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

• ClinicalTrials.gov Identifier: NCT03610724
• Recruitment Status: Active, not recruiting
• First Posted: August 1, 2018
• Last Update Posted: November 2, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: July 13, 2018
• First Posted Date: August 1, 2018
• Last Update Posted Date: November 2, 2022
• Actual Study Start Date: February 15, 2019
• Actual Primary Completion Date: July 27, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 25, 2018)

Overall response rate (ORR) [ Time Frame: 3 months post-tisagenlecleucel infusion or discontinued earlier ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 21, 2019)

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

Original Secondary Outcome Measures (submitted: July 25, 2018)

• Duration of response (DOR) [ Time Frame: Through study completion, approximately 4 years ]
  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.
• Event free survival (EFS) [ Time Frame: Through study completion, approximately 4 years ]
  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.
• Relapse free survival (RFS) [ Time Frame: Through study completion, approximately 4 years ]
  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.
• Progression free survival (PFS) [ Time Frame: Through study completion, approximately 4 years ]
  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.
• Overall survival (OS) [ Time Frame: Through study completion, approximately 4 years ]
  Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.
• Cmax [ Time Frame: Through study completion, approximately 4 years ]
  The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg)
• Tmax [ Time Frame: Through study completion, approximately 4 years ]
  The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)
• AUCs [ Time Frame: Through study completion, approximately 4 years ]
  Area Under the Concentration-time Curve (AUC) from Hour 0 to the Last Quantifiable Concentration (AUC0-t) of tisagenlecleucel, in peripheral blood (%×*days or days×*copies/μg)
• Clast [ Time Frame: Through study completion, approximately 4 years ]
  The last observed quantifiable concentration in peripheral blood (% or copies/μg)
• Tlast [ Time Frame: Through study completion, approximately 4 years ]
  The time of last observed quantifiable concentration in peripheral blood (days)
• Levels of pre-existing and treatment induced humoral/cellular immunogenicity antibody titers against tisagenlecleucel [ Time Frame: Through study completion, approximately 4 years ]
  The humoral/cellular immunogenicity assays measure the antibody titers specific to the tisagenlecleucel molecule prior to and following infusion by flow cytometry. The impact of these antibody titers on disease response, cellular kinetics and safety will be explored.
• Pre-existing and treatment induced efficacy [ Time Frame: until disease progression or through study completion, approximately 4 years ]
  Screening/Baseline, Month 3 (±14 days) response, until disease progression
• Subjects that proceed to stem cell transplant (SCT) after tisagenlecleucel infusion until end of study (EOS) [ Time Frame: Through study completion, approximately 4 years ]
  Percentage of subjects who proceed to transplant post-tisagenlecleucel therapy until EOS
• Levels of cytokines for early prediction of cytokine release syndrome (CRS) utilizing clinical and biomarker data [ Time Frame: Through study completion, approximately 4 years ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• Brief Summary: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Hodgkin Lymphoma

Intervention

• Biological: Tisagenlecleucel
  Single intravenous infusion
  Other Name: CTL019
• Drug: lymphodepleting chemotherapy
  Prior to tisagenlecleucel infusion, each subject should undergo lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)
• Drug: Bridging Therapy
  Pre-study treatment phase may also include bridging therapy of investigator's choice

Study Arms

Experimental: Tisagenlecleucel

CAR-positive viable T cells infusion

Interventions:

• Biological: Tisagenlecleucel
• Drug: lymphodepleting chemotherapy
• Drug: Bridging Therapy

• Publications *: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 4, 2022): 33
• Original Estimated Enrollment (submitted: July 25, 2018): 35
• Estimated Study Completion Date: April 7, 2023
• Actual Primary Completion Date: July 27, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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:

  1. Absolute neutrophil count (ANC) >1000/mm3
  2. Platelets ≥50000//mm3
  3. 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.
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, Denmark, Finland, France, Germany, Italy, Japan, Netherlands, Norway, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03610724
• Other Study ID Numbers: CCTL019C2202; 2017-005019-15 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

• URL: https://www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: October 2022