CD19-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory B-Lineage Leukaemia / Lymphoma - A Feasibility Protocol

Study Overview
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Brief Summary
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The purpose of this study is to describe feasibility of delivering point-of-care manufactured CD19-directed CAR T-cell therapy to patients with relapsed/ refractory B-lineage leukaemia/ lymphoma.

Detailed Description
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This is a single arm, open-label, multi-center, phase II feasibility study to deliver point-of-care manufactured CD19-directed CAR T-cell therapy to patients with relapsed / refractory B-lineage leukaemia / lymphoma. The study consists of the following phases: Screening phase: Eligibility; enrolment Preparatory phase: Bridging therapy (if required); leukapheresis; CAR T manufacturing; lymphodepletion. Treatment phase: Infusion of single dose of anti-CD19 CAR T-cells Follow-up Phase: Efficacy and safety monitoring up to 24 months

Official Title
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CD19-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory B-Lineage Leukaemia / Lymphoma - A Feasibility Protocol

Conditions
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Lymphoblastic Leukemia, Lymphoblastic Leukemia in Children, Lymphoblastic Leukemia, Acute Adult, B-cell Acute Lymphoblastic Leukemia, Large B-cell Lymphoma, CAR

Intervention / Treatment
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* Biological: Anti-CD19 CAR T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible disease conditions: Relapsed or refractory B-cell ALL (all must be satisfied) Presence of lymphoblasts in bone marrow aspirate by morphologic assessment or positive minimal residual disease at screening. Relapsed or refractory or ineligible for HSCT For relapsed B-ALL: Documentation of CD19 tumour expression (e.g. by flow cytometry) demonstrated in bone marrow or peripheral blood within 3 months of study entry Relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Age at screening: < 18 years (paediatric group); or ≥ 18 years (adult group) Adequate organ functions: Life expectancy more than 12 weeks. Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening. Must meet the institutional criteria to undergo leukapheresis or have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site. Exclusion Criteria: Patients with any of the following will be excluded: B-ALL with isolated extramedullary disease relapse Patients with concomitant genetic syndrome: such as patients with Fanconi anaemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded. Patients with Burkitt's lymphoma/leukaemia (i.e. patients with mature B-cell ALL; leukaemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation) Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines. Subjects with CNS-2 involvement or with history of CNS disease that have been actively treated are eligible. Patient has an investigational medicinal product within the last 30 days prior to screening. Pregnant or nursing women. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CAR T-cell infusion. All female patients of childbearing potential must have a negative pregnancy test performed within 48 hours before infusion of CAR T-cells. The following are not strictly exclusion criteria but must be discussed with PI/Site-PI: Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease Treatment with any prior gene therapy product Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 70 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: Single Arm<br>CD19-directed CAR T-cell therapy for relapsed/refractory B-lineage leukaemia/lymphoma. | Biological: Anti-CD19 CAR T-cells<br>* A target per-protocol dose of vi able CD19 CAR transduced T-cells will consist of a single infusion of 0.2 to 5.0 x 10e6 lentiviral-transduced viable 41BB-CD19 CAR T-cells per kg body weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protocol Feasibility | To describe feasibility of delivering point-of-care manufactured CD19-directed CAR T-cell therapy to patients with relapsed / refractory B-lineage leukaemia / lymphoma by assessing number and percentage of enrolled patients who have successful manufacturing of CAR T-cell product, and number and percentage of enrolled patients who go on to receive the CAR T-cell product. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | To evaluate percentage of patients with complete response or partial response at 28 days, 3 months and 6 months post-infusion of the CD19-directed CAR T-cells. | 6 months | 
| Toxicity Evaluations | To evaluate overall incidence (percentage of infused patients) of toxicities post-infusion of CAR T-cells, in particular cytokine release syndrome (CRS) and neurotoxicity, and percentage with Grade 3 and above CRS and neurotoxicity following ASTCT definition and severity grading, and other toxicities as assessed by CTCAE v5.0. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-ALL, CAR T-cell therapy, Relapse/Refractory, B-Lineage Lymphoma