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

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ClinicalTrials.gov Identifier: NCT03610724
Recruitment Status : Recruiting
First Posted : August 1, 2018
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma Biological: Tisagenlecleucel Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 15, 2019
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : February 15, 2023


Arm Intervention/treatment
Experimental: Tisagenlecleucel
CAR-positive viable T cells infusion
Biological: Tisagenlecleucel
Single intravenous infusion




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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)

  9. Clast [ Time Frame: Through study completion, approximately 4 years ]
    The last observed quantifiable transgene level in peripheral blood (copies/μg)

  10. Tlast [ Time Frame: Through study completion, approximately 4 years ]
    The time of last observed quantifiable transgene level in peripheral blood (days)

  11. 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.

  12. 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

  13. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03610724


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 srivani.konduri@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Shannon Drown    323-660-2450    sdrown@chla.usc.edu   
Principal Investigator: Michael Pulsipher         
United States, Georgia
Childrens Healthcare of Atlanta At Scottish Rite Recruiting
Atlanta, Georgia, United States, 30342
Contact: Pauline Newlands    *unknown*    aflacga@choa.org   
Principal Investigator: Muna Qayed         
United States, Maryland
Johns Hopkins Oncology Center ORA Recruiting
Baltimore, Maryland, United States, 21231
Contact: Genevieve Courpas    410-955-8817    Gcourpa1@jhmi.edu   
Principal Investigator: Patrick Brown         
United States, New York
Memorial Sloan Kettering Cancer Center MSKCC (8) Recruiting
New York, New York, United States, 10065
Contact: Kathryn Pickens    646-888-4234    pickensk@mskcc.org   
Principal Investigator: Kevin Curran         
United States, Ohio
Cincinnati Children s Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-3039
Contact: Courtney Blank    800-344-2462    courtney.blank@cchmc.org   
Principal Investigator: Christine Phillips         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75235
Contact: Yolanda Burnom    214-456-2382    yolanda.burnom@childrens.com   
Principal Investigator: Theodore Laetsch         
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact    608-890-8070      
Principal Investigator: Christian Capitini         
Austria
Novartis Investigative Site Recruiting
Wien, Austria, A 1090
Canada, Ontario
Novartis Investigative Site Recruiting
Toronto, Ontario, Canada, M5G 1X8
France
Novartis Investigative Site Recruiting
Paris Cedex, France, 75019
Novartis Investigative Site Recruiting
Villejuif Cedex, France, 94805
Japan
Novartis Investigative Site Recruiting
Sakyo Ku, Kyoto, Japan, 606 8507
Netherlands
Novartis Investigative Site Recruiting
Utrecht, CS, Netherlands, 3584
Spain
Novartis Investigative Site Recruiting
Barcelona, Barcelona/ Cataluny/Espanya, Spain, 08035
Novartis Investigative Site Recruiting
Madrid, Spain, 28046
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03610724     History of Changes
Other Study ID Numbers: CCTL019C2202
First Posted: August 1, 2018    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019
Individual Participant Data (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

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

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases