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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 : Completed
First Posted : August 1, 2018
Results First Posted : March 19, 2024
Last Update Posted : March 21, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:

The purpose of the study was to assess the efficacy and safety of tisagenlecleucel in pediatric, adolescent and young adult patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL) including Burkitt Lymphoma and Burkitt Leukemia.

For pediatric patients who have r/r B-NHL including Burkitt Lymphoma and Burkitt Leukemia, 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 Drug: lymphodepleting chemotherapy Drug: Bridging Therapy Phase 2

Detailed Description:
This study was part of an agreed Pediatric Investigation Plan (PIP). The single-arm study design included r/r B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia subject population with poor prognosis, lack of approved effective therapies in this setting. Subject population included aggressive subtypes of B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia who were allowed to receive "bridging therapy" of investigator's choice. After assessment of eligibility, subjects qualifying for the study were enrolled and were allowed to start lymphodepleting chemotherapy as recommended in protocol after which a single dose of tisagenlecleucel product was infused. The efficacy of tisagenlecleucel was evaluated through the primary endpoint of Overall Response Rate (ORR) which included complete response (CR) and partial response (PR) as determined by local assessment. Safety assessments were conducted until study completion.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 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 : February 15, 2019
Actual Primary Completion Date : July 27, 2021
Actual Study Completion Date : April 26, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Tisagenlecleucel
Participants were infused once with CAR-positive viable T cells
 Biological: Tisagenlecleucel
Tisagenlecleucel was infused once as an intravenous infustion at a dose of either 0.2 to 5 x 106 CAR-positive viable T cells per kg body weight for subjects ≤ 50 kg or 0.1 to 2.5 x 108 CAR-positive viable T cells for subjects > 50 kg.
Other Name: CTL019

Drug: lymphodepleting chemotherapy
Prior to tisagenlecleucel infusion, each subject underwent lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)

Drug: Bridging Therapy
Pre-treatment phase could also include bridging therapy of investigator's choice


Outcome Measures
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Primary Outcome Measures :
  1. Overall Response Rate (ORR) as Determined by Local Investigator [ Time Frame: 6 months post-tisagenlecleucel infusion ]
    The overall response rate (ORR) is defined as the percentage of subjects with a best overall disease response of complete response (CR) or partial response (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: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 ]
    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: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 ]
    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 hematopoietic stem cell transplant (HSCT).

  3. Relapse Free Survival (RFS) [ Time Frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 ]
    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: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 ]

    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.

    Progression is defined using the International non-Hodgkin Lymphoma Response Criteria. For a PET-based response, progressive disease is defined as a 4 or 5 on the 5 point scale with increased uptake compared to the nadir or new FDG-avid foci consistent with lymphoma. For a CT/MRI based response progressive disease is defined as a 25% increase in the SPD (sum of the products of two largest perpendicular diameters) of index lesions, or unequivocal progression in either non-index lesions or the spleen. Any new disease attributable to lymphoma would also constitute progressive disease.


  5. Overall Survival (OS) [ Time Frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48 ]
    Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.

  6. Cellular Kinetics Parameter: Cmax [ Time Frame: Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48 ]
    The maximum (peak) transgene level (copies/μg) observed in peripheral blood or other body fluid after single dose administration as measured by qPCR. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.

  7. Cellular Kinetics Parameter: Tmax [ Time Frame: Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48 ]
    The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.

  8. Cellular Kinetics Parameter: AUC0-28d [ Time Frame: 0 to 28 days ]
    Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/μg), from day of infusion to day 28. D28 refers to the timepoint for definition of responder populations. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.

  9. Cellular Kinetics Parameter: Clast [ Time Frame: Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48 ]
    The last observed quantifiable transgene level in peripheral blood. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.

  10. Cellular Kinetics Parameter: Tlast [ Time Frame: Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48 ]
    The time of last observed quantifiable transgene level in peripheral blood. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.

  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, up to 4 years ]
    The humoral immunogenicity assay measures the antibody titers specific to tisagenlecleucel prior to and following infusion by flow cytometry. A subject was only defined as positive for tisagenlecleucel treatment-induced or -boosted anti-mCAR19 antibodies when the anti-mCAR19 antibody median fluorescence intensity at any time post-infusion was at least 2.28-fold higher (for samples analyzed on or prior to 05-May-2021) or 2.38-fold higher (for samples analyzed on or after 06-May-2021) than pre-infusion levels for participants whose baseline status was positive (boosted) or if the baseline status was negative but any post-baseline interpretation was positive (induced).

  12. Percentage of Participants Who Proceeded to Stem Cell Transplant (SCT) After Tisagenlecleucel Infusion [ Time Frame: Through study completion, up to 4 years ]
    These participants proceeded to transplant any time post-tisagenlecleucel therapy until end of study (EOS).

  13. Maximum Positive Predictive Value (PPV) [ Time Frame: Through study completion, up to 4 years ]
    Retrospective assessment of potential cytokine release syndrome (CRS) predictive models considering also data from other CTL019 trials. The Positive Predictive Value (PVV) is the percentage of participants who actually had severe CRS out of all the cases where the prediction model predicts that severe CRS will occur. The maximum PPV is the highest value attained across all potential CRS predictive models.


Eligibility Criteria
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Ages Eligible for Study:   up to 25 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/ 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.
Contacts and Locations
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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


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] January 14, 2020
Statistical Analysis Plan  [PDF] May 17, 2023

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03610724    
Other Study ID Numbers: CCTL019C2202
2017-005019-15 ( EudraCT Number )
First Posted: August 1, 2018    Key Record Dates
Results First Posted: March 19, 2024
Last Update Posted: March 21, 2024
Last Verified: February 2024
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
CTL019
r/r
relapsed/refractory B-cell non-Hodgkin lymphoma
r/r B-cell NHL subject population
B-cell NHL including Burkitt lymphoma and Burkitt Leukemia
pediatric patients
adolescents
young adults
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)
non-Hodgkin lymphoma
NHL
r/r B-NHL
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
 Immunoproliferative Disorders
Immune System Diseases
Tisagenlecleucel
Antineoplastic Agents, Immunological
Antineoplastic Agents