Study of IBR733 Cell Injection in Acute Myeloid Leukemia

This is an open-label clinical study: phase Ia is the dose-escalation part, and phase Ib is the dose-expansion part. The phase Ia study is to evaluate the safety, tolerability, recommended phase II dose, pharmacokinetics, immunogenicity and preliminary efficacy of IBR733 cell injection in relapsed/refractory acute myeloid leukemia (AML).

Phase Ia is the dose escalation part which adopts the "3+3" dose escalation design protocol. The dose is respectively 5.0×10\^9 cells, 7.5×10\^9 cells and 10.0×10\^9 cells. 3-6 subjects will be enrolled at every dose level. Subjects who have signed the Informed Consent Form (ICF) will be reviewed for inclusion/exclusion criteria (this process is called "screening"), and eligible subjects will be treated with IBR733 cell injection after lymphodepletion therapy. The administration of IBR733 cell injection is performed on day 1 and day 8 of each cycle (21 days). The first and second subjects in the same group shall be enrolled at an interval of at least 21 days, for the purpose of ensuring their safety.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects volunteer to participate in this clinical study, are fully aware of the study and have signed the Informed Consent Form (ICF). Subjects are willing to follow and able to complete all trial procedures.
2. Age: 18-74 (both inclusive), female or male.
3. Patients with AML (including secondary AML) diagnosed according to the WHO 2022 criteria.
4. Patients with AML who meet one of the following criteria: (1) Relapsed AML: reoccurrence of leukemia cells in peripheral blood or ≥5% blasts in bone marrow after complete remission (excluding other causes such as bone marrow regrowth after consolidation chemotherapy); (2) Refractory AML: treatment-naive patients who failed to respond to 2 courses of standard treatment; The patients relapsed within 12 months after consolidated intensive treatment; Patients who relapsed after 12 months but failed to respond to conventional chemotherapy (only once); Patients who are relapsed twice; (3) Patients received up to 3 additional cycles of chemotherapy or targeted therapy after the diagnosis of relapsed/refractory AML.
5. Eastern Cooperative Oncology Group (ECOG) score ≤2.
6. Subjects of reproductive age and their partners should agree to have no family planning and to use effective contraceptive methods for 6 months from signing the ICF until the last dose of the study drug is administered.
7. Expected survival time ≥3 months.

Exclusion Criteria:

1. Acute promyelocytic leukemia.
2. Chronic myeloid leukemia with myeloid blast crisis.
3. Clinically symptomatic central nervous system involvement (no need for lumbar puncture).
4. Subjects who have undergone an allogeneic hematopoietic stem cell transplantation or other organ transplantation.
5. Subjects who have undergone autologous hematopoietic stem cell transplantation less than 3 months before the first dose of treatment.
6. Subjects who have received cell immunotherapy such as chimeric antigen receptor-modified T cells (CAR-T), chimeric antigen receptor-natural killer cells (CAR-NK), and T cell receptor gene-modified T cells (TCR-T).
7. Subjects who have received systemic antitumor therapy (except hydroxyurea) within 2 weeks before the first dose of study drug, including chemotherapy, immunotherapy, etc..
8. Subjects who have had other malignant tumors within 3 years before inclusion, except for any type of carcinoma in situ that has been cured in the past and cured skin basal cell carcinoma or skin squamous cell carcinoma.
9. The absolute peripheral blood blast count (ABC) \> 40.0×10\^9/L (ABC= total white blood cell count × blast %). The total white blood cell count can be controlled with hydroxyurea, but it must be stopped three days before the first dose of study drug or lymphodepletion.
10. Organ function: (1) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)\>3 times upper limit of normal (ULN); If AST was elevated due to leukemia but liver function was normal (e.g., normal ALT, alkaline phosphatase, and direct/indirect bilirubin measurements), participants could be enrolled after investigator consent was obtained; (2) Serum total bilirubin \>2.5×ULN (not applicable to patients with Gilbert's syndrome); (3) Creatinine clearance \<45mL/min (estimated by Cockcroft-Gault formula) or creatinine \>2×ULN; (4) Activated partial thromboplastin time \>1.5×ULN or international normalized ratio \>1.5×ULN.
11. Subjects whose cardiac function and disease meet one of the following conditions within 6 months before the first administration: (1) Any risk factors that increase QTcF (Fridericia formula) interval prolongation, such as uncorrectable hypokalemia, hereditary long QT syndrome, and use of drugs that prolong the QTcF interval; (2) New York Heart Association (NYHA) classification ≥Grade 3; (3) Unstable angina pectoris, and myocardial infarction; (4) Left ventricular ejection fraction \<50% in resting state; (5) Clinically significant pericardial effusion determined by echocardiography.
12. Subjects who have a history of autoimmune diseases (such as Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, etc.) that require systemic immunosuppressive/systemic disease modulating drugs within 2 years before the first administration.
13. Active hepatitis B (e.g., DNA copy number \> 1000 cps/mL if only hepatitis B surface antigen is positive), active hepatitis C virus infection (anti-hepatitis C antibody positive and HCV RNA positive), or human immunodeficiency virus antibody positive.
14. Women who are pregnant or lactating.
15. Subjects who have received major surgery (for the definition of major surgery, refer to the Level 3 and 4 surgeries specified in the Administrative Measures for the Clinical Application of Medical Technology) within 28 days before the first administration.
16. Subjects who have a history of alcohol, drug use or drug abuse in the past year;
17. Subjects who have participated in other clinical trials and received any unmarketed investigational drug or treatment within 4 weeks prior to first use of the study drug.
18. Subjects who are known to be allergic to the main components of the study drug.
19. Subjects who have other severe, acute, or chronic diseases or laboratory abnormalities that may increase the risk of participating in the study and receiving the study drug, or may interfere with the interpretation of study results.