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

Sponsor
Wuhan Union Hospital, China (Other)
Overall Status
Recruiting
CT.gov ID
NCT04796675
Collaborator
Shanghai Simnova Biotechnology Co.,Ltd. (Industry)
27
Enrollment
1
Location
1
Arm
35
Anticipated Duration (Months)
0.8
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells
Phase 1

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
27 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Safety and Efficacy of Cord Blood Derived Anti-CD19 CAR-Engineered NK Cells for Relapsed/Refractory B Lymphoid Malignancies: a Single-center, Open-label, Single-arm Clinical Study
Anticipated Study Start Date :
Apr 10, 2021
Anticipated Primary Completion Date :
Mar 10, 2023
Anticipated Study Completion Date :
Mar 10, 2024

Arms and Interventions

ArmIntervention/Treatment
Experimental: 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.

Drug: 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.

Outcome Measures

Primary Outcome Measures

  1. Incidence of Treatment-related Adverse Events [within 2 years after infusion]

    Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).

Secondary Outcome Measures

  1. Overall response rate(ORR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]

    ORR will be assessed from CAR T cell infusion to death or last follow-up (censored).

  2. Complete response rate(CRR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]

    CRR will be assessed from CAR T cell infusion to death or last follow-up (censored).

  3. Progress-free survival(PFS) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]

    PFS will be assessed from CAR T cell infusion to death or last follow-up (censored).

  4. Duration of Response(DOR) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]

    DOR will be assessed from CAR T cell infusion to death or last follow-up (censored).

  5. Overall survival(OS) of administering CAR-NK-CD19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies. [within 2 years after infusion]

    OS will be assessed from CAR T cell infusion to death or last follow-up (censored).

Other Outcome Measures

  1. In vivo expansion and survival of CAR-NK-CD19 cells [within 2 years after infusion]

    Quantity of CAR-NK-CD19 CAR copies in bone marrow and peripheral blood will be determined by using quantitative polymerase chain reaction.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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:

  1. 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.
  1. Negativity of blood pregnancy test for woman, and participants use effective methods of contraception until last follow-up.

  2. 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.

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Union Hospital, Huazhong University of Science and TechnologyWuhanHubeiChina430022

Sponsors and Collaborators

  • Wuhan Union Hospital, China
  • Shanghai Simnova Biotechnology Co.,Ltd.

Investigators

  • Principal Investigator: Yu Hu, Wuhan Union Hospital, China

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
MEI HENG, Proferssor, Cheif Doctor, Wuhan Union Hospital, China
ClinicalTrials.gov Identifier:
NCT04796675
Other Study ID Numbers:
  • CAR-NK-CD19 cells
First Posted:
Mar 15, 2021
Last Update Posted:
Apr 8, 2021
Last Verified:
Apr 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Apr 8, 2021