Safety and Efficacy of Allogenic CD19-CAR-NK Cells in Treatmenting r/r B-cell Hematologic Malignancies

NCT ID: NCT05739227

Last Updated: 2023-02-22

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-01
• Study Completion Date: 2025-05-31

Brief Summary

This is an open label, single-arm, Phase I study to evaluate the efficacy and safety of allogenic CD19-CAR-NK cells in subjects with refractory or relapsed B-cell hematologic malignancies. A leukapheresis procedure will be performed to manufacture Anti-CD19 chimeric antigen receptor (CAR) modified NK cells. Prior to allogenic CD19-CAR-NK cells infusion subjects will receive lymphodepleting therapy with fludarabine, cyclophosphamide and etoposide.

Detailed Description

This open label, single-arm, Phase I study aims to evaluate the efficacy and safety of allogenic CD19-CAR-NK cells in subjects with refractory or relapsed B-cell hematologic malignancies. A leukapheresis procedure will be performed to manufacture Anti-CD19 chimeric antigen receptor (CAR) modified NK cells. Prior to allogenic CD19-CAR-NK cells infusion subjects will receive lymphodepleting therapy with fludarabine, cyclophosphamide and etoposide. After infusion, the investigators will observe the characteristics of dose limited toxicity (DLT), and determine the maximum tolerable agent MTD and rp2d were confirmed. To provide basis for the dosage and treatment plan of cell products in follow-up clinical trials.

Conditions

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

Study Design

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

Study Groups

allogenic CD19-CAR-NK

Enrolled patients will receive prespecified dose of allogenic CD19-CAR-NK cells.

Group Type: EXPERIMENTAL

allogenic CD19-CAR-NK cells

Intervention Type: OTHER

The relapsed/refractory B-cell hematologic malignancies patients will receive allogenic CD19-Targeted CAR-NK cells infusion up to 3 dose levels (1x10\^6/kg, 5x10\^6/kg, 2x10\^7/kg) after FCE chemotherapy

Interventions

allogenic CD19-CAR-NK cells

The relapsed/refractory B-cell hematologic malignancies patients will receive allogenic CD19-Targeted CAR-NK cells infusion up to 3 dose levels (1x10\^6/kg, 5x10\^6/kg, 2x10\^7/kg) after FCE chemotherapy

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Age18-75years old, no gender or race;

2. Expected survival period ≥ 3 months;

3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2;

4. Confirmed relapsed/refractory B-cell tumor and tumor cells expressing CD19, including acute B-cell lymphoblastic leukemia and B-cell lymphoma; and meets the following criteria for refractory or relapsed B-cell hematologic malignancies: (1) Refractory or relapsed acute B-cell lymphoblastic leukaemia (meets one of the following four criterias): a.Relapse within 6 months after the initial remission; b. Initial refractory patients with failure to achieve complete remission(CR) after 2 cycles of standard chemotherapy; c.Failure to achieve CR or relapse after first line or multiline salvage chemotherapy; d.Patients who are not fitable for hematopoietic stem cell transplantation (HCT), or give up HCT due to limitations, or relapse after HCT.(2) Refractory or relapsed B-cell lymphoma (meets 1 of the following first 4 criterias plus the fifth): a.≤50% decrease in SPD of up to 6 target measurable nodes and extranodal sites or disease progression after 4 cycles of standard chemotherapy; b.Relapse within 6 months after CR; c.Two or more times relapse after CR; d.Subjects who are not fitable for HCT, or give up HCT due to limitations, or relapse after HCT; e.Subjects must be treated with adequate treatment, including at least monoclonal antibodies against CD20 or combination chemotherapy containing anthracyclines;

5. Measurable lesions meets at least one of the following requirements during screening: (1) For lymphoma patients, the length of a single lesion ≥15mm or two or more lesions with the length ≥10mm; (2) Acute B-cell lymphoblastic leukaemia patients with persistent positive MRD or relapse with positive MRD;

6. Within 3 days prior to initial treatment, the organ functions meet the following requirements: (1) complete blood cell count: a.Absolute neutrophil counts ≥ 1.0 ×10^9/L and not treated with G-CSF within 7 days; b.Hemoglobin ≥6g/dL(red blood cell transfusion is permitted); c.Platelet ≥50×10^9/L, (platelet transfusion is permitted);(2) Liver function: alanine transaminase (ALT)/ aspartate aminotransferase(AST) ≤ 3× times upper normal limit(ULN), total bilirubin ≤ 2 times ULN (direct bilirubin ≥1.5 times ULN is acceptable for subjects with Gilbert-Meulengracht syndrome);(3) Coagulation function: International standardized ratio (INR) or activated partial thrombin time (APTT) ≤1.5 times ULN; (4) Renal function: serum creatinine≤1.5×ULN or creatinine clearance rate ≥30mL/min; (5) Corrected serum calcium ≤14mg/dL (≤3.5mmol/L) or free calcium ≥6.5mg/dL(≥1.6mmol/L); (6) Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50%;

7. Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria

1. Central nervous system involved;

2. ≥2 grade persistent nonhematologic toxicity of associated with prior treatment;

3. Systemic steroid therapy exceeding the equivalent of ≥30mg/kg/day of prednisone within 48 hours prior to the first dose of study drug or other immunosuppressive therapies(except for topical and inhaled glucocorticoid therapy, or short-term prophylactic therapy with glucocorticoid);

4. Severe cardiovascular and cerebrovascular diseases, including: (1) Some cardiovascular and cerebrovascular diseases (such as congestive heart failure, acute myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack, deep vein thrombosis or pulmonary embolism, etc.) occurr within 6 months prior to the first dose of study drug; (2)New York Heart Association (NYHA) Class ≥3 or uncontrolled malignant arrhythmias; (3)The researchers assessed that the subjects with other cardiovascular and cerebrovascular diseases are not suitable for the study;

5. Any active infection requiring systemic therapy by intravenous infusion within 14 days prior to the first dose of study drug, including: HBV, HCV, HIV, syphilis infection, or active pulmonary tuberculosis;

6. History of hypersensitivity reactions to murine protein-containing products, or macromolecular biopharmaceuticals such as antibodies or cytokines;

7. Previous or next organ transplant(except for HCT);

8. Women who are pregnant (urine/blood pregnancy test positive) or lactating;

9. Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 6 months after enrollment;

10. Any unstable condition potentially imperiling patient safety and compliance;

11. Known alcohol dependence or drug dependence;

12. According to the investigator's judgment, the patient has other unsuitable grouping conditions.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Xuzhou Medical University

OTHER

Sponsor Role: lead

Responsible Party

Kai Lin Xu，MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kailin Xu, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Xuzhou Medical University

Locations

The Affiliated Hospital of Xuzhou Medical University

Xuzhou, Jiangsu, China

Site Status: RECRUITING

Countries

China

Central Contacts

Kailin Xu, M.D., Ph.D.

Role: CONTACT

lihmd@163.com

15162166166

Junnian Zheng, M.D., Ph.D

Role: CONTACT

Facility Contacts

Kailin Xu, M.D.,Ph.D.

Role: primary

lihmd@163.com

15162166166

Other Identifiers

XYFY2022-KL252-01

Identifier Type: -

Identifier Source: org_study_id