Cord Blood Derived Anti-CD19 CAR-Engineered NK Cells for B Lymphoid Malignancies

NCT ID: NCT04796675

Last Updated: 2021-04-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-10
• 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 anti-CD19 chimeric antigen receptor(CAR)-modified NK cells(CAR-NK-CD19) in patients with relapsed or refractory hematological malignancies.

Detailed Description

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.

Cord blood(CB) derived NK cells from healthy donor are the source for production of CAR-NK-CD19 cells. CB derived NK cells are purified and transduced with a retroviral vector encoding the anti-CD19 CAR and interleukin-15.

This is an investigational study. The objectives are to evaluate the safety and efficacy of CAR-NK-CD19 cells in patients with CD19+ B-cell malignancies.

Conditions

Acute Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; Non Hodgkin's Lymphoma

Study Design

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

Study Groups

Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells

Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (300 mg/kg) on day -5, -4, and -3, followed by one infusion of CAR-NK-CD19 cells on day 0. The study will be divided into three groups: Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, and Non Hodgkin's Lymphoma. Doses of 0.01×10\^7, 0.1×10\^7, 1.0×10\^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 dose-limited toxicity (DLT) emerges in the group, then the subsequent higher dose will be used in the next group. 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 ≥ 18 years;

2. Eastern Cooperative Oncology Group score≤ 3;

3. Diagnosed as CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and Non Hodgkin's lymphoma.

4. Patients must relapse or be refractory after at least two lines of therapy.

5. Patient's main organs functioning well:

A. Liver function: alanine aminotransferase/aspartate aminotransferase < 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.

6. Negativity of blood pregnancy test for woman, and participants use effective methods of contraception until last follow-up.

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

Exclusion Criteria

1. Investigators judge the patients with gastrointestinal lymph node and/or central nervous system involvement who may be at high-risk of receiving CAR-NK-CD19 cell treatment.

2. Patients with graft-versus-host reaction and need immunosuppressive agents, or patients with autoimmune diseases.

3. Systemic steroids are used within 5 days before apheresis.

4. Drugs to stimulate the production of bone marrow hematopoietic cells are used within 5 days before apheresis.

5. Patients receive cytotoxic chemotherapy or radiotherapy within 21 days before enrollment(Tyrosine kinase inhibitors or other targeted therapies can be used two weeks before lymphodepleting chemotherapy).

6. History of epilepsy or other central nervous system diseases.

7. Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within five years.

8. Known HIV positive patients.

9. Patients with active infections, including active replication of hepatitis B or active hepatitis C.

10. Patients receive any antitumor treatments within 4 weeks before enrollment, and the toxicity related to previous treatments don't return to < 1 level at enrollment (except for low grade toxicity such as alopecia).

11. Major surgery in the past 4 weeks.

12. Non-compliant patients.

13. Anticoagulants are being used.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Simnova Biotechnology Co.,Ltd.

INDUSTRY

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

Yu Hu

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

Countries

China

Central Contacts

Heng Mei

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

18868112136

References

Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607.

Reference Type: BACKGROUND

PMID: 32023374 (View on PubMed)

Other Identifiers

CAR-NK-CD19 cells

Identifier Type: -

Identifier Source: org_study_id