search
Back to results

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

Primary Purpose

Non-Hodgkin Lymphoma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tisagenlecleucel
lymphodepleting chemotherapy
Bridging Therapy
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-Hodgkin Lymphoma focused on measuring Tisagenlecleucel, relapsed/refractory B-cell non-Hodgkin lymphoma, pediatric patients, Burkitt lymphoma (BL), Burkitt leukemia (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

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Childrens Hospital Los Angeles
  • UCSF Medical Center
  • Johns Hopkins Oncology Center ORA
  • Dana Farber Cancer Institute Dept.of DFCI
  • Memorial Sloan Kettering Cancer Center MSKCC (8)
  • Cinn Children Hosp Medical Center
  • The Childrens Hospital of Philadelphia Drug Shipment
  • University of Texas Southwestern Medical Center .
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Kyoto University Hospital
  • Novartis Investigative Site
  • Prinses Maxima Centrum voor Kinderoncologie
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tisagenlecleucel

Arm Description

CAR-positive viable T cells infusion

Outcomes

Primary Outcome Measures

Overall response rate (ORR)
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

Duration of response (DOR)
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)
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)
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)
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)
Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.
Cmax
The maximum (peak) transgene level (copies/μg) observed in peripheral blood or other body fluid after single dose administration
Tmax
The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration
AUCs
Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/μg)
Clast
The last observed quantifiable transgene level in peripheral blood (copies/μg)
Tlast
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
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)
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
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.

Full Information

First Posted
July 13, 2018
Last Updated
July 5, 2023
Sponsor
Novartis Pharmaceuticals
search

1. Study Identification

Unique Protocol Identification Number
NCT03610724
Brief Title
Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients
Acronym
BIANCA
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)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
February 15, 2019 (Actual)
Primary Completion Date
July 27, 2021 (Actual)
Study Completion Date
April 26, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Hodgkin Lymphoma
Keywords
Tisagenlecleucel, relapsed/refractory B-cell non-Hodgkin lymphoma, pediatric patients, Burkitt lymphoma (BL), Burkitt leukemia (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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
33 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tisagenlecleucel
Arm Type
Experimental
Arm Description
CAR-positive viable T cells infusion
Intervention Type
Biological
Intervention Name(s)
Tisagenlecleucel
Other Intervention Name(s)
CTL019
Intervention Description
Single intravenous infusion
Intervention Type
Drug
Intervention Name(s)
lymphodepleting chemotherapy
Intervention Description
Prior to tisagenlecleucel infusion, each subject should undergo lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)
Intervention Type
Drug
Intervention Name(s)
Bridging Therapy
Intervention Description
Pre-study treatment phase may also include bridging therapy of investigator's choice
Primary Outcome Measure Information:
Title
Overall response rate (ORR)
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.
Time Frame
3 months post-tisagenlecleucel infusion or discontinued earlier
Secondary Outcome Measure Information:
Title
Duration of response (DOR)
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.
Time Frame
Through study completion, approximately 4 years
Title
Event free survival (EFS)
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.
Time Frame
Through study completion, approximately 4 years
Title
Relapse free survival (RFS)
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.
Time Frame
Through study completion, approximately 4 years
Title
Progression free survival (PFS)
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.
Time Frame
Through study completion, approximately 4 years
Title
Overall survival (OS)
Description
Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.
Time Frame
Through study completion, approximately 4 years
Title
Cmax
Description
The maximum (peak) transgene level (copies/μg) observed in peripheral blood or other body fluid after single dose administration
Time Frame
Through study completion, approximately 4 years
Title
Tmax
Description
The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration
Time Frame
Through study completion, approximately 4 years
Title
AUCs
Description
Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/μg)
Time Frame
Through study completion, approximately 4 years
Title
Clast
Description
The last observed quantifiable transgene level in peripheral blood (copies/μg)
Time Frame
Through study completion, approximately 4 years
Title
Tlast
Description
The time of last observed quantifiable transgene level in peripheral blood (days)
Time Frame
Through study completion, approximately 4 years
Title
Levels of pre-existing and treatment induced humoral immunogenicity and cellular immunogenicity against tisagenlecleucel cellular kinetics, safety and efficacy
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.
Time Frame
Until disease progression or through study completion, approximately 4 years
Title
Subjects that proceed to stem cell transplant (SCT) after tisagenlecleucel infusion until end of study (EOS)
Description
Percentage of subjects who proceed to transplant post-tisagenlecleucel therapy until EOS
Time Frame
Through study completion, approximately 4 years
Title
Levels of cytokines for early prediction of cytokine release syndrome (CRS) utilizing clinical and biomarker data
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.
Time Frame
Through study completion, approximately 4 years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
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: Absolute neutrophil count (ANC) >1000/mm3 Platelets ≥50000//mm3 Hemoglobin ≥8.0 g/dl Adequate organ function defined as: 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 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN) for age Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4 mg/dL) 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Childrens Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
UCSF Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Johns Hopkins Oncology Center ORA
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
Dana Farber Cancer Institute Dept.of DFCI
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center MSKCC (8)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Cinn Children Hosp Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
The Childrens Hospital of Philadelphia Drug Shipment
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
University of Texas Southwestern Medical Center .
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Novartis Investigative Site
City
Randwick
State/Province
New South Wales
ZIP/Postal Code
2031
Country
Australia
Facility Name
Novartis Investigative Site
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Facility Name
Novartis Investigative Site
City
Wien
ZIP/Postal Code
A 1090
Country
Austria
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Novartis Investigative Site
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
Novartis Investigative Site
City
Helsinki
ZIP/Postal Code
00029
Country
Finland
Facility Name
Novartis Investigative Site
City
Paris Cedex
ZIP/Postal Code
75019
Country
France
Facility Name
Novartis Investigative Site
City
Villejuif Cedex
ZIP/Postal Code
94800
Country
France
Facility Name
Novartis Investigative Site
City
Muenster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Novartis Investigative Site
City
Monza
State/Province
MB
ZIP/Postal Code
20900
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00165
Country
Italy
Facility Name
Kyoto University Hospital
City
Sakyo Ku
State/Province
Kyoto
ZIP/Postal Code
606 8507
Country
Japan
Facility Name
Novartis Investigative Site
City
Setagaya-ku
State/Province
Tokyo
ZIP/Postal Code
157-8535
Country
Japan
Facility Name
Prinses Maxima Centrum voor Kinderoncologie
City
Utrecht
State/Province
CS
ZIP/Postal Code
3584
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Oslo
ZIP/Postal Code
0424
Country
Norway
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
WC1N 1EH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing URL
https://www.clinicalstudydatarequest.com
Citations:
PubMed Identifier
34515338
Citation
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs