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Universal Chimeric Antigen Receptor-modified AT19 Cells for CD19+ Relapsed/Refractory Hematological Malignancies

Primary Purpose

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

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia

Eligibility Criteria

14 Years - 78 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Aged 14-78 years old (including 14 and 78 years old).
Clinical diagnosis of CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and lymphoma.
Refractory/Relapsed B-cell malignancies:
A. Refractory/relapsed B-cell lymphoblastic leukemia, meeting one of the following criteria:
i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen.
iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy.
iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT.
B. Refractory/relapsed B-cell lymphoma, meeting 1 of the first 4 items plus item 5: i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy.
ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. 2 or more relapses after CR. iv. Not suitable for HSCT, or abandon HSCT due to various restrictions, or relapse after HSCT.
v. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines.
Having a measurable or evaluable lesion:
A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm.
B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD.
The toxicity related to previous treatments had returned to < 1 level at enrollment (except for low grade toxicity such as alopecia).
Patients have good main organs functions:
A. Liver function: ALT/AST < 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.
Estimated survival time≥3 months.
Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.

Exclusion Criteria:

Central nervous system is involved in leukemia and lymphoma.
Known HIV positive patients.
CNS diseases, such as epilepsy, cerebral ischemia / hemorrhage, dementia, cerebellar diseases or any CNS related autoimmune diseases.
NYHA class III or higher cardiac failure, or with malignant arrhythmia.
Myocardial infarction, angioplasty or stent placement, unstable angina or other clinically significant heart history within 12 months before enrollment.
Patients who need immediate treatment to control tumor progression or relieve tumor burden.
Active autoimmune diseases requiring systemic immunosuppressive therapy.
History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before enrollment.
Severe immediate hypersensitivity to any drug to be used in this study.
Women who are pregnant or breastfeeding.
Other unsuitable conditions in the researchers' opinion.

Sites / Locations

Union Hospital, Huazhong University of Science and TechnologyRecruiting
Union Hospital, Huazhong University of Science and TechnologyRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Fludarabine + Cyclophosphamide + AT19 cells

Arm Description

Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (300 mg/kg) on days -5, -4, and -3, followed by the infusions of AT19 cells on day 0-2. The study will be divided into three groups: B-ALL, B-CLL, and B-cell lymphoma. Doses of 0.5×10^7, 1.0×10^7, and 2.0×10^7 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 DLT emerges in the group, then the next group uses the subsequent higher dose. 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.

Outcomes

Primary Outcome Measures

Incidence of Treatment-related Adverse Events

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

Overall response rate(ORR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

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

Complete response rate(CRR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

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

Progress-free survival(PFS) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

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

Duration of Response(DOR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

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

Overall survival(OS) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

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

Full Information

NCT ID

NCT04796688

First Posted

March 10, 2021

Last Updated

March 11, 2021

Sponsor

Wuhan Union Hospital, China

Collaborators

Chengdu USino Technology Biology Co., Ltd

1. Study Identification

Unique Protocol Identification Number

NCT04796688

Brief Title

Universal Chimeric Antigen Receptor-modified AT19 Cells for CD19+ Relapsed/Refractory Hematological Malignancies

Official Title

Safety and Efficacy of Universal Chimeric Antigen Receptor-modified AT19 Cells in Patients With CD19+ Relapsed/Refractory Hematological Malignancies: a Single-center, Open-label, Single-arm Clinical Study

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Recruiting

Study Start Date

March 10, 2021 (Anticipated)

Primary Completion Date

March 10, 2023 (Anticipated)

Study Completion Date

March 10, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Wuhan Union Hospital, China

Collaborators

Chengdu USino Technology Biology Co., Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

This is a single-center, open-label, single-arm study to evaluate the primary safety and efficacy of universal chimeric antigen receptor-modified AT19 cells in patients with relapsed or refractory hematological malignancies.

Detailed Description

Adoptive transfer of autologous anti-CD19 CAR-T cells can induce durable remissions in patients with relapsed/refractory hematologic malignancies, including CD19+ B-cell acute lymphoblastic leukemia(B-ALL), B-cell chronic lymphoblastic leukemia(B-CLL), and B-cell lymphoma. However, multiple challenges exist for manufacturing CAR-T cells from patients with advanced disease including inability to manufacture a product, disease progression or death while waiting for the CAR-T product to be available, and heterogeneity among autologous CAR-T products that contributes to unpredictable and variable clinical activity. Healthy donor T cells can provide a source for production of universal CAR-T cells when combined with gene editing to prevent expression of endogenous TCRs and avoid generation of GvHD in HLA mismatched recipients. Cord blood derived T cells from healthy donor are the source for production of universal anti-CD19 CAR-modified AT19 cells. CRISPR/cas9 gene-editing technology has been used to knockout TCRs and HLA-I to avoid GvHD and transplant rejection. AT19 cells have exhibited potent cytotoxicity in CD19+ tumor cells and can effectively eradicate CD19+ tumor cells in xenograft mice models, without showing GvHD. This study aims to evaluate prelimary safety and efficacy of the universal AT19 cells in patients with relapsed/refractory B-ALL, B-CLL, and B-cell lymphoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

27 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Fludarabine + Cyclophosphamide + AT19 cells

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fludarabine + Cyclophosphamide + CAR-NK-CD19 Cells

Intervention Description

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 Measure Information:

Title

Incidence of Treatment-related Adverse Events

Description

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).

Time Frame

within 2 years after infusion

Secondary Outcome Measure Information:

Title

Overall response rate(ORR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

Description

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

Time Frame

within 2 years after infusion

Title

Complete response rate(CRR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

Description

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

Time Frame

within 2 years after infusion

Title

Progress-free survival(PFS) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

Description

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

Time Frame

2 years after infusion

Title

Duration of Response(DOR) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

Description

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

Time Frame

2 years after infusion

Title

Overall survival(OS) of administering AT19 cells in Relapsed/Refractory CD19+ B-cell hematological malignancies.

Description

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

Time Frame

2 years after infusion

Other Pre-specified Outcome Measures:

Title

In vivo expansion and survival of AT19 cells

Description

Quantity of AT19 CAR copies in bone marrow and peripheral blood will be determined by using qPCR.

Time Frame

2 years after infusion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

14 Years

Maximum Age & Unit of Time

78 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Aged 14-78 years old (including 14 and 78 years old). Clinical diagnosis of CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia and lymphoma. Refractory/Relapsed B-cell malignancies: A. Refractory/relapsed B-cell lymphoblastic leukemia, meeting one of the following criteria: i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen. iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy. iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT. B. Refractory/relapsed B-cell lymphoma, meeting 1 of the first 4 items plus item 5: i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy. ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. 2 or more relapses after CR. iv. Not suitable for HSCT, or abandon HSCT due to various restrictions, or relapse after HSCT. v. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines. Having a measurable or evaluable lesion: A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm. B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD. The toxicity related to previous treatments had returned to < 1 level at enrollment (except for low grade toxicity such as alopecia). Patients have good main organs functions: A. Liver function: ALT/AST < 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. Estimated survival time≥3 months. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form. Exclusion Criteria: Central nervous system is involved in leukemia and lymphoma. Known HIV positive patients. CNS diseases, such as epilepsy, cerebral ischemia / hemorrhage, dementia, cerebellar diseases or any CNS related autoimmune diseases. NYHA class III or higher cardiac failure, or with malignant arrhythmia. Myocardial infarction, angioplasty or stent placement, unstable angina or other clinically significant heart history within 12 months before enrollment. Patients who need immediate treatment to control tumor progression or relieve tumor burden. Active autoimmune diseases requiring systemic immunosuppressive therapy. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before enrollment. Severe immediate hypersensitivity to any drug to be used in this study. Women who are pregnant or breastfeeding. Other unsuitable conditions in the researchers' opinion.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Heng Mei, M.D., Ph.D

Phone

027-8572600

hmei@hust.edu.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Chenggong Li

Phone

18868112136

chenggongli@hust.edu.cn

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Heng Mei, M.D., Ph.D

Organizational Affiliation

Wuhan Union Hospital, China

Official's Role

Principal Investigator

Facility Information:

Facility Name

Union Hospital, Huazhong University of Science and Technology

City

Wuhan

State/Province

Hubei

ZIP/Postal Code

430022

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Heng Mei, M.D., Ph.D

hmei@hust.edu.cn

First Name & Middle Initial & Last Name & Degree

Chenggong Li

chenggongli@hust.edu.cn

First Name & Middle Initial & Last Name & Degree

Heng Mei, M.D., Ph.D

Facility Name

Union Hospital, Huazhong University of Science and Technology

City

Wuhan

State/Province

Hubei

ZIP/Postal Code

430022

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Heng Mei, M.D., Ph.D

hmei@hust.edu.cn

First Name & Middle Initial & Last Name & Degree

Chenggong Li

chenggongli@hust.edu.cn

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Universal Chimeric Antigen Receptor-modified AT19 Cells for CD19+ Relapsed/Refractory Hematological Malignancies

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