Donor-Derived CD5 CAR T Cells in Subjects With Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This is a FIH, single center, open label, non-randomized, single-arm, Phase I clinical trial to evaluate the safety and tolerability of CD5 CAR T cells in subjects with relapsed or refractory T-cell acute lymphoblastic leukemia. At least 18 subjects will be enrolled. After the collection of PBMC and about 5 days before infusion, lymphodepletion (fludarabine at 30 mg/m^2/day and cyclophosphamide at 250 mg/m^2/day; for prior-SCT donor-derived CAR T-cell infusion) or intensified lymphodepletion (fludarabine at 30 mg/m^2/day and cyclophosphamide at 30 mg/kg/day; for new donor-derived CAR T-cell infusion) will be administrated for 3 days. Then this study will be using BOIN1/2 approach from starting dose 1: 1×10^6 (±20%) to dose 2: 2×10^6 (±20%). If the manufactured cells were not sufficient to meet the preassigned standard dose criteria, patients are given infusion at a low dose of 5×10^5 (±20%) /kg.

Official Title
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First-in-Human (FIH), Open-Label, Non-Randomized, Single-Arm Phase 1 Study to Evaluate the Safety and Tolerability of Donor-Derived CD5 CAR T Cells in Subjects With Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia

Conditions
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T-Cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: CD5 CART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Candidates with relapse or refractory CD5+ T cell acute lymphoblastic leukemia, who have progressed on after treatment with all standard therapies or intolerant of standard care, have limited prognosis with currently available therapies and had no available curative treatment options (such as SCT or chemotherapy) Male or female, aged 1-70 years No serious allergic constitution Eastern Cooperative Oncology Group (ECOG) performance status (Oken et al., 1982) score 0 to 2 Have life expectancy of at least 60 days based on investigator's judgement CD5 positive in bone marrow or cerebrospinal fluid (CSF) by flow cytometry, or CD5 positive in tumor tissues by immunohistochemistry; (CD5 positive criteria: Flow cytometry: Positive: > 80% of tumor cells expressed CD5 and the MFI of CD5 is the same as that in normal T cells; Dim: > 80% of tumor cells expressed CD5, but the MFI of CD5 is lower than that in normal T cells as least as 1log; Partial positive: 20-80% of tumor cells expressed CD5 and the MFI of CD5 is the same as that in normal T cells. tumor tissue immunohistochemistry: Positive > 30% tumor cells expressed CD5); Provide a signed informed consent before any screening procedure; subjects who voluntarily participate in the study should have the ability to understand and sign the informed consent form and be willing to follow the study visit schedule and relevant study procedure, as specified in the protocol. Candidates aged 19-70 years need to be sufficiently conscious and able to sign the treatment consent form and voluntary consent form; Children candidates of 8-18 years old need to be sufficiently conscious and able to sign the treatment consent form and voluntary consent form and their legal guardian or patient advocate has also need to sign the treatment consent form and voluntary consent form, respectively.Children candidates of 1-7 can be recruited after the legal guardian or patient advocate has signed the treatment consent form and voluntary consent form. Have suitable and available allogeneic hematopoietic stem cell transplantation donor, and is willing to proceed to SCT if achieve CR. Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Intracranial hypertension or disorder of consciousness Symptomatic heart failure or severe arrhythmia Symptoms of severe respiratory failure Complicated with other types of malignant tumors Diffuse intravascular coagulation Serum creatinine and / or blood urea nitrogen ≥ 1.5 times of the normal value Suffering from septicemia or other uncontrollable infections Patients with uncontrollable diabetes Severe mental disorders Obvious and active intracranial lesions were detected by cranial magnetic resonance imaging (MRI) Have received organ transplantation (excluding bone marrow transplant) Reproductive-aged female patients with positive blood HCG test Screened to be positive of infection of hepatitis (including hepatitis B and C), AIDS or syphilis Post-CAR SCT is not feasible in patients who plan to receive new-donor derived CD5 CAR T cells No donor is applicable for peripheral blood mononuclear cell (PBMC) collection or no frozen donor's PBMC is available for manufacturing CAR T cells.

Ages Eligible for Study
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Minimum Age: 1 Year
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: CD5 CART<br>All patients who receive CD5 CART cell infusion | Biological: CD5 CART<br>* Subjects will be pretreated with chemotherapy prior to infusion of CAR T cells: After the collection of PBMC and about 5 days before infusion, lymphodepletion (fludarabine at 30 mg/m^2/day and cyclophosphamide at 250 mg/m^2/day; for prior-SCT donor-derived CAR T-cell infusion) or intensified lymphodepletion (fludarabine at 30 mg/m^2/day and cyclophosphamide at 30 mg/kg/day; for new donor-derived CAR T-cell infusion) will be administrated for 3 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and type of dose-limiting toxicity (DLT) |  | 21 days post intravenous injection | 
| Incidence and severity of adverse events (AE) |  | 30 days post intravenous injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Objective response rate (ORR) according to NCCN, Complete response（CR),CR with incomplete blood count recovery(CRi) . | 30 days post infusion | 
| Quantification of CAR T cells | Quantification of CAR T cells by flow cytometry and/or quantitative PCR in peripheral blood and cerebral spinal fluid (CSF). | 2 years post infusion | 
| Severe adverse events (SAE) | The incidence of any severe adverse event (SAE) and the severity of SAE from day 30 to 2 years. | 2 years post infusion | 
| Best overall response (BOR) | Best overall response (BOR) rate at 3 months. | 3 months post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T, leukemia, acute lymphoblastic leukemia