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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03610724
Collaborator
(none)
33
26
1
49.7
1.3
0

Study Details

Study Description

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

Study Design

Study Type:
Interventional
Actual Enrollment :
33 participants
Allocation:
N/A
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 :
Feb 15, 2019
Actual Primary Completion Date :
Jul 27, 2021
Anticipated Study Completion Date :
Apr 7, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Tisagenlecleucel

CAR-positive viable T cells infusion

Biological: Tisagenlecleucel
Single intravenous infusion
Other Names:
  • 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

    Outcome Measures

    Primary Outcome Measures

    1. Overall response rate (ORR) [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) [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) [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) [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) [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) [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 [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 [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 [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 [Through study completion, approximately 4 years]

      The last observed quantifiable transgene level in peripheral blood (copies/μg)

    10. Tlast [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 [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) [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 [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 25 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age

    2. Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4 mg/dL)

    3. Adequate pulmonary function

    1. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Childrens Hospital Los Angeles Los Angeles California United States 90027
    2 UCSF Medical Center San Francisco California United States 94143
    3 Johns Hopkins Oncology Center ORA Baltimore Maryland United States 21231
    4 Dana Farber Cancer Institute Dept.of DFCI Boston Massachusetts United States 02215
    5 Memorial Sloan Kettering Cancer Center MSKCC (8) New York New York United States 10065
    6 Cincinnati Children s Hospital Medical Center Cincinnati Ohio United States 45229-3039
    7 The Childrens Hospital of Philadelphia Drug Shipment Philadelphia Pennsylvania United States 19104
    8 University of Texas Southwestern Medical Center Dallas Texas United States 75235
    9 Novartis Investigative Site Randwick New South Wales Australia 2031
    10 Novartis Investigative Site Parkville Victoria Australia 3052
    11 Novartis Investigative Site Wien Austria A 1090
    12 Novartis Investigative Site Toronto Ontario Canada M5G 1X8
    13 Novartis Investigative Site Copenhagen Denmark 2100
    14 Novartis Investigative Site Helsinki Finland 00029
    15 Novartis Investigative Site Paris Cedex France 75019
    16 Novartis Investigative Site Villejuif Cedex France 94800
    17 Novartis Investigative Site Muenster Germany 48149
    18 Novartis Investigative Site Monza MB Italy 20900
    19 Novartis Investigative Site Roma RM Italy 00165
    20 Kyoto University Hospital Sakyo Ku Kyoto Japan 606 8507
    21 Novartis Investigative Site Setagaya-ku Tokyo Japan 157-8535
    22 Prinses Maxima Centrum voor Kinderoncologie Utrecht CS Netherlands 3584
    23 Novartis Investigative Site Oslo Norway 0424
    24 Novartis Investigative Site Barcelona Catalunya Spain 08035
    25 Novartis Investigative Site Madrid Spain 28046
    26 Novartis Investigative Site London United Kingdom WC1N 1EH

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT03610724
    Other Study ID Numbers:
    • CCTL019C2202
    • 2017-005019-15
    First Posted:
    Aug 1, 2018
    Last Update Posted:
    Jul 19, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 19, 2022