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
    • Canberra, Australian Capital Territory, Australia, 2606
      • Paratus Clinical Research Woden
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Bedford PK, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Fitzroy, Victoria, Australia, 3065
      • St Vincents Hospital Melbourne
    • Frankston, Victoria, Australia, 3199
      • Peninsula Health Frankston
    • Geelong, Victoria, Australia, 3220
      • Barwon Health the Geelong Hospital
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Czechia
  • Hradec Kralove, Czechia, 50005
    • Fakultni nemocnice Hradec Kralove
  • Ostrava, Czechia, 708 00
    • Fakultni Nemocnice Ostrava
  • Praha, Czechia, 10000
    • Vseobecna fakultni nemocnice v Praze
• France
  • Lyon Cedex, France, 69373
    • Centre Léon Bérard
• Germany
  • Sigmaringen, Germany, 72488
    • Srh Kliniken Landkreis Sigmaringen
  • Ulm, Germany, 89081
    • Universitaetsklinikum Ulm, Innere Medizin Iii
• Greece
  • Athens, Greece, 11528
    • General Hospital of Athens Alexandra
• Italy
  • Bologna, Italy, 40138
    • Policlinico Sorsola Malpighi, Aou Di Bologna
  • Brescia, Italy, 25123
    • Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
  • Meldola, Italy, 47014
    • Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst
  • Milano, Italy, 20162
    • Niguarda Cancer Center Division of Hematology
  • Novara, Italy, 28100
    • AOU Maggiore della Carità
  • Pavia, Italy, 27100
    • IRCCS Policlinico San Matteo, Università degli studi di Pavi
  • Ravenna, Italy, 48121
    • Unita Di Ematologia, Dipartimento Di Ematologia Ed Oncologia
  • Roma, Italy, 168
    • Fondazione Policlinico A Gemelli
  • Torino, Italy, 10126
    • Ao Citta Della Salute E Della Scienza Di Torino Presidio O
  • Udine, Italy, 33100
    • AOU Santa Maria della Misericordia di Udine
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam Umc Amc
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Poland
  • Bialystok, Poland, 15-276
    • Uniwersytecki Szpital Kliniczny w Bialymstoku
  • Brzozow, Poland, 36-200
    • Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki Nr Im Dr Jana Biziela
  • Chorzow, Poland, 41-500
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
  • Krakow, Poland, 30-510
    • Malopolskie Centrum Medyczne Sc
• Spain
  • Badalona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol
  • Barcelona, Spain, 08025
    • Hospital De La Santa Creu I Sant Pau
  • Barcelona, Spain, 8036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall dHebron
  • Barcelona, Spain, 08907
    • Ico H Duran I Reynals
  • Madrid, Spain, 28040
    • Start Madrid Fundacion Jimenez Diaz
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset Solna
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
  • Headington, United Kingdom, OX3 7LE
    • Churchill Hospital Oxford University Hospital Nhs Trust
  • Leeds, United Kingdom, LS9 7LP
    • St Jamess Institute of Oncology
  • London, United Kingdom, EC1A 7BE
    • Barts Health NHS Trust
  • London, United Kingdom, NW1 2PG
    • University College Hospital
  • Nottingham, United Kingdom, NG51PB
    • Nottingham University Hospitals NHS Trust
  • Plymouth, United Kingdom, PL6 8DH
    • Plymouth Hospitals NHS Trust
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85254
      • Mayo Clinic Phoenix
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer Center
  • 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): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Waldenstrom Macroglobulinemia; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Zanubrutinib; Ibrutinib
• 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