This phase Ib trial studies whether anti-CD19-chimeric antigen receptor (CAR) lentiviral vector-transduced autologous T cells (JCAR014) and durvalumab are safe in combination and can work together in treating patients with non-Hodgkin lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). JCAR014 is made of each patient's immune cells (T cells) that have a new gene added to them in a laboratory, which programs them to kill lymphoma cells. Durvalumab is a type of drug called a monoclonal antibody, targeted to PD-L1 that may help immune cells attack cancer cells more effectively and thus help JCAR014 work better.
PRIMARY OBJECTIVES: I. To evaluate the safety of JCAR014 in combination with durvalumab in adult patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). II. To determine the maximum tolerated dose (MTD) of durvalumab in combination with JCAR014. III. To characterize the pharmacokinetic (PK) profile of JCAR014. SECONDARY OBJECTIVES: I. To assess the antitumor activity of JCAR014 in combination with durvalumab in R/R B-cell NHL. II. To estimate the duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in patients treated with JCAR014 in combination with durvalumab. III. To characterize the PK profile of durvalumab. IV. To assess the immunogenicity of JCAR014 and durvalumab. EXPLORATORY OBJECTIVE: I. To assess the pharmacodynamic effects of JCAR014 and durvalumab in blood and within the tumor. OUTLINE: This is a dose-escalation study of durvalumab administered with a single fixed dose of JCAR014. Patients are assigned to 1 of 2 treatment arms, listed as Groups 1 and 2 below. LYMPHODEPLETING CHEMOTHERAPY: All patients receive cyclophosphamide and fludarabine intravenously (IV) for 3 days starting approximately on day -5 or day -4. GROUP I: Patients receive JCAR014 IV over 20-30 minutes on day 0 and durvalumab IV over 60 minutes on day 21 (may occur as early as day 7) and then every 4 weeks for up to 10 doses in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive durvalumab IV over 60 minutes on day -1, JCAR014 IV over 20-30 minutes on day 0, then up to 10 additional doses of durvalumab every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 30 days for 30 months, every 3 months for 12 months, then periodically for at least 15 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Count of Participants Who Experienced Adverse Events
Toxicity graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Time frame: 28 days post last infusion of Durvalumab, up to 1 year
Dose Limiting Toxicity (DLT) Rates
Will be summarized based on the dose limiting toxicity evaluable analysis set. The target toxicity rate for the maximum tolerated dose is 30%. Outcome will be reported as a count of patients in each arm that experienced a DLT.
Time frame: 28 days post first infusion of Durvalumab (for participants in Group 1) or 28 days post infusion of JCAR (for participants in Group 2)
Highest Treatment Dose Administered on Study
Reporting outcome as the maximum durvalumab dose that we reached on the study. Patients were monitored for 28 days post infusion for dose limiting toxicities. The DLT rate was used to determine dose escalation. The study was terminated prior to reaching the maximum tolerated dose.
Time frame: 28 days
Maximum JCAR014 Cmax by Flow Cytometry
Absolute CD4+ and CD8+ CAR-T cell counts were determined by multiplying the percentages of CD3+CD4+CD8-EGFRt+ and CD3+CD4-CD8+EGFRt+ events, respectively, in a viable CD45+ lymphocyte forward/side scatter gate by an absolute lymphocyte count performed on the same day. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.
Time frame: Up to 12 months
Area Under the Curve (AUC) of JCAR014 by Flow Cytometry
Absolute CD4+ and CD8+ CAR-T cell counts were determined by multiplying the percentages of CD3+CD4+CD8-EGFRt+ and CD3+CD4-CD8+EGFRt+ events, respectively, in a viable CD45+ lymphocyte forward/side scatter gate by an absolute lymphocyte count performed on the same day. Subjects had samples analyzed at approximately days 0, 3, 7, 10, 14, 21, and 28 after CAR-T cell infusion to generate the AUC from day 0 to 28. The areas under the curve of CAR T-cell counts by flow cytometry and qPCR between time points were calculated by using a trapezoidal rule computational algorithm. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.
Time frame: Up to 28 days
Maximum JCAR014 Cmax in Blood by Quantitative Polymerase Chain Reaction (qPCR) Analysis
The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.
Time frame: Up to 12 months
AUC of JCAR014 Cells by qPCR Analysis
The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Subjects had samples analyzed at approximately days 0, 3, 7, 10, 14, 21, and 28 after CAR-T cell infusion to generate the AUC from day 0 to 28.The areas under the curve of CAR T-cell counts by flow cytometry and qPCR between time points were calculated by using a trapezoidal rule computational algorithm. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.
Time frame: Up to 28 days
Time to Loss of JCAR014 Detection in Blood by qPCR Analysis
The number of copies of the CAR transgene/μg of DNA in the blood was determined by using quantitative polymerase chain reaction (qPCR) to detect the integrated Flap-EF1⍺ sequence, with a lower limit of detection of 10 transgene copies/μg of DNA. Excluding 1 patient in Group 2 Dose Level 5 who received an out-of-specification JCAR014 product.
Time frame: Up to 12 months, +/- 30 days
Rate of Complete Response (CR) by Investigator Assessment Using Lugano Criteria
This outcome is a count of participants who experienced a best response of complete response (CR) by investigator assessment using Lugano criteria. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment.
Time frame: Up to 1 year
Rate of Partial Response (PR) by Investigator Assessment Using Lugano Criteria
This outcome is a count of participants who experienced a best response of partial response (PR) by investigator assessment using Lugano criteria. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment.
Time frame: Up to 1 year
Objective Response Rate by Investigator Assessment Using Lugano Criteria
ORR, defined as a count of participant with a best response of either complete response or partial response. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment.
Time frame: Up to 1 year
Duration of Response
Duration of response will be an average amount of days from first response assessment until progression or death for treated patients. Total number analyzed will be the patients that progressed or died, excluding those that did not progress or die. 1 patient in Group 1 Early Dose Level 2 could not be analyzed for the outcome because they expired before their first response assessment.
Time frame: From first response to progressive disease or death, assessed up to 1 year
Progression Free Survival
Outcome will be reported as a count of those who did not progress and did not die while on study.
Time frame: From date of first study treatment to progressive disease or death, assessed up to 1 year
Overall Survival
Outcome will be reported as a count of participants who survived while on study. Survival was assessed up to 1 year.
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Time frame: From date of first study treatment to death, assessed up to 1 year