Clinical trial NCT03189524: A Study to Investigate Zanubrutinib in Chinese Participants With B-cell Lymphoma
Official title: A Phase I Clinical Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of BTK Inhibitor BGB-3111 in Chinese Patients With B-cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: B-cell Lymphoma
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2017-06-16
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Key Inclusion Criteria:

* 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.

Key Exclusion Criteria:

* 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.
* Was currently taking anticoagulant drugs.
* Was currently taking potent cytochrome P450 3A inhibitor or inducer.
* Had stroke or cerebral hemorrhage within 6 months before enrollment.

Note: Other protocol defined Inclusion/Exclusion criteria may have applied.

Primary outcomes:
measure: Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events
timeFrame: From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month)
measure: Part II: Overall Response Rate (ORR) Of Zanubrutinib In Participants With FL And MZL
timeFrame: Up to 4 years and 1 month
measure: Part II: Complete Response Rate (CRR) Of Zanubrutinib In Participants With FL And MZL
timeFrame: Up to 4 years and 1 month
measure: Part II: Partial Response Rate (PRR) Of Zanubrutinib In Participants With FL And MZL
timeFrame: Up to 4 years and 1 month
measure: Part II: Duration of Response (DOR) Of Zanubrutinib In Participants With FL And MZL
timeFrame: Up to 4 years and 1 month
measure: Part II: Progression Free Survival (PFS) Of Zanubrutinib In Participants With FL And MZL
timeFrame: Up to 4 years and 1 month
Secondary outcomes:
measure: Part I and Part II: Area Under The Plasma Concentration-time Curve From Zero To The Last Measurable Concentration (AUClast) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Area Under The Plasma Concentration-time Curve Zero To Infinity (AUC0-inf) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I And Part II: Maximum Plasma Concentration (Cmax) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Time To Maximum Plasma Concentration (Tmax) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Apparent Terminal Half Life (t1/2) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Apparent Plasma Clearance (CL/F) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Terminal Apparent Volume Of Distribution (Vz/F) For Single-dose Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Area Under The Plasma Concentration-time Curve For Steady State (AUCss) Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Maximum Plasma Concentration At Steady State (Cmax,ss) For Zanubrutinib
timeFrame: 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
measure: Part I and Part II: Time To Steady Plasma Concentration (Tmax,ss) For Zanubrutinib
timeFrame: 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
measure: Part I: Percentage of BTK Occupied In Peripheral Blood Mononuclear Cells In Participants Who Received Zanubrutinib
timeFrame: DLT Period: Days 1 and 2 of Week 1 and Day 1 of Week 2
measure: Part II: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events
timeFrame: From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month)
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
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: Tianjin
country: China
facility: Institute of Hematology and Hospital of Blood Disease
state: Tianjin
Study officials:
affiliation: BeiGene
name: Study Director
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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
citation: 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.
citation: 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.