This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.
This was a single arm, open-label, multi-center, Phase II study conducted to determine the efficacy and safety of tisagenlecleucel in adult patients with r/r DLBCL. The study consisted of the following sequential periods: Screening, Pre-Treatment, Treatment and Primary follow-up, Secondary follow-up, Survival follow-up. Patients were enrolled in 2 cohorts to receive one tisagenlecleucel infusion as follows: * Main Cohort (patients treated with tisagenlecleucel manufactured at the Novartis manufacturing facility in Morris Plains, US, referred to as "US manufacturing facility") and * Cohort A (patients treated with tisagenlecleucel manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany, referred to as "EU manufacturing facility"). The study enrolled adult patients ≥ 18 years with histologically confirmed relapsed or refractory (r/r) DLBCL after ≥ 2 lines of chemotherapy, with a life expectancy of ≥ 12 weeks and not eligible or not consenting to stem cell transplantation (SCT). Patients had measurable disease at time of enrollment, adequate organ function and zero or one Eastern Cooperative Oncology Group performance status at screening. For each patient, the apheresis product of non-mobilized cells was received and accepted by the manufacturing site.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
115
The target dose of CTL019 transduced cells for adult patients consisted of a single infusion of 5 x 10\^8 viable CTL019 transduced cells, which was administered via intravenous infusion. The acceptable dose range was 1 - 5x10\^8 viable CTL019 transduced cells.
Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy cycle was planned. The use of any additional bridging therapy prior to the recommended lymphodepleting chemotherapy was at the discretion of the investigator and dependent on the patient's disease burden. Lymphodepleting chemotherapy was started 14 to 5 days before CTL019 infusion (D1) to allow for at least 48 hours from last dose of lymphodepleting chemotherapy to CTL019 infusion. The lymphodepleting regimen was: Fludarabine (25 mg/m\^2 intravenously \[i.v.\] daily for 3 doses) and cyclophosphamide (250 mg/m\^2 i.v. daily for 3 doses starting with the first dose of fludarabine).
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort
ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first. Response was assessed according to Evaluation Criteria in diffuse large B cell lymphoma studies (based on Cheson Response criteria and the Lugano Classification (2014))
Time frame: 60 months
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients
ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first.
Time frame: 5 years
Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)
TTR is the time between date of CTL019 infusion until first documented response (CR or PR).
Time frame: up to approx. 3.3 months
Duration of Overall Response (DOR) Per IRC
DOR is the time from achievement of CR or PR, whichever occurs first, to relapse or death due to diffuse large B-cell lymphoma (DLBCL).
Time frame: up to approx. 60.1 months
Event Free Survival (EFS) Per Independent Review Committee
EFS is the time from date of CTL019 infusion to the date of first documented disease progression or relapse, new treatment for lymphoma or death due to any cause.
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UCSF Medical Center .
San Francisco, California, United States
Emory University School of Medicine/Winship Cancer Institute SC CTL019
Atlanta, Georgia, United States
University of Chicago Medical Center Hematology and Oncology SC - CTL019B2207J
Chicago, Illinois, United States
University of Kansas Cancer Center SC - CTL019C2201
Westwood, Kansas, United States
Sidney Kimmel Comprehensive Cancer Center SC-2
Baltimore, Maryland, United States
Uni of Michigan Health System SC CTL019
Ann Arbor, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
Weill Cornell Medical College
New York, New York, United States
The Ohio State University James Cancer Hospital &
Columbus, Ohio, United States
Oregon Health Sciences University Oregon Health & Sci Uni
Portland, Oregon, United States
...and 16 more locations
Time frame: up to approx. 61 months
Progression Free Survival (PFS) Per Independent Review Committee
PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.
Time frame: up to approx. 61 months
Overall Survival (OS) Per Independent Review Committee
OS is the time from date of CTL019 infusion to the date of death due to any cause.
Time frame: 60 months
Pharmacokinetics (Pk): Cmax
Cmax is the maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration. Cmax, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. The reported Cmax is the summary of maximum level observed based on the data from each patient and based on all the data that's been collected for up to 60 months in a patient.
Time frame: 60 months
Pharmacokinetics (Pk): Tmax
Tmax is the time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days). Tmax, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. The time frame of 60 months refers to the duration for which the data were reviewed to identify the time of Cmax for this measure.
Time frame: 60 months
Pharmacokinetics (Pk): AUC0-28d and AUC0-84d
The AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood. AUC0-28d and AUC0-84d, based on the transgene level data by qPCR, were summarized by Month 3 response, per Independent Review Committee assessment.
Time frame: 0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d
Pharmacokinetics (Pk): T1/2
T1/2 is the half-life associated with the disposition phase slopes (alpha, beta, gamma etc.) of a semi logarithmic concentration-time curve in peripheral blood. T1/2, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame of 60 months reflects the maximum duration up to which the transgene levels were collected to measure the half life.
Time frame: 60 months
Pharmacokinetics (Pk): Clast
Clast is the last observed quantifiable concentration in peripheral blood. Clast, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame reflects maximum duration of 60 months up to which the transgene levels were collected.
Time frame: 60 months
Pharmacokinetics (Pk): Tlast
Tlast is the time of last observed quantifiable concentration in peripheral blood. Tlast, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame reflects maximum duration of 60 months up to which the transgene levels were collected.
Time frame: 60 months
Incidence of Immunogenicity to CTL019
This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by complete response (CR), partial response (PR), Stable disease (SD), progressive disease (SD), Unknown for all participants who received with tisagenlecleucel.
Time frame: pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years