This phase I trial studies the side effects of huJCAR014 in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma or acute lymphoblastic leukemia. huJCAR014 CAR-T cells are made in the laboratory by genetically modifying a patient's T cells and may specifically kill cancer cells that have a molecule CD19 on their surfaces. In Stage 1, dose-finding studies will be conducted in 3 cohorts: 1. Aggressive B cell NHL 2. Low burden ALL 3. High burden ALL In Stage 2, studies may be conducted in one or more cohorts to collect further safety, PK, and efficacy information at the huJCAR014 dose level(s) selected in Stage 1 for the applicable cohort(s). There are two separate cohorts for stage 2: 1. Cohort 2A, CAR-naïve (n=10): patients who have never received CD19 CAR-T cell therapy. 2. Cohort 2B, CAR-exposed (n=27): patients who have previously failed CD19 CAR-T cell therapy.
OUTLINE: This is a dose-escalation study of huJCAR014. Patients undergo leukapheresis. Beginning 1-2 weeks after leukapheresis, patients undergo lymphodepleting chemotherapy comprising either cyclophosphamide intravenously (IV) daily for 1 day and fludarabine IV daily for 3 days or cyclophosphamide and fludarabine IV daily for 3 days. Alternative lymphodepleting chemotherapy regimens maybe used if patient's clinical situation or other logistical factors dictate otherwise. Within 36-96 hours after completion of lymphodepleting chemotherapy, patients receive huJCAR014 IV over 20-30 minutes on day 0. After completion of study treatment, patients are followed up every 30 days for the first 3 months, every 3 months for up to 12 months, and then yearly for 15 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
55
Given IV
Given IV
Given IV
Correlative studies
Undergo leukapheresis
Correlative studies
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Incidence of toxicity
Will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All adverse events (AEs) will be listed and summarized. Summaries of laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities. Summaries of AEs and laboratory abnormalities will be based on the All Treated analysis set.
Time frame: Up to 30 days after the final dose of study therapy
Dose-limiting toxicity (DLT) rates
Observed DLT rates will be summarized based on the DLT-Evaluable analysis set. Final DLT rates at each dose level will be estimated by isotonic regression.
Time frame: Up to 28 days
Maximum concentration (Cmax) of autologous human anti-CD19CAR-4-1BB-CD3zeta-EGFRt-expressing CD4+/CD8+ T-lymphocytes (huJCAR014) cells in blood
huJCAR014 will be measured in blood using quantitative polymerase chain reaction (PCR) (qPCR) and flow cytometry over 28 days after huJCAR014 infusion. Cmax is the peak concentration of huJCAR014 cells in blood in the first 28 days after infusion.
Time frame: Up to 28 days
Time to maximum concentration (Tmax), of huJCAR014 cells in blood
huJCAR014 will be measured in blood using quantitative PCR (qPCR) and flow cytometry over 28 days after huJCAR014 infusion. Tmax is the time to reach the maximum concentration of huJCAR014 cells in blood in the first 28 days.
Time frame: Up to 28 days
Area under the curve of huJCAR014 cells in blood
huJCAR014 will be measured in blood using quantitative PCR (qPCR) and flow cytometry over 28 days after huJCAR014 infusion. AUC is the calculated area under the curve of huJCAR014 concentrations in blood by time after infusion through 28 days.
Time frame: Up to 28 days
Presence of huJCAR014 cells in bone marrow
The persistence of huJCAR014 in the bone marrow at 28 days will be assessed, based on both a qPCR assay and flow cytometry.
Time frame: Up to 28 days
Complete response (CR) rate
Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the efficacy-evaluable (EE) analysis sets. In addition, CR rate will be presented based on the all-treated analysis set
Time frame: Up to 15 years
Partial response (PR) rate
Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets.
Time frame: Up to 15 years
Objective response rate (ORR)
Will be defined as the proportion of patients with a best response of either CR or PR. Will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals based on the EE analysis sets. In addition, ORR will be presented based on the All-Treated analysis set.
Time frame: Up to 15 years
Duration of response (DOR)
Will be defined as the time from date of first response to relapse/progression or death. Kaplan-Meier (KM) methodology will be used to analyze DOR.
Time frame: Up to 15 years
Progression-free survival (PFS)
KM methodology will be used to analyze PFS.
Time frame: From date of first huJCAR014 infusion to progressive disease or death, assessed up to 15 years
Event-free survival (EFS)
KM methodology will be used to analyze EFS.
Time frame: From the date of the first huJCAR014 infusion to death from any cause, relapse, or treatment failure, whichever occurs first, assessed up to 15 years
Overall survival (OS)
KM methodology will be used to analyze OS.
Time frame: From date of first huJCAR014 infusion to death, assessed up to 15 years
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