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

A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the Efficacy and Safety of the Bruton's Tyrosine Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects With Waldenström's Macroglobulinemia (WM)

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

Study Overview

• Status: Completed
• Conditions: Waldenström's Macroglobulinemia
• Intervention / Treatment: Drug: Ibrutinib; Drug: BGB-3111

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.

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Phillip, Australian Capital Territory, Australia, 2606
      • Woden Dermatology
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Bedford Park, South Australia, Australia
      • Flinders Medical Centre
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Peninsula Health
    • Geelong, Victoria, Australia, 3220
      • Barwon Health, University Hospital Geelong
    • Melbourne, Victoria, Australia
      • Peter MacCallum Cancer Centre
    • Melbourne, Victoria, Australia, 3065
      • St. Vincent's Hospital
    • Melbourne, Victoria, Australia
      • Monash Medical Centre
  • Western Australia
    • Nedlands, Western Australia, Australia
      • Sir Charles Gairdner Hospital
• Belgium
  • Brugge, Belgium, 8000
    • AZ Sint-Jan Brugge - Oostende - Campus Sint-Jan
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium
      • University Hospital Ghent
• Czechia
  • Hradec Králové, Czechia, 50005
    • Fakultni nemocnice Hradec Kralove
  • Ostrava, Czechia, 70852
    • Fakultni Nemocnice Ostrava
  • Praha, Czechia, 12808
    • Vseobecna fakultni nemocnice v Praze
• France
  • Clermont, France
    • CHU Clermont-Ferrand - CHU Estaing
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Marseille, France
    • Institut Paoli Calmettes
  • Paris, France, 75651
    • Pitié Salpétrière Hospital
• Germany
  • Freiburg, Germany, 79106
    • Universitätsklinik Freiburg
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • Munster, Germany, 48149
    • Universitätsklinikum Münster Hämatologie und Onkologie
  • Sigmaringen, Germany, 72488
    • SRH Kliniken Landkreis Sigmaringen GmbH
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Greece
  • Attiki
    • Athens, Attiki, Greece, 11528
      • General Hospital of Athens "Alexandra"
• Italy
  • Bologna, Italy, 40138
    • Sant'Orsola-Malpighi Polyclinic
  • Brescia, Italy, 25123
    • Azienda Ospedaliera Spedali Civili di Brescia
  • Catania, Italy, 95124
    • PO A.Ferrarotto, AOU Policlinico-Vittorio Emanuele Catania
  • Firenze, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi
  • Meldola, Italy
    • Irccs Irst
  • Milan, Italy, 20133
    • Niguarda Cancer Center Division of Hematology
  • Novara, Italy, 28100
    • Azienda Ospedaliera "Maggiore della Carità" di Novara
  • Pavia, Italy, 27100
    • Università degli studi di Pavia
  • Ravenna, Italy
    • Ospedale Civile S.Maria delle
  • Rome, Italy, 00161
    • Università degli studi di Roma "La Sapienza"
  • Rome, Italy, 00168
    • PU A. Gemelli, Universität Cattolica del Sacro Cuore
  • Torino, Italy, 10126
    • Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
  • Udine, Italy, 33100
    • Azienda-Ospedaliera Udine
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum Universiteit van Amsterdam
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Poland
  • Białystok, Poland, 15-276
    • Uniwersytecki Szpital Kliniczny w Białymstoku
  • Brzozów, Poland
    • Szpital Specjalist. w Brzozowie,Podkarpacki Ośrodek Onkologiczny
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki nr 2
  • Chorzów, Poland, 41-500
    • SPZOZ - Zespół Szpitali Miejskich
  • Gdynia, Poland
    • Szpitale Pomorskie Sp. z o.o., Szpital Morski im. PCK Gdansk
  • Krakow, Poland, 30-510
    • Małopolskie Centrum Medyczne
  • Opole, Poland
    • Szpital Wojewodzki w Opolu Sp. z o.o.
  • Warsaw, Poland
    • Instytut Hematologii i Transfuzjologii w Warszawie
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 08035
    • H.U. Vall d´Herbon
  • Barcelona, Spain, 08907
    • Hospital Duran i Reynals, Instituto Catalán de Oncología
  • Barcelona, Spain, 08916
    • Germans Trias i Pujol University Hospital
  • Barcelona, Spain, 8041
    • Hospital de Sant Pau
  • Barcelona, Spain
    • ICO-H.U.G. Trias i Pujol
  • La Coruña, Spain, 15006
    • Hospital Universitario A Coruña
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Navarro, Spain
    • Clinica Universidad de Navarra
  • Salamanca, Spain, 37007
    • Complejo Asistencial Universitario de Salamanca
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• Sweden
  • Stockholm, Sweden, 14186
    • Hematology Center Karolinska
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
  • Headington, United Kingdom, OX3 7LE
    • Churchill Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • London, United Kingdom, NW1 2PG
    • University College Hospital
  • London, United Kingdom, EC1A 7BE
    • St.Bartholomew's Hospital
  • Newport, United Kingdom, NP20 2UB
    • Royal Gwent Hospital
  • Nottingham, United Kingdom, NG51PB
    • Nottingham University Hospitals NHS Trust
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85259
      • Mayo Clinic
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92093
      • University of California San Diego (UCSD) - Moores Cancer Center
    • Rancho Mirage, California, United States, 92270
      • Desert Hematology Oncology Medical Group Inc.
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02215
      • Massachussetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medial College
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • The Sarah Cannon Research Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key 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

Key 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A : Ibrutinib; Participants with the MYD88 mutation received Ibrutinib	Drug: Ibrutinib; 420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor; Other Names: IMBRUVICA
Active Comparator: Arm B: Zanubrutinib; Participants with the MYD88 mutation received zanubrutinib	Drug: BGB-3111; 160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor; Other Names: Brukinsa; Zanubrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Either a Complete Response (CR) or Very Good Partial Response (VGPR) Using an Adaptation of the Response Criteria Updated at the Sixth International Workshop on WM as Assessed by an Independent Review Committee (IRC)	Percentage of participants with CR, defined as normal serum immunoglobulin M (IgM) levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values.	Up to approximately 2 years and 7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC	MRR defined as the percentage of participants achieving a best response of response of CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) defined as ≥50% reduction of serum IgM from baseline.	Up to approximately 2 years and 7 months
Duration of Response (DOR) as Assessed by IRC	DOR defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first. CR is defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at baseline, VGPR, is defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values or partial response (PR) is defined as ≥50% reduction of serum IgM from baseline.	Up to approximately 2 years and 7 months
DOR as Assessed by IRC: Event -Free Rate	Estimated percentage of participants who were event-free based on Kaplan-Meier method.	12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)
Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator	Percentage of participants with CR, defined as normal serum IgM levels, disappearance of monoclonal protein by immunofixation, and negative cryoglobulinemia if cryoglobulinemia was positive at Baseline, or VGPR, defined as ≥90% reduction in serum IgM level from baseline or normal serum IgM values.	Up to approximately 5 years and 5 months
DOR as Assessed by the Investigator	DOR is defined as the time from first determination of response (CR, VGPR or PR) until first documentation of progression or death, whichever comes first	Up to approximately 5 years and 5 months
DOR as Assessed by the Investigator: Event-Free Rate	Estimated percentage of participants who were event-free based on Kaplan-Meier method.	24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)
Progression Free Survival (PFS) as Assessed by the IRC	PFS as assessed by the IRC, defined as time from randomization to the first documentation of progression (per modified International Workshop on Waldenström macroglobulinemia [IWWM criteria]) or death, whichever occurs first	Up to approximately 2 years and 7 months
PFS as Assessed by IRC: Event-Free Rate	Estimated percentage of participants who were event-free based on Kaplan-Meier method	12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)
PFS as Assessed by the Investigator	PFS as assessed by the Investigator, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first.	Up to approximately 5 years and 5 months
PFS as Assessed by the Investigator: Event-Free Rate	Percentage of participants who were event-free based on Kaplan-Meier method.	24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)
Percentage of Participants With Resolution of All Treatment-precipitating Symptoms		Up to approximately 5 years and 5 months
Percentage of Participants With an Anti-Lymphoma Effect	Anti-Lymphoma Effect is defined as any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by CT scan, at any time during the course of study treatment.	Up to approximately 5 years and 5 months
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		Up to approximately 5 years and 5 months

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Study Director: Study Director, BeiGene

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2017
• Primary Completion (Actual): June 21, 2022
• Study Completion (Actual): June 21, 2022

Study Registration Dates

• First Submitted: February 7, 2017
• First Submitted That Met QC Criteria: February 12, 2017
• First Posted (Actual): February 15, 2017

Study Record Updates

• Last Update Posted (Actual): June 9, 2023
• Last Update Submitted That Met QC Criteria: May 17, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Waldenstrom Macroglobulinemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Zanubrutinib
• Other Study ID Numbers: BGB-3111-302; 2016-002980-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No