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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT03570892
• Collaborator: (none)
• Enrollment: 355
• Locations: 76
• Arms: 2
• Anticipated Duration (Months): 81.1
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 355 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, Open-LabelRandomized, 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 7, 2019
• Anticipated Primary Completion Date: Dec 30, 2025
• Anticipated Study Completion Date: Feb 8, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Event-free survival (EFS) [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 [5 years]

   EFS as assessed by local investigator

2. Overall Survival (OS) [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) [5 years]

   Overall Response Rate (ORR) as per the Lugano criteria as per BIRC review and local investigator assessment

4. Duration of Response (DOR) [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. Time to Response (TTR) [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

6. SF-36v2 [5 years]

   Time to definitive deterioration in SF-36v2

7. FACT-Lym [5 years]

   Time to definitive deterioration in FACT-Lym

8. EQ-VAS [5 years]

   Time to definitive deterioration in EQ-VAS

9. Tisagenlecleucel transgene concentrations [5 years]

   qPCR will be used to measure tisagenlecleucel transgene concentrations in peripheral blood and bone marrow

10. Tisagenlecleucel immunogenicity (humoral and cellular) [5 years]

    Pre-existing and treatment related immunogenicity (humoral and cellular) of tisagenlecleucel will be characterized.

11. Presence of replication competent lentivirus (RCL) [5 years]

    The presence of RCL will be assessed by VSV-qPCR in patients receiving tisagenlecleucel

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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):

2. DLBCL, NOS,

3. FL grade 3B,

4. Primary mediastinal large B cell lymphoma (PMBCL),

5. T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),

6. DLBCL associated with chronic inflammation,

7. Intravascular large B-cell lymphoma,

8. ALK+ large B-cell lymphoma,

9. B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and classical Hodgkin's Lymphoma (HL)),

10. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,

11. High-grade B-cell lymphoma, NOS

12. HHV8+ DLBCL, NOS

13. DLBCL transforming from follicular lymphoma

14. DLBCL transforming from marginal zone lymphoma

15. DLBCL, leg type

16. 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).

17. 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

18. 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::

19. Nodal lesions >15 mm in the long axis, regardless of the length of the short axis, and/or

20. Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) >10 mm in long AND short axis

21. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

22. 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:

1. Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN

2. 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:

1. Absolute neutrophil count (ANC) >1000/mm3

2. Absolute lymphocyte count (ALC) >300/mm3 OR Absolute number of CD3+ T cells

150/mm3 (only for patients with non-historical apheresis)

1. Platelets ≥50000/mm3

2. Hemoglobin >8.0 g/dl

Adequate pulmonary function defined as:

1. No or mild dyspnea (≤ Grade 1)

2. Oxygen saturation measured by pulse oximetry > 90% on room air

3. Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level

4. 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.

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moores UC San Diego Cancer Center	La Jolla	California	United States	92093
2	University of California Los Angeles University of California LA	Los Angeles	California	United States	90095
3	UCSF Medical Center	San Francisco	California	United States	94143
4	Sarah Cannon Research Institute	Denver	Colorado	United States	80218
5	Yale Cancer Center	New Haven	Connecticut	United States	06520
6	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
7	Emory University School of Medicine/Winship Cancer Institute SC	Atlanta	Georgia	United States	30322
8	University of Chicago Medical Center Hematology and Oncology	Chicago	Illinois	United States	60637
9	University of Kansas Cancer Center SC	Kansas City	Kansas	United States	66205
10	Wayne State University - Karmanos Cancer Institute SC	Detroit	Michigan	United States	48201
11	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
12	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
13	Duke University Medical Center	Durham	North Carolina	United States	27705
14	Jewish Hospital	Cincinnati	Ohio	United States	45236
15	The Ohio State University SC	Columbus	Ohio	United States	43210
16	Oregon Health Sciences Univ SC	Portland	Oregon	United States	97239
17	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
18	MUSC Hollings Cancer Center	Charleston	South Carolina	United States	29425
19	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
20	St Davids South Austin Medical Ctr	Austin	Texas	United States	78704
21	Baylor Scott and White Research Institute	Dallas	Texas	United States	75231
22	University of Texas MD Anderson Cancer Center MD Anderson Cancer Center	Houston	Texas	United States	77030
23	Methodist Hospital	San Antonio	Texas	United States	78229
24	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792-6164
25	Novartis Investigative Site	Darlinghurst	New South Wales	Australia	2010
26	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
27	Novartis Investigative Site	Murdoch	Western Australia	Australia	6150
28	Novartis Investigative Site	Innsbruck		Austria	A-6020
29	Novartis Investigative Site	Salzburg		Austria	5020
30	Novartis Investigative Site	Vienna		Austria	A-1090
31	Novartis Investigative Site	Leuven		Belgium	3000
32	Novartis Investigative Site	Liege		Belgium	4000
33	Novartis Investigative Site	Salvador	BA	Brazil	41253-190
34	Novartis Investigative Site	Sao Paulo		Brazil	05651-901
35	Novartis Investigative Site	Xuzhou	Jiangsu	China	221003
36	Novartis Investigative Site	Hangzhou	Zhejiang	China	310002
37	Novartis Investigative Site	Hangzhou	Zhejiang	China	310003
38	Novartis Investigative Site	Hangzhou	Zhejiang	China	310022
39	Novartis Investigative Site	Beijing		China	100036
40	Novartis Investigative Site	Beijing		China	100191
41	Novartis Investigative Site	Chengdu		China	610041
42	Novartis Investigative Site	Shanghai		China
43	Novartis Investigative Site	Lille Cedex		France	59037
44	Novartis Investigative Site	Montpellier cedex 5		France	34295
45	Novartis Investigative Site	Nantes Cedex 1		France	44093
46	Novartis Investigative Site	Paris Cedex 10		France	75475
47	Novartis Investigative Site	Pierre Benite Cedex		France	69495
48	Novartis Investigative Site	Toulouse		France	31059
49	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
50	Novartis Investigative Site	Berlin		Germany	13353
51	Novartis Investigative Site	Hamburg		Germany	20246
52	Novartis Investigative Site	Koeln		Germany	50937
53	Novartis Investigative Site	Leipzig		Germany	04103
54	Novartis Investigative Site	Muenchen		Germany	81377
55	Novartis Investigative Site	Ulm		Germany	89081
56	Novartis Investigative Site	Hong Kong		Hong Kong
57	Novartis Investigative Site	Milano	MI	Italy	20133
58	Novartis Investigative Site	Rozzano	MI	Italy	20089
59	Novartis Investigative Site	Roma	RM	Italy	00168
60	Kyushu University Hospital	Fukuoka city	Fukuoka	Japan	812-8582
61	Hokkaido University Hospital	Sapporo city	Hokkaido	Japan	060 8648
62	Tohoku University Hospital	Sendai city	Miyagi	Japan	980 8574
63	Amsterdam UMC, locatie AMC	Amsterdam		Netherlands	1105 AZ
64	UMC Utrecht Cancer Center	Utrecht		Netherlands	3584CX
65	Novartis Investigative Site	Oslo		Norway	NO 0424
66	Novartis Investigative Site	Singapore		Singapore	119228
67	Novartis Investigative Site	Singapore		Singapore	169608
68	Novartis Investigative Site	Salamanca	Castilla Y Leon	Spain	37007
69	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
70	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
71	Novartis Investigative Site	Madrid		Spain	28009
72	Novartis Investigative Site	Madrid		Spain	28041
73	Novartis Investigative Site	Zurich		Switzerland	8091
74	Novartis Investigative Site	Taipei		Taiwan	10002
75	Novartis Investigative Site	Birmingham		United Kingdom	B15 2TH
76	Novartis Investigative Site	London		United Kingdom	WC1E 6HX

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03570892
• Other Study ID Numbers: CCTL019H2301; 2016-002966-29
• First Posted: Jun 27, 2018
• Last Update Posted: Aug 9, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: 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
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell

Study Results

No Results Posted as of Aug 9, 2022