This phase I trial studies the effects of CD-19 directed chimeric antigen receptor (CAR)-T cell therapy for the treatment of patients with B cell malignancies that have come back (recurrent) or have not responded to treatment (refractory). CD-19 CAR-T cells use some of a patient's own immune cells, called T cells, to kill cancer. T cells fight infections and, in some cases, can also kill cancer cells. Some T cells are removed from the blood, and then laboratory, researchers will put a new gene into the T cells. This gene allows the T cells to recognize and possibly treat cancer. The new modified T cells are called the IC19/1563 treatment. IC19/1563 may help treat patients with relapsed/refractory B cell malignancies.
PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose of in-house, point of care manufactured autologous anti-CD19 CAR-expressing T-lymphocytes IC19/1563 (IC19/1563) in patient with relapsed/refractory B cell malignancies. SECONDARY OBJECTIVES: I. Assess the feasibility of in-house, point of care manufactured IC19/1563 cells. II. Evaluate safety, including all grades of neurotoxicity (ICANS) and cytokine release syndrome as determined by the American Society for Transplantation and Cellular Therapy (ASTCT) criteria, by monitoring adverse events, laboratory abnormalities, vital signs, and other safety parameters. III. Estimate the incidence of grade 3 or higher of neurotoxicity and cytokine release syndrome by grade 3 or higher neurotoxicity (ICANS) or CRS per the ASTCT criteria. IV. Assess efficacy of a single dose of IC19/1563 cells: IVa. Overall response rate (ORR); IVb. Duration of response (DOR); IVc. Progression-free survival (PFS); IVd. Minimal residual disease (MRD) negative bone marrow disease in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), based on one month post evaluation. CORRELATIVE RESEARCH OBJECTIVES: I. Characterize the in vivo cellular kinetics profile (levels, persistence, trafficking) of CAR19 transgene and CD3+CAR+ cells into blood. II. Characterize the changes in cytokine levels over time. III. Assess hospital resource utilization and health economics. OUTLINE: This is a dose-escalation study of IC19/1563. Patients receive cyclophosphamide intravenously (IV) over 60 minutes and fludarabine IV over 30 minutes on days -5, -4, -3, or bendamustine IV over 10 minutes on days -4 and -3, and IC19/1563 IV on day 0. Patients also undergo bone marrow biopsy and aspiration, computed tomography/positron emission tomography (CT/PET) or CT scans, magnetic resonance imaging (MRI), and collection of blood and tumor samples throughout the trial. After completion of study treatment, patients are followed up on days 60, every 3 months up to year 3, every 6 months from years 3-5, and then annually for up to 15.5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
Given IV
Given IV
Undergo collection of blood and tissue samples
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Undergo CT
Given IV
Given IV
Undergo MRI
Undergo CT/PET
Mayo Clinic in Rochester
Rochester, Minnesota, United States
RECRUITINGMaximum tolerated dose (MTD)
MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients).
Time frame: 90 days
Proportion of patients who achieve a successful infusion without manufacturing failure or out of spec products
All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for assessing feasibility. Exact binomial 95% confidence intervals for the true rate of successful infusion will be calculated.
Time frame: Up to 15.5 years
Overall response rate (ORR)
ORR will be estimated by the number of patients who achieve a response divided by the total number of evaluable patients who have received a successful chimeric antigen receptor (CAR)-T19 infusion. Response criteria will follow the revised International working group Response Criteria for Malignant Lymphoma or the 2018 International Workshop for Chronic Lymphocytic Leukemia (CLL) response criteria. Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
Time frame: From a complete response (CR) or partial response (PR) noted as the objective status at any time after the start of CART19 infusion, assessed up to 15.5 years
Duration of response (DOR)
The distribution of duration of response will be estimated using the method of Kaplan Meier.
Time frame: From CR or PR to the date of progression or death, assessed up to 15.5 years
Progression-free survival
The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Time frame: From registration to disease progression or death, assessed up to 15.5 years
Rates of grade 3 or higher neurotoxicity
Assessed per American Society for Transplantation and Cellular Therapy (ASTCT) guidelines will be estimated by the number of patients who experience grade 3 or higher of neurotoxicity divided by the total number of evaluable patients. Assessed using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. In addition, neurotoxicity will be assessed by Immune Effector Cell Associated Neurotoxicity Syndrome criteria. Exact binomial 95% confidence intervals for the true rates of grade 3 or higher neurotoxicity will be calculated.
Time frame: Up to 15.5 years
Rate of cytokine release syndrome
Assessed per ASTCT guidelines will be estimated by the number of patients who experience cytokine release syndrome divided by the total number of evaluable patients. Cytokine release syndrome will be evaluated by CTCAE version 5.0 and Lee grading criteria. Exact binomial 95% confidence intervals will be used.
Time frame: Up to 15.5 years
Minimal residual disease (MRD)
MRD negative rate will be estimated by the number of CLL/small lymphocytic lymphoma (SLL) patients with MRD negative bone marrow divided by the total number of evaluable CLL/SLL patients. Exact binomial 95% confidence intervals for the true rate of MRD negativity will be calculated.
Time frame: 1 month
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