A Study of Zanubrutinib (BGB-3111) Versus Ibrutinib in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia
ALPINE
A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared With Ibrutinib in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
3 other identifiers
interventional
652
15 countries
115
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Nov 2018
Longer than P75 for phase_3
115 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
November 1, 2018
CompletedFirst Submitted
Initial submission to the registry
November 2, 2018
CompletedFirst Posted
Study publicly available on registry
November 7, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 8, 2022
CompletedResults Posted
Study results publicly available
July 27, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
February 28, 2024
CompletedMarch 30, 2025
March 1, 2025
3.8 years
November 2, 2018
July 7, 2023
March 27, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Overall Response Rate (ORR) Assessed by the Investigator
ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) per investigator assessment. Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL.
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).
ORR Assessed by the Independent Review Committee (IRC)
ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) assessed by a blinded independent review committee. Overall response was assessed by the IRC for the purpose of regulatory filing with the Food and Drug Administration (FDA). Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL.
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 (13)
Progression-free Survival (PFS) Assessed by the Investigator
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).
Progression-free Survival Assessed by the Independent Review Committee
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).
Percentage of Participants With Atrial Fibrillation or Atrial Flutter
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).
Duration of Response Assessed by the Independent Review Committee
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).
Duration of Response (DOR) Assessed by the Investigator
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).
- +8 more secondary outcomes
Study Arms (2)
Zanubrutinib
EXPERIMENTALParticipants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.
Ibrutinib
ACTIVE COMPARATORParticipants received Ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.
Interventions
Eligibility Criteria
You may qualify if:
- Confirmed diagnosis of CLL or SLL that meets the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
- CLL/SLL requiring treatment per 2008 IWCLL criteria
- Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL
- Measurable disease by computerized tomography (CT)/magnetic resonance imaging (MRI)
- 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
You may not qualify if:
- Known prolymphocytic leukemia or history of, or currently 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 or breast
- History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention
- History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
- Severe or debilitating pulmonary disease
- Active fungal, bacterial, and/or viral infection requiring systemic therapy
- Known central nervous system involvement by leukemia or lymphoma
- Known infection with HIV or active viral hepatitis B or C infection
- Moderate or severe hepatic impairment, ie, Child-Pugh class B or C
- Major surgery within 4 weeks of the first dose of study drug
- Prior treatment with a (Burton's Kinase) BTK inhibitor
- Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1
- Pregnant or lactating women
- Vaccination with a live vaccine within 35 days prior to the first dose of study drug
- +2 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- BeiGenelead
Study Sites (115)
Carti Cancer Center
Little Rock, Arkansas, 72205, United States
David Geffen School of Medicine At UCLA
Los Angeles, California, 90095, United States
Rocky Mountain Cancer Centers Boulder
Boulder, Colorado, 80303, United States
Scri Florida Cancer Specialists South
Fort Myers, Florida, 33901, United States
Scri Florida Cancer Specialists North
St. Petersburg, Florida, 33705, United States
Augusta University
Augusta, Georgia, 30912, United States
Norton Cancer Institute Pavilion
Louisville, Kentucky, 40207, United States
Dana Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Forrest General Hospital Cancer Center
Hattiesburg, Mississippi, 39401, United States
Scri Hca Midwest Health
Kansas City, Missouri, 64132, United States
Nebraska Medical Center
Omaha, Nebraska, 68198, United States
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, 89169, United States
Atlantic Health System
Morristown, New Jersey, 07960, United States
Morristown Medical Center
Morristown, New Jersey, 07960, United States
Columbia University Medical Center
New York, New York, 10032, United States
Clinical Research Alliance, Inc
Westbury, New York, 11590, United States
Duke University Hospital
Durham, North Carolina, 27705, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
Willamette Valley Cancer Center
Springfield, Oregon, 97477, United States
Scri Tennessee Oncology Chattanooga
Chattanooga, Tennessee, 37404, United States
Sarah Cannon Cancer Center
Nashville, Tennessee, 37203, United States
Texas Oncology Fort Worth Cancer Center
Fort Worth, Texas, 76104-2150, United States
The University of Texas Md Anderson Cancer Center
Houston, Texas, 77030-4009, United States
Joe Arrington Cancer Research and Treatment Center
Lubbock, Texas, 79410, United States
Texas Oncology San Antonio Medical Center Usor
San Antonio, Texas, 78240, United States
Texas Oncology Tyler Longview
Tyler, Texas, 75702, United States
Blue Ridge Cancer Care (Oncology and Hematology Associates of Southwest Virginia)
Roanoke, Virginia, 24014, United States
Va Puget Sound Health Care System
Seattle, Washington, 98108, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109, United States
Medical Oncology Associates
Spokane, Washington, 99208, United States
Calvary Mater Newcastle
Waratah, New South Wales, 2298, Australia
Princess Alexandra Hospital
Brisbane, Queensland, 4102, Australia
Icon Cancer Foundation
South Brisbane, Queensland, 4101, Australia
Box Hill Hospital
Box Hill, Victoria, 3128, Australia
Monash Health
Clayton, Victoria, 3168, Australia
Peninsula Private Hospital
Frankston, Victoria, 3199, Australia
Royal Perth Hospital
Perth, Western Australia, 6000, Australia
Gasthuiszusters Antwerpen Sint Augustinus
Wilrijk, 2610, Belgium
Peking University Third Hospital
Beijing, Beijing Municipality, 100000, China
Beijing Friendship Hospital, Capital Medical University
Beijing, Beijing Municipality, 100050, China
Peking Union Medical College Hospital
Beijing, Beijing Municipality, 100730, China
Fujian Medical University Union Hospital
Fuzhou, Fujian, 350001, China
Quanzhou First Affliated Hospital of Fujian Medical University
Quanzhou, Fujian, 362000, China
Guangdong Provincial Peoples Hospital
Guangzhou, Guangdong, 510080, China
Nanfang Hospital of Southern Medical University
Guangzhou, Guangdong, 510515, China
Henan Cancer Hospital
Zhengzhou, Henan, 450000, China
Union Hospital of Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, 430022, China
Jiangsu Province Hospital
Nanjing, Jiangsu, 210029, China
The First Hospital of Jilin University
Changchun, Jilin, 130021, China
Shengjing Hospital of China Medical University
Shenyang, Liaoning, 110004, China
Affiliated Zhongshan Hospital of Fudan University
Shanghai, Shanghai Municipality, 200032, China
Tongji Hospital of Tongji University
Shanghai, Shanghai Municipality, 200092, China
West China Hospital, Sichuan University
Chengdu, Sichuan, 610041, China
Institute of Hematology and Hospital of Blood Disease
Tianjin, Tianjin Municipality, 300020, China
Tianjin Medical University Cancer Institute and Hospital
Tianjin, Tianjin Municipality, 300060, China
The First Affiliated Hospital, Zhejiang University School of Medicine
Hangzhou, Zhejiang, 310003, China
The First Provincial Wenzhou Hospital of Zhejiang
Wenzhou, Zhejiang, 325000, China
Fakultni Nemocnice Brno
Brno, 62500, Czechia
Fakultni Nemocnice Hradec Kralove
Hradec Králové, 50005, Czechia
Fakultni Nemocnice Olomouc
Olomouc, 77900, Czechia
Fakultni Nemocnice Ostrava
Ostrava, 708 00, Czechia
Hopital Prive Sevigne
Cesson-Sévigné, 35510, France
Centre Hospitalier Departemental de Vendee
La Roche-sur-Yon, 85925, France
Centre Hospitalier Le Mans
Le Mans, 72037, France
Chu Hopital Lyon Sud
PierreBenite, 69495, France
Centre Hospitalier Universitaire de Poitier Hopital de La Miletrie Hopital Jean Bernard
Poitiers, 86000, France
Chu Tours Hopital Bretonneau Service Pneumologie
Tours, 37000, France
Uniklinik Koln (Aor)
Cologne, 50937, Germany
Evangelisches Krankenhaus Hamm
Hamm, 59063, Germany
Ospedale San Raffaele
Milan, 20132, Italy
Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
Milan, 20162, Italy
Fondazione Policlinico Universitario Agostino Gemelli
Roma, 00168, Italy
Azienda Ospedaliera Citta Della Salute E Della Scienza Di Torino
Torino, 10126, Italy
Gelre Ziekenhuizen
Apeldoorn, 7334 DZ, Netherlands
Albert Schweitzer Ziekenhuis
Nijmegen, 6525 GA, Netherlands
Middlemore Clinical Trials
Auckland, 2025, New Zealand
Christchurch Hospital (Canterbury Health Laboratories)
Christchurch, 8011, New Zealand
Waikato Hospital
Hamilton, 3204, New Zealand
North Shore Hospital
Takapuna, 0622, New Zealand
Tauranga Hospital
Tauranga, 3112, New Zealand
Wellington Regional Hospital (Ccdhb)
Wellington, 6021, New Zealand
Interhem Opieka Szpitalna
Bialystok, 15748, Poland
Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
Brzozów, 36-200, Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
Chorzów, 41-500, Poland
Copernicus Podmiot Leczniczy Sp Z Oo Wojewodzkie Centrum Onkologii
Gdansk, 80-219, Poland
Uniwersyteckie Centrum Kliniczne
Gdansk, 80-952, Poland
Malopolskie Centrum Medyczne Sc
Krakow, 30-510, Poland
Wojewodzki Szpital Specjalistyczny W Legnicy
Legnica, 59-220, Poland
Wielospecjalistyczne Centrum Onkologii I Traumatologii Im M Kopernika W Lodzi
Lodz, 93-510, Poland
Examen Sp Z Oo
Poznan, 60-569, Poland
Hospital Universitari Germans Trias I Pujol
Badalona, 08916, Spain
Hospital de La Santa Creu I Sant Pau
Barcelona, 08025, Spain
Hospital Universitario Vall Dhebron
Barcelona, 08035, Spain
Hospital Clinic I Provincial
Barcelona, 08036, Spain
Ico Girona
Girona, 17007, Spain
Hospital Universitario Ramon Y Cajal
Madrid, 28034, Spain
Hospital Universitario La Paz
Madrid, 28046, Spain
Hospital Universitario Puerta de Hierro Majadahonda
Majadahonda, 28222, Spain
Hospital Universitario Marques de Valdecilla
Santander, 39008, Spain
Hospital Virgen de La Salud
Toledo, 45004, Spain
Skanes Universitetssjukhus I Lund
Lund, 221 85, Sweden
Karolinska Universitetssjukhuset Solna
Stockholm, 171 76, Sweden
Namik Kemal University
Tekirdağ, 59100, Turkey (Türkiye)
Nhs Grampian Ppds
Aberdeen, AB25 2ZN, United Kingdom
Birmingham Heartlands Hospital
Birmingham, B9 5SS, United Kingdom
The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
Bournemouth, BH7 7DW, United Kingdom
Kent and Canterbury Hospital
Canterbury, CT1 3NG, United Kingdom
St Jamess Institute of Oncology
Leeds, LS9 7LP, United Kingdom
Barts Health Nhs Trust
London, EC1A 7BE, United Kingdom
Norfolk and Norwich University Hospitals Nhs Foundation Trust
Norwich, NR4 7UY, United Kingdom
Nottingham University Hospitals Nhs Trust
Nottingham, NG51PB, United Kingdom
Derriford Hospital
Plymouth, PL6 8DH, United Kingdom
Southampton General Hospital
Southampton, SO16 6YD, United Kingdom
Sunderland Royal Hospital
Sunderland, SR4 7TP, United Kingdom
Genesiscare Oxford
Waterlooville, PO7 7XX, United Kingdom
Related Publications (10)
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.
PMID: 36511784BACKGROUNDHillmen 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.
PMID: 36395435BACKGROUNDHillmen 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.
PMID: 32207333RESULTRhee JW, Lamanna N, Aldairy W, Chen L, Zhang J, Ramirez D, White WB. Hypertension in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma in ALPINE: a secondary analysis. Blood Neoplasia. 2025 Aug 4;2(4):100150. doi: 10.1016/j.bneo.2025.100150. eCollection 2025 Nov.
PMID: 41424932DERIVEDBrown JR, Li J, Eichhorst BF, Lamanna N, O'Brien SM, Tam CS, Qiu L, Huang R, Shi Y, Idoine A, Salmi T, Cohen AC, Shadman M. Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study. Blood Adv. 2025 Apr 22;9(8):1918-1926. doi: 10.1182/bloodadvances.2024014206.
PMID: 39853273DERIVEDBrown JR, Eichhorst B, Lamanna N, O'Brien SM, Tam CS, Qiu L, Jurczak W, 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, Wang M, Salmi T, Wang L, Li J, Wu K, Cohen A, Shadman M. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024 Dec 26;144(26):2706-2717. doi: 10.1182/blood.2024024667.
PMID: 39316666DERIVEDZhou K, Wang T, Pan L, Xu W, Jin J, Zhang W, Hu Y, Hu J, Feng R, Li P, Liu Z, Liu P, Jing H, Gao S, Zhang H, Yu K, Wang Z, Zhu X, Sun Z, Li F, Yan D, Weng J, Fu L, Wang L, Salmi T, Wu K, Qiu L. Improved efficacy and safety of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) in China: a subgroup of ALPINE. Ann Hematol. 2024 Oct;103(10):4183-4191. doi: 10.1007/s00277-024-05823-8. Epub 2024 Jun 18.
PMID: 38888616DERIVEDMoslehi JJ, Furman RR, Tam CS, Salem JE, Flowers CR, Cohen A, Zhang M, Zhang J, Chen L, Ma H, Brown JR. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024 May 28;8(10):2478-2490. doi: 10.1182/bloodadvances.2023011641.
PMID: 38502198DERIVEDBrown 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. Plain language summary of zanubrutinib or ibrutinib in chronic lymphocytic leukemia that is resistant to treatment or has come back after treatment. Future Oncol. 2024 Apr;20(12):717-726. doi: 10.2217/fon-2023-0849. Epub 2023 Dec 13.
PMID: 38088119DERIVEDTam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. doi: 10.1080/03007995.2023.2262378. Epub 2023 Oct 27.
PMID: 37752892DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Results Point of Contact
- Title
- Study Director
- Organization
- BeiGene
Study Officials
- STUDY DIRECTOR
Study Director
BeiGene
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 2, 2018
First Posted
November 7, 2018
Study Start
November 1, 2018
Primary Completion
August 8, 2022
Study Completion
February 28, 2024
Last Updated
March 30, 2025
Results First Posted
July 27, 2023
Record last verified: 2025-03
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, CSR
- Time Frame
- See plan description
- Access Criteria
- See plan description
BeiGene shares data on completed studies responsibly and provides qualified scientific and medical researchers access to data and supporting documentation for clinical trials in dossiers for medicines and indications after submission and approval in the United States, China, and Europe. Clinical trials supporting subsequent local approvals, new indications, or combination products are eligible for sharing once corresponding regulatory approvals are achieved. BeiGene shares data only when permitted by applicable data privacy and security laws and regulations, when it is feasible to do so without compromising the privacy of study participants, and other considerations. Qualified researchers with appropriate competencies who are engaged in novel scientific research may submit a request for participant-level data with a research proposal for BeiGene review. Research teams must include a biostatistician and sign a Data Sharing Agreement prior to receiving access to clinical trial data.