Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients
- Conditions
- Diffuse Large B-cell Lymphoma (DLBCL)
- Interventions
- Biological: TisagenlecleucelDrug: Lymphodepleting chemotherapy
- Registration Number
- NCT02445248
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 115
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Written informed consent must be obtained prior to any screening procedures
-
Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment.
.- Relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT
-
Measurable disease at time of enrollment
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Life expectancy ≥12 weeks
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Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening
-
Adequate organ function:
-
Renal function defined as:
- A serum creatinine of ≤1.5 x Upper Limit of Normal ULN OR
- Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m^2
-
Liver function defined as:
- Alanine Aminotransferase (ALT) ≤ 5 times the Upper Limit of Normal (ULN) for age
- Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
-
Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air
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Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
-
Adequate bone marrow reserve without transfusions defined as:
- Absolute neutrophil count (ANC) > 1.000/mm^3
- Absolute lymphocyte count (ALC) ≥ 300/mm^3 and absolute number of CD3+ T cells > 150/mm^3
- Platelets ≥ 50.000//mm^3
- Hemoglobin > 8.0 g/dl
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Must have an apheresis product of non-mobilized cells accepted for manufacturing
-
Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests
-
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Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
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Treatment with any prior gene therapy product
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Active Central Nervous System (CNS) involvement by malignancy
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Prior allogeneic HSCT
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Eligible for and consenting to HSCT
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Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
-
Investigational medicinal product within the last 30 days prior to screening
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The following medications are excluded:
- Steroids: Therapeutic doses of steroids must be stopped >72 hours prior to leukapheresis and >72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: < 12 mg/m^2/day hydrocortisone or equivalent
- Immunosuppression: Any other immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators)
- Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
-
Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior to CTL019 infusion
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Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion
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Fludarabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis collection.
- Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer
- CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
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Prior radiation therapy within 2 weeks of infusion
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Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive )
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HIV positive patients
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Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
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Unstable angina and/or myocardial infarction within 6 months prior to screening
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Previous or concurrent malignancy with the following exceptions:
- Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
- In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
- A primary malignancy which has been completely resected and in complete remission for ≥ 5 years
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Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before lymphodepletion
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Intolerance to the excipients of the CTL019 cell product
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Cardiac arrhythmia not controlled with medical management
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Prior treatment with any adoptive T cell therapy
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Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter's transformation, and Burkitt lymphoma
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Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Tisagenlecleucel Tisagenlecleucel Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel. Tisagenlecleucel Lymphodepleting chemotherapy Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel.
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort 60 months 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))
- Secondary Outcome Measures
Name Time Method Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients) up to approx. 3.3 months TTR is the time between date of CTL019 infusion until first documented response (CR or PR).
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients 5 years 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.
Duration of Overall Response (DOR) Per IRC up to approx. 60.1 months 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).
Progression Free Survival (PFS) Per Independent Review Committee up to approx. 61 months PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.
Overall Survival (OS) Per Independent Review Committee 60 months OS is the time from date of CTL019 infusion to the date of death due to any cause.
Pharmacokinetics (Pk): Tlast 60 months 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.
Incidence of Immunogenicity to CTL019 pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years 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.
Event Free Survival (EFS) Per Independent Review Committee up to approx. 61 months 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.
Pharmacokinetics (Pk): Cmax 60 months 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.
Pharmacokinetics (Pk): Tmax 60 months 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.
Pharmacokinetics (Pk): AUC0-28d and AUC0-84d 0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for 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.
Pharmacokinetics (Pk): T1/2 60 months 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.
Pharmacokinetics (Pk): Clast 60 months 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.
Trial Locations
- Locations (13)
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
MD Anderson Cancer Center SC
🇺🇸Houston, Texas, United States
The Ohio State University James Cancer Hospital &
🇺🇸Columbus, Ohio, United States
Sidney Kimmel Comprehensive Cancer Center SC-2
🇺🇸Baltimore, Maryland, United States
Oregon Health Sciences University Oregon Health & Sci Uni
🇺🇸Portland, Oregon, United States
Novartis Investigative Site
🇳🇴Oslo, Norway
Uni of Michigan Health System SC CTL019
🇺🇸Ann Arbor, Michigan, United States
University of Pennsylvania Perelman School of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Weill Cornell Medical College
🇺🇸New York, New York, United States
UCSF Medical Center .
🇺🇸San Francisco, California, United States
Emory University School of Medicine/Winship Cancer Institute SC CTL019
🇺🇸Atlanta, Georgia, United States