Clinical trial NCT03570892: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Non-Hodgkin Lymphoma
Keywords: Non-Hodgkin's Lympoma
B-Cell Lymphoma
Diffuse Large B-cell Lymphoma
High Grade B-cell Lymphoma
Follicular Lymphoma grade 3B
CAR-T
Tisagenlecleucel
Kymriah
Immunotherapy
Cellular therapy
CTL019
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-06-27
Enrollment: 331
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Open-Label
Primary purpose: TREATMENT

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: Approximately 318 subjects were planned to be randomized; 322 subjects were analyzed (Full analysis set): 162 subjects in the tisagenlecleucel arm and 160 subjects in the SOC arm.

The target population consisted of adult participants with aggressive B-cell non-Hodgkin lymphoma (NHL) who were relapsed/refractory within 365 days of their last dose of first line immunochemotherapy and eligible for autologous hematopoietic stem cell transplantation (HSCT).

The duration of treatment in the tisagenlecleucel treatment strategy is from the start of bridging chemotherapy (if applicable) until the infusion of tisagenlecleucel (expected on average at approximately 6 weeks from randomization). The duration of the treatment in the SOC treatment strategy is from the start of salvage chemotherapy until autologous HSCT. In either treatment arm, if infusion of tisagenlecleucel or autologous HSCT is not possible, the duration of treatment is until the last dose of study treatment prior to discontinuation of the treatment strategy.

Eligibility criteria: Inclusion Criteria:

* 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):

  * DLBCL, NOS,
  * FL grade 3B,
  * Primary mediastinal large B cell lymphoma (PMBCL),
  * T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),
  * DLBCL associated with chronic inflammation,
  * Intravascular large B-cell lymphoma,
  * ALK+ large B-cell lymphoma,
  * B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin's Lymphoma (HL)),
  * High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,
  * High-grade B-cell lymphoma, NOS
  * HHV8+ DLBCL, NOS
  * DLBCL transforming from follicular lymphoma
  * DLBCL transforming from marginal zone lymphoma
  * DLBCL, leg type
* 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).
* 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
* 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::

  * Nodal lesions \>15 mm in the long axis, regardless of the length of the short axis, and/or
  * Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) \>10 mm in long AND short axis
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Adequate organ function:

Renal function defined as:

* 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:

* Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN
* 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:

* Absolute neutrophil count (ANC) \>1000/mm3
* Absolute lymphocyte count (ALC) \>300/mm3 OR Absolute number of CD3+ T cells \>150/mm3 (only for patients with non-historical apheresis)
* Platelets ≥50000/mm3
* Hemoglobin \>8.0 g/dl

Adequate pulmonary function defined as:

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

Exclusion Criteria:

* Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapy product
* Treatment with any systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation are permitted for disease control
* 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
* Prior allogeneic HSCT
* Clinically significant active infection
* 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.
* 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))

Primary outcomes:
measure: Event-free Survival (EFS) Per Blinded Independent Review Committee (BIRC) Assessment
timeFrame: appro. 24 months
Secondary outcomes:
measure: Event Free Survival (EFS) as Assessed by Local Investigator
timeFrame: 5 years
measure: Overall Survival (OS)
timeFrame: 5 years
measure: Overall Response Rate (ORR)
timeFrame: 5 years
measure: Duration of Response (DOR)
timeFrame: 5 years
measure: Time to Response (TTR)
timeFrame: 5 years
measure: SF-36v2
timeFrame: 24 Months
measure: FACT-Lym
timeFrame: 24 Months
measure: EQ-VAS
timeFrame: 24 Months
measure: Tisagenlecleucel Transgene Concentrations
timeFrame: 5 years
measure: Tisagenlecleucel Immunogenicity (Humoral and Cellular)
timeFrame: 5 years
measure: Presence of Replication Competent Lentivirus (RCL)
timeFrame: 5 years
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Moores UC San Diego Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Denver
country: United States
facility: Sarah Cannon Research Institute
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Uni of Chi Medi Ctr Hema and Onco
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Detroit
country: United States
facility: Wayne State University-Karmanos Cancer Institute
state: Michigan
city: Omaha
country: United States
facility: Uni of Nebraska Med Ctr
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Cincinnati
country: United States
facility: Jewish Hospital
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences Univ
state: Oregon
city: Philadelphia
country: United States
facility: Uni Pennsylvania Abramson Cncr Ctr
state: Pennsylvania
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Chattanooga
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Austin
country: United States
facility: St Davids South Austin Medical Ctr
state: Texas
city: Dallas
country: United States
facility: Texas Oncology-Baylor Scott and White
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Hospital
state: Texas
city: Madison
country: United States
facility: Uni of Wisconsin Carbone Cancer Ctr
state: Wisconsin
city: Darlinghurst
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Murdoch
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Fukuoka city
country: Japan
facility: Kyushu University Hospital
state: Fukuoka
city: Sapporo city
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Sendai city
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, locatie AMC
city: Utrecht
country: Netherlands
facility: UMC Utrecht Cancer Center
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
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.
citation: Thiruvengadam SK, 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.