Clinical trial NCT03332173: Study of BTK Inhibitor BGB-3111 in Chinese Subjects With Relapsed/Refractory Waldenström's Macroglobulinemia (WM)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Waldenström's Macroglobulinemia (WM)
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-11-06
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Major Response Rate (MRR) as Assessed by the Independent Review Committee
timeFrame: Up to approximately 1 year and 9 months
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to approximately 1 year and 9 months
measure: PFS: Event-free Rate
timeFrame: Up to approximately 1 year and 9 months
measure: Overall Response Rate (ORR)
timeFrame: Up to approximately 1 year and 9 months
measure: Duration of Major Response (DOMR)
timeFrame: Up to approximately 1 year and 9 months
measure: DOMR: Event-free Rate
timeFrame: Up to approximately 1 year and 9 months
measure: Number of Participants With Resolution of Treatment-precipitating Symptoms
timeFrame: Up to approximately 1 year and 9 months
measure: Number of Participants With an Anti-lymphoma Effect
timeFrame: Up to approximately 1 year and 9 months
measure: Number of Participants With Adverse Events
timeFrame: Up to approximately 3 years and 5 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Cancer Hospital Chinese Academy of Medical Sciences
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Guangzhou
country: China
facility: Guangdong Provincial Peoples Hospital
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology
state: Hubei
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University Branch Shizi
state: Jiangsu
city: Shanghai
country: China
facility: Rui Jin Hospital Shanghai Jiao Tong University School of Medicine
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University School of Medicine
state: Zhejiang
Study officials:
affiliation: BeiGene
name: Study Director
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.