P-BCMA-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects With Multiple Myeloma

Study Overview
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Brief Summary
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Phase 1 study comprised of open-label, dose escalation, multiple cohorts of P-BCMA-ALLO1 allogeneic T stem cell memory (Tscm) CAR-T cells in subjects with relapsed / refractory Multiple Myeloma (RRMM).

Detailed Description
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Phase 1 study consisting of two parts. Part 1 is a weight-based dose escalation following a 3+3 design of dose-escalating cohorts. Part 2 includes administration at fixed doses. After enrollment, subjects may receive a lymphodepletion therapy regimen before administration of allogeneic CAR-T cells, administered as a single or multiple doses. Treated subjects will undergo serial measurements of safety, tolerability and response. Rimiducid may be administered as indicated.

Official Title
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Open-Label, Multicenter, Phase 1 Study to Assess the Safety of P-BCMA-ALLO1 in Subjects With Relapsed / Refractory Multiple Myeloma (MM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: P-BCMA-ALLO1 CAR-T cells
* Drug: Rimiducid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have signed written, informed consent. Males or females, ≥18 years of age. Must have a confirmed diagnosis of active MM. Must have measurable MM. Must have relapsed / refractory MM, having received treatment with a proteasome inhibitor, immunomodulatory agent (IMiD), and anti-CD38 therapy. Must be willing to practice birth control from the time of Screening and throughout the first year of the study after P-BCMA-ALLO1 administration. Must have a negative serum pregnancy test at Screening and a negative urine pregnancy test within 3 days prior to initiating the lymphodepletion therapy regimen (females of childbearing potential). Must be at least 90 days since autologous stem cell transplant, if performed. Must have adequate vital organ function within pre-determined parameters. Must have recovered from toxicities due to prior therapies. Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Exclusion Criteria: Is pregnant or lactating. Has inadequate venous access. Has active hemolytic anemia, plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, disseminated intravascular coagulation, leukostasis, or amyloidosis. Has an active second malignancy (not disease-free for at least 5 years) in addition to MM, excluding low-risk neoplasms such as non-metastatic basal cell or squamous cell skin carcinoma. Has active autoimmune disease. Has a history of significant central nervous system (CNS) disease, such as stroke, epilepsy, etc. Has an active systemic infection. Has a history of hepatitis B, hepatitis C virus, human immunodeficiency virus (HIV), or human T-lymphotropic virus (HTLV) infection, or any immunodeficiency syndrome. Subjects with a history of treated hepatitis C can be enrolled if negative by Hepatitis C PCR on multiple occasions and with medical monitor approval. Has New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, or a history of myocardial infarction or significant arrhythmia. Has any psychiatric or medical disorder that would preclude safe participation in and/or adherence to the protocol. Has received prior allogeneic cellular therapy or gene therapy. Has received anti-cancer medications within 2 weeks of the time of initiating conditioning LD therapy. Has received monoclonal antibody therapy within 4 weeks of initiating conditioning LD therapy. Has received immunosuppressive medications within 2 weeks of the time of administration of P-BCMA-ALLO1, and/or expected to require them while on study. Has received systemic corticosteroid therapy within 1 week or 5 half-lives (whichever is shorter) of the administration of P-BCMA-ALLO1 or is expected to require it during the course of the study. Has CNS metastases or symptomatic CNS involvement of their myeloma. Has a history of severe immediate hypersensitivity reaction to any of the agents used in this study. Has a history of having undergone allogeneic stem cell transplantation, or any other allogeneic or xenogeneic transplant, or has undergone autologous transplantation within 90 days. Arms R and RS Only: a) Has received a live vaccine within the last 28 days of the first administration of agents used in Arm R or RS, b) Has any known hypersensitivity or severe reactions or toxicity to agents used in Arms R or RS.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm S)<br>Single weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen S. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm F)<br>Single weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen F. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm N)<br>Single weight-based IV administration of P-BCMA-ALLO1. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm P1)<br>Single weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen P1. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm P2)<br>Single weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen P2. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm R)<br>Single weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen R. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm RS)<br>Single weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen RS. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm C)<br>Cyclic weight-based IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen S. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm160)<br>Single fixed dose IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen S. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|
| Experimental: P-BCMA-ALLO1 CAR-T cells (Arm480)<br>Single fixed dose IV administration of P-BCMA-ALLO1 following conditioning chemotherapy regimen S. Rimiducid may be administered as indicated. | Biological: P-BCMA-ALLO1 CAR-T cells<br>* Allogeneic BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy<br>Drug: Rimiducid<br>* Safety switch activator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Assess the maximum tolerated dose (MTD) of P-BCMA-ALLO1 based on dose limiting toxicities (DLT) | Rate of dose limiting toxicities (DLT) | Baseline through Day 28 | 
| Part 2: Assess the safety and tolerability of P-BCMA-ALLO1 when administered as a fixed dose of cells. | Frequency and severity of adverse events, including cytokine release syndrome. | Baseline through 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of P-BCMA-ALLO1 | Incidence and severity of treatment-emergent adverse events | Baseline through 15 years | 
| The anti-myeloma effect of P-BCMA-ALLO1 (ORR) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Overall Response Rate (ORR) - Percentage of patients with complete response (CR), very good partial response (VGPR), or partial response (PR) | Baseline through 15 years | 
| The anti-myeloma effect of P-BCMA-ALLO1 (TTR) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Time to Response (TTR) - Time to complete response (CR), very good partial response (VGPR), or partial response (PR) to progressive disease | Baseline through 15 years | 
| The anti-Myeloma effect of P-BCMA-ALLO1 (DOR) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Duration of Response - Time from complete response (CR), very good partial response (VGPR), or partial response (PR) to progressive disease | Baseline through 15 years | 
| The anti-Myeloma effect of P-BCMA-ALLO1 (PFS) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Progression Free Survival (PFS) - Time from P-BCMA-ALLO1 treatment to progressive disease | Baseline through 15 years | 
| The anti-Myeloma effect of P-BCMA-ALLO1 (OS) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Overall Survival (OS) - Duration of survival from time of treatment with P-BCMA-ALLO1 | Baseline through 15 years | 
| The effect of cell dose and study arm to guide selection of doses and LD regimen for further assessment in Phase 2/3 studies | Incidence and severity of CRS events graded using American Society for Transplantation and Cellular Therapy (ASTCT) criteria (Lee, 2019) | Baseline through 36 months |