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

NCT03610724

Description:

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.

Related Conditions:
  • B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
  • Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Mediastinal Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients
  • Official 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)

Clinical Trial IDs

  • ORG STUDY ID: CCTL019C2202
  • NCT ID: NCT03610724

Conditions

  • Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
TisagenlecleucelTisagenlecleucel

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
TisagenlecleucelExperimentalCAR-positive viable T cells infusion
  • Tisagenlecleucel

Eligibility Criteria

        Inclusion Criteria:

          -  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:

               1. Absolute neutrophil count (ANC) >1000/mm3

               2. Absolute lymphocyte count (ALC) >300/mm3

               3. absolute number of CD3+ T cells >150/mm3

               4. Platelets ≥50000//mm3

               5. 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.

        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.

          -  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.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:3 months post-tisagenlecleucel infusion or discontinued earlier
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description: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.
Measure:Event free survival (EFS)
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description: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.
Measure:Relapse free survival (RFS)
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.
Measure:Cmax
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:The maximum (peak) transgene level (copies/μg) observed in peripheral blood or other body fluid after single dose administration
Measure:Tmax
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration
Measure:AUCs
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/μg)
Measure:Clast
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:The last observed quantifiable transgene level in peripheral blood (copies/μg)
Measure:Tlast
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:The time of last observed quantifiable transgene level in peripheral blood (days)
Measure:Levels of pre-existing and treatment induced humoral immunogenicity and cellular immunogenicity against tisagenlecleucel safety and efficacy
Time Frame:Until disease progression or through study completion, approximately 4 years
Safety Issue:
Description: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.
Measure:Subjects that proceed to stem cell transplant (SCT) after tisagenlecleucel infusion until end of study (EOS)
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description:Percentage of subjects who proceed to transplant post-tisagenlecleucel therapy until EOS
Measure:Levels of cytokines for early prediction of cytokine release syndrome (CRS) utilizing clinical and biomarker data
Time Frame:Through study completion, approximately 4 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Tisagenlecleucel
  • relapsed/refractory B-cell non-Hodgkin lymphoma
  • pediatric patients
  • Burkitt's lymphoma (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

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