Safety and Efficacy Study of CI-135 CAR-T Cells in Subjects with Relapsed or Refractory Acute Myeloid Leukemia

First-in-Human (FIH), Open-Label, Non-Randomized, Single-Arm Phase 1 Study to Evaluate the Safety and Efficacy of CI-135 CAR-T Cells in Subjects with Relapsed or Refractory Acute Myeloid Leukemia

This is a FIH, single center, open label, non-randomized, single-arm, Phase I clinical trial to evaluate the safety and efficacy of CI-135 CAR-T cells in subjects with relapsed or refractory Acute Lymphoblastic Leukemia. This study is a dose-escalation study that includes 2 dose levels, and a total of 4-7 subjects will be enrolled. CI-135 CAR-T cells will be manufactured using PBMC collected from the subjects, and will be infused intravenously into subjects after lymphodepletion.

Inclusion Criteria:

1. Age ≥5 years old and ≤70 years old, male or female;

2. Expected survival exceeds 12 weeks;

3. Diagnosed as primary or secondary AML patients that meet the World Health Organization (WHO) classification, and meet any of the following conditions: a) AML patients who have not reached complete remission after at least 3 cycles of standard induction chemotherapy B) AML patients who have achieved complete remission after induction chemotherapy and relapse within 1 year; c) AML patients who have relapsed after achieving complete remission after induction chemotherapy for more than 1 year and have not remitted after 1 course of induction chemotherapy; d) AML patients who have relapsed after transplantation ; E) AML patients who have experienced 2 or more relapses. For patients who meet one of a), b), and c) and have FLT-3 mutations, in addition to induction therapy, they should also receive at least one TKI treatment and has not achieved complete remission or relapsed after complete remission (except patients who cannot tolerate TKI treatment or have contraindications to TKI treatment).

4. The FLT-3 mutation is positive by the leukemia cell gene detection, or the FLT-3 expression is ≥35%;

5. ECOG score 1-2;

6. Liver, kidney, heart and lung functions meet the following requirements:

   1. Glomerular filtration rate ≥60 ml/min/1.73 m2 or serum creatinine ≤2 times the upper limit of normal;
   2. Serum AST, ALT≤3 times the upper limit of normal, and total bilirubin≤1.5 times the upper limit of normal;
   3. Blood oxygen saturation> 92%;
   4. The ventricular ejection fraction ≥50%, there is no pericardial effusion detected by ultrasound, and no clinically significant ECG changes.

7. Able to understand this experiment and sign the informed consent form.

Exclusion Criteria:

1. Diagnosed as acute promyelocytic leukemia (APL M3);
2. Accompanied with other uncontrolled malignant tumors (except those that would not interfere with the safety or efficacy evaluation of the trial).
3. Have received CAR-T cell or other genetically modified cell therapy in the past;
4. Medical history or evidence of significant cardiovascular risk, including any of the following conditions: congestive heart failure, unstable angina, clinically significant arrhythmia (such as ventricular fibrillation, ventricular tachycardia, etc.), performed coronary angioplasty 6 months before infusion, intracardiac defibrillator or any clinically-related complications that may pose a risk to the safety of the subject or interfere with the evaluation, procedures or completion of the research;
5. Subjects who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and whose peripheral blood HBV DNA titer test is greater than or equal to the lower limit of detection; those who are positive for hepatitis C virus (HCV) antibody and positive for peripheral blood HCV RNA; Human immunodeficiency virus (HIV) antibody positive; syphilis test positive;
6. Acute or chronic hepatitis C is positive. Exceptions: acute hepatitis C with complete clearance of the virus; chronic hepatitis C, with a sustained virological response 24 weeks after completion of hepatitis C treatment (SVR24) determined an undetectable viral load;
7. A history of arterial or venous thrombosis within 3 months before enrollment;
8. Any graft-versus-host disease that requires systemic application of immunomodulators;
9. A history of central nervous system disease or subjects who need treatment (for example, uncontrolled seizures);
10. Active infection that cannot be controlled.
11. Subjects who are known to be allergic to the components of CI-135 CAR-T cells or any components of the lymphodepletion regimen (cyclophosphamide and fludarabine).
12. Women who are pregnant or breastfeeding, and female patients who plan to become pregnant within 1 year after cell infusion, or male patients whose partners plan to become pregnant within 1 year after their infusion.
13. Other situations that are considered to be unsuitable to participate in the study by researchers.