Study of BTK Inhibitor BGB-3111 in Chinese Subjects With Relapsed/Refractory Waldenström's Macroglobulinemia (WM)

• ClinicalTrials.gov Identifier: NCT03332173
• Recruitment Status: Completed
• First Posted: November 6, 2017
• Results First Posted: March 8, 2022
• Last Update Posted: March 9, 2022
• Sponsor: BeiGene
• Information provided by (Responsible Party): BeiGene

Study Description

Brief Summary:

This was a single-arm, multicenter Phase 2 study in Chinese participants with relapsed or refractory Waldenström's macroglobulinemia who exhibited one or more of the criteria for requiring treatment based on consensus guidelines from the Seventh International Workshop on Waldenström's Macroglobulinemia (IWWM). The study comprised an initial screening phase (up to 28 days), a single-arm treatment phase, and a follow-up phase.

Condition or disease	Intervention/treatment	Phase
Waldenström's Macroglobulinemia (WM)	Drug: Zanubrutinib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 44 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Single-Arm, Open-Label, Multicenter Study of Bruton's Tyrosine Kinase (BTK) Inhibitor BGB-3111 in Chinese Subjects With Relapsed/Refractory Waldenström's Macroglobulinemia (WM)
• Actual Study Start Date: August 31, 2017
• Actual Primary Completion Date: May 8, 2019
• Actual Study Completion Date: January 11, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Zanubrutinib; Zanubrutinib 160 mg orally twice daily with or without food until progressive disease or intolerable toxicity	Drug: Zanubrutinib; Oral administration using 80 mg capsules; Other Names: BGB-3111; Brukinsa

Outcome Measures

Primary Outcome Measures :

1. Major Response Rate (MRR) as Assessed by the Independent Review Committee [ Time Frame: Up to approximately 1 year and 9 months ]
   MRR is defined as the percentage of participants who achieved complete response (CR) + very good partial response (VGPR) + partial response (PR), as assessed by an independent review committee according to modified Owen's criteria

Secondary Outcome Measures :

1. Progression Free Survival (PFS) [ Time Frame: Up to approximately 1 year and 9 months ]
   PFS is defined as the time from first dose until first documentation of progression or death, whichever comes first, as assessed by an independent review committee using modified Owen's criteria
2. PFS: Event-free Rate [ Time Frame: Up to approximately 1 year and 9 months ]
   Progression/death event-free rates were estimated by Kaplan-Meier method with 95% confidence intervals (CIs) estimated using Greenwood's formula
3. Overall Response Rate (ORR) [ Time Frame: Up to approximately 1 year and 9 months ]
   ORR is defined as the percentage of participants with a minor, partial, very good partial, and complete response, as assessed by an independent review committee using modified Owen's criteria
4. Duration of Major Response (DOMR) [ Time Frame: Up to approximately 1 year and 9 months ]
   DOMR is defined as the time from the date that the major response criteria are first met to the date that progressive disease (PD) is objectively documented or death, whichever comes first, as assessed by an independent review committee using modified Owen's criteria
5. DOMR: Event-free Rate [ Time Frame: Up to approximately 1 year and 9 months ]
   DOMR event-free rates were estimated by Kaplan-Meier method with 95% CIs estimated using Greenwood's formula
6. Number of Participants With Resolution of Treatment-precipitating Symptoms [ Time Frame: Up to approximately 1 year and 9 months ]
   Number of participants with resolution of treatment-precipitating symptoms, defined as any resolution (from "Yes" at baseline to "No" at any postbaseline point onwards during study) of the indications for initiation of therapy in WM signs and symptoms evaluation.
7. Number of Participants With an Anti-lymphoma Effect [ Time Frame: Up to approximately 1 year and 9 months ]
   Number of participants with an anti-lymphoma effect, defined as any reduction during the course of study in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or splenomegaly by computed tomography scan as assessed by an independent review committee; lymphadenopathy is defined as any node with longest diameter (LDi) > 1.5 cm and splenomegaly is defined as vertical spleen length > 13 cm
8. Number of Participants With Adverse Events [ Time Frame: Up to approximately 3 years and 5 months ]
   Number of participants with treatment-emergent adverse events (TEAEs), grade 3 or higher TEAEs, serious adverse events (SAEs), treatment-related adverse events (AEs), adverse events of special interest, and TEAEs leading to study drug discontinuation, dose reduction and treatment interruption

Eligibility Criteria

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

Criteria

Key Inclusion Criteria:

1. Clinical and definitive histologic diagnosis of WM, meeting at least one criterion for treatment according to consensus panel criteria from the Seventh IWWM.
2. WM pathology confirmation by central lab prior to study enrollment. Previous pathology report, concurrently with newly generated central lab report to be reviewed to support WM diagnosis.
3. Men and women ≥ 18 years of age.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
5. Previously treated with a minimum of 1 prior line of standard chemotherapy-containing regimen (with completion of ≥ 2 continuous treatment cycles).
6. Documented failure to achieve at least minor response or documented disease progression after response to the most recent treatment regimen.
7. Neutrophils ≥ 0.75 x 10^9/L independent of growth factor support within 7 days of first dose.
8. Platelets ≥ 50 x 10^9/L, independent of growth factor support or transfusion within 7 days of first dose.
9. Hemoglobin ≥80 g/L, independent of erythropoietin (EPO) support or transfusion within 7 days of first dose of study drug.
10. Creatinine clearance of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD]).
11. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN).
12. Bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome).
13. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN. Participants with lupus anticoagulant or acquired von Willebrand disease due to WM may be enrolled after discussion with the medical monitor.
14. ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥50%.
15. Participants who relapse after autologous stem cell transplant may be enrolled if they are at least 6 months after transplant at screening. To be eligible after transplant, participants should have no active related infections.
16. 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. Highly effective forms of birth control can be defined as abstinence, hysterectomy, bilateral oophorectomy with no menstrual bleeding for up to 6 months, intrauterine contraception, hormonal methods such as contraceptive injection, oral contraceptive, etc. Males must have undergone sterilization-vasectomy, or use a barrier method where the female partner uses the effective forms of birth control noted above and must not donate sperm for at least 90 days after last dose of study drug.
17. Life expectancy of > 4 months.
18. Able to provide written informed consent and can understand and comply with the requirements of the study.

Key Exclusion Criteria:

1. Central nervous system (CNS) involvement by WM.
2. Prior exposure to a BTK inhibitor.
3. Evidence of disease transformation.
4. Prior corticosteroids given in excess of prednisone 10 mg/day or its equivalent with antineoplastic intent within 7 days, prior chemotherapy, targeted therapy, or radiation therapy within 3 weeks, antineoplastic therapy with Chinese herbal medicine or antibody based therapies within 4 weeks of the start of study drug.
5. Major surgery within 4 weeks of randomization.
6. Toxicity of ≥ Grade 1 from prior anti-cancer therapy (except for absolute neutrophil count [ANC], platelets, and hemoglobin. For ANC, platelets, and hemoglobin, please follow inclusion criteria #7 [neutrophils], #8 [platelets], and #9 [hemoglobin]).
7. 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 (surgery or other modality) with curative intent.
8. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, uncontrolled hypertension, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 6 months of screening.
9. QTcF prolongation (defined as a QTc >480 msecs based on Fridericia's formula) or other significant ECG abnormalities including second degree atrioventricular (AV) block Type II, or third degree AV block.
10. 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.
11. Active infection including infections requiring oral or intravenous anti-microbial therapy.
12. Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction [PCR]).
13. Pregnant or lactating women.
14. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, or put the study at risk.
15. On medications which are strong CYP3A inhibitors or strong CYP3A inducers.
16. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
17. Has received allogenic hematopoietic stem cell transplantation prior to enrollment.

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

Contacts and Locations

Locations

China, Beijing

Peking Union Medical College Hospital

Beijing, Beijing, China

Peking University People's Hospital

Beijing, Beijing, China

China, Guangdong

Guangdong General Hospital

Guangzhou, Guangdong, China

China, Henan

Henan Cancer Hospital

Zhengzhou, Henan, China

China, Hubei

Tongji Hospital affiliated with Tongji Medical College of Huazhong University of Science and Technology

Wuhan, Hubei, China

China, Jiangsu

Jiangsu Province Hospital

Nanjing, Jiangsu, China

The First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, China

China, Shanghai

Ruijin Hospital, Shanghai Jiaotong University School of Medicine

Shanghai, Shanghai, China

China, Sichuan

West China Hospital, Sichuan University

Chengdu, Sichuan, China

China, Tianjin

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences

Tianjin, Tianjin, China

China, Zhejiang

The First Affiliated Hospital, College of Medicine, Zhejiang University

Hangzhou, Zhejiang, China

Sponsors and Collaborators

BeiGene

Investigators

• Principal Investigator: Study Director; BeiGene

  Study Documents (Full-Text)

Documents provided by BeiGene:

Study Protocol  [PDF] March 30, 2018

Statistical Analysis Plan  [PDF] May 15, 2019

More Information

Publications:

An G, Zhou D, Cheng S, Zhou K, Li J, Zhou J, Xie L, Jin J, Zhong L, Yan L, Guo H, Du C, Zhong J, Yu Y, Wu B, Qiu L. A Phase II Trial of the Bruton Tyrosine-Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Waldenstrom Macroglobulinemia. Clin Cancer Res. 2021 Oct 15;27(20):5492-5501. doi: 10.1158/1078-0432.CCR-21-0539. Epub 2021 Jul 12.

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT03332173
• Other Study ID Numbers: BGB-3111-210; CTR20170208 ( Registry Identifier: Center for drug evaluation, NMPA )
• First Posted: November 6, 2017
• Results First Posted: March 8, 2022
• Last Update Posted: March 9, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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