Clinical trial NCT03053440: A Study Comparing BGB-3111 and Ibrutinib in Participants With Waldenström's Macroglobulinemia (WM)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Waldenström's Macroglobulinemia
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-02-15
Enrollment: 201
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Up to approximately 2 years and 7 months
Secondary outcomes:
measure: Percentage of Participants Achieving Major Response Rate (MRR) as Assessed by IRC
timeFrame: Up to approximately 2 years and 7 months
measure: Duration of Response (DOR) as Assessed by IRC
timeFrame: Up to approximately 2 years and 7 months
measure: DOR as Assessed by IRC: Event -Free Rate
timeFrame: 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)
measure: Percentage of Participants Achieving Either CR or VGPR in as Assessed by the Investigator
timeFrame: Up to approximately 5 years and 5 months
measure: DOR as Assessed by the Investigator
timeFrame: Up to approximately 5 years and 5 months
measure: DOR as Assessed by the Investigator: Event-Free Rate
timeFrame: 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)
measure: Progression Free Survival (PFS) as Assessed by the IRC
timeFrame: Up to approximately 2 years and 7 months
measure: PFS as Assessed by IRC: Event-Free Rate
timeFrame: 12 and 18 months from the date of randomization (up to approximately 2 years and 7 months)
measure: PFS as Assessed by the Investigator
timeFrame: Up to approximately 5 years and 5 months
measure: PFS as Assessed by the Investigator: Event-Free Rate
timeFrame: 24,36 and 48 months from the date of randomization (up to approximately 5 years and 5 months)
measure: Percentage of Participants With Resolution of All Treatment-precipitating Symptoms
timeFrame: Up to approximately 5 years and 5 months
measure: Percentage of Participants With an Anti-Lymphoma Effect
timeFrame: Up to approximately 5 years and 5 months
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to approximately 5 years and 5 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Phoenix
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Canberra
country: Australia
facility: Paratus Clinical Research Woden
state: Australian Capital Territory
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Bedford PK
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincents Hospital Melbourne
state: Victoria
city: Frankston
country: Australia
facility: Peninsula Health Frankston
state: Victoria
city: Geelong
country: Australia
facility: Barwon Health the Geelong Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Hradec Kralove
country: Czechia
facility: Fakultni Nemocnice Hradec Kralove
city: Ostrava
country: Czechia
facility: Fakultni Nemocnice Ostrava
city: Praha
country: Czechia
facility: Vseobecna Fakultni Nemocnice V Praze
city: Lyon Cedex
country: France
facility: Centre Leon Berard
city: Sigmaringen
country: Germany
facility: Srh Kliniken Landkreis Sigmaringen
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm, Innere Medizin Iii
city: Athens
country: Greece
facility: General Hospital of Athens Alexandra
city: Bologna
country: Italy
facility: Policlinico Sorsola Malpighi, Aou Di Bologna
city: Brescia
country: Italy
facility: Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
city: Meldola
country: Italy
facility: Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst
city: Milano
country: Italy
facility: Niguarda Cancer Center Division of Hematology
city: Novara
country: Italy
facility: Aou Maggiore Della Carita
city: Pavia
country: Italy
facility: Irccs Policlinico San Matteo, Universita Degli Studi Di Pavi
city: Ravenna
country: Italy
facility: Unita Di Ematologia, Dipartimento Di Ematologia Ed Oncologia
city: Roma
country: Italy
facility: Fondazione Policlinico A Gemelli
city: Torino
country: Italy
facility: Ao Citta Della Salute E Della Scienza Di Torino Presidio O
city: Udine
country: Italy
facility: Aou Santa Maria Della Misericordia Di Udine
city: Amsterdam
country: Netherlands
facility: Amsterdam Umc Amc
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny W Bialymstoku
city: Brzozow
country: Poland
facility: Szpital Specjalist W Brzozowie,Podkarpacki Osrodek Onkologiczny
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki Nr Im Dr Jana Biziela
city: Chorzow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne Sc
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall Dhebron
city: Barcelona
country: Spain
facility: Ico H Duran I Reynals
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Start Madrid Fundacion Jimenez Diaz
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari I Politecnic La Fe
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: Bournemouth
country: United Kingdom
facility: The Royal Bournemouth and Christchurch Hospitals Nhs Foundation
city: Headington
country: United Kingdom
facility: Churchill Hospital Oxford University Hospital Nhs Trust
city: Leeds
country: United Kingdom
facility: St Jamess Institute of Oncology
city: London
country: United Kingdom
facility: Barts Health Nhs Trust
city: London
country: United Kingdom
facility: University College Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals Nhs Trust
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals Nhs Trust
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.