A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL
- Conditions
- Chronic Lymphocytic LeukemiaSmall Lymphocytic Lymphoma
- Interventions
- Registration Number
- NCT03336333
- Lead Sponsor
- BeiGene
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 590
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1: Bendamustine + Rituximab Rituximab Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B) Cohort 1: Bendamustine + Rituximab Bendamustine Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B) Cohort 1a (China only): Bendamustine + Rituximab Rituximab Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only) Cohort 1: Zanubrutinib Zanubrutinib Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A) Cohort 1a (China only): Bendamustine + Rituximab Bendamustine Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only) Cohort 1a (China only): Zanubrutinib Zanubrutinib Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only) Cohort 2: Zanubrutinib Zanubrutinib Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C) Cohort 3: Venetoclax + Zanubrutinib Zanubrutinib Approximately 110 participants, 50 without del17p and 60 with del\[17p\] or TP53 mutation will receive zanubrutinib plus venetoclax; Participants will also receive zanubrutinib starting on Cycle 1 Day 1 then daily for a minimum of 27 cycles, or until unacceptable toxicity or disease progression, whichever occurs first. Participants will receive venetoclax starting Cycle 4 Day 1 according to a 5-week dose-up schedule then daily until unacceptable toxicity, disease progression, or for a maximum of 24 cycles. Each cycle is 28 days. (Arm D) Cohort 3: Venetoclax + Zanubrutinib Venetoclax Approximately 110 participants, 50 without del17p and 60 with del\[17p\] or TP53 mutation will receive zanubrutinib plus venetoclax; Participants will also receive zanubrutinib starting on Cycle 1 Day 1 then daily for a minimum of 27 cycles, or until unacceptable toxicity or disease progression, whichever occurs first. Participants will receive venetoclax starting Cycle 4 Day 1 according to a 5-week dose-up schedule then daily until unacceptable toxicity, disease progression, or for a maximum of 24 cycles. Each cycle is 28 days. (Arm D)
- Primary Outcome Measures
Name Time Method Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR) Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021) PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the ICR per 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with small lymphocytic lymphoma (SLL).
- Secondary Outcome Measures
Name Time Method Cohort 3: Overall Response Rate (ORR) Up to 5 years Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to 5 years Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) Up to 5 years Cohort 2: Overall Response Rate (ORR) Up to 5 years Cohort 2: Progression-free Survival (PFS) Up to 5 years Cohort 2: Duration of Response (DOR) Up to 5 years Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib Predose up to 12 hours postdose Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR Up to 5 years ORR in Cohort 1 is defined as the percentage of participants who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by the ICR.
Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups Up to 5 years Cohort 3: Progression-free Survival (PFS) Up to 5 years Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4) Up to 5 years Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire Up to 5 years Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) Up to 5 years PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the investigator per iwCLL guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL.
Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR Up to 5 years OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.
Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups Up to 5 years Cohort 3: Duration of Response (DOR) Up to 5 years Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR Up to 5 years Duration of response in Cohort 1 determined using the iwCLL criteria with modification for treatment related lymphocytosis (in participants with CLL) and the Lugano Classification for non-Hodgkin lymphoma (NHL; in participants with SLL), is defined as the time from the date that criteria for response (ie, partial response with lymphocytosis \[PR-L\] or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first.
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. Up to 5 years Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) Predose up to 12 hours postdose Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F Predose up to 12 hours postdose
Trial Locations
- Locations (158)
Augusta University
🇺🇸Augusta, Georgia, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Wuxi Peoples Hospital
🇨🇳Wuxi, Jiangsu, China
Wielospecjalistyczne Centrum Onkologii I Traumatologii Im M Kopernika W Lodzi
🇵🇱Lodz, Poland
Centrum Onkologii Ziemi Lubelskiej
🇵🇱Lublin, Poland
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Malopolskie Centrum Medyczne Sc
🇵🇱Krakow, Poland
Research Medical Center
🇺🇸Kansas City, Missouri, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Summit Medical Group
🇺🇸Florham Park, New Jersey, United States
Icahn School of Medicine At Mount Sinai
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Duke University
🇺🇸Durham, North Carolina, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Prairie Lakes Healthcare System
🇺🇸Watertown, South Dakota, United States
Tennessee Oncology, Pllc Nashville
🇺🇸Nashville, Tennessee, United States
Joe Arrington Cancer Research and Treatment Center
🇺🇸Lubbock, Texas, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
Va Puget Sound Health Care System
🇺🇸Seattle, Washington, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
Concord Repatriation General Hospital
🇦🇺Concord, New South Wales, Australia
The Tweed Valley Hospital
🇦🇺Cudgen, New South Wales, Australia
Calvary Mater Newcastle
🇦🇺Waratah, New South Wales, Australia
Icon Cancer Centre Wesley
🇦🇺Auchenflower, Queensland, Australia
Princess Alexandra Hospital
🇦🇺Brisbane, Queensland, Australia
Royal Brisbane and Womens Hospital
🇦🇺Herston, Queensland, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
The Queen Elizabeth Hospital
🇦🇺Woodville South, South Australia, Australia
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
Monash Health
🇦🇺Clayton, Victoria, Australia
St Vincents Hospital Melbourne
🇦🇺Fitzroy, Victoria, Australia
Peninsula Private Hospital
🇦🇺Frankston, Victoria, Australia
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
Medizinische Universitatsklinik Innsbruck
🇦🇹Innsbruck, Austria
Krankenhaus Der Barmherzigen Schwestern Linz
🇦🇹Linz, Austria
Allgemeines Krankenhaus Der Stadt Linz
🇦🇹Linz, Austria
Universitatsklinik Fur Innere Medizin Iii Universitatsklinikum Der Pmu Landeskrankenhaus Salzburg
🇦🇹Salzburg, Austria
Klinikum Wels Grieskirchen
🇦🇹Wels, Austria
Universitair Ziekenhuis Brussel
🇧🇪Brussels, Belgium
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Centre Hospitalier Universitaire (Chu) de Liege Site Du Sart Tilman
🇧🇪Liege, Belgium
Clinique Saint Pierre
🇧🇪Ottignies, Belgium
Centre Hospitalier Universitaire Universite Catholique de Louvain Site Godinne
🇧🇪Yvoir, Belgium
Anhui Provincial Hospital
🇨🇳Hefei, Anhui, China
Peking University Third Hospital
🇨🇳Beijing, Beijing, China
Beijing Friendship Hospital, Capital Medical University
🇨🇳Beijing, Beijing, China
Peking Union Medical College Hospital
🇨🇳Beijing, Beijing, China
Second Affiliated Hospital of Army Medical University (Xinqiao Hospital)
🇨🇳Chongqing, Chongqing, China
Fujian Medical University Union Hospital
🇨🇳Fuzhou, Fujian, China
Quanzhou First Affliated Hospital of Fujian Medical University
🇨🇳Quanzhou, Fujian, China
Guangdong Provincial Peoples Hospital
🇨🇳Guangzhou, Guangdong, China
Henan Cancer Hospital
🇨🇳Zhengzhou, Henan, China
Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
🇨🇳Wuhan, Hubei, China
Jiangsu Province Hospital
🇨🇳Nanjing, Jiangsu, China
The First Affiliated Hospital of Soochow University Branch Shizi
🇨🇳Suzhou, Jiangsu, China
The First Affiliated Hospital of Nanchang University Branch Donghu
🇨🇳Nanchang, Jiangxi, China
The First Hospital of Jilin University
🇨🇳Changchun, Jilin, China
West China Hospital, Sichuan University
🇨🇳Chengdu, Sichuan, China
Institute of Hematology and Hospital of Blood Disease
🇨🇳Tianjin, Tianjin, China
Tianjin Medical University Cancer Institute and Hospital
🇨🇳Tianjin, Tianjin, China
The First Affiliated Hospital, Zhejiang University School of Medicine
🇨🇳Hangzhou, Zhejiang, China
Fakultni Nemocnice Brno
🇨🇿Brno, Czechia
Fakultni Nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Fakultni Nemocnice Olomouc
🇨🇿Olomouc, Czechia
Vseobecna Fakultni Nemocnice V Praze
🇨🇿Praha, Czechia
Centre Hospitalier Victor Dupouy Dargenteuil
🇫🇷Argenteuil cedex, France
Centre de Lutte Contre Le Cancer Institut Bergonie
🇫🇷Bordeaux, France
Chu Caen Normandie
🇫🇷Caen cedex, France
Centre Hospitalier Departemental de Vendee
🇫🇷La Roche sur Yon, France
Centre Hospitalier Le Mans
🇫🇷Le Mans, France
Centre Hospitalier Universitaire Limoges Chu de Limoges
🇫🇷Limoges Cedex, France
Institut Paoli Calmettes
🇫🇷Marseille, France
Centre Hospitalier Universitaire Nantes Hotel Dieu
🇫🇷Nantes Cedex, France
Hopital de La Pitie Salpetriere
🇫🇷Paris, France
Groupe Hospitalier Du Haut Leveque
🇫🇷Pessac Cedex, France
Chu Hopital Lyon Sud
🇫🇷PierreBenite, France
Centre Hospitalier Universitaire de Poitier Hopital de La Miletrie Hopital Jean Bernard
🇫🇷Poitiers, France
Hopital Robert Debre
🇫🇷Reims Cedex, France
Hopital Pontchaillou
🇫🇷Rennes Cedex, France
Centre Henri Becquerel
🇫🇷Rouen Cedex, France
Chu Tours Hopital Bretonneau Service Pneumologie
🇫🇷Tours, France
Chu Nancy Hopital Brabois
🇫🇷VandoeuvrelesNancy, France
Wojewodzki Szpital Specjalistyczny W Legnicy
🇵🇱Legnica, Poland
Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
🇮🇹Brescia, Italy
Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst
🇮🇹Meldola, Italy
Fondazione Irccs Ca Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
Ospedale San Raffaele
🇮🇹Milano, Italy
Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Italy
Universita Degli Studi Di Modena Azienda Ospedaliere Policlinco
🇮🇹Modena, Italy
Azienda Unita Sanitaria Locale Di Ravenna
🇮🇹Ravenna, Italy
Universita Degli Studi La Sapienza
🇮🇹Roma, Italy
Fondazione Policlinico Universitario Agostino Gemelli
🇮🇹Roma, Italy
Azienda Ospedaliera S Maria Di Terni
🇮🇹Terni, Italy
Ao Citta Della Salute E Della Scienza Di Torino Presidio O
🇮🇹Torino, Italy
Auckland City Hospital
🇳🇿Auckland, New Zealand
Christchurch Hospital
🇳🇿Christchurch, New Zealand
Palmerston North Hospital
🇳🇿Palmerston North, New Zealand
North Shore Hospital
🇳🇿Takapuna, New Zealand
Tauranga Hospital
🇳🇿Tauranga, New Zealand
Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
🇵🇱Brzozow, Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
🇵🇱Chorzow, Poland
Copernicus Podmiot Leczniczy Sp Z Oo Wojewodzkie Centrum Onkologii
🇵🇱Gdansk, Poland
Szpitale Pomorskie Spolka Z Ograniczona Odpowiedzialnoscia
🇵🇱Gdynia, Poland
Centrum Onkologii Instytut Im Marii Sklodowskiej Curie, Oddzial W Gliwicach
🇵🇱Gliwice, Poland
Kaluga Regional Hospital
🇷🇺Kaluga, Kaluzhskaya Oblast', Russian Federation
State Healthcare Institution Oncologic Dispensary No Health Department of Krasnodar Region
🇷🇺Sochi, Krasnodarskiy Kray, Russian Federation
N N Blokhin Russian Cancer Research Center Konstantin Laktionov
🇷🇺Moscow, Moskva, Russian Federation
Russian Academy of Advanced Medical Studies, City Clinical Hospital
🇷🇺Moscow, Moskva, Russian Federation
Nizhniy Novgorod Regional Clinical Hospital Nasemashko
🇷🇺Nizhniy Novgorod, Nizhegorodskaya Oblast', Russian Federation
State Budgetary Healthcare Institution Regional Clinical Dispensary
🇷🇺Penza, Penzenskaya Oblast', Russian Federation
State Budgetary Healthcare Institution of Perm Krai Clinical Medical Sanitary Establishment
🇷🇺Perm, Permskiy Kray, Russian Federation
Kemerovo Regional Clinical Hospital Na Sv Belyaev
🇷🇺Kemerovo, Pskovskaya Oblast', Russian Federation
Ryazan Regional Clinical Hospital
🇷🇺Ryazan, Ryazanskaya Oblast', Russian Federation
Fgu Russian Scientific Research Institute of Hematology and Transfusiology
🇷🇺Saint Petersburg, Sankt-Peterburg, Russian Federation
Sverdlovsk Regional Clinical Hospital
🇷🇺Ekaterinburg, Sverdlovskaya Oblast', Russian Federation
Central City Hospital
🇷🇺Yekaterinburg, Sverdlovskaya Oblast', Russian Federation
Clinical Oncology Dispensary
🇷🇺Kazan, Tambovskaya Oblast', Russian Federation
Tula Area Clinical Hospital
🇷🇺Tula, Tul'skaya Oblast', Russian Federation
State Budgetary Healthcare Institution Volgograd Regional Clinical Oncology Dispensary
🇷🇺Volgograd, Volgogradskaya Oblast', Russian Federation
Hospital Universitari Germans Trias I Pujol
🇪🇸Badalona, Spain
Hospital Del Mar
🇪🇸Barcelona, Spain
Institut Catala Doncologia
🇪🇸Barcelona, Spain
Hospital de La Princesa
🇪🇸Madrid, Spain
Clinica Universidad de Navarra
🇪🇸Madrid, Spain
Hospital Universitario Puerta de Hierro Majadahonda
🇪🇸Majadahonda, Spain
Clinica Universidad de Navarra Pamplona
🇪🇸Pamplona, Spain
Hospital Universitari I Politecnic La Fe
🇪🇸Valencia, Spain
Hospital de Dia Quironsalud Zaragoza
🇪🇸Zaragoza, Spain
Medicinkliniken
🇸🇪Boras, Sweden
Sahlgrenska Universitetssjukhuset
🇸🇪Goteborg, Sweden
Skanes Universitetssjukhus I Lund
🇸🇪Lund, Sweden
Universitetssjukhuset Orebro
🇸🇪Orebro, Sweden
Karolinska Universitetssjukhuset Solna
🇸🇪Stockholm, Sweden
Uppsala Akademiska Sjukhus
🇸🇪Uppsala, Sweden
Hualien Tzu Chi Hospital
🇨🇳Hualien, Taiwan
Taipei Medical University Shuang Ho Hospital
🇨🇳New Taipei City, Taiwan
National Taiwan University Hospital East Campus
🇨🇳Taipei, Taiwan
The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
🇬🇧Bournemouth, United Kingdom
Cambridge University Hospitals Nhs Foundation Trust
🇬🇧Cambridge, United Kingdom
Kent and Canterbury Hospital
🇬🇧Canterbury, United Kingdom
The Christie Hospital
🇬🇧Greater Manchester, United Kingdom
The Leeds Teaching Hospitals Nhs Trust
🇬🇧Leeds, United Kingdom
Barts and the London Nhs Trust
🇬🇧London, United Kingdom
Royal Marsden Hospital
🇬🇧London, United Kingdom
Sarah Cannon Research Institute Uk
🇬🇧London, United Kingdom
Maidstone and Tunbridge Wells Nhs Trust, Kent Oncology Centre, Maidstone Hospital
🇬🇧Maidstone, United Kingdom
Norfolk and Norwich University Hospitals Nhs Foundation Trust
🇬🇧Norwich, United Kingdom
Nottingham University Hospitals Nhs Trust
🇬🇧Nottingham, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Sunderland Royal Hospital
🇬🇧Sunderland, United Kingdom
The Royal Wolverhampton Nhs Trust
🇬🇧Wolverhampton, United Kingdom