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

Waldenström's Macroglobulinemia Clinical Trial

— ASPEN  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03053440
• Other study ID #: BGB-3111-302
• Secondary ID: 2016-002980-33
• Status: Completed
• Phase: Phase 3
• Start date: January 25, 2017
• Est. completion date: June 21, 2022

Study information

• Verified date: May 2023
• Source: BeiGene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 201
• Est. completion date: June 21, 2022
• Est. primary completion date: June 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Waldenstrom Macroglobulinemia
• Waldenström's Macroglobulinemia

Intervention

Drug:
• BGB-3111
160 mg PO BID until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor
• Ibrutinib
420 mg PO QD until progressive disease, unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Peninsula Health	Frankston	Victoria
Australia	Barwon Health, University Hospital Geelong	Geelong	Victoria
Australia	St George Hospital	Kogarah	New South Wales
Australia	Monash Medical Centre	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	St. Vincent's Hospital	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Woden Dermatology	Phillip	Australian Capital Territory
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Belgium	AZ Sint-Jan Brugge - Oostende - Campus Sint-Jan	Brugge
Belgium	University Hospital Ghent	Gent	Oost-Vlaanderen
Czechia	Fakultní nemocnice Hradec Králové	Hradec Králové
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Všeobecná fakultní nemocnice v Praze	Praha
France	CHU Clermont-Ferrand - CHU Estaing	Clermont
France	Centre Leon Berard	Lyon
France	Institut Paoli Calmettes	Marseille
France	Pitié Salpêtrière Hospital	Paris
Germany	Universitätsklinik Freiburg	Freiburg
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Germany	Universitätsklinikum Münster Hämatologie und Onkologie	Munster
Germany	SRH Kliniken Landkreis Sigmaringen GmbH	Sigmaringen
Germany	Universitätsklinikum Ulm	Ulm
Greece	General Hospital of Athens "Alexandra"	Athens	Attiki
Italy	Sant'Orsola-Malpighi Polyclinic	Bologna
Italy	Azienda Ospedaliera Spedali Civili Di Brescia	Brescia
Italy	PO A.Ferrarotto, AOU Policlinico-Vittorio Emanuele Catania	Catania
Italy	Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	Irccs Irst	Meldola
Italy	Niguarda Cancer Center Division of Hematology	Milan
Italy	Azienda Ospedaliera "Maggiore della Carità" di Novara	Novara
Italy	Università degli studi di Pavia	Pavia
Italy	Ospedale Civile S.Maria delle	Ravenna
Italy	PU A. Gemelli, Universität Cattolica del Sacro Cuore	Rome
Italy	Università degli Studi di Roma "La Sapienza"	Rome
Italy	Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino	Torino
Italy	Azienda-Ospedaliera Udine	Udine
Netherlands	Academisch Medisch Centrum Universiteit van Amsterdam	Amsterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Poland	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok
Poland	Szpital Specjalist. w Brzozowie,Podkarpacki Osrodek Onkologiczny	Brzozów
Poland	Szpital Uniwersytecki nr 2	Bydgoszcz
Poland	SPZOZ - Zespól Szpitali Miejskich	Chorzów
Poland	Szpitale Pomorskie Sp. z o.o., Szpital Morski im. PCK Gdansk	Gdynia
Poland	Malopolskie Centrum Medyczne	Krakow
Poland	Szpital Wojewodzki w Opolu Sp. z o.o.	Opole
Poland	Instytut Hematologii i Transfuzjologii w Warszawie	Warsaw
Spain	Germans Trias i Pujol University Hospital	Barcelona
Spain	H.U. Vall d´Herbon	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de Sant Pau	Barcelona
Spain	Hospital Duran i Reynals, Instituto Catalán de Oncología	Barcelona
Spain	ICO-H.U.G. Trias i Pujol	Barcelona
Spain	Hospital Universitario A Coruña	La Coruña
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Clinica Universidad de Navarra	Navarro
Spain	Complejo Asistencial Universitario de Salamanca	Salamanca
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Sweden	Hematology Center Karolinska	Stockholm
United Kingdom	The Royal Bournemouth and Christchurch Hospitals NHS Foundation	Bournemouth
United Kingdom	Churchill Hospital	Headington
United Kingdom	St James's University Hospital	Leeds
United Kingdom	St.Bartholomew's Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	Royal Gwent Hospital	Newport
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Derriford Hospital	Plymouth
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachussetts General Hospital	Boston	Massachusetts
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	City Of Hope National Medical Center	Duarte	California
United States	University of California San Diego (UCSD) - Moores Cancer Center	La Jolla	California
United States	The Sarah Cannon Research Institute	Nashville	Tennessee
United States	Weill Cornell Medial College	New York	New York
United States	Mayo Clinic	Phoenix	Arizona
United States	Desert Hematology Oncology Medical Group Inc.	Rancho Mirage	California
United States	Mayo Clinic	Rochester	Minnesota
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
BeiGene

Countries where clinical trial is conducted

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

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	Percentage of Participants With Resolution of All Treatment-precipitating Symptoms		Up to approximately 5 years and 5 months
Secondary	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
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		Up to approximately 5 years and 5 months