Optimized Dual CD33/CLL1 CAR T Cells in Subjects With Refractory or Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This is a single-center, open-label, non-randomized, single-arm Phase 1 Study to evaluate safety and tolerability of optimized Dual CD33/CLL1 CAR T Cells in subjects with refractory or relapsed acute myeloid leukemia. Maximum of twenty subjects will be enrolled. After the collection of PBMC and about 5 days before infusion, lymphodepletion chemotherapy (fludarabine at 30 mg/m^2/day and cyclophosphamide at 250 mg/m^2/day) 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: 5×10^6 (±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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Single-center, Open-Label, Non-randomized, Single-Arm Phase 1 Study to Evaluate the Safety and Tolerability of Optimized Dual CD33/CLL1 CAR T Cells in Subjects With Refractory or Relapsed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: Dual CD33/CLL1 CAR T


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: Co-expression of tumor surface antigens CD33 and CLL1 was confirmed (among which, the proportion of cells expressing CD33 was ≥ 80%; and the proportion of cells expressing CLL1 ≥ 80%); patients with primary drug resistance, chemotherapy relapse, extramedullary relapse, persistent residual disease positive or relapsed/refractory acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation; 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; 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. 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; For patients with CAR-T cells derived from autologous lymphocytes, leukemia blasts accounted for more than 30% of all cells in peripheral blood; Patients unable to provide a transplant donor about 30 days after the CAR-T cell transfusion.

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: Dual CD33/CLL1 CAR T<br>All patients who receive Dual CD33/CLL1 CAR T Cell infusion | Biological: Dual CD33/CLL1 CAR T<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 chemotherapy (fludarabine at 30 mg/m^2/day and cyclophosphamide at 250 mg/m^2/day) 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: 5×10^6 (±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%)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | DLT assessment according to the clinical study protocol | 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) | 28 days post infusion | 
| Concentration of PK CAR positive T cells in peripheral blood | Proliferation and survival of CAR T cells in peripheral blood. | 30 days 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 Myeloid Leukemia