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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04796675
Recruitment Status : Recruiting
First Posted : March 15, 2021
Last Update Posted : April 8, 2021
Sponsor:
Collaborator:
Shanghai Simnova Biotechnology Co.,Ltd.
Information provided by (Responsible Party):
MEI HENG, Wuhan Union Hospital, China

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 disease Intervention/treatment Phase
Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Non Hodgkin's Lymphoma 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : April 10, 2021
Estimated Primary Completion Date : March 10, 2023
Estimated Study Completion Date : March 10, 2024


Arm Intervention/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.




Primary Outcome Measures :
  1. Incidence of Treatment-related Adverse Events [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04796675


Contacts
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Contact: Heng Mei 027-8572600 hmei@hust.edu.cn
Contact: Chenggong Li 18868112136 chenggongli@hust.edu.cn

Locations
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China, Hubei
Union Hospital, Huazhong University of Science and Technology Recruiting
Wuhan, Hubei, China, 430022
Contact: Heng Mei, M.D., Ph.D       hmei@hust.edu.cn   
Contact: Chenggong Li    18868112136    chenggongli@hust.edu.cn   
Principal Investigator: Yu Hu, M.D., Ph.D         
Sponsors and Collaborators
Wuhan Union Hospital, China
Shanghai Simnova Biotechnology Co.,Ltd.
Investigators
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Principal Investigator: Yu Hu Wuhan Union Hospital, China
Publications:
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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: March 15, 2021    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists