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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03610724
Registration number
NCT03610724
Ethics application status
Date submitted
13/07/2018
Date registered
1/08/2018
Date last updated
21/03/2024
Titles & IDs
Public title
Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients
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Scientific title
A Phase II, Single Arm, Multicenter Open Label Trial to Determine the Safety and Efficacy of Tisagenlecleucel in Pediatric Subjects With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma (NHL)
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Secondary ID [1]
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2017-005019-15
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Secondary ID [2]
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CCTL019C2202
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Universal Trial Number (UTN)
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Trial acronym
BIANCA
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Non-Hodgkin Lymphoma
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Condition category
Condition code
Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Tisagenlecleucel
Treatment: Drugs - lymphodepleting chemotherapy
Treatment: Drugs - Bridging Therapy
Experimental: Tisagenlecleucel - Participants were infused once with CAR-positive viable T cells
Other interventions: Tisagenlecleucel
Tisagenlecleucel was infused once as an intravenous infustion at a dose of either 0.2 to 5 x 106 CAR-positive viable T cells per kg body weight for subjects = 50 kg or 0.1 to 2.5 x 108 CAR-positive viable T cells for subjects > 50 kg.
Treatment: Drugs: lymphodepleting chemotherapy
Prior to tisagenlecleucel infusion, each subject underwent lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)
Treatment: Drugs: Bridging Therapy
Pre-treatment phase could also include bridging therapy of investigator's choice
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Intervention code [1]
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Other interventions
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Intervention code [2]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Response Rate (ORR) as Determined by Local Investigator
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Assessment method [1]
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The overall response rate (ORR) is defined as the percentage of subjects with a best overall disease response of complete response (CR) or partial response (PR), where the best overall disease response is defined as the best disease response recorded from tisagenlecleucel infusion until progressive disease or start of new anticancer therapy, whichever comes first.
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Timepoint [1]
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6 months post-tisagenlecleucel infusion
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Secondary outcome [1]
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Duration of Response (DOR)
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Assessment method [1]
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Duration of response (DOR) is defined as the time from the date of first documented disease response (CR or PR) as determined by local investigator assessments to the date of first documented progression or death due to underlying cancer.
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Timepoint [1]
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Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
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Secondary outcome [2]
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Event Free Survival (EFS)
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Assessment method [2]
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Event free survival (EFS) is defined as the time from date of first tisagenlecleucel infusion to the earliest date of death from any cause, disease progression as determined by local investigator assessments, or starting new anticancer therapy for underlying cancer, excluding hematopoietic stem cell transplant (HSCT).
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Timepoint [2]
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Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
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Secondary outcome [3]
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Relapse Free Survival (RFS)
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Assessment method [3]
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Relapse free survival (RFS) is defined as the time from the date of first documented disease response (CR or PR) as determined by local investigator assessments to the date of first documented disease progression or death due to any cause.
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Timepoint [3]
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Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
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Secondary outcome [4]
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Progression Free Survival (PFS)
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Assessment method [4]
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Progression free survival (PFS) is defined as the time from the date of first tisagenlecleucel infusion to the date of first documented disease progression as determined by local investigator assessments or death due to any cause.
Progression is defined using the International non-Hodgkin Lymphoma Response Criteria. For a PET-based response, progressive disease is defined as a 4 or 5 on the 5 point scale with increased uptake compared to the nadir or new FDG-avid foci consistent with lymphoma. For a CT/MRI based response progressive disease is defined as a 25% increase in the SPD (sum of the products of two largest perpendicular diameters) of index lesions, or unequivocal progression in either non-index lesions or the spleen. Any new disease attributable to lymphoma would also constitute progressive disease.
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Timepoint [4]
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Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
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Secondary outcome [5]
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Overall Survival (OS)
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Assessment method [5]
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Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.
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Timepoint [5]
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Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
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Secondary outcome [6]
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Cellular Kinetics Parameter: Cmax
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Assessment method [6]
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The maximum (peak) transgene level (copies/µg) observed in peripheral blood or other body fluid after single dose administration as measured by qPCR. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.
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Timepoint [6]
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Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
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Secondary outcome [7]
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Cellular Kinetics Parameter: Tmax
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Assessment method [7]
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The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.
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Timepoint [7]
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Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
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Secondary outcome [8]
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Cellular Kinetics Parameter: AUC0-28d
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Assessment method [8]
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Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/µg), from day of infusion to day 28. D28 refers to the timepoint for definition of responder populations. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.
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Timepoint [8]
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0 to 28 days
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Secondary outcome [9]
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Cellular Kinetics Parameter: Clast
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Assessment method [9]
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The last observed quantifiable transgene level in peripheral blood. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.
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Timepoint [9]
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Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
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Secondary outcome [10]
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Cellular Kinetics Parameter: Tlast
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Assessment method [10]
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The time of last observed quantifiable transgene level in peripheral blood. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.
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Timepoint [10]
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Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
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Secondary outcome [11]
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Levels of Pre-existing and Treatment Induced Humoral Immunogenicity and Cellular Immunogenicity Against Tisagenlecleucel Cellular Kinetics, Safety and Efficacy
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Assessment method [11]
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The humoral immunogenicity assay measures the antibody titers specific to tisagenlecleucel prior to and following infusion by flow cytometry. A subject was only defined as positive for tisagenlecleucel treatment-induced or -boosted anti-mCAR19 antibodies when the anti-mCAR19 antibody median fluorescence intensity at any time post-infusion was at least 2.28-fold higher (for samples analyzed on or prior to 05-May-2021) or 2.38-fold higher (for samples analyzed on or after 06-May-2021) than pre-infusion levels for participants whose baseline status was positive (boosted) or if the baseline status was negative but any post-baseline interpretation was positive (induced).
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Timepoint [11]
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Until disease progression or through study completion, up to 4 years
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Secondary outcome [12]
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Percentage of Participants Who Proceeded to Stem Cell Transplant (SCT) After Tisagenlecleucel Infusion
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Assessment method [12]
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These participants proceeded to transplant any time post-tisagenlecleucel therapy until end of study (EOS).
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Timepoint [12]
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Through study completion, up to 4 years
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Secondary outcome [13]
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Maximum Positive Predictive Value (PPV)
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Assessment method [13]
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Retrospective assessment of potential cytokine release syndrome (CRS) predictive models considering also data from other CTL019 trials. The Positive Predictive Value (PVV) is the percentage of participants who actually had severe CRS out of all the cases where the prediction model predicts that severe CRS will occur. The maximum PPV is the highest value attained across all potential CRS predictive models.
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Timepoint [13]
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Through study completion, up to 4 years
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Eligibility
Key inclusion criteria
- Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL)
including the following subtypes; Burkitt lymphoma/ Burkitt leukemia (BL), diffuse
large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone
lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with B-cell NHL associated
with Nijmegen breakage syndrome will be allowed.
- Patients <25 years of age and weighing at least 6 kg at the time of screening
- Patients who have relapsed after one or more prior therapies (can include allogeneic
and autologous hematopoietic stem cell transplant) or are primary refractory (have not
achieved a CR or PR after the first line of therapy)
- Measurable disease by radiological criteria in all patients at the time of screening.
Patients with Burkitt leukemia who don't meet radiological criteria must have bone
marrow involvement of >25% by local assessment of bone marrow aspirate and/or biopsy.
- Karnofsky (age =16 years) or Lansky (age <16 years) performance status =60.
- Adequate bone marrow reserve without transfusions (transfusion >2 weeks prior to
laboratory assessment is allowed) defined as:
1. Absolute neutrophil count (ANC) >1000/mm3
2. Platelets =50000//mm3
3. Hemoglobin =8.0 g/dl
- Adequate organ function defined as:
1. a serum creatinine (sCR) based on gender/age as follows: Maximum Serum Creatinine
(mg/dL) Age Male Female
1 to <2 years 0.6 0.6 2 to <6 years 0.8 0.8 6 to <10 years 1.0 1.0 10 to <13
years 1.2 1.2 13 to <16 years 1.5 1.4
=16 years 1.7 1.4
2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =5 times the
upper limit of normal (ULN) for age
3. Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4
mg/dL)
4. Adequate pulmonary function
i. Oxygen saturation of >91% on room air ii. No or mild dyspnea (=Grade 1)
- Must have a leukapheresis material of non-mobilized cells accepted for manufacturing.
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Minimum age
No limit
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Maximum age
25
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Prior gene therapy or engineered T cell therapy.
- Prior treatment with any anti-CD19 therapy.
- Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and
=4 months prior to infusion.
- Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
in patients who received prior allogeneic HSCT.
- Prior diagnosis of malignancy other than study indication, and not disease free for 5
years.
- Clinically significant active infection confirmed by clinical evidence, imaging, or
positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
- Presence of active hepatitis B or C as indicated by serology.
- Human Immunodeficiency Virus (HIV) positive test.
- Active neurological autoimmune or inflammatory disorders not related to B cell NHL
(eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
- Active central nervous system (CNS) involvement by malignancy.
- Patients with B-cell NHL in the context of post-transplant lymphoproliferative
disorders (PTLD) associated lymphomas.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
15/02/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
26/04/2023
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Sample size
Target
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Accrual to date
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Final
34
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Randwick
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Recruitment hospital [2]
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Novartis Investigative Site - Parkville
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Recruitment postcode(s) [1]
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2031 - Randwick
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Recruitment postcode(s) [2]
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3052 - Parkville
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Recruitment outside Australia
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United States of America
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State/province [1]
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California
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United States of America
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Maryland
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United States of America
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Massachusetts
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United States of America
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New York
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United States of America
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Ohio
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United States of America
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Pennsylvania
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United States of America
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Texas
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Austria
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Wien
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Canada
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Ontario
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Denmark
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Copenhagen
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Finland
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Helsinki
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France
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Paris
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France
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Villejuif
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Germany
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Muenster
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Italy
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MB
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Italy
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RM
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Japan
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Kyoto
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Japan
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Tokyo
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Netherlands
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CS
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Norway
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Oslo
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Spain
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State/province [21]
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Catalunya
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Spain
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Madrid
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Country [23]
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United Kingdom
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State/province [23]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of the study was to assess the efficacy and safety of tisagenlecleucel in
pediatric, adolescent and young adult patients with relapsed/refractory B-cell non-Hodgkin
lymphoma (r/r B-NHL) including Burkitt Lymphoma and Burkitt Leukemia.
For pediatric patients who have r/r B-NHL including Burkitt Lymphoma and Burkitt Leukemia,
survival rates are dismal, only ~20-50% subjects are alive at 2 years with overall response
rate (ORR) of 20-30% after conventional salvage chemotherapy.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03610724
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Email
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03610724
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