pediatric and adolescents patients with CD19positive r/r mature B-cell NHL who have relapsed after one or more prior therapies or are primary refractory. MedDRA version: 20.0 Level: HLGT Classification code 10025320 Term: Lymphomas non-Hodgkin's B-cell System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Sponsors
Novartis Farmacéutica, S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Signed informed consent and assent forms if applicable must be obtained prior to participation in the study. 2.Histologically confirmed (local evaluation) 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). a.Note: Subjects 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. b.Sufficient formalin-fixed, paraffin-embedded (FFPE) tumor sample must be available for correlative analyses. A recent tumor sample obtained for the purpose of the study must be submitted, however if not clinically feasible, an archival tumor biopsy from the most recent relapse may be submitted instead. Excisional biopsies should be submitted wherever possible; in cases where this is not possible a core needle biopsy is allowed. Fine needle aspiration (FNA) is not suitable. 3.Patients 2 weeks prior to laboratory assessment is allowed) defined as: a.Absolute neutrophil count (ANC) >1000/mm3 b.Absolute lymphocyte count (ALC) >300/mm3 c.absolute number of CD3+ T cells >150/mm3 d.Platelets more or equal to 50000//mm3 e.Hemoglobin more or equal to 8.0 g/dl 8.Adequate organ function: a.a serum creatinine (sCR) based on gender/age as described in detail the protocol b.AST (aspartate aminotransferase) and ALT (alanine aminotransferase)less or equal to 5 times the upper limit of normal (ULN) for age. c.Bilirubin 91% on room air. ii.No or mild dyspnea ( less or equal to Grade 1) 9.Must have a leukapheresis material of non-mobilized cells accepted for manufacturing. Note: Leukapheresis material will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other eligibility criteria is received. Other protocol-defined inclusion criteria may apply. Are the trial subjects under 18? yes Number of subjects for this age range: 35 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.Prior gene therapy or engineered T cell therapy 2.Prior treatment with any anti-CD19 therapy 3.Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and less or equal than 4 months prior to infusion 4.Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT. 5.Prior diagnosis of malignancy other than study indication, and not disease free for 5 years 6.Active, uncontrolled infection despite treatment at screening 7.Presence of active or prior hepatitis B or C as indicated by serology. Repeat serology is required if the interval between serology performed at screening and tisagenlecleucel infusion exceeds 8 weeks. 8.Human Immunodeficiency Virus (HIV) positive test. Repeat serology is required if the interval between serology performed at screening and tisagenlecleucel infusion exceeds 8 weeks 9.Active neurological autoimmune or inflammatory disorders not related to B cell NHL (e.g., Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis) 10.Active CNS involvement by malignancy. Note: Patients with history of CNS disease that have been effectively treated will be eligible. 11.Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders (PTLD) associated lymphomas. 12.Patients with concomitant genetic syndromes associated with bone marrow failure status such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Note: Patients with Down syndrome will not be excluded. 13.Intolerance to the excipients of the tisagenlecleucel cell product 14.Cardiac disorder defined as: a.Cardiac or cardiac repolarization abnormality, including any of the following: i.History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment ii.Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) b.LVEF <45% as determined by ECHO or MRA or MUGA c.NYHA functional class III or IV 15.Subjects enrolled in this study are not permitted to participate in additional parallel investigational drug or device studies 16.Pregnant or nursing (lactating) women. Note: Women of child-bearing potential must have a negative serum pregnancy test performed at screening, within 24 hours prior to leukapheresis, within 24 hours prior to lymphodepletion Serum or urine, within 24 hours prior to tisagenlecleucel infusion and at EOS. 17.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. 18.Sexually active males who do not agree to use a condom during intercourse while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. Other protocol-defined exclusion criteria may apply.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluate the efficacy of tisagenlecleucel therapy as measured by ORR and determined by local investigator assessments in subjects with aggressive r/r B-cell NHL.;Secondary Objective: 1-Evaluate the duration of response (DOR) 2-Evaluate event free survival (EFS) 3-Evaluate relapse free survival (RFS) 4-Evaluate progression free survival (PFS) 5-Evaluate overall survival (OS) 6-Evaluate the safety of tisagenlecleucel therapy 7-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. 8-Characterize the presence of pre-existing and treatment induced immunogenicity and impact on cellular kinetics and response 9-Assess the proportion of subjects who proceed to transplant post-tisagenlecleucel therapy until end of study. 10-Retrospective assessment of potential CRS predictive models considering also data from other CTL019 trials;Primary end point(s): Overall response rate (ORR), which includes complete response (CR) and partial response (PR) determined by local investigator assessments.;Timepoint(s) of evaluation of this end point: as defined per protocol | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1-DOR 2-EFS 3-RFS 4-PFS 5-OS 6- Physical examination, vital signs, adverse events, , laboratory abnormalities, performance status and as applicable physical development 7- Cellular kinetics parameters and/or other relevant parameters in peripheral blood, bone marrow, lymph nodes, cerebrospinal fluid and other tissues as appropriate, month 3 response, safety endpoint (CRS grade). 8-Levels of pre-existing and treatment induced immunogenicity, cellular kinetic parameters, and efficacy (Month 3 response) 9-Number of subjects that proceed to SCT after tisagenlecleucel infusion until EOS will be described 10-Assess the ability for early prediction of cytokine release syndrome utilizing clinical and biomarker data;Timepoint(s) of evaluation of this end point: as defined per protocol | — |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Italy, Japan, Netherlands, Norway, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactTrial Monitoring Organization (TMO)
Novartis Farmacéutica, S.A.
Outcome results
None listed