A Study Comparing Zanubrutinib With Bendamustine Plus Rituximab in Participants With Previously Untreated CLL or SLL

Chronic Lymphocytic Leukemia Clinical Trial

— SEQUOIA  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03336333
• Other study ID #: BGB-3111-304
• Secondary ID: 2017-001551-31CT
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 31, 2017
• Est. completion date: September 2026

Study information

• Verified date: November 2023
• Source: BeiGene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 590
• Est. completion date: September 2026
• Est. primary completion date: May 7, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Small Lymphocytic Lymphoma

Intervention

Drug:
• Zanubrutinib
Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
• Bendamustine
Administered intravenously (IV) at a dose of 90 mg/m^2/day on the first 2 days of each cycle for 6 cycles.
• Rituximab
Administered intravenously (IV) at a dose of 375 mg/m^2 on day 0 of cycle 1, and at a dose of 500 mg/m^2 on day 1 of cycles 2 to 6
• Venetoclax
400 mg tablets administered orally once daily.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Icon Cancer Care - Wesley	Auchenflower	Queensland
Australia	Monash Medical Centre	Bentleigh East	Victoria
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Concord Hospital	Concord	New South Wales
Australia	Peter MacCallum Cancer Centre	East Melbourne	Victoria
Australia	Saint Vincent's Hospital Melbourne	Fitzroy	Victoria
Australia	Peninsula Private Hospital	Frankston	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Icon Cancer Care - South Brisbane	South Brisbane
Australia	The Tweed Hospital	Tweed Heads	New South Wales
Australia	Calvary Mater Newcastle Hospital	Waratah	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Medizinische Universitätsklinik Innsbruck	Innsbruck
Austria	Allgemeines Krankenhaus der Stadt Linz	Linz
Austria	Krankenhaus der Barmherzigen Schwestern Linz	Linz
Austria	Universitätsklinik für Innere Medizin Salzburg	Salzburg
Austria	Klinikum Wels-Grieskirchen	Wels
Belgium	Cliniques du Sud-Luxembourg Site Clinique Saint-Joseph	Arlon
Belgium	Universitair Ziekenhuis Brussel	Brussels
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Centre Hospitalier Universitaire (CHU) de Liège - Site du Sart Tilman	Liège
Belgium	Clinique Saint-Pierre	Ottignies
Belgium	GasthuisZusters Antwerpen Sint-Augustinus	Wilrijk	Antwerpen
Belgium	Centre Hospitalier Universitaire Universite Catholique de Louvain Site Godinne	Yvoir	Namur
China	Beijing Friendship Hospital, Capital Medical University	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Peking University Third Hospital	Beijing	Beijing
China	The First Hospital of Jilin University	Changchun	Jilin
China	West China Hospital, Sichuan University	Chengdu	Sichuan
China	Xinqiao Hospital	Chongqing	Chongqing
China	Fujian Medical University Union Hospital	Fuzhou	Fujian
China	Guangdong Provincial People's Hospital	Guangzhou	Guangdong
China	The First Affiliated Hospital, Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Anhui Provincial Hospital	Hefei	Anhui
China	The First Affiliated Hospital of Nanchang University Branch Donghu	Nanchang	Jiangxi
China	Jiangsu Province Hospital	Nanjing	Jiangsu
China	Quanzhou First Affiliated Hospital of Fujian Medical University	Quanzhou	Fujian
China	The First Affiliated Hospital of Soochow University Branch Shizi	Suzhou	Jiangsu
China	Institute of Hematology and Hospital of Blood Disease	Tianjin	Tianjin
China	Tianjin Medical University Cancer Institute and Hospital	Tianjin	Tianjin
China	Union Hospital of Tongji Medical College, Huazhong University of Science and Technology	Wuhan	Hubei
China	Wuxi People's Hospital	Wuxi	Jiangsu
China	Henan Cancer Hospital	Zhengzhou	Henan
Czechia	Fakultní Nemocnice Brno	Brno
Czechia	Fakultní Nemocnice Hradec Králové - Ústav Klinické Imunologie a Alergologie	Hradec Králové
Czechia	Fakultní Nemocnice Olomouc	Olomouc
Czechia	Fakultní Nemocnice Ostrava	Ostrava-Poruba
Czechia	Všeobecná Fakultní Nemocnice v Praze	Praha
France	Centre Hospitalier Victor Dupouy d'Argenteuil	Argenteuil
France	Institut Bergonié	Bordeaux
France	CHU de Caen Côte de Nacre	Caen
France	Centre Hospitalier Départemental Vendée	La Roche sur Yon
France	Centre Hospitalier Le Mans	Le Mans
France	Centre Hospitalier Universitaire Limoges CHU de Limoges	Limoges
France	Centre Léon Bérard	Lyon
France	Institut Paoli Calmettes	Marseille
France	Centre Hospitalier Universitaire Nantes - Hotel Dieu	Nantes
France	Groupe Hospitalier Pitie-Salpetriere	Paris
France	Groupe Hospitalier du Haut Leveque	Pessac
France	Centre hospitalier Lyon Sud	Pierre-Bénite
France	Centre Hospitalier Universitaire de Poitier- Hopital de la Miletrie - Hopital Jean Bernard	Poitiers Cedex	Poitou-charentes
France	Hôpital Robert Debré	Reims
France	Hôpital Pontchaillou	Rennes
France	Centre Henri-Becquerel	Rouen
France	Centre Hospitalier Régional et Universitaire de Tours Hôpital Bretonneau	Tours
France	Centre Hospitalier Universitaire de Nancy - Hôpital de Brabois	Vandoeuvre-lès-Nancy
Italy	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia	Brescia
Italy	Presidio Ospedale di Montichiari	Brescia
Italy	Presidio Ospedaliero di Gardone Val Trompia	Brescia
Italy	Azienda Ospedaliera Universitaria San Martino	Genova
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda	Milano
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	Ospedale San Raffaele	Milano
Italy	Universita Degli Studi di Modena-Azienda Ospedaliere Policlinco	Modena
Italy	Azienda Unita Sanitaria Locale di Ravenna	Ravenna
Italy	Fondazione Policlinico Universitario Agostino Gemelli	Roma
Italy	Universita degli Studi di Roma "La Sapienza" - Umberto I Policlinico di Roma	Roma
Italy	Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	Azienda Ospedaliera Santa Maria di Terni	Terni
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Auckland City Hospital	Grafton	Aukland
New Zealand	North Shore Hospital	North Shore	Auckland
New Zealand	Palmerston North Hospital	Palmerston North	Manawatu-wanganui
New Zealand	Tauranga Hospital	Tauranga
Poland	Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. Ks. B. Markiewicza	Brzozów
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespól Szpitali Miejskich	Chorzów
Poland	Copernicus Podmiot Leczniczy Wojewódzkiego Centrum Onkologii	Gdansk
Poland	Szpitale Pomorskie Spólka z ograniczona odpowiedzialnoscia	Gdynia
Poland	Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie, Oddzial w Gliwicach	Gliwice
Poland	Malopolskie Centrum Medyczne	Kraków
Poland	Wojewódzki Szpital Specjalistyczny w Legnicy	Legnica	Dolnoslaskie
Poland	Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi	Lódz
Poland	Centrum Onkologii Ziemi Lubelskiej	Lublin
Russian Federation	Sverdlovsk Regional Clinical Hospital #1	Ekaterinburg
Russian Federation	Kaluga Regional Hospital	Kaluga
Russian Federation	Clinical Oncology Dispensary, Kazan	Kazan
Russian Federation	Kemerovo Regional Clinical Hospital n.a. S.V. Belyaev	Kemerovo
Russian Federation	City Clinical Hospital No. 52 of the Moscow Healthcare Department	Moscow
Russian Federation	N. N. Blokhin Russian Cancer Research Center	Moscow
Russian Federation	Nizhniy Novgorod Regional Clinical Hospital N.A.	Nizhny Novgorod
Russian Federation	Penza Regional Oncology Dispensary	Penza
Russian Federation	Municipal Healthcare Institution "Clinical Medical Sanitary Establishment #1"	Perm
Russian Federation	Ryazan Regional Clinical Hospital	Ryazan
Russian Federation	FGU Russian Scientific Research Institute of Hematology and Transfusiology	Saint Petersburg
Russian Federation	State Healthcare Institution Oncologic Dispensary No. 2 - Health Department of Krasnodar Region	Sochi
Russian Federation	Tula Area Clinical Hospital	Tula
Russian Federation	State Budgetary Healthcare Institution "Volgograd Regional Clinical Oncology Dispensary #1"	Volgograd
Russian Federation	Central City Hospital # 7	Yekaterinburg
Spain	Institut Català d'Oncologia	Badalona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Institut Català d'Oncologia - L'Hospitalet de Llobregat	Barcelona
Spain	Clinica Universidad de Navarra Madrid	Madrid
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario Ramón Y Cajal	Madrid
Spain	MD Anderson Cancer Center - Madrid	Madrid
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda
Spain	Clínica Universidad de Navarra Pamplona	Pamplona
Spain	Hospital Universitari Parc Taulí	Sabadell	Barcelona
Spain	Hospital Universitario La Fe	Valencia
Spain	Hospital de Día Quirónsalud Zaragoza	Zaragoza
Sweden	Södra Älvsborgs Sjukhus - Borås	Borås	Vastra Gotaland
Sweden	Sahlgrenska Universitetssjukhuset, Östra sjukhuset	Göteborg	Vastra Gotaland
Sweden	Sunderby Sjukhus	Lulea
Sweden	Skånes Universitetssjukhus i Lund	Lund	Skane
Sweden	Universitetssjukhuset Örebro	Orebro
Sweden	Karolinska Universitetssjukhuset - Solna	Stockholm
Sweden	Uppsala Akademiska Sjukhus	Uppsala
Taiwan	Hualien Tzu Chi Hospital	Hualien City
Taiwan	Taipei Medical University - Shuang Ho Hospital	New Taipei City
Taiwan	Chi Mei Hospital Liouying	Tainan City
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Heart of England NHS Foundation Trust	Birmingham	England
United Kingdom	The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust	Bournemouth
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge	England
United Kingdom	East Kent Hospitals University NHS Foundation Trust	Canterbury	England
United Kingdom	The Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	Barts and The London NHS Trust	London
United Kingdom	Sarah Cannon Research Institute London	London	England
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	Maidstone and Tunbridge Wells NHS Trust	Maidstone	England
United Kingdom	The Christie NHS Foundation Trust	Manchester	England
United Kingdom	Norfolk and Norwich University Hospital	Norwich
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	City Hospitals Sunderland NHS Foundation Trust	Sunderland
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton
United Kingdom	The Royal Wolverhampton NHS Trust	Wolverhampton
United States	Emory University	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Duke University Medical Center	Durham	North Carolina
United States	Summit Medical Group, PA	Florham Park	New Jersey
United States	Research Medical Center - Kansas City	Kansas City	Missouri
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Joe Arrington Cancer Research and Treatment Center	Lubbock	Texas
United States	Montgomery Cancer Center	Mount Sterling	Kentucky
United States	Tennessee Oncology - Centennial Clinic	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai	New York	New York
United States	Oregon Health & Science University	Portland	Oregon
United States	University of Rochester	Rochester	New York
United States	Washington University	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	VA Puget Sound Health Care System, Pathology and Laboratory Medicine Services 113	Seattle	Washington
United States	Texas Oncology - Tyler	Tyler	Texas
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Prairie Lakes Healthcare System	Watertown	South Dakota

Sponsors (1)

Lead Sponsor	Collaborator
BeiGene

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  China,  Czechia,  France,  Italy,  New Zealand,  Poland,  Russian Federation,  Spain,  Sweden,  Taiwan,  United Kingdom, 

References & Publications (2)

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 F — View 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, Hillme — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR)	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).	Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021)
Secondary	Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR	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.	Up to 5 years
Secondary	Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups		Up to 5 years
Secondary	Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR	OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.	Up to 5 years
Secondary	Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR	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.	Up to 5 years
Secondary	Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups		Up to 5 years
Secondary	Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)	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.	Up to 5 years
Secondary	Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)		Up to 5 years
Secondary	Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire		Up to 5 years
Secondary	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
Secondary	Cohort 2: Overall Response Rate (ORR)		Up to 5 years
Secondary	Cohort 2: Progression-free Survival (PFS)		Up to 5 years
Secondary	Cohort 2: Duration of Response (DOR)		Up to 5 years
Secondary	Cohort 3: Overall Response Rate (ORR)		Up to 5 years
Secondary	Cohort 3: Progression-free Survival (PFS)		Up to 5 years
Secondary	Cohort 3: Duration of Response (DOR)		Up to 5 years
Secondary	Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4)		Up to 5 years
Secondary	Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)		Up to 5 years
Secondary	Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F		Predose up to 12 hours postdose
Secondary	Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12)		Predose up to 12 hours postdose
Secondary	Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib		Predose up to 12 hours postdose