | Up to approximately 5 years | 
| Duration of response (DoR) | Time from first documentation of response (PR or greater) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first | Up to approximately 5 years | 
| Progression-free survival (PFS) | 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) | Up to approximately 5 years | 
| Time to progression (TTP) | 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) | Up to approximately 5 years | 
| Overall survival (OS) | 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) | Up to approximately 5 years | 
| Adverse Events (AEs) | 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. | Up to approximately 5 years | 
| Percentage of participants who received lenalidomide maintenance for the first 3 cycles following bb2121 infusion with at least 75% dose compliance - Cohort 3 |  | Up to 3 months | 
| Pharmacokinetics - Cmax | Maximum expansion of bb2121 chimeric antigen receptor (CAR) T cells | Minimum 5 years after bb2121 infusion | 
| Pharmacokinetics - tmax | Time to peak of bb2121 CAR T cells | Minimum 5 years after bb2121 infusion | 
| Pharmacokinetics - AUC | Area under the curve of CAR T cells | Minimum 5 years after bb2121 infusion | 
| Pharmacokinetics - tlast | Time to last measurable CAR T cells | Minimum 5 years after bb2121 infusion | 
| Pharmacokinetics - AUC0-28days | Area under the curve of CAR T cells from time zero to Day 28 | Minimum 5 years after bb2121 infusion | 
| Immunogenicity | Development of an anti-CAR antibody response | Minimum of 2 years after bb2121 infusion | 
| Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30) | Questionnaire will be used as a measure of health-related quality of life | Minimum 5 years after bb2121 infusion | 
| Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire | 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 | Minimum 5 years after bb2121 infusion | 
| Subject-reported outcomes as measured by EORTC-QLQ-MY20 | Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality | Minimum 5 years after bb2121 infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, bb2121, Relapsed and Refractory Multiple Myeloma, High Risk Multiple Myeloma, Phase 2, Multi-cohort, Open-label