Safety and Efficacy of Anti-CD123 CAR-T Therapy in Patients With Refractory/ Relapsed CD123+ Acute Myeloid Leukemia.

Study Overview
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Brief Summary
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This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia.

Detailed Description
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CD123 is a transmembrane subunit of the IL-3 receptor expressed on AML blasts. The investigators have conducted a third generationCD123-targeted CAR containing CD137 and CD28 costimulatory domains.This study aims to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with relapsed/refractory CD123+ Acute Myeloid Leukemia.

Official Title
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Single-center, Open-label, Single-arm Clinical Study of Efficacy and Safety of Anti-CD123 CAR-T Therapy in Patients With Refractory/Relapsed CD123+ Acute Myeloid Leukemia.

Conditions
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CD123+ Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: Third-generation anti-CD123 CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathological and histological examination confirmed CD123+ refractory or relapsed Acute Myeloid Leukemia. A. Diagnostic criteria for recurrent AML: After complete remission (CR), leukemia cells or bone marrow primordial cells > 0.050 (except for bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemia cell infiltration appears again in peripheral blood. B．Diagnostic criteria for refractory AML(Meeting one of the following) i. ineffectiveness after the first standard regimen treatment of 2 courses. ii. patients relapse within 12 months after consolidation and intensive treatment after CR. iii. Patients relapse 12 months later and fail to respond to conventional chemotherapy. iv. Patients with two or more recurrences. v. Patients with persistent extramedullary leukemia. vi. Patients with recurrence after CR and unsuitable for HSCT (auto/allo-HSCT). Aged 18 to 70 years (including 18 and 70 years old). At least one measurable or evaluable lesion：AML patients with positive or relapsed positive bone marrow MRD. ECOG≤ 2 and expected lifetime ≥3 months. Adequate organ function: A. Liver function: ALT/AST≤3 ULN. Total bilirubin≤2 ULN. B. Renal function: eGFR> 60 mL/min/1.73 m2, or creatinine clearance ≥45mL/min. C. Lung function: Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1) > 45% predicted. D. Cardiac function: LVEF ≥ 50%. The patients did not receive any anticancer treatments such as chemotherapy, radiotherapy and immunotherapy (such as immunosuppressive drugs) within 4 weeks before admission, and the toxicity related to previous treatments had returned to < 1 level at admission (except for low toxicity such as alopecia). Women of child-bearing potential and all male participants must use effective methods of contraception for at least 12 months after infusion. Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: Women who are pregnant (urine/blood pregnancy test positive) or lactating. Male or female with a conception plan in the past 1 years. Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 1 years after enrollment. Uncontrolled infectious disease within 4 weeks prior to enrollment. Active hepatitis B/C virus. HIV infected patients. Suffering from a serious autoimmune disease or immunodeficiency disease. The patient is allergic and is allergic to macromolecular biopharmaceuticals such as antibodies or cytokines. The patient participated in other clinical trials within 6 weeks prior to enrollment. Systemic use of hormones within 4 weeks prior to enrollment (except for patients with inhaled corticosteroids). Suffering from mental illness. Patient has drug abuse/addiction. Central nervous system involvement. According to the investigator's judgment, the patient has other unsuitable grouping conditions.

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
Interventional Model Description: This study was a single-center, open-label, single-arm, non-randomized,3+3 dose escalation clinical trial.Each dose group has 3 patients.If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level. The maximum dose could be extended.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD123+ Acute Myeloid Leukemia<br>Patients will receive CD123-targeted CAR-T cells in the dose-climbing trial. Each dose group has 3 patients and the the maximum dose can be extended. | Biological: Third-generation anti-CD123 CAR-T cells<br>* From the minimum dose, If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-related Adverse Events | Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0). | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall remission rate(ORR) of anti-CD123 CAR-T Therapy in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia | ORR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Overall survival(OS) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia | OS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Duration of Response(DOR) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia | DOR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Progress-free survival(PFS) of anti-CD123 CAR-T cells in patients with refractory/relapsed CD123+ Acute Myeloid Leukemia | PFS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Rate of anti-CD123 CAR-T cells in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) rate and quantity of anti-CD123 CAR-T cells were determined by means of flow cytometry. | 3 years | 
| Quantity of anti-CD123 CAR copies in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) quantity of anti-CD123 CAR copies were determined by means of qPCR. | 3 years |