A Study Comparing BGB-3111 and Ibrutinib in Participants With Waldenström's Macroglobulinemia (WM)
- Registration Number
- NCT03053440
- Lead Sponsor
- BeiGene
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 201
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B: Zanubrutinib BGB-3111 Participants with the MYD88 mutation received zanubrutinib Arm A : Ibrutinib Ibrutinib Participants with the MYD88 mutation received Ibrutinib
- Primary Outcome Measures
Name Time Method 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) Up to approximately 2 years and 7 months 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC Up to approximately 2 years and 7 months 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.
Duration of Response (DOR) as Assessed by IRC Up to approximately 2 years and 7 months 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.
DOR as Assessed by IRC: Event -Free Rate 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months) Estimated percentage of participants who were event-free based on Kaplan-Meier method.
Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator Up to approximately 5 years and 5 months 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.
DOR as Assessed by the Investigator Up to approximately 5 years and 5 months 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
DOR as Assessed by the Investigator: Event-Free Rate 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months) Estimated percentage of participants who were event-free based on Kaplan-Meier method.
Progression Free Survival (PFS) as Assessed by the IRC Up to approximately 2 years and 7 months 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
PFS as Assessed by IRC: Event-Free Rate 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months) Estimated percentage of participants who were event-free based on Kaplan-Meier method
PFS as Assessed by the Investigator Up to approximately 5 years and 5 months 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.
PFS as Assessed by the Investigator: Event-Free Rate 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months) Percentage of participants who were event-free based on Kaplan-Meier method.
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 Up to approximately 5 years and 5 months 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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Up to approximately 5 years and 5 months
Trial Locations
- Locations (58)
Mayo Clinic Phoenix
🇺🇸Phoenix, Arizona, United States
City of Hope National Medical Center
🇺🇸Duarte, California, 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
Paratus Clinical Research Woden
🇦🇺Canberra, Australian Capital Territory, 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
Fakultni Nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Fakultni Nemocnice Ostrava
🇨🇿Ostrava, Czechia
Srh Kliniken Landkreis Sigmaringen
🇩🇪Sigmaringen, Germany
Universitaetsklinikum Ulm, Innere Medizin Iii
🇩🇪Ulm, Germany
Vseobecna Fakultni Nemocnice V Praze
🇨🇿Praha, Czechia
Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst
🇮🇹Meldola, Italy
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
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
Uniwersytecki Szpital Kliniczny W Bialymstoku
🇵🇱Bialystok, Poland
Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
🇵🇱Brzozow, Poland
Szpital Uniwersytecki Nr Im Dr Jana Biziela
🇵🇱Bydgoszcz, Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
🇵🇱Chorzow, 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
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
Nottingham University Hospitals Nhs Trust
🇬🇧Nottingham, United Kingdom
Plymouth Hospitals Nhs Trust
🇬🇧Plymouth, United Kingdom
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
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
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Centre Leon Berard
🇫🇷Lyon Cedex, France
Niguarda Cancer Center Division of Hematology
🇮🇹Milano, Italy
Universitair Medisch Centrum Utrecht
🇳🇱Utrecht, Netherlands
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
University College Hospital
🇬🇧London, United Kingdom