A Study to Investigate Zanubrutinib in Chinese Participants With B-cell Lymphoma

NCT03189524 | Completed Phase 1 Results

• 2 other identifiers: BGB-3111-1002CTR20160204
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 4

Brief Summary

This phase I clinical study was to investigate the safety, tolerability, and pharmacokinetics/pharmacodynamics of Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111) in Chinese participants with B-cell lymphoma by conducting in two stages, the first stage being the safety assessment of dose and the second stage being the dose expansion. Part I: Safety evaluation - according to the results of preclinical toxicological trials and the results of the phase I clinical study conducted in Australia and New Zealand, two regimens of zanubrutinib 320 milligrams (mg) daily (160 mg twice daily \[BID\]), administered in the morning and at night, or 320 mg once daily \[QD\]) and "3+3" design was adopted for the assessment. The recommended dose and method of administration of the phase II clinical study was determined according to the Part I results. Part II: Dose expansion - this stage was to further evaluate the preliminary anti-tumor effects of zanubrutinib in Chinese participants with follicular lymphoma (FL) or marginal zone lymphoma (MZL), approximately 20 participants with relapsed or refractory FL or MZL were to be enrolled. The recommended Phase 2 dose (RP2D) was used in Part II.

Conditions

B-cell Lymphoma

Outcome Measures

Primary Outcomes (6)

• Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events

  All adverse events were treatment emergent and were defined as an adverse event with a reported onset time or increase in severity after the initial dose of study drug and within 30 days after the last dose of study drug or initiation of new anticancer therapy, whichever was sooner. A serious adverse event was any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is significant medical event requiring intervention. All toxicity and adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) grading criteria. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

  From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month)

• Part II: Overall Response Rate (ORR) Of Zanubrutinib In Participants With FL And MZL

  Overall response in overall response rate (ORR) was defined as a participant's best overall response: CR or PR for NHL participants; CR, complete remission with incomplete blood count recovery, nodular PR, PR, or PR with lymphocytosis for the CLL participants; CR, very good PR, PR, or minor response for the Waldenström macroglobulinemia participants. ORR was defined as the percentage of participants who achieved an overall response.

  Up to 4 years and 1 month

• Part II: Complete Response Rate (CRR) Of Zanubrutinib In Participants With FL And MZL

  CRR was defined as the percentage of participants who achieved CR as the best overall response.

  Up to 4 years and 1 month

• Part II: Partial Response Rate (PRR) Of Zanubrutinib In Participants With FL And MZL

  PRR was defined as the percentage of participants who achieved PR or higher as the best overall response.

  Up to 4 years and 1 month

• Part II: Duration of Response (DOR) Of Zanubrutinib In Participants With FL And MZL

  Duration of response for responders (those who achieved an overall response of PR or better) was defined as the time interval (in number of days) between the date of the earliest qualifying response and the date of progressive disease or death for any cause (whichever occurs earlier). Duration of response analysis included only responders.

  Up to 4 years and 1 month

• Part II: Progression Free Survival (PFS) Of Zanubrutinib In Participants With FL And MZL

  Progression-free survival was defined as the time (in months) from the date of first study treatment to disease progression or death (due to any cause), whichever occurred first. For purposes of calculating PFS, the start date of progressive disease was the date at which progression was first observed. The duration and primary analysis of PFS was right-censored for participants who met 1 of the following conditions: 1) no baseline disease assessments; 2) starting a new anticancer therapy before documentation of disease progression or death; 3) death or disease progression immediately after more than 1 consecutively missed disease assessment visit; and 4) alive without documentation of disease progression before the data cutoff date.

  Up to 4 years and 1 month

Secondary Outcomes (12)

• Part I and Part II: Area Under The Plasma Concentration-time Curve From Zero To The Last Measurable Concentration (AUClast) For Single-dose Zanubrutinib

  Part 1 and 2 : Week 1 day1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, 12 and 24 hours, and Week 2-day 1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, and 12 hours (part2 only), and Week 5 and Week 9 Day 1 Pre-dose

• Part I and Part II: Area Under The Plasma Concentration-time Curve Zero To Infinity (AUC0-inf) For Single-dose Zanubrutinib

  Part 1 and 2 : Week 1 day1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, 12 and 24 hours, and Week 2-day 1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, and 12 hours (part2 only), and Week 5 and Week 9 Day 1 Pre-dose

• Part I And Part II: Maximum Plasma Concentration (Cmax) For Single-dose Zanubrutinib

  Part 1 and 2 : Week 1 day1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, 12 and 24 hours, and Week 2-day 1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, and 12 hours (part2 only), and Week 5 and Week 9 Day 1 Pre-dose

• Part I and Part II: Time To Maximum Plasma Concentration (Tmax) For Single-dose Zanubrutinib

  Part 1 and 2 : Week 1 day1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, 12 and 24 hours, and Week 2-day 1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, and 12 hours (part2 only), and Week 5 and Week 9 Day 1 Pre-dose

• Part I and Part II: Apparent Terminal Half Life (t1/2) For Single-dose Zanubrutinib

  Part 1 and 2 : Week 1 day1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, 12 and 24 hours, and Week 2-day 1 Pre-dose, 0.5, 1, 2, 3, 4, 6 (part2 only), 8, and 12 hours (part2 only), and Week 5 and Week 9 Day 1 Pre-dose

Study Arms (3)

Part I: 160 mg BID

EXPERIMENTAL

Safety Evaluation: Two regimens of zanubrutinib 320 milligrams (mg) daily (160 mg twice daily \[BID\]) administered in the morning and at night, or 320 mg (once daily \[QD\]), and a "3+3" design was adopted for Part I of the study to determine recommended Phase 2 dose (RP2D).

Drug: Zanubrutinib

Part I: 320 mg QD

EXPERIMENTAL

Safety Evaluation: Two regimens of zanubrutinib 320 mg daily (160 mg BID, administered in the morning and at night, or 320 mg QD) and a "3+3" design was adopted for Part I of the study to determine RP2D.

Drug: Zanubrutinib

Part II: 160 mg BID

EXPERIMENTAL

Dose Expansion: The RP2D determined in Part I was used in Part II to further evaluate the preliminary anti-tumor effects of zanubrutinib in Chinese participants with follicular lymphoma (FL) or marginal zone lymphoma (MZL).

Drug: Zanubrutinib

Interventions

Zanubrutinib DRUG

Zanubrutinib is a white to off-white solid that is slightly hygroscopic. The drug product was formulated as 20-mg (blue, size 3) and 80-mg (white, size 0) hard gelatin, opaque oral capsules. Zanubrutinib is classified as a Biopharmaceutics Classification System Class II compound.

Also known as: BGB-3111

Part I: 160 mg BID; Part I: 320 mg QD; Part II: 160 mg BID

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women between the age of 18-75 years.
• Participants with B-cell lymphoma (defined by World Health Organization classification) refractory or relapsed following at least one line of therapy.
• Judged by the investigator as requiring treatment.
• Eastern Cooperative Oncology Group performance status of 0-1.
• Life expectancy of at least 4 months.
• Adequate hematological function.
• Adequate renal function.
• Adequate liver function.
• Adequate coagulation function.
• Female participants of childbearing potential and non-sterile males must have practiced at least one of the following methods of birth control with partner(s) throughout the study and for 90 days after discontinuing study drug: total abstinence from sexual intercourse, double-barrier contraception, intrauterine device or hormonal contraceptive initiated at least 3 months prior to first dose of study drug.
• Male participants must not have donated sperm from start of study drug administration, until 90 days after discontinuation of treatment.

You may not qualify if:

• With central nervous system involvement of the disease.
• The pathological type of the disease had disease transformation.
• Had underdone allogeneic hematopoietic stem cell transplantation.
• Had received corticosteroid anti-neoplastic treatment within 7 days before the first dose, has received radiotherapy and chemotherapy within 4 weeks before the first dose or has received treatment with monoclonal antibody within 4 weeks before the first dose.
• Had received BTK inhibitor treatment prior to enrollment.
• Had received chemotherapy and has not yet recovered from toxicity
• Had received Chinese herbal medicine as anti-neoplastic therapy within 4 weeks before starting study treatment.
• History of other malignancies within 2 years before study.
• With uncontrolled systemic infection.
• Major surgery in the past 4 weeks.
• With known HIV, or active hepatitis B or hepatitis C virus infection.
• With cardiovascular disease of New York Heart Association Classification ≥ 3.
• Significant electrocardiogram abnormalities.
• Significant active renal, neurologic, psychiatric, hepatic or endocrinologic disease that in the investigator's opinion would adversely impact on his/her participation in the study.
• Inability to comply with study procedures.

Sponsors & Collaborators

• BeiGene: lead

Study Sites (4)

Beijing Cancer Hospital

Beijing, Beijing Municipality, 100142, China

Location

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

Wuhan, Hubei, 430030, China

Location

Jiangsu Province Hospital

Nanjing, Jiangsu, 210029, China

Location

Institute of Hematology and Hospital of Blood Disease

Tianjin, Tianjin Municipality, 300020, China

Location

Related Publications (4)

• Jun Zhu, BS, Jianyong Li, MD, Jianfeng Zhou, Yuqin Song, MD, Junyuan Qi, Wei Xu, Dengju Li, MD, Mingyuan Sun, Ling Xue, PhD, Liudi Yang, Yinwei Zhang, Lai Wang, PhD, Jane Huang, MD, Shibao Feng, PhD, Lugui Qiu, MD. BGB-3111, a Highly Specific BTK Inhibitor, Is Well Tolerated and Highly Active in Chinese Patients with Relapsed/Refractory B-Cell Malignancies: Initial Report of a Phase 1 Trial in China. Blood. 2017; 130(1): 5347. https://doi.org/10.1182/blood.V130.Suppl_1.5347.5347

  BACKGROUND

• Moslehi JJ, Furman RR, Tam CS, Salem JE, Flowers CR, Cohen A, Zhang M, Zhang J, Chen L, Ma H, Brown JR. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024 May 28;8(10):2478-2490. doi: 10.1182/bloodadvances.2023011641.

  PMID: 38502198 DERIVED

• Xu W, Yang S, Tam CS, Seymour JF, Zhou K, Opat S, Qiu L, Sun M, Wang T, Trotman J, Pan L, Gao S, Zhou J, Zhou D, Zhu J, Song Y, Hu J, Feng R, Huang H, Su D, Shi M, Li J. Zanubrutinib Monotherapy for Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. Adv Ther. 2022 Sep;39(9):4250-4265. doi: 10.1007/s12325-022-02238-7. Epub 2022 Jul 28.

  PMID: 35900694 DERIVED

• Song Y, Sun M, Qi J, Xu W, Zhou J, Li D, Li J, Qiu L, Du C, Guo H, Huang J, Tang Z, Ou Y, Wu B, Yu Y, Zhu J. A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. Br J Haematol. 2022 Jul;198(1):62-72. doi: 10.1111/bjh.18162. Epub 2022 Apr 5.

  PMID: 35383885 DERIVED

MeSH Terms

Conditions

Lymphoma, B-Cell

Interventions

zanubrutinib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Study Director
• Organization: BeiGene

clinicaltrials@beigene.com

+1-877-828-5568

Study Officials

• Study Director

  BeiGene

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2017
• First Posted: June 16, 2017
• Study Start: July 5, 2016
• Primary Completion: August 26, 2020
• Study Completion: August 26, 2020
• Last Updated: December 27, 2024
• Results First Posted: October 22, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share

Locations

CN (4)