Clinical trial NCT03336333: A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL
Official title: An International, Phase 3, Open-Label, Randomized Study of BGB-3111 Compared With Bendamustine Plus Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Keywords: zanubrutinib
BTK inhibitor
bendamustine
rituximab
venetoclax
BGB-3111
Phase 3
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-11-08
Enrollment: 590
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as measured by progression free survival assess by Independent Central Review.

Detailed description: This is a global phase 3, open label, randomized study of zanubrutinib versus bendamustine plus rituximab (B+R) in participants with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), including participants without del(17p) \[Cohort 1\] and participants with del(17p) \[Cohort 2 and Cohort 3\]. Participants in Cohort 1 are randomized 1:1 to zanubrutinib (Arm A) or bendamustine plus rituximab (Arm B). Randomization will be stratified by age, Binet stage, immunoglobulin variable region heavy chain (IGHV) mutational status, and geographic region. Participants in Cohort 2 will receive treatment with zanubrutinib. Participants in Cohort 3 will receive treatment with zanubrutinib and venetoclax.

Eligibility criteria: Key Inclusion Criteria:

* Unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR)
* Confirmed diagnosis of CD20-positive CLL or SLL, requiring treatment
* Measurable disease by imaging
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Life expectancy ≥ 6 months
* Adequate bone marrow function
* Adequate renal and hepatic function

Key Exclusion Criteria:

* Previous systemic treatment for CLL/SLL
* Requires ongoing need for corticosteroid treatment
* Known prolymphocytic leukemia or history of or suspected Richter's transformation.
* Clinically significant cardiovascular disease
* Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix of breast, or localized Gleason score 6 prostate cancer
* History of severe bleeding disorder
* History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug
* Severe or debilitating pulmonary disease
* Inability to swallow capsules or disease affecting gastrointestinal function
* Active infection requiring systemic treatment
* Known central nervous system involvement by leukemia or lymphoma
* Underlying medical condition that will render the administration of study drug hazardous or obscure interpretation of toxicity or AEs
* Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C infection
* Major surgery ≤ 4 weeks prior to start of study treatment
* Pregnant or nursing females
* Vaccination with live vaccine within 35 days prior to the first dose of study drug.
* Ongoing alcohol or drug addiction
* Known hypersensitivity to zanubrutinib, bendamustine, rituximab, or venetoclax (as applicable) or any other ingredients of the study drugs
* Requires ongoing treatment with strong cytochrome P450 (CYP3A) inhibitor or inducer
* Concurrent participation in another therapeutic clinical study

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR)
timeFrame: Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021)
Secondary outcomes:
measure: Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR
timeFrame: Up to 5 years
measure: Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups
timeFrame: Up to 5 years
measure: Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR
timeFrame: Up to 5 years
measure: Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR
timeFrame: Up to 5 years
measure: Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups
timeFrame: Up to 5 years
measure: Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
timeFrame: Up to 5 years
measure: Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
timeFrame: Up to 5 years
measure: Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire
timeFrame: Up to 5 years
measure: Cohort 1: Patient-reported Outcomes as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Questionnaire.
timeFrame: Up to 5 years
measure: Cohort 2: Overall Response Rate (ORR)
timeFrame: Up to 5 years
measure: Cohort 2: Progression-free Survival (PFS)
timeFrame: Up to 5 years
measure: Cohort 2: Duration of Response (DOR)
timeFrame: Up to 5 years
measure: Cohort 3: Overall Response Rate (ORR)
timeFrame: Up to 5 years
measure: Cohort 3: Progression-free Survival (PFS)
timeFrame: Up to 5 years
measure: Cohort 3: Duration of Response (DOR)
timeFrame: Up to 5 years
measure: Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4)
timeFrame: Up to 5 years
measure: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 5 years
measure: Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F
timeFrame: Predose up to 12 hours postdose
measure: Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12)
timeFrame: Predose up to 12 hours postdose
measure: Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib
timeFrame: Predose up to 12 hours postdose
Other outcomes:
Locations:
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Florham Park
country: United States
facility: Summit Medical Group
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine At Mount Sinai
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Watertown
country: United States
facility: Prairie Lakes Healthcare System
state: South Dakota
city: Nashville
country: United States
facility: Tennessee Oncology, Pllc Nashville
state: Tennessee
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Va Puget Sound Health Care System
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Cudgen
country: Australia
facility: The Tweed Valley Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: Icon Cancer Centre Wesley
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Womens Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincents Hospital Melbourne
state: Victoria
city: Frankston
country: Australia
facility: Peninsula Private Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Innsbruck
country: Austria
facility: Medizinische Universitatsklinik Innsbruck
city: Linz
country: Austria
facility: Krankenhaus Der Barmherzigen Schwestern Linz
city: Linz
country: Austria
facility: Allgemeines Krankenhaus Der Stadt Linz
city: Salzburg
country: Austria
facility: Universitatsklinik Fur Innere Medizin Iii Universitatsklinikum Der Pmu Landeskrankenhaus Salzburg
city: Wels
country: Austria
facility: Klinikum Wels Grieskirchen
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Liege
country: Belgium
facility: Centre Hospitalier Universitaire (Chu) de Liege Site Du Sart Tilman
city: Ottignies
country: Belgium
facility: Clinique Saint Pierre
city: Yvoir
country: Belgium
facility: Centre Hospitalier Universitaire Universite Catholique de Louvain Site Godinne
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Friendship Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Chongqing
country: China
facility: Second Affiliated Hospital of Army Medical University (Xinqiao Hospital)
state: Chongqing
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Quanzhou
country: China
facility: Quanzhou First Affliated Hospital of Fujian Medical University
state: Fujian
city: Guangzhou
country: China
facility: Guangdong Provincial Peoples Hospital
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University Branch Shizi
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi Peoples Hospital
state: Jiangsu
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University Branch Donghu
state: Jiangxi
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Tianjin
country: China
facility: Institute of Hematology and Hospital of Blood Disease
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University School of Medicine
state: Zhejiang
city: Brno
country: Czechia
facility: Fakultni Nemocnice Brno
city: Hradec Kralove
country: Czechia
facility: Fakultni Nemocnice Hradec Kralove
city: Olomouc
country: Czechia
facility: Fakultni Nemocnice Olomouc
city: Praha
country: Czechia
facility: Vseobecna Fakultni Nemocnice V Praze
city: Argenteuil cedex
country: France
facility: Centre Hospitalier Victor Dupouy Dargenteuil
city: Bordeaux
country: France
facility: Centre de Lutte Contre Le Cancer Institut Bergonie
city: Caen cedex
country: France
facility: Chu Caen Normandie
city: La Roche sur Yon
country: France
facility: Centre Hospitalier Departemental de Vendee
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
city: Limoges Cedex
country: France
facility: Centre Hospitalier Universitaire Limoges Chu de Limoges
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nantes Cedex
country: France
facility: Centre Hospitalier Universitaire Nantes Hotel Dieu
city: Paris
country: France
facility: Hopital de La Pitie Salpetriere
city: Pessac Cedex
country: France
facility: Groupe Hospitalier Du Haut Leveque
city: PierreBenite
country: France
facility: Chu Hopital Lyon Sud
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitier Hopital de La Miletrie Hopital Jean Bernard
city: Reims Cedex
country: France
facility: Hopital Robert Debre
city: Rennes Cedex
country: France
facility: Hopital Pontchaillou
city: Rouen Cedex
country: France
facility: Centre Henri Becquerel
city: Tours
country: France
facility: Chu Tours Hopital Bretonneau Service Pneumologie
city: VandoeuvrelesNancy
country: France
facility: Chu Nancy Hopital Brabois
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
city: Meldola
country: Italy
facility: Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst
city: Milano
country: Italy
facility: Fondazione Irccs Ca Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
city: Modena
country: Italy
facility: Universita Degli Studi Di Modena Azienda Ospedaliere Policlinco
city: Ravenna
country: Italy
facility: Azienda Unita Sanitaria Locale Di Ravenna
city: Roma
country: Italy
facility: Universita Degli Studi La Sapienza
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Terni
country: Italy
facility: Azienda Ospedaliera S Maria Di Terni
city: Torino
country: Italy
facility: Ao Citta Della Salute E Della Scienza Di Torino Presidio O
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Takapuna
country: New Zealand
facility: North Shore Hospital
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
city: Brzozow
country: Poland
facility: Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
city: Chorzow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
city: Gdansk
country: Poland
facility: Copernicus Podmiot Leczniczy Sp Z Oo Wojewodzkie Centrum Onkologii
city: Gdynia
country: Poland
facility: Szpitale Pomorskie Spolka Z Ograniczona Odpowiedzialnoscia
city: Gliwice
country: Poland
facility: Centrum Onkologii Instytut Im Marii Sklodowskiej Curie, Oddzial W Gliwicach
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne Sc
city: Legnica
country: Poland
facility: Wojewodzki Szpital Specjalistyczny W Legnicy
city: Lodz
country: Poland
facility: Wielospecjalistyczne Centrum Onkologii I Traumatologii Im M Kopernika W Lodzi
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej
city: Kaluga
country: Russian Federation
facility: Kaluga Regional Hospital
state: Kaluzhskaya Oblast'
city: Sochi
country: Russian Federation
facility: State Healthcare Institution Oncologic Dispensary No Health Department of Krasnodar Region
state: Krasnodarskiy Kray
city: Moscow
country: Russian Federation
facility: N N Blokhin Russian Cancer Research Center Konstantin Laktionov
state: Moskva
city: Moscow
country: Russian Federation
facility: Russian Academy of Advanced Medical Studies, City Clinical Hospital
state: Moskva
city: Nizhniy Novgorod
country: Russian Federation
facility: Nizhniy Novgorod Regional Clinical Hospital Nasemashko
state: Nizhegorodskaya Oblast'
city: Penza
country: Russian Federation
facility: State Budgetary Healthcare Institution Regional Clinical Dispensary
state: Penzenskaya Oblast'
city: Perm
country: Russian Federation
facility: State Budgetary Healthcare Institution of Perm Krai Clinical Medical Sanitary Establishment
state: Permskiy Kray
city: Kemerovo
country: Russian Federation
facility: Kemerovo Regional Clinical Hospital Na Sv Belyaev
state: Pskovskaya Oblast'
city: Ryazan
country: Russian Federation
facility: Ryazan Regional Clinical Hospital
state: Ryazanskaya Oblast'
city: Saint Petersburg
country: Russian Federation
facility: Fgu Russian Scientific Research Institute of Hematology and Transfusiology
state: Sankt-Peterburg
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital
state: Sverdlovskaya Oblast'
city: Yekaterinburg
country: Russian Federation
facility: Central City Hospital
state: Sverdlovskaya Oblast'
city: Kazan
country: Russian Federation
facility: Clinical Oncology Dispensary
state: Tambovskaya Oblast'
city: Tula
country: Russian Federation
facility: Tula Area Clinical Hospital
state: Tul'skaya Oblast'
city: Volgograd
country: Russian Federation
facility: State Budgetary Healthcare Institution Volgograd Regional Clinical Oncology Dispensary
state: Volgogradskaya Oblast'
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Institut Catala Doncologia
city: Madrid
country: Spain
facility: Hospital de La Princesa
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra Pamplona
city: Valencia
country: Spain
facility: Hospital Universitari I Politecnic La Fe
city: Zaragoza
country: Spain
facility: Hospital de Dia Quironsalud Zaragoza
city: Boras
country: Sweden
facility: Medicinkliniken
city: Goteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus I Lund
city: Orebro
country: Sweden
facility: Universitetssjukhuset Orebro
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: Uppsala
country: Sweden
facility: Uppsala Akademiska Sjukhus
city: Hualien
country: Taiwan
facility: Hualien Tzu Chi Hospital
city: New Taipei City
country: Taiwan
facility: Taipei Medical University Shuang Ho Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital East Campus
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Bournemouth
country: United Kingdom
facility: The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals Nhs Foundation Trust
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Greater Manchester
country: United Kingdom
facility: The Christie Hospital
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals Nhs Trust
city: London
country: United Kingdom
facility: Barts and the London Nhs Trust
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute Uk
city: Maidstone
country: United Kingdom
facility: Maidstone and Tunbridge Wells Nhs Trust, Kent Oncology Centre, Maidstone Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals Nhs Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals Nhs Trust
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Wolverhampton
country: United Kingdom
facility: The Royal Wolverhampton Nhs Trust
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Mu S, Tang Z, Novotny W, Tawashi M, Li TK, Ou Y, Sahasranaman S. Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. Cancer Chemother Pharmacol. 2020 Feb;85(2):391-399. doi: 10.1007/s00280-019-04015-w. Epub 2019 Dec 26.
citation: Tam CS, Robak T, Ghia P, Kahl BS, Walker P, Janowski W, Simpson D, Shadman M, Ganly PS, Laurenti L, Opat S, Tani M, Ciepluch H, Verner E, Simkovic M, Osterborg A, Trneny M, Tedeschi A, Paik JC, Kuwahara SB, Feng S, Ramakrishnan V, Cohen A, Huang J, Hillmen P, Brown JR. Zanubrutinib monotherapy for patients with treatment naive chronic lymphocytic leukemia and 17p deletion. Haematologica. 2021 Sep 1;106(9):2354-2363. doi: 10.3324/haematol.2020.259432.
citation: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Simkovic M, Shadman M, Osterborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trneny M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5. Epub 2022 Jul 7.