Study of BTK Inhibitor Zanubrutinib in Participants With Relapsed/Refractory Non-GCB Type Diffuse Large B Cell Lymphoma

A Phase 2, Single Arm, Multicenter, Open-label Study of Bruton's Tyrosine Kinase (BTK) Inhibitor BGB-3111 in Subjects With Relapsed/Refractory Non-GCB Type Diffuse Large B Cell Lymphoma

Screening (up to 28 days); daily treatment until disease progression, unacceptable toxicity or death, withdrawal of consent, lost to follow-up, or study termination from sponsor; treatment (up to 2 years), safety follow-up (30 days); survival follow-up until data cutoff for final analysis.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-cell Lymphoma
• Intervention / Treatment: Drug: Zanubrutinib

Detailed Description

This is a single-arm, multicenter, open-label Phase 2 study to evaluate efficacy, safety, tolerability of BGB-3111 (zanubrutinib) in participants with relapsed/refractory non-germinal center B-cell (GCB) type diffuse large B-cell lymphoma (DLBCL).

The study will enroll approximately 40 participants treated with zanubrutinib (160 milligrams [mg]) twice daily (BID). All participants in the study were treated until disease progression, unacceptable toxicity, death, withdrawal of consent, or the study was terminated by the sponsor for final analysis. At the time of final analysis, participants who remained on treatment were considered for participation in the extension study when eligible. A treatment cycle consisted of 28 days.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150000
      • Harbin Medical University Cancer Hospital
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Henan Cancer Hospital
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • The First Affiliated Hospital of Soochow University Branch Shizi
  • Jilin
    • Changchun, Jilin, China, 130021
      • The First Hospital of Jilin University
  • Shanghai
    • Shanghai, Shanghai, China, 200000
      • Fudan University Shanghai Cancer Center
    • Shanghai, Shanghai, China, 200025
      • Rui Jin Hospital Shanghai Jiao Tong University School of Medicine
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital, Sichuan University
  • Tianjin
    • Tianjin, Tianjin, China, 300060
      • Tianjin Medical University Cancer Institute and Hospital
    • Tianjin, Tianjin, China, 300020
      • Institute of Hematology and Hospital of Blood Disease
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

1. Histologically confirmed non-germinal center DLBCL, by immunohistochemistry using the Hans algorithm:

   1. Cluster of differentiation 10 (CD10)- and B-cell lymphoma 6 protein (BCL6)-,
   2. CD10-, BCL6+, but maximal unique match+
2. Men and women ≥ 18 years of age.
3. Eastern Cooperative Oncology Group performance status of 0-2.
4. Measurable disease was defined as at least 1 lymph node > 1.5 centimeters in longest diameter and measurable in 2 perpendicular dimensions.
5. All participants must have provided fresh tumor biopsy or recent tumor tissue samples (within 2 years of study entry [informed consent form signed]).
6. Received at least one prior therapy for DLBCL that included anthracycline-based chemotherapy.
7. Participant not eligible for or refused intensive chemotherapy and hematopoietic stem cell transplant.
8. Documented failure to achieve at least partial response with, or documented disease progression after response to, the most recent treatment regimen.
9. Neutrophils ≥ 1 x 10^9/liter (L) independent of growth factor support within 7 days of study entry.
10. Platelets ≥ 75 x 10^9/L, independent of growth factor support or transfusion within 7 days of study entry.
11. Creatinine clearance of ≥ 30 milliliters/minute (as estimated by the Cockcroft-Gault equation or estimated glomerular filtration rate).
12. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN).
13. Bilirubin ≤ 2 x ULN (unless documented Gilbert's syndrome), then up to 5 x ULN allowed.
14. Independent of erythropoietin support or transfusion within 7 days of first dose of study drug.
15. International normalized ratio ≤ 1.5 and activated partial thromboplastin time ≤ 1.5 x ULN.
16. Participants may be enrolled who relapsed after autologous stem cell transplant if they are at least 6 months after transplant, participants should have had no active infections (that is, fungal or viral).
17. Females of childbearing potential must have agreed 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 were 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. Males must have undergone sterilization-vasectomy, or utilized a barrier method where the female partner utilized the effective forms of birth control noted above.
18. Life expectancy of > 3 months.
19. Able to provide written informed consent and could understand and comply with the requirements of the study.

Key Exclusion Criteria:

1. Current or history of central nervous system lymphoma.
2. Prior exposure to a BTK inhibitor.
3. Prior corticosteroids (at dosages equivalent to prednisone > 20 mg/day) given with anti-neoplastic intent within 7 days, prior chemotherapy, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapies or Chinese anti-cancer herbal therapies within 4 weeks of the start of study drug.
4. Major surgery within 4 weeks of screening.
5. Toxicity of ≥ Grade 2 from prior anti-cancer therapy (except for alopecia, absolute neutrophil count [ANC]) and platelets. For ANC and platelets, please follow inclusion criteria #9 [neutrophils] and #10 [platelets]).
6. 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.
7. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months of screening. Left ventricular ejection fraction is lower than 50% measured by echocardiography.
8. QTcF (Fridericia's correction) > 450 milliseconds or other significant electrocardiogram abnormalities including second degree atrioventricular (AV) block Type II, or third-degree AV block.
9. 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.
10. Uncontrolled systemic infection or infection requiring parenteral anti-microbial therapy.
11. Known human immunodeficiency virus, or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction).
12. Pregnant or lactating women.
13. Any life-threatening illness, medical condition or organ system dysfunction, which, in the investigator's opinion, could compromise the participant's safety, or put the study at risk.
14. On medications that were strong cytochrome P450 (CYP), family 3, subfamily A (CYP3A) inhibitors or CYP3A inducers.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zanubrutinib; Participants received zanubrutinib BID.	Drug: Zanubrutinib; Administered at a dose of 160 mg BID orally.; Other Names: BGB-3111; BRUKINSA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall response rate was defined as the percentage of participants achieving either a partial response (PR) or complete response (CR) as determined by investigator according to the 2014 modification of the International Working Group (IWG) in Non-Hodgkin's lymphoma (NHL) Criteria.	Up to approximately 23 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival was defined as the time from first dose of zanubrutinib until first documentation of progression (by IWG on NHL criteria) or death, whichever occurred first.	Up to 3 years and 2 months
Duration Of Response	Duration of response was defined as the time from the date that the response criteria were first met to the date that progressive disease was objectively documented or death, whichever occurred first. Duration of response was summarized for responders (with a best overall response of CR or PR) only.	Up to 3 years and 2 months
Time To Response	Time to response was defined as the time from the first dose of zanubrutinib to the documentation of first response. Time to response was summarized for responders (with a best overall response of CR or PR) only.	Up to 3 years and 2 months
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	A treatment-emergent adverse event was defined as an adverse event that had an onset date or a worsening in severity from baseline (pretreatment) on or after the date of first dose of study drug up to 30 days following study drug discontinuation (Safety Follow-up Visit) or initiation of new anticancer therapy, whichever occurred first.	From the time of informed consent to 30 days after the last dose of study drug (approximately Up to 3 years and 2 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival was defined as the time from first dose of zanubrutinib until death due to any cause.	Up to 3 years and 2 months

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Principal Investigator: Study Director, BeiGene

Publications and helpful links

General Publications

• Yang H, Xiang B, Song Y, Zhang H, Zhao W, Zou D, Lv F, Bai O, Liu A, Li C, Tan Z, Wang W, Gui H, Novotny W, Huang J, Li Y. Zanubrutinib monotherapy for patients with relapsed or refractory non-germinal center diffuse large B-cell lymphoma: results from a phase II, single-arm, multicenter, study. American Society of Clinical Oncology. 2020

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2017
• Primary Completion (Actual): May 24, 2019
• Study Completion (Actual): September 3, 2020

Study Registration Dates

• First Submitted: May 5, 2017
• First Submitted That Met QC Criteria: May 5, 2017
• First Posted (Actual): May 9, 2017

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Relapsed/refractory non-GCB type
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Zanubrutinib
• Other Study ID Numbers: BGB-3111-207; CTR20170091 (Registry Identifier: Center for drug evaluation, CFDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No