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Tisagenlecleucel in Adult Patients With Aggressive B-cell Non-Hodgkin Lymphoma (BELINDA)

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ClinicalTrials.gov Identifier: NCT03570892
Recruitment Status : Recruiting
First Posted : June 27, 2018
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy.

Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma Drug: Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy Drug: Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT) Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 318 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, Open-Label
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Tisagenlecleucel Versus Standard of Care in Adult Patients With Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma: A Randomized, Open Label, Phase III Trial (BELINDA)
Actual Study Start Date : May 6, 2019
Estimated Primary Completion Date : October 3, 2025
Estimated Study Completion Date : October 3, 2025


Arm Intervention/treatment
Experimental: Tisagenlecleucel treatment strategy
Patients will receive investigator's choice of optional platinum-based immunochemotherapy followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel
Drug: Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy
Investigator's choice of optional platinum-based immunochemotherapy (ie. R-ICE, R-GemOx, R-GDP, R-DHAP) + Lymphodepleting chemotherapy (fludarabine with cyclophosphamide or bendamustine) + Tisagenlecleucel (a second generation CAR-T composed of a CD19 antigen-binding domain, a 4-1BB costimulatory domain and a CD3-ζ signaling domain)

Active Comparator: Standard of care treatment strategy
Patients will receive investigator's choice of platinum-based immunochemotherapy followed in responding patients by high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)
Drug: Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)

Investigator's choice of platinum-based immunochemotherapy (ie. R-ICE, R-GemOx, R-GDP, R-DHAP)+ High dose chemotherapy (ie. BEAM) + autologous HSCT.

*Ibrutinib or lenalidomide may be used in patients who are no longer eligible for autologous HSCT after 2 cycles of immunochemotherapy





Primary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: 5 years ]
    Event-free survival (EFS) is defined as the time from the date of randomization to the date of the first documented disease progression or stable disease at or after the week 12 (+/- 1 week) assessment, as assessed by Blinded Independent Review Committee (BIRC) per Lugano criteria, or death due to any cause, at any time.


Secondary Outcome Measures :
  1. EFS as assessed by local investigator [ Time Frame: 5 years ]
    EFS as assessed by local investigator

  2. Overall Survival (OS) [ Time Frame: 5 years ]
    Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause

  3. Overall Response Rate (ORR) [ Time Frame: 5 years ]
    Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment

  4. Duration of Response (DOR) [ Time Frame: 5 years ]
    Duration of response: time from the date of first documented response of CR or PR to the date of first documented progression (SD or PD at or after the week 12 assessment will be considered progression) or death due to aggressive B-cell NHL. DOR will be summarized by BIRC and local response

  5. SF-36v2 [ Time Frame: 5 years ]
    Time to definitive deterioration in SF-36v2

  6. FACT-Lym [ Time Frame: 5 years ]
    Time to definitive deterioration in FACT-Lym

  7. EQ-VAS [ Time Frame: 5 years ]
    Time to definitive deterioration in EQ-VAS

  8. Tisagenlecleucel transgene concentrations [ Time Frame: 5 years ]
    qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow

  9. Tisagenlecleucel immunogenicity (humoral and cellular) [ Time Frame: 5 years ]
    Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.

  10. Presence of replication competent lentivirus (RCL) [ Time Frame: 5 years ]
    The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed, aggressive B-cell NHL at relapse/progression after front line therapy. Aggressive B-cell NHL is heretofore defined by the following list of subtypes (Swerdlow et al 2016):

    1. DLBCL, NOS,
    2. FL grade 3B,
    3. Primary mediastinal large B cell lymphoma (PMBCL),
    4. T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),
    5. DLBCL associated with chronic inflammation,
    6. Intravascular large B-cell lymphoma,
    7. ALK+ large B-cell lymphoma,
    8. B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin's Lymphoma (HL)),
    9. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
    10. High-grade B-cell lymphoma, NOS
    11. HHV8+ DLBCL, NOS
    12. DLBCL transforming from follicular lymphoma
    13. DLBCL transforming from marginal zone lymphoma
    14. DLBCL, leg type
  2. Relapse or progression within 365 days from last dose of rituximab and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR or PR).
  3. Patient is considered eligible for autologous HSCT as per local investigator assessment. Note: Intention to transplant and type of high dose chemotherapy (HDCT) regimen will be documented at the time of study entry
  4. Measurable disease:

    a. Nodal lesions >15 mm in the long axis, regardless of the length of the short axis, and/or b. Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) >10 mm in long AND short axis

  5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  6. Adequate organ function:

Renal function defined as:

  1. Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2

    Hepatic function defined as:

  2. Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN
  3. Total bilirubin ≤ 1.5 x ULN with the exception of patients with Gilbert syndrome who may be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin ≤1.5 × ULN

    Hematologic Function (regardless of transfusions) defined as:

  4. Absolute neutrophil count (ANC) >1000/mm3
  5. Absolute lymphocyte count (ALC) >300/mm3
  6. Absolute number of CD3+ T cells >150/mm3
  7. Platelets ≥50000/mm3
  8. Hemoglobin >8.0 g/dl

Adequate pulmonary function defined as:

i. No or mild dyspnea (≤ Grade 1) j. Oxygen saturation measured by pulse oximetry > 90% on room air k. Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level 7. Must have a leukapheresis material of non-mobilized cells available for manufacturing.

Exclusion Criteria:

  1. Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapy product
  2. Treatment with any lymphoma-directed second line anticancer therapy prior to randomization. Only steroids are permitted for disease control
  3. Patients with active central nervous system (CNS) involvement by disease under study are excluded, except if the CNS involvement has been effectively treated (i.e. patient is asymptomatic) and local treatment was >4 weeks before randomization

3. Prior allogeneic HSCT 4. Clinically significant active infection 5. Any of the following cardiovascular conditions:

• Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or stroke within 6 months prior to screening,

  • Left ventricle ejection fraction (LVEF) <45% as determined by echocardiogram (ECHO) or magnetic resonance angiography (MRA) or multigated acquisition (MUGA) at the screening assessment.
  • New York Heart Association (NYHA) functional class III or IV (Chavey et al 2001), within the past 12 months.
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II) and third degree AV block unless adequately controlled by pacemaker implantation.
  • Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to determine the QTcF interval
  • Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, or any of the following:
  • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
  • Concomitant medication(s) with a "Known Risk of Torsades de Pointes" per www.qtdrugs.org that cannot be discontinued or replaced by safe alternative medication.

    6. Patients with active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinically significant active cerebrovascular disorders (e.g. cerebral edema, posterior reversible encephalopathy syndrome (PRES))

Other protocol-defined inclusion and 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): NCT03570892


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

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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: NCT03570892     History of Changes
Other Study ID Numbers: CCTL019H2301
2016-002966-29 ( EudraCT Number )
First Posted: June 27, 2018    Key Record Dates
Last Update Posted: September 27, 2019
Last Verified: September 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.


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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
Non-Hodgkin's Lympoma
B-Cell Lymphoma
Diffuse Large B-cell Lymphoma
High Grade B-cell Lymphoma
Follicular Lymphoma grade 3B
CAR-T
Kymriah
Immunotherapy
Cellular therapy
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