Safety and Efficacy of ALLO-501A Anti-CD19 Allogeneic CAR T Cells in Adults With Relapsed/Refractory Large B Cell Lymphoma (ALPHA2)

Study Overview
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Brief Summary
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The purpose of the ALPHA-2 study is to assess the safety, efficacy, and cell kinetics of ALLO-501A in adults with relapsed or refractory large B-cell lymphoma after a lymphodepletion regimen comprising fludarabine, cyclophosphamide, and ALLO-647

Official Title
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A Single-Arm, Open-Label, Phase 1/2 Study Evaluating the Safety, Efficacy, and Cellular Kinetics/Pharmacodynamics of ALLO-501A, an Anti-CD19 Allogeneic CAR T Cell Therapy, and ALLO-647, an Anti-CD52 Monoclonal Antibody, in Subjects With Relapsed/Refractory Large B-Cell Lymphoma (LBCL)

Conditions
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Relapsed/Refractory Large B Cell Lymphoma

Intervention / Treatment
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* Genetic: ALLO-501A
* Biological: ALLO-647
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of relapsed/refractory large B-cell lymphoma at last relapse per WHO 2017 At least 1 measurable lesion at time of enrollment Relapsed or refractory disease after at least 2 lines of chemotherapy ECOG performance status 0 or 1 Absence of donor (product)-specific anti-HLA antibodies (DSA) Adequate hematological, renal, and liver function Exclusion Criteria: Active central nervous system (CNS) involvement by malignancy Current thyroid disorder (including hyperthyroidism), except for subjects with hypothyroidism controlled on a stable dose of hormone replacement therapy Any other active malignancies that required systemic treatment within 3 years prior to enrollment Radiation therapy within 2 weeks prior to ALLO-647 Prior irradiation to >25% of the bone marrow Hypocellular bone marrow for age by institutional standard as determined from a bone marrow biopsy performed at time of screening Autologous hematopoietic stem cell transplant (HSCT) within last 6 months (24 weeks) Systemic anti-cancer therapy within 2 weeks prior to receiving ALLO-647 Subjects with active systemic bacterial, fungal, or viral infection requiring systemic treatment (including positive blood cultures within 7 days before starting lymphodepletion)

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-501A, ALLO-647<br> | Genetic: ALLO-501A<br>* ALLO-501A is an allogeneic CAR T cell therapy targeting CD19<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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Proportion of subjects experiencing Dose Limiting Toxicities (DLT) at increasing doses of ALLO-501A | Dose limiting toxicity is defined as protocol-defined ALLO-501A-related adverse events with onset within 28 days following infusion | 28 days | 
| Phase 1: Proportion of patients experiencing Dose Limiting Toxicity with ALLO-647 in combination with fludarabine/cyclophosphamide administered prior to ALLO-501A | DLT is defined as protocol-defined ALLO-647-related adverse events with onset within 33 days following 1st infusion | 33 days | 
| Phase 2: Overall Response Rate (ORR) assessed per Independent Review Committee (IRC) | ORR defined as assessment of CR and PR using Lugano classification criteria 2014 | Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Duration of Response (DOR) assessed per IRC (Phase 2 only) and per investigator | DOR is defined only for subjects who experience an objective response and is the time from the first objective response to disease progression or death, whichever comes first per (Cheson et al, 2014) | Up to 60 months | 
| Phase 1 and 2: Overall Response Rate (ORR) assessed per investigator |  | Up to 60 months | 
| Phase 1 and 2: Best overall response (CR, PR, SD, PD) assessed per IRC (Phase 2 only) and per investigator | CR Complete Response, PR Partial Response, SD Stable Disease, PD Progressive Disease | Up to 60 months | 
| Phase 1 and 2: Progression Free Survival (PFS) assessed per IRC (Phase 2 only) and per investigator | PFS, defined as time from the enrollment date to progression, relapse, or death | Up to 60 months | 
| Phase 1 and 2: Time to Response (TTR) assessed per IRC (Phase 2 only) and per investigator | TTR, defined as the time from the enrollment date to the first observed response | Up to 60 months | 
| Phase 1 and 2: Overall Survival (OS) | OS, defined as the time from the enrollment date to death | Up to 60 months | 
| Phase 1 and 2: Depth of lymphodepletion as assessed by lymphocyte count |  | Up to 9 months | 
| Phase 1 and 2: Duration of lymphodepletion as assessed by lymphocyte recovery |  | Up to 9 months | 
| Phase 1 and 2: Serum concentration of ALLO-647 as measured by microgram per microliter for use in a population PK model |  | Up to 9 months | 
| Phase 1 and 2: ALLO-501A expansion assessed by peak blood concentration (Cmax) |  | Up to 9 months | 
| Phase 1 and 2: ALLO-501A expansion assessed by area under the curve (AUC) |  | Up to 9 months | 
| Phase 1 and 2: ALLO-501A persistence assessed by peak blood concentration (Cmax) |  | Up to 9 months | 
| Phase 1 and 2: ALLO-501A persistence assessed by area under the curve (AUC) |  | Up to 9 months | 
| Phase 1 and 2: Pharmacodynamics will be evaluated on host T cell counts |  | Up to 9 months | 
| Phase 1 and 2: The incidence of anti-drug antibodies against ALLO-501A scFv and/or TALEN® |  | Up to 9 months | 
| Phase 1 and 2: The incidence of anti-drug antibodies against ALLO-647 |  | Up to 9 months | 
| Phase 1 and 2: Adverse Events (AEs) as characterized by preferred term, frequency, severity timing, seriousness, and relationship to ALLO-501A | The incidence and severity of Cytokine Release Syndrome (CRS), Graft-Versus-Host Disease (GVHD), infections, cytopenias, and neurotoxicity | Up to 60 months | 
| Phase 1 and 2: AEs as characterized by preferred term, frequency, severity, timing, seriousness, and relationship to ALLO-647 | The incidence of infusion-related reactions, cytopenias, and infections | Up to 60 months | 
| Phase 1 and 2: The incidence and severity of clinically significant laboratory toxicities |  | Up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR T, Cell Therapy, Allogeneic Cell Therapy, Cellular Immuno-therapy, AlloCAR T, ALLO-501A, ALLO-647, LBCL, Lymphoma, Large B-Cell Lymphoma