Administration of Anti Tim-3/CD123 CAR-T Cell Therapy in Relapsed and Refractory Acute Myeloid Leukemia (rr/AML)

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of anti Tim3/CD123 CAR-T cells in the treatment of relapsed and refractory acute myeloid leukemia.

Detailed Description
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Cluster of Differentiation 123 (CD123) is usually overexpressed on leukemia stem cells (LSCs) in acute myeloid leukemia (AML). However, CD123 has poor specificity and is also expressed on normal hematopoietic stem cells (HSC), myeloid cells, and some non-hematopoietic cells. This leads to widespread on-target off-tumor effect in the clinical application of anti CD123 CAR-T cells, manifested as severe bone marrow suppression, organ damage, and patients experiencing infections, bleeding, and organ dysfunction. T cell immunoglobulin and mucin domain 3 (Tim-3) belongs to the Tim gene family. 85% of LSCs highly express Tim-3, while normal hematopoietic stem/progenitor cells (HSC/P), granulocytes, and macrophages do not express Tim-3. Compared with CD123, seeing Tim-3 as a recognition tool for LSCs has higher specificity. In vivo and in vitro studies have confirmed that anti Tim-3 CAR-T cells have significant anti LSCs effects, while not affecting the ability of normal HSC/P to form colonies and differentiate lineages. We believe that using both Tim-3 and CD123 as targets for CAR-T cells can improve the specificity of recognizing LSCs, reduce the killing effect of CAR-T cells on HSC/P expressing CD123, and thus reduce the on-target off-tumor effect.

Official Title
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Application of Anti Tim-3/CD123 CAR-T Cell Therapy in Relapsed and Refractory Acute Myeloid Leukemia (rr/AML)

Conditions
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Acute Myeloid Leukemia Refractory, Acute Myeloid Leukemia, in Relapse

Intervention / Treatment
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* Drug: anti Tim-3/CD123 CAR-T cell therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must sign and date the Informed Consent before initiating any study specific procedures or activities; At the age of 18-70 years old; Diagnosed as relapse/refractory (r/r) de novo or secondary acute myeloid leukemia (AML); The patient has recovered from the toxicity of previous treatment; ECOG score ≤ 2 and expected survival period is not less than 3 months; Adequate organ function defined as:AST ≤3×ULN; ALT ≤3×ULN; Total bilirubin ≤1.5×ULN; Serum creatinine ≤1.5×ULN, or CCR≥60 mL/min; Hemoglobin ≥60g/L ; Indoor oxygen saturation ≥92%; LVEF≥45%; Pregnancy testing: females of childbearing potential must have a negative serum or urine pregnancy test; From the use of study drug to 2 years after treatment, males and female of childbearing potential must agree to use an effective method of contraception. Exclusion Criteria: Diagnosis of acute promyelocytic leukemia; History or presence of a CNS disorder; HBsAg is positive; HCV #HIV or Syphilis antibody are positive, CMV-DNA in peripheral blood is more than≥500 copies /mL; History of severe hypersensitivity reaction; History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, atrial fibrillation, or other clinically significant cardiac disease within 12 months before enrollment; History of organ transplant surgery; Required systemic application of immunosuppressive or other drugs; Auto-SCT within the 3 months before enrollment; Active autoimmune or inflammatory diseases of the nervous system (e.g., Guillain-Barre syndrome (GBS), amyotrophic lateral sclerosis (ALS)) and clinically active cerebrovascular diseases (e.g., cerebral edema, posterior reversible encephalopathy syndrome (PRES)); Requirement for urgent therapy due to ongoing or impending oncologic emergency (eg, leukostasis or tumor lysis syndrome (TLS)) ; Presence or suspicion of a fungal, bacterial, viral, or other infection that is uncontrolled or requiring antimicrobials for management; Live vaccine received within the ≤ 4 weeks before enrollment; Persons with serious mental illness; History of major surgical operations four weeks before enrollment; History of alcoholism or substance abuse; Was identified by the investigators as unsuitable to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 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: anti Tim-3/CD123 CAR-T cell therapy<br>Enrolled patients will receive prespecified dose of autologous CAR-T cells. | Drug: anti Tim-3/CD123 CAR-T cell therapy<br>* Enrolled patients will receive prespecified dose of autologous CAR-T cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity #DLT# | Adverse events assessed according to NCI-CTCAE v5.0 | Baseline up to 28 days after CAR-T cells infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD negative overall response rate (MRD- ORR) | Assessment of MRD negative overall response rate (MRD- ORR) at 3 months of treatment | 3 months | 
| Overall response rate (ORR) | Assessment of ORR (ORR = CR + CRi ) at Month 6, 12, 18 and 24 | Month 6, 12, 18 and 24 | 
| Event-free survival (EFS) | Assessment of EFS at Month 6, 12, 18 and 24 | Month 6, 12, 18 and 24 | 
| Overall survival (OS) | Assessment of OS at Month 6, 12, 18 and 24 | Month 6, 12, 18 and 24 |