This phase I trial tests the safety, side effects and best infusion dose of genetically engineered cells called anti-CD19/CD20/CD22 chimeric antigen receptor (CAR) T-cells following a short course of chemotherapy with cyclophosphamide and fludarabine in treating patients with lymphoid cancers (malignancies) that have come back (recurrent) or do not respond to treatment (refractory). Lymphoid malignancies eligible for this trial are: non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-prolymphocytic leukemia (B-PLL). T-cells (a type of white blood cell) form part of the body's immune system. CAR-T is a type of cell therapy that is used with gene-based therapies. CAR T-cells are made by taking a patient's own T-cells and genetically modifying them with a virus so that they are recognized by a group of proteins called CD19/CD20/CD22 which are found on the surface of cancer cells. Anti-CD19/CD20/CD22 CAR T-cells can recognize CD19/CD20/CD22, bind to the cancer cells and kill them. Giving combination chemotherapy helps prepare the body before CAR T-cell therapy. Giving CAR-T after cyclophosphamide and fludarabine may kill more tumor cells.
PRIMARY OBJECTIVE: I. To determine the safety of the treatment of relapsed/refractory non-Hodgkin lymphoma, relapsed/refractory chronic lymphocytic leukemia, refractory B-prolymphocytic leukemia and relapsed/refractory acute lymphoblastic leukemia with chimeric antigen receptor T cells targeting CD19/20/22 and to find the recommended phase II dose for this cellular therapy. SECONDARY OBJECTIVES: I. To describe the safety profile of the infusion of CAR-T cells targeting CD19/20/22 in relapsed/refractory Non-Hodgkin lymphoma, relapsed/refractory chronic lymphocytic leukemia, refractory B-prolymphocytic leukemia and in relapsed/refractory acute lymphoblastic leukemia. II. To describe the toxicities related to infusion of CAR-T cells targeting CD19/20/22. III. To describe the overall response rate and complete response rate of relapsed B cell malignancies treated with CAR-T cells targeting CD19/20/22. IV. To describe the overall and progression free survival of patients with relapsed lymphoma, CLL, B-PLL and ALL treated with anti-CD19/20/22 CAR-T cells. EXPLORATORY OBJECTIVES: I. To describe the persistence of anti-CD19/20/22 CAR-T cells, measured by flow cytometry and quantitative polymerase chain reaction (qPCR). II. To describe the T cell subpopulations of the anti-CD19/20/22 CAR-T cell product before infusion. III. To describe the changes in anti-CD19/20/22 CAR-T cells after infusion and their correlation with disease response and adverse events. IV. To investigate the correlation between changes in cytokine plasma concentrations and changes in anti-CD19/20/22 CAR-T cell subpopulations over time. V. To investigate proteomic changes in anti-CD19/20/22 CAR-T cell subpopulations over time. VI.To investigate whether antigen escape occurs in patients treated with anti-CD19/20/22 CAR-T. OUTLINE: This is a phase I dose-escalation study of anti-CD19/CD20/CD22 CAR-T cells. Patients with NHL with lesions =\< 5 cm, indolent lymphomas, CLL (without Richter's transformation), or B-PLL are assigned to Cohort A. Patients with ALL, CLL (with Richter's transformation), NHL with lesions \> 5 cm and/or lymphoblastic lymphoma, or NHL with circulating lymphoma cells are assigned to Cohort B. COHORT A: LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and may undergo tissue biopsy during screening, undergo apheresis on study, and undergo bone marrow biopsy and aspiration and blood sample collection throughout the study. COHOHRT B: LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide IV over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0 and 7. Patients undergo ECHO or MUGA and may undergo tissue biopsy during screening, undergo apheresis on study, and undergo bone marrow biopsy and aspiration and blood sample collection throughout the study. COHORT C: LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide IV on days -6 and -5 and fludarabine IV on days -6 to -3 in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0 and 7. Patients undergo ECHO or MUGA and may undergo tissue biopsy during screening, undergo apheresis on study, and undergo bone marrow biopsy and aspiration and blood sample collection throughout the study. After completion of study treatment, patients in Cohort A are followed up on days 1-7, 14, 21, 30, 60, 90, at months 6, 24, 36, 48, and 60, and then annually for 6-15 years. Patients in Cohort B and Cohort C are followed up on days 9, 14, 21, 30, 60, 90, at months 6, 24, 36, 48, and 60, and then annually for 6-15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
54
Given IV
Given IV
Given IV
Undergo echocardiography
Undergo MUGA scan
Undergo tissue biopsy
Undergo apheresis
Undergo bone marrow aspiration and biopsy
Undergo blood sample collection
Nationwide Children's Hospital
Columbus, Ohio, United States
RECRUITINGOhio State University Comprehensive Cancer Center
Columbus, Ohio, United States
RECRUITINGRecommended phase II dose of anti-CD19/CD20/CD22 CAR-T cells for each study group (Cohort A, Cohort B, and Cohort C)
Time frame: Up to 30 days after CAR T-cell infusion
Incidence of adverse events
Will be evaluated with descriptive statistics for the frequencies of adverse events of different grades.
Time frame: Up to 12 months after completion of study treatment
Overall response rate
Will be evaluated with descriptive statistics with proportions used to describe response rates.
Time frame: Up to 15 years
Complete response rate
Will be evaluated with descriptive statistics with proportions used to describe response rates.
Time frame: Up to 15 years
Overall survival
Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.
Time frame: Up to 15 years
Progression-free survival
Will be calculated using Kaplan Meier method, comparisons between groups will be done using the log rank test.
Time frame: From entry onto study until lymphoma progression or death from any cause, assessed up to 15 years
The Ohio State University Comprehensive Cancer Center
CONTACT
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