Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients
- Conditions
- Non-Hodgkin Lymphoma
- Interventions
- Biological: TisagenlecleucelDrug: lymphodepleting chemotherapyDrug: Bridging Therapy
- Registration Number
- NCT03610724
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
- Detailed Description
This study was part of an agreed Pediatric Investigation Plan (PIP). The single-arm study design included r/r B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia subject population with poor prognosis, lack of approved effective therapies in this setting. Subject population included aggressive subtypes of B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia who were allowed to receive "bridging therapy" of investigator's choice. After assessment of eligibility, subjects qualifying for the study were enrolled and were allowed to start lymphodepleting chemotherapy as recommended in protocol after which a single dose of tisagenlecleucel product was infused. The efficacy of tisagenlecleucel was evaluated through the primary endpoint of Overall Response Rate (ORR) which included complete response (CR) and partial response (PR) as determined by local assessment. Safety assessments were conducted until study completion.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 34
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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.
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Patients <25 years of age and weighing at least 6 kg at the time of screening
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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)
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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.
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Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status ≥60.
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Adequate bone marrow reserve without transfusions (transfusion >2 weeks prior to laboratory assessment is allowed) defined as:
- Absolute neutrophil count (ANC) >1000/mm3
- Platelets ≥50000//mm3
- Hemoglobin ≥8.0 g/dl
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Adequate organ function defined as:
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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
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Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age
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Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4 mg/dL)
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Adequate pulmonary function
i. Oxygen saturation of >91% on room air ii. No or mild dyspnea (≤Grade 1)
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Must have a leukapheresis material of non-mobilized cells accepted for manufacturing.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Tisagenlecleucel Tisagenlecleucel Participants were infused once with CAR-positive viable T cells Tisagenlecleucel Bridging Therapy Participants were infused once with CAR-positive viable T cells Tisagenlecleucel lymphodepleting chemotherapy Participants were infused once with CAR-positive viable T cells
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) as Determined by Local Investigator 6 months post-tisagenlecleucel infusion 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.
- Secondary Outcome Measures
Name Time Method Duration of Response (DOR) Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 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.
Overall Survival (OS) Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.
Cellular Kinetics Parameter: Cmax 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 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.
Cellular Kinetics Parameter: Clast 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 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.
Levels of Pre-existing and Treatment Induced Humoral Immunogenicity and Cellular Immunogenicity Against Tisagenlecleucel Cellular Kinetics, Safety and Efficacy Until disease progression or through study completion, up to 4 years 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).
Maximum Positive Predictive Value (PPV) Through study completion, up to 4 years 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.
Event Free Survival (EFS) Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 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).
Progression Free Survival (PFS) Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 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.Relapse Free Survival (RFS) Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 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.
Percentage of Participants Who Proceeded to Stem Cell Transplant (SCT) After Tisagenlecleucel Infusion Through study completion, up to 4 years These participants proceeded to transplant any time post-tisagenlecleucel therapy until end of study (EOS).
Cellular Kinetics Parameter: Tmax 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 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.
Cellular Kinetics Parameter: AUC0-28d 0 to 28 days 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.
Cellular Kinetics Parameter: Tlast 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 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.
Trial Locations
- Locations (11)
Childrens Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Johns Hopkins Oncology Center ORA
🇺🇸Baltimore, Maryland, United States
Cinn Children Hosp Medical Center
🇺🇸Cincinnati, Ohio, United States
Dana Farber Cancer Institute Dept.of DFCI
🇺🇸Boston, Massachusetts, United States
The Childrens Hospital of Philadelphia Drug Shipment
🇺🇸Philadelphia, Pennsylvania, United States
University of Texas Southwestern Medical Center .
🇺🇸Dallas, Texas, United States
Kyoto University Hospital
🇯🇵Sakyō-ku, Kyoto, Japan
UCSF Medical Center
🇺🇸San Francisco, California, United States
Memorial Sloan Kettering Cancer Center MSKCC (8)
🇺🇸New York, New York, United States
Novartis Investigative Site
🇬🇧London, United Kingdom
Prinses Maxima Centrum voor Kinderoncologie
🇳🇱Utrecht, CS, Netherlands