Clinical trial NCT03734016: A Study of Zanubrutinib (BGB-3111) Versus Ibrutinib in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia
Official title: A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared With Ibrutinib in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Keywords: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
CLL
SLL
relapsed
refractory
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2018-11-07
Enrollment: 652
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: This study is designed to compare the overall response rate of zanubrutinib versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed description: This is a global, Phase 3, randomized study of zanubrutinib versus ibrutinib in 652 participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

The primary efficacy endpoint is overall response rate determined by investigator assessment. Participants were randomized in a 1:1 manner to either zanubrutinib or ibrutinib. Treatment with zanubrutinib and ibrutinib was open label.

Eligibility criteria: Key Inclusion Criteria

1. Confirmed diagnosis of CLL or SLL that meets the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
2. CLL/SLL requiring treatment per 2008 IWCLL criteria
3. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL
4. Measurable disease by computerized tomography (CT)/magnetic resonance imaging (MRI)
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
6. Life expectancy ≥ 6 months
7. Adequate bone marrow function
8. Adequate renal and hepatic function

Key Exclusion Criteria

1. Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
2. Clinically significant cardiovascular disease.
3. 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 or breast
4. History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention
5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
6. Severe or debilitating pulmonary disease
7. Active fungal, bacterial, and/or viral infection requiring systemic therapy
8. Known central nervous system involvement by leukemia or lymphoma
9. Known infection with HIV or active viral hepatitis B or C infection
10. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C
11. Major surgery within 4 weeks of the first dose of study drug
12. Prior treatment with a (Burton's Kinase) BTK inhibitor
13. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1
14. Pregnant or lactating women
15. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
16. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug
17. Concurrent participation in another therapeutic clinical trial

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

Primary outcomes:
measure: Overall Response Rate (ORR) Assessed by the Investigator
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: ORR Assessed by the Independent Review Committee (IRC)
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Secondary outcomes:
measure: Progression-free Survival (PFS) Assessed by the Investigator
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Progression-free Survival Assessed by the Independent Review Committee
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Percentage of Participants With Atrial Fibrillation or Atrial Flutter
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Duration of Response Assessed by the Independent Review Committee
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Duration of Response (DOR) Assessed by the Investigator
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Time to Treatment Failure
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Overall Survival (OS)
timeFrame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
measure: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS)
timeFrame: Baseline and Weeks 24 and 48
measure: Number of Participants With Treatment-emergent Adverse Events (TEAE)
timeFrame: From first dose of study drug up to 30 days after last dose, up to the end of study data cutoff (28 February 2024); median (range) time on treatment was 41.2 (0.4-59.1) months in the zanubrutinib arm and 37.8 (0.1-60.4) months in the ibrutinib arm.
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Carti Cancer Center
state: Arkansas
city: Los Angeles
country: United States
facility: David Geffen School of Medicine At UCLA
state: California
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers Boulder
state: Colorado
city: Fort Myers
country: United States
facility: Scri Florida Cancer Specialists South
state: Florida
city: Saint Petersburg
country: United States
facility: Scri Florida Cancer Specialists North
state: Florida
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Louisville
country: United States
facility: Norton Cancer Institute Pavilion
state: Kentucky
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Hattiesburg
country: United States
facility: Forrest General Hospital Cancer Center
state: Mississippi
city: Kansas City
country: United States
facility: Scri Hca Midwest Health
state: Missouri
city: Omaha
country: United States
facility: Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Westbury
country: United States
facility: Clinical Research Alliance, Inc
state: New York
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Springfield
country: United States
facility: Willamette Valley Cancer Center
state: Oregon
city: Chattanooga
country: United States
facility: Scri Tennessee Oncology Chattanooga
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Oncology Fort Worth Cancer Center
state: Texas
city: Houston
country: United States
facility: The University of Texas Md Anderson Cancer Center
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology San Antonio Medical Center Usor
state: Texas
city: Tyler
country: United States
facility: Texas Oncology Tyler Longview
state: Texas
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care (Oncology and Hematology Associates of Southwest 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: Spokane
country: United States
facility: Medical Oncology Associates
state: Washington
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Icon Cancer Foundation
state: Queensland
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Frankston
country: Australia
facility: Peninsula Private Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Wilrijk
country: Belgium
facility: Gasthuiszusters Antwerpen Sint Augustinus
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: 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: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
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: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Shenyang
country: China
facility: Shengjing Hospital of China Medical University
state: Liaoning
city: Shanghai
country: China
facility: Affiliated Zhongshan Hospital of Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Tongji Hospital of Tongji University
state: Shanghai
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: Wenzhou
country: China
facility: The First Provincial Wenzhou Hospital of Zhejiang
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: Ostrava
country: Czechia
facility: Fakultni Nemocnice Ostrava
city: Cesson Sevigne
country: France
facility: Hopital Prive Sevigne
city: La Roche sur Yon
country: France
facility: Centre Hospitalier Departemental de Vendee
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
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: Tours
country: France
facility: Chu Tours Hopital Bretonneau Service Pneumologie
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm
city: Koln
country: Germany
facility: Uniklinik Koln (Aor)
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Torino
country: Italy
facility: Azienda Ospedaliera Citta Della Salute E Della Scienza Di Torino
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Nijmegen
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Auckland
country: New Zealand
facility: Middlemore Clinical Trials
city: Christchurch
country: New Zealand
facility: Christchurch Hospital (Canterbury Health Laboratories)
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Takapuna
country: New Zealand
facility: North Shore Hospital
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
city: Wellington
country: New Zealand
facility: Wellington Regional Hospital (Ccdhb)
city: Bialystok
country: Poland
facility: Interhem Opieka Szpitalna
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: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
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: Poznan
country: Poland
facility: Examen Sp Z Oo
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall Dhebron
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial
city: Girona
country: Spain
facility: Ico Girona
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Toledo
country: Spain
facility: Hospital Virgen de La Salud
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus I Lund
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: Tekirdag
country: Turkey
facility: Namik Kemal University
city: Aberdeen
country: United Kingdom
facility: Nhs Grampian Ppds
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Bournemouth
country: United Kingdom
facility: The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Leeds
country: United Kingdom
facility: St Jamess Institute of Oncology
city: London
country: United Kingdom
facility: Barts Health Nhs Trust
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: Waterlooville
country: United Kingdom
facility: Genesiscare Oxford
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kazmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. doi: 10.1056/NEJMoa2211582. Epub 2022 Dec 13.
citation: Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. doi: 10.1200/JCO.22.00510. Epub 2022 Nov 17.
citation: Hillmen P, Brown JR, Eichhorst BF, Lamanna N, O'Brien SM, Qiu L, Salmi T, Hilger J, Wu K, Cohen A, Huang J, Tam CS. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020 Apr;16(10):517-523. doi: 10.2217/fon-2019-0844. Epub 2020 Mar 24.