Anti-CD7 CAR-Engineered T Cells for T Lymphoid Malignancies Malignancies

Sponsor

Wuhan Union Hospital, China (Other)

Overall Status

Recruiting

CT.gov ID

NCT04823091

Collaborator

Beijing GoBroad Hospital Management Co.,Ltd (Other), Shanghai YaKe Biotechnology Ltd. (Other)

Enrollment

Location

Arm

35.7

Anticipated Duration (Months)

0.7

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-CD7 chimeric antigen receptor(CAR)-modified T cells(CAR7-Ts) in patients with relapsed or refractory T lymphoid malignancies.

Condition or Disease	Intervention/Treatment	Phase
T-Cell Lymphocytic Leukemia T-Cell Chronic Lymphocytic Leukemia T Cell Non-Hodgkin Lymphoma	Drug: Fludarabine + Cyclophosphamide + CAR7-T Cells	Phase 1

Detailed Description

Chimeric antigen receptor-T cells (CAR-T) have made breakthroughs in the treatment of B-cell tumors, especially refractory/relapsed acute B lymphocytes. CD7 is a transmembrane glycoprotein expressed by T cells and natural killer cells and their precursors; it is also expressed in >95% of lymphoblastic T-cell leukemias and lymphomas . CD7 was previously evaluated as a target for immunotoxin-loaded antibodies in patients with T-cell malignancies, but tumor responses were limited.

Enhancing the potency of CD7-directed cytotoxicity by substituting donor-derived CAR-T cells for a monoclonal antibody would augment the efficacy of CD7-targeted therapy in patients with T-cell malignancies. To prepare CAR7-T cells, CD7 expression is suppressed on donor-derived T cells by unique blocking technique, and CD7-negative T cells are transduced with a humanized anti-CD7-41BB-CD3ζ lentiviral vector.

This is an investigational study. The objectives are to evaluate the safety and efficacy of CAR7-T cells in patients with CD7+ T-cell malignancies.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Safety and Efficacy of Anti-CD7 CAR-Engineered T Cells for Relapsed/Refractory T Lymphoid Malignancies: a Single-center, Open-label, Non-randomized, Single-arm Clinical Study

Actual Study Start Date :

Apr 15, 2021

Anticipated Primary Completion Date :

Apr 7, 2023

Anticipated Study Completion Date :

Apr 7, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fludarabine + Cyclophosphamide + anti-CD7 CAR-T Cells Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (250 mg/kg) on day -5, -4, and -3, followed by the infusion of CAR7-T cells with the dose of 1×10^6/kg and 2×10^6/kg (with an allowance of ±20%). 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 + CAR7-T Cells fludarabine 30 mg/kg on day -5, -4, and -3; cyclophosphamide 250 mg/kg on day -5, -4, and -3; CAR7-T Cells on day 0.

Arm

Intervention/Treatment

Experimental: Fludarabine + Cyclophosphamide + anti-CD7 CAR-T Cells

Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (250 mg/kg) on day -5, -4, and -3, followed by the infusion of CAR7-T cells with the dose of 1×10^6/kg and 2×10^6/kg (with an allowance of ±20%). 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 + CAR7-T Cells

fludarabine 30 mg/kg on day -5, -4, and -3; cyclophosphamide 250 mg/kg on day -5, -4, and -3; CAR7-T Cells on day 0.

Outcome Measures

Primary Outcome Measures

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

Overall response rate(ORR) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. [within 2 years after infusion]
ORR will be assessed from CAR T cell infusion to death or last follow-up (censored).
Complete response rate(CRR) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. [within 2 years after infusion]
CRR will be assessed from CAR T cell infusion to death or last follow-up (censored).
Progress-free survival(PFS) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. [within 2 years after infusion]
PFS will be assessed from CAR T cell infusion to death or last follow-up (censored).
Duration of Response(DOR) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. [within 2 years after infusion]
DOR will be assessed from CAR T cell infusion to death or last follow-up (censored).
Overall survival(OS) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-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

In vivo expansion and survival of CAR7-T cells [within 2 years after infusion]
Quantity of CAR copies in bone marrow and peripheral blood will be determined by using quantitative polymerase chain reaction.

Eligibility Criteria

Criteria

Ages Eligible for Study:

14 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged from 14 to 70 years;
Expected survival over 60 days;
Eastern Cooperative Oncology Group score 0-2;
Diagnosed as T-cell hematologic malignancies (including leukemia and lymphoma) according to WHO2016 criteria;
Patients must relapse or be refractory after at least two lines of therapy.
CD7 were positive in bone marrow or cerebrospinal fluid by immunohistochemistry or flow cytometry at screening, and one of the following conditions is satisfied:

No remission was achieved after at least 2 lines of standard therapy; B. Relapse or progression after standard treatment; C. Relapse after autologous or allogeneic hematopoietic stem cell transplantation;

Have no fertility requirements or plans for one year since enrollment in this clinical trial;
Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.

Exclusion Criteria:

Complicated with central system leukemia/lymphoma with active intracranial lesions;
Existing or preexisting CNS conditions, such as epileptic seizures, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any CNS related autoimmune disease;
Symptomatic heart failure or severe arrhythmias;
Symptoms of severe respiratory failure;
Complicated with other types of malignant tumors;
Serum creatinine and/or urea nitrogen ≥ 1.5 times of normal value;
Suffer from sepsis or other uncontrollable infections;
Intracranial hypertension or brain consciousness disorder;
Severe mental disorders;
Have received organ transplantation (excluding bone marrow transplantation);
Female patients (fertile patients) had positive blood HCG test;
Hepatitis (including hepatitis B and C), AIDS and syphilis were screened positive;
Patients with graft-versus-host disease (GVHD) or who require immunosuppressant treatment;
The absolute value of lymphocytes was too low to manufacture CART cells;
Other conditions considered inappropriate by the researcher.