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Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients (BIANCA)
Study ID: STU 072018-038
This study is part of an agreed Pediatric Investigation Plan (PIP). The single-arm study design includes r/r B-cell NHL subject population with poor prognosis, lack of approved effective therapies in this setting. Subject population will include aggressive subtypes of B-cell NHL and will be allowed to receive "bridging therapy" of investigator's choice After assessment of eligibility, subjects qualifying for the study will be enrolled and are allowed to start lymphodepleting chemotherapy as recommended in protocol after which a single dose of tisagenlecleucel product will be infused. The efficacy of tisagenlecleucel will be evaluated through the primary endpoint of Overall Response Rate (ORR) which includes complete response (CR) and partial response (PR) as determined by local assessment. Safety assessments will be conducted through the study completion.
- Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with bone marrow involvement of >25% lymphoma cells by bone marrow biopsy/aspirate evaluation, will be excluded. Patients with B-cell NHL associated with Nijmegen breakage syndrome will be allowed.
- Patients <18 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.
- 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:
- Absolute neutrophil count (ANC) >1000/mm3
- Absolute lymphocyte count (ALC) >300/mm3
- absolute number of CD3+ T cells >150/mm3
- Platelets ≥50000//mm3
- Hemoglobin ≥8.0 g/dl
- Adequate organ function defined as:
- 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
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age
- Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4 mg/dL)
- 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.
- 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.
- Active, uncontrolled infection despite treatment at screening.
- Presence of active or prior 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.
Other protocol-defined inclusion/exclusion criteria may apply.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- THEODORE W LAETSCH
NOVARTIS PHARMACEUTICALS CORPORATION
For the 10-20% of pediatric subjects who have r/r B-cell nHL, survival rates are dismal, only ~20-50% subjects are alive at 2 years with oRR of 20-30% after conventional salvage chemotherapy. Patients who respond to rituximab based chemotherapy (R-iCe), benefit from a subsequent transplant and achieve modest survival advantage (~30-50% eFS at 5 years). However, those patients who are r/r to R-iCe (~40%) are not candidates for a transplant and have median overall survival of only 2.5 months. The purpose of the study is to assess the efficacy and safety of tisagenlecleucel in children and adolescents with r/r B-cell nHL. Primary objective: evaluate the efficacy of tisagenlecleucel therapy as measured by oRR and determined by local investigator assessments in subjects with aggressive r/r Bcell nHL (efficacy of tisagenlecleucel therapy in subjects with follicular lymphoma (FL) is an exploratory objective) endpoint for primary objective: overall response rate (oRR), which includes complete response (CR) and partial response (PR) determined by local investigator assessments. Secondary objectives: * *evaluate the duration of response (DoR) in subjects with aggressive r/r B-cell nHL *evaluate event free survival (eFS) in subjects with aggressive r/r B-cell nHL evaluate relapse free survival (RFS) in subjects with aggressive r/r B-cell nHL *evaluate progression free survival (PFS) in subjects with aggressive r/r B-cell nHL *evaluate overall survival (oS) in subjects with aggressive r/r B-cell nHL *evaluate the safety of tisagenlecleucel therapy *Characterize the in vivo cellular kinetics (levels, expansion, persistence) of tisagenlecleucel cells into target tissues (blood, bone marrow, lymph nodes, cerebral spinal fluid and other tissues if available), as measured by qPCR in relation to safety and efficacy Characterize the presence of pre-existing and treatment induced immunogenicity and impact on cellular kinetics and response * *assess the proportion of subjects who proceed to transplant posttisagenlecleucel therapy until end of study (eoS) *Retrospective assessment of potential CRS predictive models considering also data from other CTL019 trials exploratory objectives: *explore the efficacy among subjects with follicular lymphoma (FL) and subtypes of DLBCL *explore relationship between biomarker expression in tumor biopsy specimens and clinical response *Describe the composition of T-cell subsets (immunophenotyping in peripheral blood), summarized by clinical response