Universal Chimeric Antigen Receptor-modified AT19 Cells for CD19+ Relapsed/Refractory Hematological Malignancies

NCT ID: NCT04796688

Last Updated: 2021-03-15

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-10
• Study Completion Date: 2024-03-10

Brief Summary

This is a single-center, open-label, single-arm study to evaluate the primary safety and efficacy of universal chimeric antigen receptor-modified AT19 cells in patients with relapsed or refractory hematological malignancies.

Detailed Description

• Adoptive transfer of autologous anti-CD19 CAR-T cells can induce durable remissions in patients with relapsed/refractory hematologic malignancies, including CD19+ B-cell acute lymphoblastic leukemia(B-ALL), B-cell chronic lymphoblastic leukemia(B-CLL), and B-cell lymphoma.
• However, multiple challenges exist for manufacturing CAR-T cells from patients with advanced disease including inability to manufacture a product, disease progression or death while waiting for the CAR-T product to be available, and heterogeneity among autologous CAR-T products that contributes to unpredictable and variable clinical activity.
• Healthy donor T cells can provide a source for production of universal CAR-T cells when combined with gene editing to prevent expression of endogenous TCRs and avoid generation of GvHD in HLA mismatched recipients.
• Cord blood derived T cells from healthy donor are the source for production of universal anti-CD19 CAR-modified AT19 cells. CRISPR/cas9 gene-editing technology has been used to knockout TCRs and HLA-I to avoid GvHD and transplant rejection.
• AT19 cells have exhibited potent cytotoxicity in CD19+ tumor cells and can effectively eradicate CD19+ tumor cells in xenograft mice models, without showing GvHD.
• This study aims to evaluate prelimary safety and efficacy of the universal AT19 cells in patients with relapsed/refractory B-ALL, B-CLL, and B-cell lymphoma.

Conditions

Acute Lymphoblastic Leukemia; Chronic Lymphoblastic Leukemia; B-cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Fludarabine + Cyclophosphamide + AT19 cells

Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (300 mg/kg) on days -5, -4, and -3, followed by the infusions of AT19 cells on day 0-2. The study will be divided into three groups: B-ALL, B-CLL, and B-cell lymphoma. Doses of 0.5×10\^7, 1.0×10\^7, and 2.0×10\^7 CAR+ T cells (with an allowance of ±20%) will be tested in each group in the 3+3 dose-escalation study. 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.

Group Type: EXPERIMENTAL

Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells

Intervention Type: DRUG

fludarabine 30 mg/kg on day -5, -4, and -3; cyclophosphamide 300 mg/kg on day -5, -4, and -3; CAR-NK-CD19 Cells on day 0.

Interventions

Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells

fludarabine 30 mg/kg on day -5, -4, and -3; cyclophosphamide 300 mg/kg on day -5, -4, and -3; CAR-NK-CD19 Cells on day 0.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Aged 14-78 years old (including 14 and 78 years old).

2. Clinical diagnosis of CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and lymphoma.

3. Refractory/Relapsed B-cell malignancies:

A. Refractory/relapsed B-cell lymphoblastic leukemia, meeting one of the following criteria:

i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen.

iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy.

iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT.

B. Refractory/relapsed B-cell lymphoma, meeting 1 of the first 4 items plus item 5: i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy.

ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. 2 or more relapses after CR. iv. Not suitable for HSCT, or abandon HSCT due to various restrictions, or relapse after HSCT.

v. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines.

4. Having a measurable or evaluable lesion:

A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm.

B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD.

5. The toxicity related to previous treatments had returned to < 1 level at enrollment (except for low grade toxicity such as alopecia).

6. Patients have good main organs functions:

A. Liver function: ALT/AST < 2.5 times the upper limit of normal (ULN) and total bilirubin≤ 1.5 times ULN; B. Renal function: Creatinine clearance rate ≥ 60ml/min. C. Pulmonary function: Indoor oxygen saturation ≥ 95%. D. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥50%, no clinically-significant ECG findings.

7. Estimated survival time≥3 months.

8. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.

Exclusion Criteria

1. Central nervous system is involved in leukemia and lymphoma.

2. Known HIV positive patients.

3. CNS diseases, such as epilepsy, cerebral ischemia / hemorrhage, dementia, cerebellar diseases or any CNS related autoimmune diseases.

4. NYHA class III or higher cardiac failure, or with malignant arrhythmia.

5. Myocardial infarction, angioplasty or stent placement, unstable angina or other clinically significant heart history within 12 months before enrollment.

6. Patients who need immediate treatment to control tumor progression or relieve tumor burden.

7. Active autoimmune diseases requiring systemic immunosuppressive therapy.

8. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before enrollment.

9. Severe immediate hypersensitivity to any drug to be used in this study.

10. Women who are pregnant or breastfeeding.

11. Other unsuitable conditions in the researchers' opinion.

• Minimum Eligible Age: 14 Years
• Maximum Eligible Age: 78 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chengdu USino Technology Biology Co., Ltd

UNKNOWN

Sponsor Role: collaborator

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

OTHER

Sponsor Role: lead

Responsible Party

MEI HENG

Proferssor, Cheif Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Heng Mei, M.D., Ph.D

Role: PRINCIPAL_INVESTIGATOR

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Locations

Union Hospital, Huazhong University of Science and Technology

Wuhan, Hubei, China

Site Status: RECRUITING

Union Hospital, Huazhong University of Science and Technology

Wuhan, Hubei, China

Site Status: RECRUITING

Countries

China

Central Contacts

Heng Mei, M.D., Ph.D

Role: CONTACT

hmei@hust.edu.cn

027-8572600

Chenggong Li

Role: CONTACT

chenggongli@hust.edu.cn

18868112136

Facility Contacts

Heng Mei, M.D., Ph.D

Role: primary

hmei@hust.edu.cn

Chenggong Li

Role: backup

chenggongli@hust.edu.cn

Heng Mei, M.D., Ph.D

Role: primary

hmei@hust.edu.cn

Chenggong Li

Role: backup

chenggongli@hust.edu.cn

Other Identifiers

Universal AT19 cells

Identifier Type: -

Identifier Source: org_study_id