Clinical trial NCT03473457: CAR-T Cells Therapy in Relapsed/Refractory Acute Myeloid Leukemia
Official title: The Prospective, Multi-center And Single-arm Clinical Study of Chimeric Antigen Receptor T(CAR-T) Cells Therapy in Relapsed/Refractory Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Relapsed/Refractory Acute Myeloid Leukemia(AML)
Keywords: CD38-CART
CD33-CART
CD56-CART
CD123-CART
CD117-CART
CD133-CART
CD34-CART
Mucl-CART
Lead sponsor: Zhujiang Hospital
Sponsor class: OTHER
Collaborators: name: Nanfang Hospital, Southern Medical University
name: The Third Affiliated Hospital of Southern Medical University
name: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
First posted: 2018-03-22
Enrollment: 2
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Acute myeloid leukemia (AML) is a group of genetically highly heterogeneous malignant disease . The disease is the most common type of adult acute leukemia. Overall survival (OS) was less than 50% in 5 years. Chimeric Antigen Receptor-transduced T cell (CAR-T) therapy is one of revolutionary targeted immunotherapy. The efficacy of CAR-T cells for the treatment of acute B lymphocytic leukemia has been widely recognized, although it start late, several clinical trials have been register in ClinicalTrials.gov.

Detailed description: Acute myeloid leukemia (AML) is a group of genetically highly heterogeneous malignant disease ,its' character is immature myeloid protocel abnormal differentiation and proliferation in the bone marrow. The disease is the most common type of adult acute leukemia, Overall survival (OS) was less than 50% in 5 years. Chimeric Antigen Receptor-transduced T cell (CAR-T) therapy is one of revolutionary targeted immunotherapy.

CAR - T cells are taken in the form of genetic modification, and specific identified target antigen monoclonal antibody of single variable region (scFv) expression in T cell surface, and coupled with the activation of intracellular proliferation signal domain.When scFv recognizes antigens expressed in malignant cells, it stimulates the activation signal of downstream T cells and produces specific killing effects. CAR-T therapy is one of revolutionary targeted immunotherapy.The efficacy of CAR-T cells for the treatment of acute B lymphocytic leukemia has been widely recognized, although it start late, several clinical trials have been register in ClinicalTrials.gov.

The cluster of differentiation (CD) antigen serves as the target for identification and research in the immuno-phenotype detection of cells.As the surface markers of immune typing, CD molecules can be used as cell identification for expression types and levels on the cell surface.Cell surface of AML has a specific type of CD molecule expression,such as cluster of differentiation antigen 33(CD33),cluster of differentiation 38(CD38),cluster of differentiation 56 (CD56), cluster of differentiation 123(CD123), cluster of differentiation 117(CD117), cluster of differentiation 133(CD133), cluster of differentiation 34(CD34) and Mucl.Therefore, it provides some good targets for the immunotherapy of CAR T cells.In AML cells and mouse model,some studies have confirmed anti-CD33 CAR-T and anti-CD123 CAR-T with good similar lethality, but the toxicity of CAR-T to myeloid hematopoietic stem/progenitor cells and mononuclear cells is widespread.In comparison,CD123 CAR-T Off-target effects slighter than CD33 CAR-T.

In order to lay a foundation for the application of relapsed/refractory AML patients with CAR-T therapy，objects are refractory/ relapsed patients with AML,and plans to into the group of the number of cases in 50 cases.The main content is safety, efficacy and feasibility analysis of the CAR-T cells （single CAR-T or double CAR-T cells with CD33,CD38,CD56,CD123,CD117,CD133,CD34 or Mucl ) in the treatment of refractory/relapsed AML.

Eligibility criteria: Inclusion Criteria:

1. Relapsed/Refractory AML patients
2. Positive for any of CD33, CD38, CD56, CD117, CD123, CD34, or Muc1.(cytology, genetic testing)
3. Estimated survival time is more than 3 months in multiple myeloma,and Karnofsky Performance Status（KPS) score is more than 80.
4. No cytapheresis and cell separation contraindication.
5. Hemoglobin is more than 80 gram per litre.
6. The function of important organ was satisfied:(1)cardiac ultrasound indicated that cardiac ejection fractions is more than 50%（EF≥50%）, and the electrocardiogram showed no obvious abnormality;(2)Blood oxygen saturation is more than 90%（SpO2≥90%）;(3)Creatinine（Cr） is less than 2.5 times the upper limit of normal;(4)Alanine transaminase（ALT）and glutamic-oxalacetic transaminase（AST）is less than 3 times the upper limit of normal,and total bilirubin is less than 2 milligram per deciliter(TBil≤2.0mg/dL).
7. After discussion by the expert group, the patient's condition was analyzed and combined with the general physical condition of the patient, the benefit of participating in the clinical trial was greater than the risk.
8. Volunteered for this clinical trail and signed a consent form .
9. Currently, chemotherapy and approved targeted therapies are ineffective for the patients.Or patients cannot tolerate current chemotherapy.

Exclusion Criteria:

1. Active other disease and cannot control after treatment.
2. Patients with actively infection of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).
3. Severe psychiatric disorder or other disease in central nervous system.
4. Patients are infected with fungus,bacteria or virus,and are difficult to control after treatment.
5. Patients with infection of HIV .
6. Pregnant or lactating women.
7. Patients who have Graft-Versus-Host Disease (GVHD) should receive systemic administration of immunosuppressive agents.
8. Patients have received other genetic therapy products.
9. Patients who have received systemic administration of glucocorticoid agents in one week before CART therapy.
10. Any situation may do harm to the subjects or interfere the results.
11. Have had Prolonged QT interval or severe heart disease in the past.

Primary outcomes:
measure: Adverse events that Are related to treatment
timeFrame: 2 years
Secondary outcomes:
measure: Estimate 2 year overall survival(OS) after infusion of CD38/CD33/CD56/CD123/ CD117/CD133/CD34/Mucl-CART and sequential treatment
timeFrame: 2 years
measure: Estimate 2 year relapse rate after infusion of CD38/CD33/CD56/CD123/CD117/CD133/ CD34/Mucl-CART and sequential treatment
timeFrame: 2 years
measure: Estimate 2 year progression free survival after CD117/CD133/CD34/ Mucl-CART and sequential treatment
timeFrame: 2 years
Other outcomes:
Locations:
city: Guangdong
country: China
facility: Southern Medical University Zhujiang Hospital
state: Guangdong
Study officials:
affiliation: Zhujiang Hospital
name: Yanjie He
role: PRINCIPAL_INVESTIGATOR
References: