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

Primary Purpose

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

Status
Recruiting
Phase
Early Phase 1
Locations
China
Study Type
Interventional
Intervention
allogenic CD19-CAR-NK cells
Sponsored by
Xuzhou Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring B-cell hematologic malignancies, allogenic CD19-CAR-NK cells

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age18-75years old, no gender or race; Expected survival period ≥ 3 months; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2; 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; 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; 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%; Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: Central nervous system involved; ≥2 grade persistent nonhematologic toxicity of associated with prior treatment; 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); 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; 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; History of hypersensitivity reactions to murine protein-containing products, or macromolecular biopharmaceuticals such as antibodies or cytokines; Previous or next organ transplant(except for HCT); Women who are pregnant (urine/blood pregnancy test positive) or lactating; Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 6 months after enrollment; Any unstable condition potentially imperiling patient safety and compliance; Known alcohol dependence or drug dependence; According to the investigator's judgment, the patient has other unsuitable grouping conditions.

Sites / Locations

  • The Affiliated Hospital of Xuzhou Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

allogenic CD19-CAR-NK

Arm Description

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

Outcomes

Primary Outcome Measures

Dose-limiting toxicities
Adverse events assessed according to NCI-CTCAE v5.0 criteria
Objective Response Rate(ORR)
Assessment of ORR (ORR = CR + CRi + PR) at 3 months of treatment

Secondary Outcome Measures

Progression free survival(PFS)
Assessment of PFS at month 6,12
Overall Survival(OS)
Assessment of OS at month 6, 12, 18 and 24
Minimal-residual disease negative overall response rate(MRD-ORR)
Assessment of MRD- ORR at month 6,12

Full Information

First Posted
February 11, 2023
Last Updated
February 11, 2023
Sponsor
Xuzhou Medical University
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1. Study Identification

Unique Protocol Identification Number
NCT05739227
Brief Title
Safety and Efficacy of Allogenic CD19-CAR-NK Cells in Treatmenting r/r B-cell Hematologic Malignancies
Official Title
Early Clinical Study of Allogenic CD19-CAR-NK Cells (JD001) in the Treatment of Refractory or Relapsed(r/r) B-cell Hematologic Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2023 (Anticipated)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
May 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Xuzhou Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, B-cell Lymphoma, Chronic Lymphocytic Leukemia
Keywords
B-cell hematologic malignancies, allogenic CD19-CAR-NK cells

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
allogenic CD19-CAR-NK
Arm Type
Experimental
Arm Description
Enrolled patients will receive prespecified dose of allogenic CD19-CAR-NK cells.
Intervention Type
Other
Intervention Name(s)
allogenic CD19-CAR-NK cells
Intervention Description
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
Primary Outcome Measure Information:
Title
Dose-limiting toxicities
Description
Adverse events assessed according to NCI-CTCAE v5.0 criteria
Time Frame
1 month
Title
Objective Response Rate(ORR)
Description
Assessment of ORR (ORR = CR + CRi + PR) at 3 months of treatment
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Progression free survival(PFS)
Description
Assessment of PFS at month 6,12
Time Frame
Month 6,12
Title
Overall Survival(OS)
Description
Assessment of OS at month 6, 12, 18 and 24
Time Frame
Month 6, 12, 18 and 24
Title
Minimal-residual disease negative overall response rate(MRD-ORR)
Description
Assessment of MRD- ORR at month 6,12
Time Frame
Month 6, 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age18-75years old, no gender or race; Expected survival period ≥ 3 months; Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2; 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; 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; 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%; Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: Central nervous system involved; ≥2 grade persistent nonhematologic toxicity of associated with prior treatment; 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); 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; 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; History of hypersensitivity reactions to murine protein-containing products, or macromolecular biopharmaceuticals such as antibodies or cytokines; Previous or next organ transplant(except for HCT); Women who are pregnant (urine/blood pregnancy test positive) or lactating; Patients cannot guarantee effective contraception (condom or contraceptives, etc.) within 6 months after enrollment; Any unstable condition potentially imperiling patient safety and compliance; Known alcohol dependence or drug dependence; According to the investigator's judgment, the patient has other unsuitable grouping conditions.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kailin Xu, M.D., Ph.D.
Phone
15162166166
Email
lihmd@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Junnian Zheng, M.D., Ph.D
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kailin Xu, M.D., Ph.D.
Organizational Affiliation
Xuzhou Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Affiliated Hospital of Xuzhou Medical University
City
Xuzhou
State/Province
Jiangsu
ZIP/Postal Code
221000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kailin Xu, M.D.,Ph.D.
Phone
15162166166
Email
lihmd@163.com

12. IPD Sharing Statement

Learn more about this trial

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

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