Safety and Efficacy of bb2121 (Ide-cel) Combinations in Multiple Myeloma

Study Overview
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Brief Summary
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This is a global, open-label, multi-arm, multi-cohort, multi-center, phase 1/2 study to determine the safety, tolerability, efficacy, PK of bb2121 in combination with other therapies in adult subjects with R/RMM. The following combinations will be Arm A will test bb2121 in combination with CC-220 (± low-dose dexamethasone) Arm B will test bb2121 in combination with BMS-986405 (JSMD194) Combination agents being tested may be administered before, concurrently with and/or following (ie, maintenance) bb2121 infusion. The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.

Official Title
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An Exploratory Phase 1/2 Trial to Determine Recommended Phase 2 Dose (RP2D), Safety and Preliminary Efficacy of bb2121 (Ide-cel) Combinations in Subjects With Relapsed/Refractory Multiple Myeloma (KarMMa-7)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: BB2121
* Drug: CC-220
* Drug: BMS-986405


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must satisfy the following criteria to be enrolled in the study: Participant has documented diagnosis of MM and measurable disease, defined as: M-protein (serum protein electrophoresis [sPEP ≥ 0.5 g/dL] or urine protein electrophoresis [uPEP]): 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 Participant has received: at least 3 prior MM regimens for Arm A Cohort 1 and Arm B at least 1 but no greater than 3 prior MM regimens for Arm A Cohort 2 Arm A Cohort 1 and Arm B: Participant has received prior treatment with an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody-containing regimen for at least 2 consecutive cycles. Arm A Cohort 2: Participant has received prior treatment with an immunomodulatory agent for at least 2 consecutive cycles. Evidence of PD during or within 6 months (measured from the last dose of any drug within the regimen) of completing treatment with the last antimyeloma regimen before study entry. Participant achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: The presence of any of the following will exclude a participant from enrollment: Participant has non-secretory MM or has history of or active plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis. Participant has any of the following laboratory abnormalities: ANC and Platelets count as reported below Hemoglobin < 8 g/dL (< 4.9 mmol/L) (transfusion is not permitted within 21 days of screening) Creatinine clearance (CrCl) as reported below Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L) Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 ×upper limit of normal (ULN) Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for participants with documented Gilbert's syndrome International normalized ratio (INR) or activated partial thromboplastin time (aPTT) 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or participant requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors) Participant has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on room air. Participant has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal. Prior exposure to CC-220 (± low-dose dexamethasone) as part of their most recent antimyeloma treatment regimen (Arm A). Prior exposure to BMS-986405 (JSMD194) (Arm B). 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. Treatment Arm A Cohort 1 and Arm B: participant has received autologous stem cell transplantation (ASCT) within 12 weeks prior to leukapheresis. Treatment Arm A Cohort 2: participant has received autologous stem cell transplantation (ASCT) within 12 months prior to leukapheresis.

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: Arm A- bb2121 in combination with CC-220 (± low-dose dexamethasone)<br>bb2121 will be administered at a target dose of 450 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/ or schedules, depending on dose limiting toxicity (DLT) evaluation. | Biological: BB2121<br>* CAR T Cell Therapy<br>* Other names: ide-cel;Drug: CC-220<br>* Cereblon (CRBN) E3 ligase modulatory compound (CELMoD)<br>|
| Experimental: Arm B- bb2121 in combination with BMS-986405 (JSMD194)<br>bb2121 will be administered at a target dose of 450 x 10^6 CAR+T cells. The combination agent will be administered during Month 1 starting from the day of bb2121 infusion Enrollment is closed for this Arm | Biological: BB2121<br>* CAR T Cell Therapy<br>* Other names: ide-cel;Drug: BMS-986405<br>* gamma secretase inhibitor (GSI)<br>* Other names: JSMD194;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Does Limiting Toxicity (DLT) rates _Phase 1 | Percentage of participants experiencing DLTs | Up to 28 days from start of the combination therapy | 
| Complete Response Rate (CRR)_ Phase 2 | Proportion of participants who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by investigator's review | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Event (AEs) | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. | Up to 24 months after the last participant received any study treatment | 
| Overall Response Rate (ORR) | Proportion of participants who achieved PR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed investigator's review | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Progression-free Survival (PFS) | Time from first study treatment (whichever is given earlier) start date to the date of either first observation of progressive disease or death due to any cause | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Overall Survival (OS) | Time from first study treatment (whichever is given earlier) start date to death due to any cause | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Time to response (TTR) | Time from first study treatment start date to the first date of documented response (PR or better) | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Duration of Response (DoR) | Time from first documentation of response (PR or better) to first documentation of PD or death due to any cause | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Time to next antimyeloma treatment (TTNT) | Time from first study treatment (whichever is given earlier) start date to first day when participant receives another antimyeloma treatment | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Progression-free survival after next antimyeloma therapy (PFS2) | Time from first study treatment (whichever is given earlier) start date to documentation of PD on the next-line treatment or death from any cause, whichever is first. | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Feasibility of maintenance therapy in combination with bb2121 | Cumulative incidence of the maintenance therapy starting from bb2121 infusion with death as the competing risk | Up to 4 months after bb2121 infusion in the respective cohort | 
| Pharmacokinetics - Cmax_Phase 1 and 2 | Maximum transgene level | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Pharmacokinetics - Tmax_Phase 1 and 2 | Time to maximum observed transgene level | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Pharmacokinetics - AUC_Phase 1 and 2 | Area under the curve of transgene level | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Pharmacokinetics - AUC0-28days _Phase 1 and 2 | Area under the curve of transgene level from time 0 to 28 days | Up to 24 months after the last participant received any study treatment in the respective cohort | 
| Pharmacokinetics - Tlast _Phase 1 and 2 | Time of last measurable transgene level | Up to 24 months after the last participant received any study treatment in the respective cohort | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DPd, Relapsed/Refractory Multiple Myeloma, BB2121, ide-cel, CC-220, JSMD194, BMS-986405, PVd, CAR T, KarMMa-7, Phase I, Phase II, DARA, POM, BTZ