This phase I trial tests the safety, side effects, and best dose of autologous anti-CD19 CAR-expressing T lymphocytes (CD19-CAR T cells) in older adults with B-cell acute lymphoblastic leukemia. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of B-cell acute lymphoblastic leukemia.
PRIMARY OBJECTIVE: I. Assess the safety and tolerability of autologous CD19-CAR T cell therapy by evaluation of toxicities including type, frequency, severity, attribution, time course and duration in older patients with B-cell acute lymphoblastic leukemia (ALL) in first morphological complete remission (CR1). SECONDARY OBJECTIVES: I. Assess the feasibility of manufacturing and infusing CD19-CAR T cells in older adults with B-cell ALL in CR1. II. Evaluate the rate of MRD- remission in patients who had MRD+ disease at the time of infusion. III. Evaluate the overall risk of relapse. IV. Evaluate the risk of central nervous system (CNS) relapse (isolated and combined with bone marrow relapse). V. Estimate the 1-year event-free survival (EFS) rate post CD19-CAR T cell therapy. VI. Estimate 1-year overall survival (OS) post CD19-CAR T cell therapy. VII. Describe development of frailty after CD19-CAR T cell therapy. EXPLORATORY OBJECTIVES: I. Measure expansion and persistence of CD19-CAR T cells in peripheral blood (PB), bone marrow (BM) and cerebrospinal fluid (CSF). II. Assess the duration of B-cell aplasia. III. Describe cytokine levels in PB over the study period. OUTLINE: This is a dose-escalation study of CD19-CAR T cell therapy followed by a dose-expansion study. Patients undergo T cell leukapheresis, receive fludarabine and cyclophosphamide intravenously (IV), and then receive CD19-CAR T cell infusion IV on study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Undergo blood sample collection
Undergo bone marrow aspirate
Given IV
Given IV
Undergo T-cell leukapheresis
Complete questionnaires
City of Hope Medical Center
Duarte, California, United States
Incidence of dose-limiting toxicity (DLT)
Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, attribution, time of onset, duration, and reversibility or outcome.
Time frame: Up to 28 days after CD19-chimeric antigen receptor (CAR) T cell infusion
Incidence of adverse events
Assessed using CTCAE version 5.0. Cytokine release syndrome adverse events will be characterized using the descriptions and grading scales found in the Lee, et. al. publication: 'ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, attribution, time of onset, duration, and reversibility or outcome.
Time frame: Up to 15 years
Percentage of consented older B-acute lymphoblastic leukemia (ALL) patients undergoing leukapheresis who get sufficient CD19-CAR T cells manufactured and infused at their assigned dose level
Feasibility will be assessed by the percentage of consented subjects undergoing leukapheresis who have sufficient CD19-CAR T cells manufactured and infused successfully. The rate and its 95% Clopper Pearson binomial confidence intervals (CIs) will be calculated. If it's 50% or higher, then the CD19-CAR T therapy is feasible to older B-ALL complete remission patients.
Time frame: At T cell infusion (Day 0)
Minimal residual disease (MRD) response rate
Defined as minimal residual disease level below 10\^-4 by either polymerase chain reaction, next generation sequencing, or multicolor flow cytometry. Will be calculated with 95% Clopper Pearson binomial confidence intervals (CIs).
Time frame: Up to 12 months post T cell infusion
Event-free survival
Calculated by their 95% Clopper Pearson binomial CIs. Censored at the last follow-up if patients are known to be alive and free of event.
Time frame: From the start of CD19-CAR T cell infusion to the date of death or disease progression/relapse, whichever occurring first, assessed up to 15 years
Overall survival rate
Will be estimated using the product-limit method of Kaplan and Meier.
Time frame: From start of protocol therapy to death, or last follow-up, whichever comes first, assessed up to 15 years
Rate of relapse, including MRD and extramedullary relapse
MRD relapse defined as detectable of leukemic cells at \> 0.01% in morphological remission bone marrow. Extramedullary relapse defined as documented ALL relapse outside the bone marrow. 95% Clopper Pearson binomial CIs will be calculated.
Time frame: Up to 2 years post treatment
Frailty phenotype score
Patients who score as frail at day 100 (3 or more of 5 points) or 1 point worsening for those with a baseline score of 3 or 4, they will be considered frail at day 100.
Time frame: Pre-CAR T and at day 100
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