B-cell Lymphoma
Conditions
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.
Interventions
DRUGZanubrutinib
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.
Sponsors
BeiGene
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month) | 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. |
| Part II: Overall Response Rate (ORR) Of Zanubrutinib In Participants With FL And MZL | Up to 4 years and 1 month | 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. |
| Part II: Complete Response Rate (CRR) Of Zanubrutinib In Participants With FL And MZL | Up to 4 years and 1 month | CRR was defined as the percentage of participants who achieved CR as the best overall response. |
| Part II: Partial Response Rate (PRR) Of Zanubrutinib In Participants With FL And MZL | Up to 4 years and 1 month | PRR was defined as the percentage of participants who achieved PR or higher as the best overall response. |
| Part II: Duration of Response (DOR) Of Zanubrutinib In Participants With FL And MZL | Up to 4 years and 1 month | 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. |
| Part II: Progression Free Survival (PFS) Of Zanubrutinib In Participants With FL And MZL | Up to 4 years and 1 month | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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: 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: Percentage of BTK Occupied In Peripheral Blood Mononuclear Cells In Participants Who Received Zanubrutinib | DLT Period: Days 1 and 2 of Week 1 and Day 1 of Week 2 | 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. |
| Part II: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month) | 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. |
| 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 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 | — |
Countries
China
Participant flow
Recruitment details
This study was conducted at 4 centers in China, all of which enrolled participants. The first participant was dosed on 05 July 2016. As of the final database lock (15 October 2020), 44 participants were enrolled and treated with zanubrutinib (BGB-3111). Once the final analysis was completed, the study was terminated and all participants who were still on treatment were transferred to long term extension study.
Participants by arm
| Arm | Count |
|---|---|
| Part I: 160 mg BID Safety Evaluation: The participants in this dose regimen received zanubrutinib 320 mg daily (160 mg BID, administered in the morning and at night) and a 3+3 design was adopted for Part I of the study to determine RP2D. | 11 |
| Part I: 320 mg QD Safety Evaluation: The participants in this dose regimen received zanubrutinib 320 mg daily (320 mg QD) and a 3+3 design was adopted for Part I of the study to determine RP2D. | 10 |
| Part II: 160 mg BID 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 FL or MZL. | 23 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 2 | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 8 |
| Overall Study | Progressive Disease | 0 | 2 | 0 |
| Overall Study | Study terminated by Sponsor after final analysis and all remaining participants transferred to LTE | 7 | 5 | 11 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Part I: 160 mg BID | Part I: 320 mg QD | Part II: 160 mg BID | Total |
|---|---|---|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 10.65 | 52.1 years STANDARD_DEVIATION 10.57 | 48.4 years STANDARD_DEVIATION 11.85 | 50.1 years STANDARD_DEVIATION 11.18 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 10 Participants | 23 Participants | 44 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 15 Participants | 20 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 8 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 11 | 3 / 10 | 1 / 23 |
| other Total, other adverse events | 11 / 11 | 10 / 10 | 22 / 23 |
| serious Total, serious adverse events | 2 / 11 | 2 / 10 | 5 / 23 |
Outcome results
Primary
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.
Time frame: Up to 4 years and 1 month
Population: Safety Analysis Set: Included all participants who received ≥ 1 dose of zanubrutinib. The Safety Analysis Set was used for all summaries (except DLT and PK).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part I: 160 mg BID | Part II: Complete Response Rate (CRR) Of Zanubrutinib In Participants With FL And MZL | 13 Percentage of Participants |
Primary
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.
Time frame: Up to 4 years and 1 month
Population: Safety Analysis Set: Included all participants who received ≥ 1 dose of zanubrutinib. The Safety Analysis Set was used for all summaries (except DLT and PK).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part I: 160 mg BID | Part II: Duration of Response (DOR) Of Zanubrutinib In Participants With FL And MZL | 11.2 Months |
Primary
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.
Time frame: Up to 4 years and 1 month
Population: Safety Analysis Set: Included all participants who received ≥ 1 dose of zanubrutinib. The Safety Analysis Set was used for all summaries (except DLT and PK).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part I: 160 mg BID | Part II: Overall Response Rate (ORR) Of Zanubrutinib In Participants With FL And MZL | 30.4 Percentage of Participants |
Primary
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.
Time frame: Up to 4 years and 1 month
Population: Safety Analysis Set: Included all participants who received ≥ 1 dose of zanubrutinib. The Safety Analysis Set was used for all summaries (except DLT and PK).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part I: 160 mg BID | Part II: Partial Response Rate (PRR) Of Zanubrutinib In Participants With FL And MZL | 30.4 Percentage of Participants |
Primary
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.
Time frame: Up to 4 years and 1 month
Population: Safety Analysis Set: Included all participants who received ≥ 1 dose of zanubrutinib. The Safety Analysis Set was used for all summaries (except DLT and PK).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part I: 160 mg BID | Part II: Progression Free Survival (PFS) Of Zanubrutinib In Participants With FL And MZL | 5.5 Months |
Primary
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.
Time frame: From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month)
Population: Safety Analysis Set: Included all participants who received ≥ 1 dose of zanubrutinib. The Safety Analysis Set was used for all summaries (except DLT and PK).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part I: 160 mg BID | Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | Participants with ≥ 1 adverse event | 11 Participants |
| Part I: 160 mg BID | Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | Participants with serious adverse events | 2 Participants |
| Part I: 320 mg QD | Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | Participants with ≥ 1 adverse event | 10 Participants |
| Part I: 320 mg QD | Part I: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | Participants with serious adverse events | 2 Participants |
Secondary
Part I and Part II: Apparent Plasma Clearance (CL/F) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed. Participants with available data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Apparent Plasma Clearance (CL/F) For Single-dose Zanubrutinib | 251 liter/hour | Standard Deviation 194 |
| Part I: 320 mg QD | Part I and Part II: Apparent Plasma Clearance (CL/F) For Single-dose Zanubrutinib | 235 liter/hour | Standard Deviation 93.7 |
Secondary
Part I and Part II: Apparent Terminal Half Life (t1/2) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Apparent Terminal Half Life (t1/2) For Single-dose Zanubrutinib | 2.27 hour | Standard Deviation 1.21 |
| Part I: 320 mg QD | Part I and Part II: Apparent Terminal Half Life (t1/2) For Single-dose Zanubrutinib | 3.43 hour | Standard Deviation 2.23 |
Secondary
Part I and Part II: Area Under The Plasma Concentration-time Curve For Steady State (AUCss) Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed. Participants with available data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Area Under The Plasma Concentration-time Curve For Steady State (AUCss) Zanubrutinib | 738.3 nanogram/milliliter*hour | Standard Deviation 425.2 |
| Part I: 320 mg QD | Part I and Part II: Area Under The Plasma Concentration-time Curve For Steady State (AUCss) Zanubrutinib | 1277 nanogram/milliliter*hour | Standard Deviation 607.4 |
Secondary
Part I and Part II: Area Under The Plasma Concentration-time Curve From Zero To The Last Measurable Concentration (AUClast) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Area Under The Plasma Concentration-time Curve From Zero To The Last Measurable Concentration (AUClast) For Single-dose Zanubrutinib | 981.6 nanogram/milliliter*hour | Standard Deviation 619.6 |
| Part I: 320 mg QD | Part I and Part II: Area Under The Plasma Concentration-time Curve From Zero To The Last Measurable Concentration (AUClast) For Single-dose Zanubrutinib | 1404 nanogram/milliliter*hour | Standard Deviation 560.7 |
Secondary
Part I and Part II: Area Under The Plasma Concentration-time Curve Zero To Infinity (AUC0-inf) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Area Under The Plasma Concentration-time Curve Zero To Infinity (AUC0-inf) For Single-dose Zanubrutinib | 1025 nanogram/milliliter*hour | Standard Deviation 633.5 |
| Part I: 320 mg QD | Part I and Part II: Area Under The Plasma Concentration-time Curve Zero To Infinity (AUC0-inf) For Single-dose Zanubrutinib | 1537 nanogram/milliliter*hour | Standard Deviation 519 |
Secondary
Part I and Part II: Maximum Plasma Concentration At Steady State (Cmax,ss) For Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed. Participants with available data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Maximum Plasma Concentration At Steady State (Cmax,ss) For Zanubrutinib | 257 nanogram/milliliter | Standard Deviation 147 |
| Part I: 320 mg QD | Part I and Part II: Maximum Plasma Concentration At Steady State (Cmax,ss) For Zanubrutinib | 389 nanogram/milliliter | Standard Deviation 185 |
Secondary
Part I And Part II: Maximum Plasma Concentration (Cmax) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I And Part II: Maximum Plasma Concentration (Cmax) For Single-dose Zanubrutinib | 319 nanogram/milliliter | Standard Deviation 217 |
| Part I: 320 mg QD | Part I And Part II: Maximum Plasma Concentration (Cmax) For Single-dose Zanubrutinib | 409 nanogram/milliliter | Standard Deviation 149 |
Secondary
Part I and Part II: Terminal Apparent Volume Of Distribution (Vz/F) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed. Participants with available data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Terminal Apparent Volume Of Distribution (Vz/F) For Single-dose Zanubrutinib | 713 liter | Standard Deviation 512 |
| Part I: 320 mg QD | Part I and Part II: Terminal Apparent Volume Of Distribution (Vz/F) For Single-dose Zanubrutinib | 1120 liter | Standard Deviation 738 |
Secondary
Part I and Part II: Time To Maximum Plasma Concentration (Tmax) For Single-dose Zanubrutinib
Time frame: 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
Population: The PK analysis set included all participants who received ≥ 1 dose of zanubrutinib. The analysis was pre-specified to be a pooled analysis by dose level; therefore, data by individual arms was not analyzed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Time To Maximum Plasma Concentration (Tmax) For Single-dose Zanubrutinib | 2.00 hour |
| Part I: 320 mg QD | Part I and Part II: Time To Maximum Plasma Concentration (Tmax) For Single-dose Zanubrutinib | 2.50 hour |
Secondary
Part I and Part II: Time To Steady Plasma Concentration (Tmax,ss) For Zanubrutinib
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part I: 160 mg BID | Part I and Part II: Time To Steady Plasma Concentration (Tmax,ss) For Zanubrutinib | 2.00 hour |
| Part I: 320 mg QD | Part I and Part II: Time To Steady Plasma Concentration (Tmax,ss) For Zanubrutinib | 2.0 hour |
Secondary
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.
Time frame: From the date of informed consent until 30 +/- 7 days after treatment discontinuation (up to 4 years and 1 month)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part I: 160 mg BID | Part II: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | Participants with ≥ 1 adverse event | 22 Participants |
| Part I: 160 mg BID | Part II: Number Of Participants Experiencing Treatment-emergent Adverse Events And Treatment-emergent Serious Adverse Events | Participants with serious adverse events | 5 Participants |
Secondary
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.
Time frame: DLT Period: Days 1 and 2 of Week 1 and Day 1 of Week 2
Population: DLT Evaluable Set: Included all participants who received ≥ 75% of the planned doses of treatment during the DLT observation period (Day 28).Only participants with sufficient sample availability were used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part I: 160 mg BID | Part I: Percentage of BTK Occupied In Peripheral Blood Mononuclear Cells In Participants Who Received Zanubrutinib | 96.69 Percentage | Standard Deviation 5.297 |