BCMA-directed CAR-T Cell Therapy in Adult Patients With Multiple Myeloma

Study Overview
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Brief Summary
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This is a first-in-human study to evaluate the feasibility, safety and preliminary antitumor efficacy of autologous T cells genetically engineered with a novel B-cell Maturation Antigen (BCMA)-specific chimeric antigen receptor (CAR) and manufactured with a new process. CAR-T cells will be investigated as a single agent in multiple myeloma

Detailed Description
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This is a phase I, open label study to characterize the safety and tolerability of a novel B-cell Maturation Antigen (BCMA)-specific chimeric antigen receptor (CAR) manufactured with a new process. In the dose escalation part (Part A) of the study, the anti-BCMA CAR-T cell therapy will be studied in adult multiple myeloma (MM) subjects who are relapsed and/or refractory. In the dose evaluation part (Part B) of the study, the anti-BCMA CAR-T cell therapy will be studied in newly diagnosed adult subject with MM.

Official Title
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Phase I, Open Label, Study of B-cell Maturation Antigen (BCMA)-Directed CAR-T Cells in Adult Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: PHE885


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A: Subjects with MM who are relapsed and/or refractory to at least 2 prior treatment regimens, including an IMiD (e.g. lenalidomide or pomalidomide), a proteasome inhibitor (e.g. bortezomib, carfilzomib), and an approved anti-CD38 antibody (e.g. daratumumab), if available, and have documented evidence of disease progression (IMWG criteria) Part A: ECOG performance status that is either 0 or 1 at screening Part B: Subjects with newly diagnosed multiple myeloma (NDMM) who have received a minimum of 4 and up to 6 cycles of standard induction therapy with VRd, D-VRd, or D-Rd, and have achieved a response of PR or better. One cycle of CyBorDex is allowed prior to induction. Part B: ECOG performance status that is either 0,1 or 2 at screening Measurable disease as defined by the protocol Adequate hematological values Must have a leukapheresis material of non-mobilized cells accepted for manufacturing Exclusion Criteria: Prior administration of a genetically modified cellular product including prior BCMA CAR-T therapy. Patients who have received prior BCMA-directed bi-specific antibodies or antibody-drug conjugates (ADC) are not excluded. Autologous HSCT within 6 weeks prior to enrollment or any prior history of allogeneic hematopoietic stem cell transplant (HSCT) Chemotherapy or any concomitant anti-cancer therapies (other than protocol prescribed lymphodepletion (LD) chemotherapy) within 2 weeks prior to apheresis Treatment with small molecule targeted antineoplastics within 2 weeks of apheresis collection or 5 half-lives whichever is shorter Have received antibodies or immunotherapies (other than daratumumab) within 4 weeks prior to apheresis collection. Daratumumab within 3 weeks prior to apheresis collection.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PHE885 (Part A)<br>Relapsed and/or refractory multiple myeloma (r/r MM) patients will receive PHE885. | Biological: PHE885<br>* Infusion<br>|
| Experimental: PHE885 (Part B)<br>Newly diagnosed multiple myeloma (NDMM) patients will receive PHE885. | Biological: PHE885<br>* Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose limiting toxicities (DLT) | Incidence of Dose Limiting Toxicities (DLTs) during the first 28 days after anti-BCMA CAR-T cell administration | 28 days | 
| Nature of Dose limiting toxicities (DLT) | Nature of Dose Limiting Toxicities (DLTs) during the first 28 days after anti-BCMA CAR-T cell administration | 28 days | 
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Manufacture success rate (defined as number of subjects treated with planned target dose divided by total number of subjects treated) | evaluate the feasibility of the manufacturing process | 24 Months | 
| Overall Response Rate (ORR) | Proportion of subjects with the best overall response (BOR) of sCR (stringent complete response) + CR (complete response) + VGPR (very good partial response) + PR (partial response), as determined by local investigator using the IMWG Criteria | 24 months | 
| Response rate at 3 and 6 months in Part A | Proportion of subjects with the overall response of sCR+CR+VGPR+PR at months 3 and 6 respectively, as determined by local investigator using the IMWG Criteria | 3 months, 6 months | 
| Overall response rate at 3 and 6 months in Part B | Proportion of subjects without progressive disease at month 3 and month 6 after infusion as determined by local investigator using the IMWG Criteria | 3 months, 6 months | 
| Overall Complete Response Rate (CRR) | Proportion of subjects with the BOR of sCR+CR, as determined by local investigator using the IMWG Criteria | 24 months | 
| CRR at months 3 and 6 in Part A | Proportion of subjects with the overall response of sCR+CR at months 3 and 6 respectively, as determined by local investigator using the IMWG Criteria | 3 months, 6 months | 
| CRR at months 3 and 6 in Part B | Proportion of subjects with measurable disease at baseline with the overall response of sCR+CR at month 3 and month 6 as determined by local investigator using the IMWG Criteria | 3 months, 6 months | 
| DOR (duration of response) in Part A | DOR as assessed by local investigator: the time from achievement of sCR+CR+VGPR+PR to relapse or death due to MM (multiple myeloma) | from disease response to disease progression, assessed up to approximately 24 months | 
| Cmax of BCMA CAR-T cells | through qPCR-detected transgene of CART concentrations over time in peripheral blood and bone marrow | 24 months | 
| Tmax of BCMA CAR-T cells | through qPCR-detected transgene of CART concentrations over time in peripheral blood and bone marrow | 24 months | 
| AUC of BCMA CAR-T cells | through qPCR-detected transgene of CART concentrations over time in peripheral blood and bone marrow | 24 months | 
| Clast of BCMA CAR-T cells | through qPCR-detected transgene of CART concentrations over time in peripheral blood and bone marrow | 24 months | 
| number of patients with pre-existing and treatment induced immunogenicity (cellular and humoral) of BCMA CAR-T cell therapy |  | 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, B-cell maturation antigen, BCMA, anti-BCMA, BCMA-directed, chimeric antigen receptor, CAR-T, PHE885