Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients

Study Overview
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Brief Summary
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The purpose of the study is to assess the efficacy and safety of tisagenlecleucel in children and adolescents with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). For pediatric patients who have r/r B-NHL, 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
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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.

Official Title
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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)

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Tisagenlecleucel
* Drug: lymphodepleting chemotherapy
* Drug: Bridging Therapy


Participation Criteria
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Eligibility Criteria
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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: Absolute neutrophil count (ANC) >1000/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. 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. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tisagenlecleucel<br>CAR-positive viable T cells infusion | Biological: Tisagenlecleucel<br>* Single intravenous infusion<br>* Other names: CTL019;Drug: lymphodepleting chemotherapy<br>* Prior to tisagenlecleucel infusion, each subject should undergo lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)<br>Drug: Bridging Therapy<br>* Pre-study treatment phase may also include bridging therapy of investigator's choice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The overall response rate (ORR) is defined as the proportion of subjects 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 tisagenlecleucel infusion until progressive disease or start of new anticancer therapy, whichever comes first. | 3 months post-tisagenlecleucel infusion or discontinued earlier | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | 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. | Through study completion, approximately 4 years | 
| Event free survival (EFS) | 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 HSCT. | Through study completion, approximately 4 years | 
| Relapse free survival (RFS) | 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. | Through study completion, approximately 4 years | 
| Progression free survival (PFS) | 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. | Through study completion, approximately 4 years | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause. | Through study completion, approximately 4 years | 
| Cmax | The maximum (peak) transgene level (copies/μg) observed in peripheral blood or other body fluid after single dose administration | Through study completion, approximately 4 years | 
| Tmax | The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration | Through study completion, approximately 4 years | 
| AUCs | Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/μg) | Through study completion, approximately 4 years | 
| Clast | The last observed quantifiable transgene level in peripheral blood (copies/μg) | Through study completion, approximately 4 years | 
| Tlast | The time of last observed quantifiable transgene level in peripheral blood (days) | Through study completion, approximately 4 years | 
| Levels of pre-existing and treatment induced humoral immunogenicity and cellular immunogenicity against tisagenlecleucel cellular kinetics, safety and efficacy | The humoral immunogenicity assay measures the antibody titers specific to tisagenlecleucel prior to and following infusion by flow cytometry. The impact of humoral and cellular immunogenicity on cellular kinetics, safety and disease response will be explored. | Until disease progression or through study completion, approximately 4 years | 
| Subjects that proceed to stem cell transplant (SCT) after tisagenlecleucel infusion until end of study (EOS) | Percentage of subjects who proceed to transplant post-tisagenlecleucel therapy until EOS | Through study completion, approximately 4 years | 
| Levels of cytokines for early prediction of cytokine release syndrome (CRS) utilizing clinical and biomarker data | Retrospective assessment of potential CRS predictive models considering also data from other CTL019 trials. Soluble immune and inflammatory cytokines (eg: IL-10, interferon gamma, IL-6, CRP, and ferritin) will be measured. These levels may also be summarized by severity of CRS and potentially graphed using strip plots. | Through study completion, approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tisagenlecleucel, relapsed/refractory B-cell non-Hodgkin lymphoma, pediatric patients, Burkitt lymphoma (BL), Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), follicular lymphoma (FL), leukapheresis, lymphodepleting chemotherapy (LD), NHL