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

• ClinicalTrials.gov Identifier: NCT03570892
• Recruitment Status: Active, not recruiting
• First Posted: June 27, 2018
• Last Update Posted: March 22, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 18, 2018
• First Posted Date: June 27, 2018
• Last Update Posted Date: March 22, 2024
• Actual Study Start Date: May 7, 2019
• Estimated Primary Completion Date: February 13, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 12, 2019)

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.

Original Primary Outcome Measures (submitted: June 18, 2018)

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 assessment, as assessed by Blinded Independent Review Committee (BIRC) per Lugano criteria, or death due to any cause, at any time.

Current Secondary Outcome Measures (submitted: March 20, 2024)

• EFS as assessed by local investigator [ Time Frame: 5 years ]
  EFS as assessed by local investigator
• 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
• 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
• 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
• Time to Response (TTR) [ Time Frame: 5 years ]
  Time from the date of randomization to the date of a patient's first achieved a response of CR or PR on or after the Week 12 assessment
• SF-36v2 [ Time Frame: 24 Months ]
  Time to definitive deterioration in SF-36v2
• FACT-Lym [ Time Frame: 24 Months ]
  Time to definitive deterioration in FACT-Lym
• EQ-VAS [ Time Frame: 24 Months ]
  Time to definitive deterioration in EQ-VAS
• Tisagenlecleucel transgene concentrations [ Time Frame: 5 years ]
  qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow
• Tisagenlecleucel immunogenicity (humoral and cellular) [ Time Frame: 5 years ]
  Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.
• Presence of replication competent lentivirus (RCL) [ Time Frame: 5 years ]
  The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel

Original Secondary Outcome Measures (submitted: June 18, 2018)

• EFS as assessed by local investigator [ Time Frame: 5 years ]
  EFS as assessed by local investigator
• 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
• 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
• 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 (±1w) assessment will be considered progression) or death due to aggressive B-cell NHL. DOR will be summarized by BIRC and local response
• SF-36v2 [ Time Frame: 5 years ]
  Time to definitive deterioration in SF-36v2
• FACT-Lym [ Time Frame: 5 years ]
  Time to definitive deterioration in FACT-Lym
• EQ-VAS [ Time Frame: 5 years ]
  Time to definitive deterioration in EQ-VAS
• Tisagenlecleucel transgene concentrations [ Time Frame: 5 years ]
  qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow
• Tisagenlecleucel immunogenicity (humoral and cellular) [ Time Frame: 5 years ]
  Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.
• Presence of replication competent lentivirus (RCL) [ Time Frame: 5 years ]
  The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tisagenlecleucel in Adult Patients With Aggressive B-cell Non-Hodgkin Lymphoma
• 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized, Open-Label

Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Non-Hodgkin Lymphoma

Intervention

• 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)
• 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

Study Arms

• 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
  Intervention: Drug: Tisagenlecleucel after optional bridging and lymphodepleting chemotherapy
• 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)
  Intervention: Drug: Platinum-based immunochemotherapy followed in responding patients with high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)

Publications *

• Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Muller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jager U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. doi: 10.1056/NEJMoa2116596. Epub 2021 Dec 14.
• 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.
• Kambhampati S, Hunter B, Varnavski A, Fakhri B, Kaplan L, Ai WZ, Pampaloni M, Huang CY, Martin T 3rd, Damon L, Andreadis CB. Ofatumumab, Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):246-256.e2. doi: 10.1016/j.clml.2020.11.005. Epub 2020 Nov 11.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 15, 2022): 331
• Original Estimated Enrollment (submitted: June 18, 2018): 318
• Estimated Study Completion Date: February 14, 2026
• Estimated Primary Completion Date: February 13, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed, aggressive B-cell NHL at relapse/progression or PR 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 anti CD20 antibody and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR).
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. Disease that is both active on PET scan (defined as 5-Deauville scorepoint-scale of 4 or 5) and measurable on CT scan, defined as::

   1. Nodal lesions >15 mm in the long axis, regardless of the length of the short axis, and/or
   2. 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 OR Absolute number of CD3+ T cells >150/mm3 (only for patients with non-historical apheresis)
   6. Platelets ≥50000/mm3

   7. Hemoglobin >8.0 g/dl

      Adequate pulmonary function defined as:

   8. No or mild dyspnea (≤ Grade 1)
   9. Oxygen saturation measured by pulse oximetry > 90% on room air
   10. 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 systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation 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 and local treatment was >4 weeks before randomization
4. Prior allogeneic HSCT
5. Clinically significant active infection

6. 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 crediblemeds.org that cannot be discontinued or replaced by safe alternative medication.
7. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Brazil, China, France, Germany, Hong Kong, Italy, Japan, Netherlands, Norway, Singapore, Spain, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03570892
• Other Study ID Numbers: CCTL019H2301; 2016-002966-29 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2024