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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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B-cell Lymphoma

Intervention / Treatment
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* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: 160 mg BID<br>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<br>* 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.<br>* Other names: BGB-3111;|
| Experimental: Part I: 320 mg QD<br>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<br>* 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.<br>* Other names: BGB-3111;|
| Experimental: Part II: 160 mg BID<br>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<br>* 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.<br>* Other names: BGB-3111;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Part I and Part II: Apparent Plasma Clearance (CL/F) 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: Terminal Apparent Volume Of Distribution (Vz/F) 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 For Steady State (AUCss) 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 At Steady State (Cmax,ss) For 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 Steady Plasma Concentration (Tmax,ss) For 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: Percentage of BTK Occupied In Peripheral Blood Mononuclear Cells In Participants Who Received Zanubrutinib | The percentage of BTK occupied in peripheral blood mononuclear cells was evaluated as a biomarker for the inhibition of BTK on specified days and the average value is reported. | DLT Period: Days 1 and 2 of Week 1 and Day 1 of Week 2 | 
| Part II: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | All adverse events are treatment emergent, 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 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) |