Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This is an open label, single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of bb2121 in subjects with relapsed and refractory multiple myeloma. A leukapheresis procedure will be performed to manufacture bb2121 chimeric antigen receptor (CAR) modified T cells. Prior to bb2121 infusion subjects will receive lymphodepleting therapy with fludarabine and cyclophosphamide.

Detailed Description
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Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured.

Official Title
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A Phase 2, Multicenter Study to Determine the Efficacy and Safety of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: bb2121


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligibility is determined prior to leukapheresis. 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). Documented diagnosis of multiple myeloma Must have received at least 3 prior MM treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen. Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen. Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody. Must be refractory to the last treatment regimen. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Subjects must have measurable disease, including at least one of the criteria below: Serum M-protein greater or equal to 1.0 g/dL Urine M-protein greater or equal to 200 mg/24 h Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal 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: Subjects with known central nervous system involvement with myeloma. History or presence of clinically relevant central nervous system (CNS) pathology. Subjects with active or history of plasma cell leukemia. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease Inadequate organ function 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 Evidence of human immunodeficiency virus (HIV) infection. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV) Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission Pregnant or lactating women. Subject with known hypersensitivity to any component of bb2121 productThe presence of any of the following will exclude a subject from enrollment: 1. Subjects with known central nervous system involvement with myeloma. 2. History or presence of clinically relevant central nervous system (CNS) pathology. 3. Subjects with active or history of plasma cell leukemia. 4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease 5. Inadequate organ function 6. Ongoing treatment with chronic immunosuppressants 7. 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 8. Evidence of human immunodeficiency virus (HIV) infection. 9. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV) 10. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months. 11. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission 12. Pregnant or lactating women. 13 Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, or tocilizumab.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of bb2121<br>bb2121 autologous CAR T cells will be infused at a dose ranging from 15 - 450 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy. | Biological: bb2121<br>* : bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA02 CAR lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma. | Minimum of 24 months post-bb2121 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate | Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma | Minimum of 24 months post-bb2121 infusion | 
| Time to Response | Time from first bb2121 infusion to first documentation of response | Minimum of 24 months post-bb2121 infusion | 
| Duration of Response | Time from first response to disease progression or death from any cause | Minimum of 24 months post-bb2121 infusion | 
| Progression-free Survival (PFS) | Time from first bb2121 infusion to first documentation of progressive disease (PD), or death due to any cause, whichever occurs first | Minimum of 24 months post-bb2121 infusion | 
| Time to Progression (TTP) | Time from first bb2121 infusion to first documentation of PD | Minimum of 24 months post-bb2121 infusion | 
| Overall Survival (OS) | Time from first bb2121 infusion to time of death due to any cause | Minimum of 24 months post-bb2121 infusion | 
| Adverse Events (AEs) | Number of participants with adverse events (AEs), severity of adverse events, adverse events of special interest (AESI), and serious adverse events (SAEs) | Minimum of 24 months post-bb2121 infusion | 
| Pharmacokinetics - Cmax | The maximum transgene level at Tmax | Minimum of 24 months post-bb2121 infusion | 
| Pharmacokinetics - Tmax | Time to peak transgene level | Minimum of 24 months post-bb2121 infusion | 
| Pharmacokinetics - AUC | Area under the curve of the transgene level | Minimum of 24 months post-bb2121 infusion | 
| Immunogenicity | Development of an anti-CAR antibody response | Minimum of 24 months post-bb2121 infusion | 
| Minimal Residual Disease (MRD) | Proportion of MRD evaluable subjects that are MRD negative | Minimum of 24 months post-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 of 24 months post-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 of 24 months post-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 of 24 months post-bb2121 infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Efficacy and Safety, BB2121, CAR T Cell, BCMA, Relapsed and Refractory