Safety and Efficacy of ALLO-715 BCMA Allogenic CAR T Cells in in Adults With Relapsed or Refractory Multiple Myeloma (UNIVERSAL)

Study Overview
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Brief Summary
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The purpose of the UNIVERSAL study is to assess the safety, efficacy, cell kinetics, and immunogenicity of ALLO-715 with or without Nirogacestat in adults with relapsed or refractory multiple myeloma after a lymphodepletion regimen of ALLO-647 in combination with fludarabine and/or cyclophosphamide, or ALLO-647 alone.

Official Title
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A Single-Arm, Open-Label, Phase 1 Study of the Safety, Efficacy, and Cellular Kinetics/Pharmacodynamics of ALLO-715 to Evaluate an Anti-BCMA Allogeneic CAR T Cell Therapy With or Without Nirogacestat in Subjects With Relapsed/Refractory Multiple Myeloma

Conditions
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Relapsed/Refractory Multiple Myeloma

Intervention / Treatment
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* Genetic: ALLO-715
* Biological: ALLO-647
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Nirogacestat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of relapsed/refractory multiple myeloma (MM) with measurable disease (serum, urine, or free light chain [FLC]) per International Myeloma Working Group (IMWG) criteria At least 3 prior lines of MM therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody (unless contraindicated), and refractory to the last treatment line. Eastern Cooperative Oncology Group (ECOG) 0 or 1 Absence of donor (product)-specific anti-HLA antibodies Adequate hematologic, renal, hepatic, pulmonary, and cardiac function Exclusion Criteria: Current or history of Central Nervous System (CNS) involvement of myeloma or plasma cell leukemia Clinically significant CNS disorder Current or history of thyroid disorder Autologous stem cell transplant within the last 6 weeks, or any allogeneic stem cell transplant Prior treatment with anti-BCMA therapy, any gene therapy, any genetically modified cell therapy, or adoptive T cell therapy History of HIV infection or acute or chronic active hepatitis B or C infection Patients unwilling to participate in an extended safety monitoring period Additional Exclusion Criteria for Nirogacestat plus ALLO-715 Cohorts Inability to swallow tablets Subject has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat Use of strong/moderate CYP3A4 inhibitors, and strong CYP3A4 inducers within 14 days before starting nirogacestat. Use of concomitant medications that are known to prolong the QT/QTcF interval

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: ALLO-647, ALLO-715, Nirogacestat<br> | Genetic: ALLO-715<br>* ALLO-715 is an allogeneic CAR T cell therapy targeting BCMA<br>Biological: ALLO-647<br>* ALLO-647 is a monoclonal antibody that recognizes a CD52 antigen<br>Drug: Fludarabine<br>* Chemotherapy for lymphodepletion<br>Drug: Cyclophosphamide<br>* Chemotherapy for lymphodepletion<br>Drug: Nirogacestat<br>* a small molecule, selective, reversible, noncompetitive inhibitor of γsecretase (GSI) that increases BCMA target density on the surface of multiple myeloma cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects experiencing Dose Limiting Toxicities at increasing doses of ALLO-715 | Dose limiting toxicities are defined as ALLO-715-related adverse events with onset within 28 days following infusion of ALLO-715. | 28 Days | 
| To assess the overall safety profile and tolerability of ALLO-647 in combination with Fludarabine and/or cyclophosphamide or ALLO-647 alone, prior to ALLO-715 to confirm the dose of ALLO-647. | The proportion of subjects in a dose cohort with DLTs of ALLO-647 | 33 days | 
| To assess the overall safety profile and tolerability of nirogacestat given concomitantly with ALLO-715 following lymphodepletion with Flu/ Cy/ ALLO-647. | Dose limiting toxicities are defined as ALLO-715-related adverse events with onset within 28 days following infusion of ALLO-715. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cellular kinetics of ALLO-715 | Levels of anti-BCMA CAR T cells in blood | up to 60 months | 
| antitumor activity of ALLO-715 in combination with nirogacestat | overall -response rate (ORR) | up to 60 months | 
| Cellular kinetics of ALLO-715 in combination with nirogacestat | Levels of anti-BCMA CAR T cells in blood | up to 60 months | 
| Pharmacokinetics of ALLO-647 | Serum concentration levels of ALLO-647 | up to 60 months | 
| Pharmacokinetics of nirogacestat | Serum concentration levels of nirogacestat | up to 60 months | 
| Incidence of immunogenicity against ALLO-715 and ALLO-647 | detection and levels of anti-drug antibodies | up to 60 months | 
| Immune monitoring after lymphodepletion regimen | Detection of the following circulating cells: T cell subset, B lymphocytes, and NK cells | up to 60 months | 
| Anti-tumor activity of ALLO-715 | overall response rate | up to 60 months | 
| Anti-tumor activity of ALLO-715 | duration of response | up to 60 months | 
| Anti-tumor activity of ALLO-715 | overall survival | up to 60 months | 
| Anti-tumor activity of ALLO-715 | minimal residual disease | up to 60 months | 
| To evaluate the expression of BCMA in bone marrow plasma cells with and without nirogacestat | Overall response rate of ALLO-715 with and without Nirogacestat | up to 60 months |