A Study Comparing BGB-3111 and Ibrutinib in Participants With Waldenström's Macroglobulinemia (WM)

NCT ID: NCT03053440

Last Updated: 2024-10-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 201 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-25
• Study Completion Date: 2022-06-21

Brief Summary

This study evaluated the safety, efficacy and clinical benefit of BGB-3111 (zanubrutinib) vs ibrutinib in participants with MYD88 Mutation Waldenström's Macroglobulinemia.

Detailed Description

This open-label, randomized study compared the efficacy and safety of the Bruton's Tyrosine Kinase (BTK) inhibitors BGB-3111 and ibrutinib in participants with Waldenström's Macroglobulinemia who require therapy. Participants had baseline bone marrow samples assayed for sequencing of the MYD88 gene. 201 participants with the MYD88 mutation were enrolled and randomized to receive 160 mg BGB-3111 orally twice per day (PO BID) (treatment Arm A) or to receive 420mg ibrutinib orally once per day (PO QD) (treatment Arm B) until disease progression or unacceptable toxicity.

Conditions

Waldenström's Macroglobulinemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A : Ibrutinib

Participants with the MYD88 mutation received Ibrutinib

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: DRUG

420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Arm B: Zanubrutinib

Participants with the MYD88 mutation received zanubrutinib

Group Type: ACTIVE_COMPARATOR

BGB-3111

Intervention Type: DRUG

160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Interventions

BGB-3111

160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Intervention Type: DRUG

Ibrutinib

420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Intervention Type: DRUG

Other Intervention Names

Zanubrutinib; Brukinsa; IMBRUVICA

Eligibility Criteria

Inclusion Criteria

• Clinical and definitive histologic diagnosis of WM
• Measurable disease, requiring treatment
• Participants with no prior therapy for WM, must be considered inappropriate candidates for treatment with a standard chemoimmunotherapy regimen
• Age ≥ 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Adequate bone marrow function
• Adequate renal and hepatic function
• Electrocardiogram/multigated acquisition scan (ECHO/MUGA) demonstrating left ventricular ejection fraction (LVEF)≥ the lower limit of institutional normal
• Participants may be enrolled who relapse after autologous stem cell transplant if they are at least 3 months after transplant, and after allogeneic transplant if they are at least 6 months post-transplant.
• Females of childbearing potential must agree to use highly effective forms of birth control throughout the course of the study and at least up to 90 days after last dose of study drug. Males must have undergone sterilization- vasectomy, or utilize a barrier method
• Life expectancy of > 4 months

Exclusion Criteria

• Prior exposure to a BTK inhibitor
• Evidence of disease transformation at the time of study entry
• Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy given with antineoplastic intent, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapy within 4 weeks of the start of study drug
• Major surgery within 4 weeks of study treatment
• Toxicity of ≥ Grade 2 from prior anticancer therapy
• History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally with curative intent
• Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease within 6 months of screening
• QTcF prolongation (defined as a QTcF > 480 msec)
• Active, clinically significant Electrocardiogram (ECG) abnormalities
• Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
• Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy
• Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C
• Pregnant or lactating women
• Any life-threatening illness, medical condition, organ system dysfunction, need for profound anticoagulation, or bleeding disorder, which, in the investigator's opinion, could compromise the subject's safety
• Any medications which are strong or moderate cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BeiGene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

BeiGene

Locations

Mayo Clinic Phoenix

Phoenix, Arizona, United States

City of Hope National Medical Center

Duarte, California, United States

Colorado Blood Cancer Institute

Denver, Colorado, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Sarah Cannon Cancer Center

Nashville, Tennessee, United States

Seattle Cancer Care Alliance

Seattle, Washington, United States

Paratus Clinical Research Woden

Canberra, Australian Capital Territory, Australia

St George Hospital

Kogarah, New South Wales, Australia

Royal North Shore Hospital

St Leonards, New South Wales, Australia

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Flinders Medical Centre

Bedford PK, South Australia, Australia

Monash Health

Clayton, Victoria, Australia

St Vincents Hospital Melbourne

Fitzroy, Victoria, Australia

Peninsula Health Frankston

Frankston, Victoria, Australia

Barwon Health the Geelong Hospital

Geelong, Victoria, Australia

Peter Maccallum Cancer Centre

Melbourne, Victoria, Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Fakultni Nemocnice Hradec Kralove

Hradec Králové, , Czechia

Fakultni Nemocnice Ostrava

Ostrava, , Czechia

Vseobecna Fakultni Nemocnice V Praze

Prague, , Czechia

Centre Leon Berard

Lyon, , France

Srh Kliniken Landkreis Sigmaringen

Sigmaringen, , Germany

Universitaetsklinikum Ulm, Innere Medizin Iii

Ulm, , Germany

General Hospital of Athens Alexandra

Athens, , Greece

Policlinico Sorsola Malpighi, Aou Di Bologna

Bologna, , Italy

Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia

Brescia, , Italy

Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst

Meldola, , Italy

Niguarda Cancer Center Division of Hematology

Milan, , Italy

Aou Maggiore Della Carita

Novara, , Italy

Irccs Policlinico San Matteo, Universita Degli Studi Di Pavi

Pavia, , Italy

Unita Di Ematologia, Dipartimento Di Ematologia Ed Oncologia

Ravenna, , Italy

Fondazione Policlinico A Gemelli

Roma, , Italy

Ao Citta Della Salute E Della Scienza Di Torino Presidio O

Torino, , Italy

Aou Santa Maria Della Misericordia Di Udine

Udine, , Italy

Amsterdam Umc Amc

Amsterdam, , Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Uniwersytecki Szpital Kliniczny W Bialymstoku

Bialystok, , Poland

Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny

Brzozów, , Poland

Szpital Uniwersytecki Nr Im Dr Jana Biziela

Bydgoszcz, , Poland

Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich

Chorzów, , Poland

Malopolskie Centrum Medyczne Sc

Krakow, , Poland

Hospital Universitari Germans Trias I Pujol

Badalona, , Spain

Hospital de La Santa Creu I Sant Pau

Barcelona, , Spain

Hospital Universitario Vall Dhebron

Barcelona, , Spain

Ico H Duran I Reynals

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Start Madrid Fundacion Jimenez Diaz

Madrid, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Hospital Universitari I Politecnic La Fe

Valencia, , Spain

Karolinska Universitetssjukhuset Solna

Stockholm, , Sweden

The Royal Bournemouth and Christchurch Hospitals Nhs Foundation

Bournemouth, , United Kingdom

Churchill Hospital Oxford University Hospital Nhs Trust

Headington, , United Kingdom

St Jamess Institute of Oncology

Leeds, , United Kingdom

Barts Health Nhs Trust

London, , United Kingdom

University College Hospital

London, , United Kingdom

Nottingham University Hospitals Nhs Trust

Nottingham, , United Kingdom

Plymouth Hospitals Nhs Trust

Plymouth, , United Kingdom

Countries

United States; Australia; Czechia; France; Germany; Greece; Italy; Netherlands; Poland; Spain; Sweden; United Kingdom

References

Tam CS, LeBlond V, Novotny W, Owen RG, Tedeschi A, Atwal S, Cohen A, Huang J, Buske C. A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia. Future Oncol. 2018 Sep;14(22):2229-2237. doi: 10.2217/fon-2018-0163. Epub 2018 Jun 5.

Reference Type: RESULT

PMID: 29869556 (View on PubMed)

Garcia-Sanz R, Owen RG, Jurczak W, Dimopoulos MA, McCarthy H, Cull G, Opat SS, Castillo JJ, Kersten MJ, Wahlin BE, Grosicki S, Prathikanti R, Tian T, Allewelt H, Cohen A, Tam CS. Outcomes following transition from ibrutinib to zanubrutinib in patients with Waldenstrom macroglobulinemia from ASPEN. Blood Adv. 2025 Sep 9:bloodadvances.2024015596. doi: 10.1182/bloodadvances.2024015596. Online ahead of print.

Reference Type: DERIVED

PMID: 40924923 (View on PubMed)

Heyman BM, Opat SS, Wahlin BE, Dimopoulos MC, Castillo JJ, Tedeschi A, Tam CS, Buske C, Owen RG, Leblond V, Trotman J, Barnes G, Chan WY, Schneider J, Allewelt H, Cohen A, Matous JV. Peripheral neuropathy in the phase 3 ASPEN study of Bruton tyrosine kinase inhibitors for Waldenstrom macroglobulinemia. Blood Adv. 2025 Feb 25;9(4):722-728. doi: 10.1182/bloodadvances.2024014115.

Reference Type: DERIVED

PMID: 39626287 (View on PubMed)

Tedeschi A, Tam CS, Owen RG, Buske C, Leblond V, Dimopoulos M, Garcia-Sanz R, Castillo JJ, Trotman J, Treon SP, Yang K, Tang B, Allewelt H, Patel S, Chan WY, Cohen A, Chen S, Barnes G. Health-related quality of life in patients with Waldenstrom macroglobulinemia: results from the ASPEN trial. Future Oncol. 2024;20(25):1789-1798. doi: 10.1080/14796694.2024.2355079. Epub 2024 Jul 29.

Reference Type: DERIVED

PMID: 39072392 (View on PubMed)

Moslehi 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.

Reference Type: DERIVED

PMID: 38502198 (View on PubMed)

Dimopoulos MA, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Garcia-Sanz R, McCarthy H, Mulligan S, Tedeschi A, Castillo JJ, Czyz J, Fernandez de Larrea C, Belada D, Libby E, Matous J, Motta M, Siddiqi T, Tani M, Trneny M, Minnema MC, Buske C, Leblond V, Treon SP, Trotman J, Chan WY, Schneider J, Allewelt H, Patel S, Cohen A, Tam CS. Zanubrutinib Versus Ibrutinib in Symptomatic Waldenstrom Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study. J Clin Oncol. 2023 Nov 20;41(33):5099-5106. doi: 10.1200/JCO.22.02830. Epub 2023 Jul 21.

Reference Type: DERIVED

PMID: 37478390 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002980-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BGB-3111-302

Identifier Type: -

Identifier Source: org_study_id