This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL.
This was a initially a one cohort, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL. This main cohort completed enrollment. Two new cohorts were added via an amendment, Cohort 1 for high risk B-cell ALL patients at first relapse, and Cohort 2 for feasibility and safety of CTL019 in high risk B-cell ALL in patients that relapsed \<6 months post allo-HSCT. Due to lack of recruitment, Cohort 1 and Cohort 2 halted recruitment. This decision was not related to any safety issue. The study had the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation \& Lymphodepleting Chemotherapy), Treatment and Primary Follow-up, Secondary Follow-up (if applicable) and Survival Follow-up. The total duration of the study is 5 years from CTL019 cell infusion. Efficacy analyses were performed only on the Main Cohort (n=79) who were infused with tisagenlecleucel. However, the data on disposition and demographics presented in this section includes all patients enrolled to the study (98) and all infused patients (80) (Main Cohort + Cohort 1). No patients were enrolled in Cohort 2.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Tisagenlecleucel was administered as a single iv infusion. Dose: 2.0 to 5.0x10\^6 tisagenlecleucel per kg body weight (for patients ≤ 50 kg) or 1.0 to 2.5x10\^8 tisagenlecleucel (for patients \>50 kg).
Childrens Hospital Los Angeles SC CTL019
Los Angeles, California, United States
Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.
Evaluating the efficacy of tisagenlecleucel therapy from all manufacturing facilities as measured by overall remission rate (ORR) during the 3 months after tisagenlecleucel administration. ORR included complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by an Independent Review Committee assessment. Per response criteria defined by National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH) and International Working Group (IWG) guidelines. CR is defined as: Bone marrow \<5% blasts, Peripheral blood: Neutrophils \>1.0 x 10\^9/L, and Platelets \>100 x 10\^9/L and Circulating blasts \<1% and No evidence of extramedullary disease, at least 7 days transfusion independency. CRi is defined as all the prior criteria being met, except that the following exists: Neutrophils ≤1.0 x 10\^9/L, and/or Platelets ≤100 x 10\^9/L, and/or Platelet and/or neutrophil transfusions ≤7 days before the date of the peripheral blood sample for disease assessment.
Time frame: during the 3 months after tisagenlecleucel administration
Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary)
These are the percentage of participants with ORR who achieved overall remission rate which includes complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by IRC assessment after having been infused with tisagenlecleucel from US manufacturing facilities.
Time frame: 3 months after tisagenlecleucel administration
Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From US Manufacturing Facility as Per IRC in the Main Cohort Only (Key Secondary)
These are the percentage of participants who achieved Best Overall Response (BOR) of complete response (CR) or complete response with incomplete blood count recovery (CRi) with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from US manufacturing facilities only, by IRC assessment.
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Stanford Universtiy Medical Center SC - CTL019B2205J - B2206
Stanford, California, United States
Children's Healthcare of Atlanta SC CTL019
Atlanta, Georgia, United States
University of Michigan .
Ann Arbor, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
Children s Mercy Hospital SC - CTL019B2205J
Kansas City, Missouri, United States
Duke Unversity Medical Center .
Durham, North Carolina, United States
Oregon Health and Science University Doernbecher Children's Hosp.
Portland, Oregon, United States
The Childrens Hospital of Philadelphia CHOP
Philadelphia, Pennsylvania, United States
University of Texas Southwestern Medical Center .
Dallas, Texas, United States
...and 13 more locations
Time frame: 3 months after tisagenlecleucel administration
Percentage of Participants With Best Overall Response (BOR) of CR or CRi With MRD Negative Bone Marrow by Flow Cytometry From All Manufacturing Facilities as Per IRC in the Main Cohort Only (Key Secondary)
These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from all manufacturing facilities by IRC assessment. MRD negative = MRD% \< 0.01%
Time frame: 3 months after tisagenlecleucel administration
Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT)
These are the participants who achieved CR or CRi without HSCT between tisagenlecleucel (CTL019) infusion and Month 6 response assessment.
Time frame: 6 months after tisagenlecleucel administration
Percentage of Participants Who Achieved CR or CRi and Then Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) While in Remission Prior to Month 6 Resoonse
These are the participants who achieved CR or CRi and then proceeded to HSCT while in remission prior to Month 6 response assessment
Time frame: 6 months
Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion
These are the participants who achieved CR or CRi and then proceeded to SCT after being infused by tisagenlecleucel.
Time frame: up to 6 months
Duration of Remission (DOR)
DOR is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death.
Time frame: 60 months
Site of Involvement of Subsequent Relapse
Anatomical location of relapse in participants who achieved prior CR/CRi subsequent to tisagenlecleucel infusion.
Time frame: 60 months
Relapse-free Survival Per IRC Assessment
RFS is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death due to any cause during CR or CRi.
Time frame: 60 months
Event-free Survival Per IRC Assessment
EFS is the time from date of tisagenlecleucel infusion to the earliest of death, relapse or treatment failure.
Time frame: 60 months
Overall Survival (OS)
OS, is the time from date of tisagenlecleucel infusion to the date of death due to any reason.
Time frame: 60 months
Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment
These are participants who had a day 28 response (CR or CRi response) by IRC assessment.
Time frame: 1 month
Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only
Percentage of participants who achieved BOR of CR or CRi by flow cytometry as a function of baseline bone marrow tumor burden.
Time frame: 3 months
Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment
Percentage of participants who achieved CR or CRi response with bone marrow MRD negative (MRD \< 0.01%) after tisagenlecleucel infusion by flow cytometry.
Time frame: 28 days
Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment
This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in peripheral blood.
Time frame: Month 60
Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment
This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in bone marrow.
Time frame: Month 6
Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment
This is the summary cellular kinetic concentrations for CTL019 by flow cytometry in peripheral blood. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 60 for peripheral blood.
Time frame: Month 60
Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment
This is the summary cellular kinetic concentrations for CTL019 by flow cytometry. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 6 for bone marrow.
Time frame: Month 6
Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC
Cmax is the maximum (peak) observed in peripheral blood drug concentration after single dose administration reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint 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) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC
Tmax is the time to reach maximum (peak) peripheral blood drug concentration after single dose administration (days)", reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint 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) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC
AUC (area under curve) from day of infusion to day 28 or other disease assessment days, in peripheral blood (% or copies/μg x days), reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas 84 days is the actual timepoint for endpoint assessment. : AUC is defined based on the time window i.e., AUC from 0 to 84 days after infusion. Therefore, the time frame specifies the maximum time for up to which the data are used for estimation of AUC (84 days for AUC84d).
Time frame: 0 to 84 days after infusion
Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC
Persistence is defined as the time corresponding to last quantifiable transgene level in peripheral blood (Tlast), reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment.
Time frame: 60 months
Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019)
This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by CR/CRi, no response (NR), Unknown and by All participants. .
Time frame: At any time post-baseline, up to a max. of 60 months
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire
The PedsQL questionnaire was for patients ≥ 8-years-old who achieved BOR as CR or CRi within 3 months and the questionnaire was on emotional, social, school, physical, and psychosocial health. Scores are transformed on a scale from 0 to 100, with the sum of all the items over the number of items answered on all the scales. The total scale score is the averaged value of scores of subscales, which means for each subscale and the total scale, the allowed ranges are 0-100. Higher scores on the PedsQL questionnaire for these subscales indicate consistent improvement of health-related quality of life (HRQol).
Time frame: Month 3, M6, M12, M24, M60
Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire
Results from the EQ-5D questionnaire is for number of participants who achieved CR or CRi at month 60. The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain \& discomfort, anxiety \& depression. Respondents are asked to choose the statement in each dimension that best describes their health status on the day surveyed. Their responses are coded as a number (1, 2, or 3) that corresponds to the respective level of severity: 1 indicates no problems, 2 some problems, and 3 severe problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes the patient's health state. The scores are then normalized to a value from 0-100 where higher scores = better HRQOL \& fewer problems or symptoms.
Time frame: Month 60
Develop a Score Utilizing Clinical and Biomarker Data and Assess Its Ability for Early Prediction of Cytokine Release Syndrome (CRS)
Derivation of a score to predict cytokine release syndrome. Considering the complexity and challenges of building a scoring system based on limited data from the trial, this analysis was not performed.
Time frame: 3 months
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin)
Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).
Time frame: Maximum post-baseline (approx. 60 months)
Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers)
Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).
Time frame: Maximum post-baseline (approx. 60 months)
Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion
Levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring
Time frame: Month 3, Month 12, Maximum post-baseline (approx. 60 months)
Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility
These are the percentage of participants with ORR who achieved overall remission rate which includes complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by IRC assessment after having been infused with tisagenlecleucel from Fraunhofer Institute manufacturing facility.
Time frame: 60 months
Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From Fraunhofer Institute Manufacturing Facility as Per IRC
These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from Fraunhofer Institute manufacturing facilities only, by IRC assessment.
Time frame: 3 months
Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute
This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR, by disease response in blood by IRC assessment. The assessment of the efficacy, safety and in vivo cellular pharmacokinetics are for patients infused with tisagenlecleucel manufactured by Fraunhofer Institute.
Time frame: Month 60
Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute
This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR, by disease response in bone marrow by IRC assessment. The assessment of the efficacy, safety and in vivo cellular pharmacokinetics are for patients infused with tisagenlecleucel manufactured by Fraunhofer Institute.
Time frame: Month 3