P-BCMA-101 Tscm CAR-T Cells in the Treatment of Patients With Multiple Myeloma (MM)

Study Overview
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Brief Summary
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Phase 1 of the study is comprised of an open-label, single ascending dose (SAD), multiple cohort study; a multiple dose cycle administration cohort study; and a combination administration study of P-BCMA-101 autologous T stem cell memory (Tscm) CAR-T cells in patients with relapsed / refractory MM. Followed by a Phase 2, open-label, efficacy and safety study. Rimiducid may be administered as indicated.

Detailed Description
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Phase 1 follows a 3 + 3 design of dose-escalating cohorts. Phase 2 of the study is an open-label multi-center efficacy and safety study. After a patient enrolls, leukapheresis will be performed to obtain peripheral blood mononuclear cells which will be sent to a manufacturing site to produce P-BCMA-101 CAR-T cells. The cells will then be returned to the investigational site and, after a standard chemotherapy based conditioning regimen, will be administered to the patient across 1-3 infusions, with or without combination therapy. Treated patients 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-101 in Subjects With Relapsed / Refractory Multiple Myeloma (MM) Followed by a Phase 2 Assessment of Response and Safety (PRIME)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: P-BCMA-101 CAR-T cells
* Drug: Rimiducid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 proteasome inhibitor and IMiD [Phase 2: Must have relapsed / refractory MM, and refractory to last line of therapy, having received treatment with proteasome inhibitor, an IMiD, CD38 targeted therapy and undergone autologous stem cell transplant (ASCT) or not a candidate for ASCT.] Must have adequate hepatic, renal, cardiac and hematopoietic function Exclusion Criteria: Is pregnant or lactating Has inadequate venous access and/or contraindications to leukapheresis Has active hemolytic anemia, plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, disseminated intravascular coagulation, leukostasis, amyloidosis, significant autoimmune, CNS or other malignant disease 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 hepatitis B or C virus, human immunodeficiency virus (HIV), or human T-lymphotropic virus (HTLV) infection, or any immunodeficiency syndrome. Has any psychiatric or medical disorder that would preclude safe participation in and/or adherence to the protocol Has receiving immunosuppressive or other contraindicated therapies within the excluded time frame from entry Has CNS metastases or symptomatic CNS involvement 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. Unable to take acetylsalicylic acid (ASA) daily as prophylactic anticoagulation. (Cohorts R and RP only). History of thromboembolic disease within the past 6 months, regardless of anticoagulation (Cohorts R and RP only).

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: Sequential Assignment
Interventional Model Description: Phase 1: open label, 3 + 3 design of dose-escalating cohorts Phase 2: open label, administered as a total dose
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: P-BCMA-101 CAR-T cells<br>Single ascending dose cohorts, given in a single intravenous infusion of CAR-T cells. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 1 P-BCMA-101 CAR-T cells (Cohort A)<br>Single dose given across two intravenous infusions of CAR-T cells. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 1 P-BCMA-101 CAR-T cells (Cohort B)<br>Single dose given across three intravenous infusions of CAR-T cells. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 1 P-BCMA-101 CAR-T cells (Cohort C)<br>Single dose given across two intravenous infusions of CAR-T cells. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 1 P-BCMA-101 CAR-T cells with Comb.Therapy (Cohort R)<br>Single intravenous infusion of CAR-T cells, with combination therapy, beginning one week before CAR-T infusion. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 1 P-BCMA-101 CAR-T cells with Comb.Therapy (Cohort RP)<br>Single intravenous infusion of CAR-T cells, with combination therapy, beginning one week before apheresis. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 1 P-BCMA-101 CAR-T cells with Comb.Therapy (Cohort RIT)<br>Single intravenous infusion of CAR-T cells, with combination therapy, beginning one week before CAR-T infusion. Rimiducid may be administered as indicated. | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|
| Experimental: Phase 2: P-BCMA-101 CAR-T Cells<br>CAR-T cells administered via intravenous infusion as a total dose | Biological: P-BCMA-101 CAR-T cells<br>* P-BCMA-101 is an autologous, principally Tscm, CAR-T cell product (also called called a CARTyrin T cell product) targeting the myeloma selective protein BCMA. P-BCMA-101 cells are produced using a non-viral vector carrying the gene for an anti-BCMA Centyrin-based (small, fully human binding domain, designed to increase T cell persistence and decrease exhaustion) chimeric antigen receptor (CAR). Secondary to the large carrying capacity of the non-viral vector, P-BCMA-101 cells carry two additional genes, a selection gene used to manufacture a purified product and a safety switch gene to allow the cells to be eliminated if desired. Rimiducid (safety switch activator) may be administered as indicated.<br>Drug: Rimiducid<br>* Rimiducid (safety switch activator) may be administered as indicated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Assess the Safety of P-BCMA-101 | Incidence and severity of treatment-emergent adverse events | Baseline through Day 28 | 
| Phase 1: Maximum Tolerated Dose of P-BCMA-101 | Rate of dose limiting toxicities (DLT) | Baseline through Day 28 | 
| Phase 2: Assess the Safety of P-BCMA-101 | Incidence and severity of treatment-emergent adverse events | Baseline through 24 months | 
| Phase 2: Assess the Efficacy of P-BCMA-101 (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 24 months | 
| Phase 2: Assess the Efficacy of P-BCMA-101 (DOR) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Duration of Response (DOR)-Time from complete response (CR), very good partial response (VGPR), or partial response (PR) to progressive disease. | Baseline through 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1:Assess the Safety of P-BCMA-101 | Incidence and severity of treatment-emergent adverse events | Baseline through Month 24 | 
| Phase 1:Assess the Feasibility P-BCMA-101 | Ability to generate protocol-prescribed doses of P-BCMA-101. | Baseline through Month 24 | 
| Phase 1: Anti-myeloma Effect of P-BCMA-101 (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 Month 24 | 
| Phase 1: Anti-myeloma Effect of P-BCMA-101 (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 Month 24 | 
| Phase 1: Anti-myeloma Effect of P-BCMA-101 (DOR) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Duration of Response (DOR)-Time from complete response (CR), very good partial response (VGPR), or partial response (PR) to progressive disease. | Baseline through Month 24 | 
| Phase 1: Anti-myeloma Effect of P-BCMA-101 (PFS) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Progression Free Survival (PFS)-Time from P-BCMA-101 treatment to progressive disease. | Baseline through Month 24 | 
| Phase 1: Anti-myeloma Effect of P-BCMA-101 (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-101. | Baseline through Month 24 | 
| Phase 1: The Effect of Cell Dose to Guide Selection of Doses for Further Assessment in Phase 2/3 Studies | Incidence and severity of CRS events graded using Lee criteria (Lee, 2014) | Baseline through Month 24 | 
| Phase 2: Incidence and Severity of Cytokine Release Syndrome (CRS) | Incidence and severity of CRS events graded using Lee criteria (Lee, 2014) | Baseline through Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (IL-6) | Rate of IL-6 antagonist | Baseline through Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (C) | Corticosteroid Use | Baseline through Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (R) | Rimiducid Use | Baseline through Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (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-101. | Baseline through Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (PFS) | According to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma: Progression Free Survival (PFS)-Time from P-BCMA-101 treatment to progressive disease. | Baseline through Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (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 Month 24 | 
| Phase 2: Evaluate Efficacy Endpoints (MRD) | Minimum residual disease negative rate | Baseline through Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T cells