B-cell Malignancies
Conditions
Brief summary
This study evaluated the safety, tolerability, pharmacokinetic profile and efficacy of BGB-3111 in participants with B-cell lymphoid malignancies.
Interventions
DRUGZanubrutinib
Oral administration by capsule
Sponsors
BeiGene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Aged ≥ 18 years, voluntarily consented to the study. 2. WHO classification defined B-lymphoid malignancy, with the exception of Burkitt lymphoma/leukemia, plasma cell myeloma, acute lymphoblastic leukemia, lymphoblastic lymphoma, and plasmablastic lymphoma. 3. Requirement for treatment in the opinion of the investigator. 4. Disease which has relapsed, or is refractory, following at least one line of therapy, with no therapy of higher priority available. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. Adequate hematologic function, as defined by neutrophils ≥ 1.0 x 10\^9/L and platelets ≥ 50 x 10\^9/L; participants with neutrophils \< 1.0 x 10\^9/L due to marrow infiltration are allowed to receive growth factors to bring pre-treatment neutrophils to ≥ 1.0 x 10\^9/L. 7. Adequate renal function, as defined by creatinine clearance of ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24 hour urine collection). 8. Adequate liver function, as defined by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN), and bilirubin ≤ 1.5 x ULN (unless documented Gilbert's syndrome). 9. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN. 10. Female participants of childbearing potential and non-sterile males must practice 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, IUD or hormonal contraceptive initiated at least 3 months prior to first dose of study drug. 11. Male participants must not donate sperm from initial study drug administration, until 90 days after drug discontinuation.
Exclusion criteria
1. Current central nervous system (CNS) involvement by disease 2. Current histologically transformed disease. 3. Prior Bruton's tyrosine kinase (BTK) inhibitor treatment. 4. Allogeneic stem cell transplantation within 6 months, or has active graft-versus-host disease (GVHD) requiring ongoing immunosuppression. 5. Receipt of the following treatment prior to first dose of zanubrutinib: corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 2 weeks, monoclonal antibody within 4 weeks. 6. Not recovered from toxicity of any prior chemotherapy to grade ≤ 1. 7. 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. 8. Uncontrolled systemic infection requiring parenteral anti-microbial therapy. 9. Major surgery in the past 4 weeks. 10. Known HIV, or active hepatitis B or hepatitis C infection (detected positive by PCR). 11. Cardiovascular disease resulting in New York Heart Association function status of ≥ 3. 12. Significant active renal, neurologic, psychiatric, hepatic or endocrinologic disease that in the investigator's opinion would adversely impact on his/her participating in the study. 13. Inability to comply with study procedures. 14. On medications which are cytochrome P450 (CYP) 3A inhibitors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and Part 2: Number of Participants With Adverse Events | Up to approximately 6 years and 7 months | Number of participants with adverse events and serious adverse events, including clinically relevant physical examinations and laboratory measurements |
| Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib | Month 9 | RP2D for zanubrutinib was the maximum tolerated dose (MTD) or less, which was determined by testing increasing doses up to 320 mg QD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
| Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
| Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
| Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
| Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F) | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
| Part 1 and Part 2: Overall Response Rate (ORR) | Up to 6 years and 7 months | ORR is defined as the percentage of participants with partial or complete response (CR), as assessed by the investigator. For CLL/SLL, ORR includes partial response (PR) with lymphocytosis (PR-L) or better (includes PR-L, PR, nodular PR or nPR and CR with incomplete marrow recovery or CRi) and for MW, ORR includes minor response or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL). |
| Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
| Part 1 and Part 2: Partial Response (PR) or Better | Up to 6 years and 7 months | PR or better is defined as the percentage of participants who achieve a partial response or better, as assessed by the investigator. For CLL/SLL, includes PR, nPR, CRi, CR and for WM includes PR, VGPR, and CR. Efficacy results are reported for the B-cell malignancy subtypes chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Waldenström macroglobulinemia (WM). |
| Part 1 and Part 2: Progression-free Survival (PFS) | Up to 6 years and 7 months | PFS is defined as the time from the first dose date of study drug to the date of the earliest occurrence of progressive disease or death due to any cause, whichever occurs first. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL). |
| Part 1 and Part 2: Overall Survival (OS) | Up to 6 years and 7 months | OS is defined as the time from the date of the first dose to death due to any cause. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL). |
| Part 1 and Part 2: Duration of Response (DOR) | Up to 6 years and 7 months | DOR for responders is defined as time from the date of the earliest qualifying response to the date of progressive disease or death for any cause, whichever occurs earlier. Efficacy results are reported for responders (defined as PR or better, except CLL/SLL and WM) in each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; PR with lymphocytosis or better), Waldenstrom macroglobulinemia (WM; minor response or better), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL). |
| Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy | Week 1 Day 1 (W1D1) predose, W1D1 4 hours, W1D2 24 hours, W1D3 predose, and W2D1 predose | Number of participants with greater than 75% BTK occupancy of zanubrutinib in peripheral blood mononuclear cells (PBMCs) |
| Part 1 and Part 2: Complete Response Rate (CRR) | Up to 6 years and 7 months | CRR is defined as the percentage of participants who achieve a complete response, as assessed by the investigator. For CLL/SLL, CRR includes CRi or better. For WM, CRR includes very good partial response (VGPR) or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL). |
| Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib | Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours | — |
Countries
Australia, Italy, New Zealand, South Korea, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 2 parts. The dose escalation part (Part 1) determined the recommended phase 2 dose (RP2D) and regimen and the dose expansion part (Part 2) further characterized the safety and efficacy at the RP2D.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: 40 mg QD Participants received 40 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up | 3 |
| Part 1: 80 mg QD Participants received 80 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up | 4 |
| Part 1: 160 mg QD Participants received 160 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up | 5 |
| Part 1 and Part 2: 160 mg BID Part 1: Participants received 160 mg of zanubrutinib twice daily (BID) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types. | 278 |
| Part 1 and Part 2: 320 mg QD Part 1: Participants received 320 mg of zanubrutinib once daily (QD) orally until disease progression, intolerance or death, withdrawal of consent, or loss to follow-up were evaluated. Part 2: This dose regimen was selected for further evaluation in various expansion cohorts that span multiple disease types. | 95 |
| Total | 385 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part 1: Dose Escalation | Death | 1 | 2 | 2 | 2 | 1 |
| Part 1: Dose Escalation | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Part 1: Dose Escalation | Sponsor decision | 1 | 2 | 3 | 2 | 0 |
| Part 2: Expansion | Adverse Event | 0 | 0 | 0 | 1 | 1 |
| Part 2: Expansion | Death | 0 | 0 | 0 | 74 | 17 |
| Part 2: Expansion | Lost to Follow-up | 0 | 0 | 0 | 5 | 2 |
| Part 2: Expansion | Other | 0 | 0 | 0 | 1 | 5 |
| Part 2: Expansion | Sponsor decision | 0 | 0 | 0 | 165 | 67 |
| Part 2: Expansion | Withdrawal by Subject | 0 | 0 | 0 | 28 | 2 |
Baseline characteristics
| Characteristic | Part 1: 40 mg QD | Part 1: 80 mg QD | Part 1: 160 mg QD | Part 1 and Part 2: 160 mg BID | Part 1 and Part 2: 320 mg QD | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.7 Years STANDARD_DEVIATION 9.45 | 62.3 Years STANDARD_DEVIATION 14.38 | 72.6 Years STANDARD_DEVIATION 8.88 | 66.4 Years STANDARD_DEVIATION 11.21 | 65.8 Years STANDARD_DEVIATION 11.24 | 66.3 Years STANDARD_DEVIATION 11.19 |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 47 Participants | 5 Participants | 53 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiians or other Pacific Islanders | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 18 Participants | 2 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 4 Participants | 5 Participants | 205 Participants | 87 Participants | 303 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 86 Participants | 20 Participants | 109 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 192 Participants | 75 Participants | 276 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 4 | 2 / 5 | 76 / 278 | 19 / 95 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 5 / 5 | 273 / 278 | 94 / 95 |
| serious Total, serious adverse events | 1 / 3 | 2 / 4 | 3 / 5 | 157 / 278 | 45 / 95 |
Outcome results
Primary
Part 1 and Part 2: Number of Participants With Adverse Events
Number of participants with adverse events and serious adverse events, including clinically relevant physical examinations and laboratory measurements
Time frame: Up to approximately 6 years and 7 months
Population: The Safety Analysis Set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | At least one treatment-emergent adverse event | 3 Participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | Serious adverse events | 1 Participants |
| Part 1: 80 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | Serious adverse events | 2 Participants |
| Part 1: 80 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | At least one treatment-emergent adverse event | 4 Participants |
| Part 1: 160 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | Serious adverse events | 3 Participants |
| Part 1: 160 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | At least one treatment-emergent adverse event | 5 Participants |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Number of Participants With Adverse Events | At least one treatment-emergent adverse event | 274 Participants |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Number of Participants With Adverse Events | Serious adverse events | 157 Participants |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | Serious adverse events | 45 Participants |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Number of Participants With Adverse Events | At least one treatment-emergent adverse event | 94 Participants |
Primary
Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib
RP2D for zanubrutinib was the maximum tolerated dose (MTD) or less, which was determined by testing increasing doses up to 320 mg QD
Time frame: Month 9
Population: The Safety Analysis Set included all participants who received ≥ 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: 40 mg QD | Part 1: Recommended Phase 2 Dose (RP2D) for Zanubrutinib | 320 milligrams |
Secondary
Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy
Number of participants with greater than 75% BTK occupancy of zanubrutinib in peripheral blood mononuclear cells (PBMCs)
Time frame: Week 1 Day 1 (W1D1) predose, W1D1 4 hours, W1D2 24 hours, W1D3 predose, and W2D1 predose
Population: Pharmacodynamic analysis set consisted of participants in which PBMCs were collected and evaluable samples were obtained.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: 40 mg QD | Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy | 3 Participants |
| Part 1: 80 mg QD | Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy | 4 Participants |
| Part 1: 160 mg QD | Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy | 5 Participants |
| Parts 1 and 2: 160 mg BID | Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy | 20 Participants |
| Parts 1 and 2: 320 mg QD | Number of Participants With Greater Than 75% Bruton's Tyrosine Kinase (BTK) Occupancy | 9 Participants |
Secondary
Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib | 133 Liters/hour | Geometric Coefficient of Variation 51.5 |
| Part 1: 80 mg QD | Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib | 174 Liters/hour | Geometric Coefficient of Variation 100.6 |
| Part 1: 160 mg QD | Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib | 106 Liters/hour | Geometric Coefficient of Variation 52.7 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib | 128 Liters/hour | Geometric Coefficient of Variation 59.4 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Apparent Clearance (CL/F) of Zanubrutinib | 126 Liters/hour | Geometric Coefficient of Variation 47.8 |
Secondary
Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib | 1.94 Hours | Geometric Coefficient of Variation 28.5 |
| Part 1: 80 mg QD | Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib | 1.97 Hours | Geometric Coefficient of Variation 29.8 |
| Part 1: 160 mg QD | Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib | 3.87 Hours | Geometric Coefficient of Variation 24.9 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib | 2.73 Hours | Geometric Coefficient of Variation 60.2 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Apparent Terminal Half-life (t1/2) of Zanubrutinib | 3.30 Hours | Geometric Coefficient of Variation 61.2 |
Secondary
Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F)
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F) | 371 Liters | Geometric Coefficient of Variation 47.5 |
| Part 1: 80 mg QD | Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F) | 494 Liters | Geometric Coefficient of Variation 78.9 |
| Part 1: 160 mg QD | Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F) | 593 Liters | Geometric Coefficient of Variation 61.6 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F) | 530 Liters | Geometric Coefficient of Variation 70 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Apparent Volume of Distribution of Zanubrutinib During the Terminal Phase (Vz/F) | 600 Liters | Geometric Coefficient of Variation 97.6 |
Secondary
Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib | 301.1 nanograms/milliliters*hour | Geometric Coefficient of Variation 51.5 |
| Part 1: 80 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib | 460.0 nanograms/milliliters*hour | Geometric Coefficient of Variation 100.6 |
| Part 1: 160 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib | 1505 nanograms/milliliters*hour | Geometric Coefficient of Variation 52.7 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib | 1253 nanograms/milliliters*hour | Geometric Coefficient of Variation 59 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Zanubrutinib | 2538 nanograms/milliliters*hour | Geometric Coefficient of Variation 47.8 |
Secondary
Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The pharmacokinetic (PK) analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib | 274.7 nanograms/milliliters*hour | Geometric Coefficient of Variation 47.8 |
| Part 1: 80 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib | 436.8 nanograms/milliliters*hour | Geometric Coefficient of Variation 103.5 |
| Part 1: 160 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib | 1480 nanograms/milliliters*hour | Geometric Coefficient of Variation 53 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib | 1132 nanograms/milliliters*hour | Geometric Coefficient of Variation 61.1 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Area Under the Curve From Time 0 to the Last Sampling Time Point Within the Dose Interval (AUClast) of Zanubrutinib | 2281 nanograms/milliliters*hour | Geometric Coefficient of Variation 60.5 |
Secondary
Part 1 and Part 2: Complete Response Rate (CRR)
CRR is defined as the percentage of participants who achieve a complete response, as assessed by the investigator. For CLL/SLL, CRR includes CRi or better. For WM, CRR includes very good partial response (VGPR) or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time frame: Up to 6 years and 7 months
Population: Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | CLL/SLL | 16.8 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | HCL | 16.7 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | WM | 46.6 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | MCL | 28.1 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | MZL | 20.0 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | FL | 18.2 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | DLBCL | 24.4 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Complete Response Rate (CRR) | RT | 15.4 Percentage of participants |
Secondary
Part 1 and Part 2: Duration of Response (DOR)
DOR for responders is defined as time from the date of the earliest qualifying response to the date of progressive disease or death for any cause, whichever occurs earlier. Efficacy results are reported for responders (defined as PR or better, except CLL/SLL and WM) in each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; PR with lymphocytosis or better), Waldenstrom macroglobulinemia (WM; minor response or better), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time frame: Up to 6 years and 7 months
Population: Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | WM | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | CLL/SLL | 58.6 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | MCL | 28.2 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | MZL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | FL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | DLBCL | 14.2 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | RT | 25.9 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Duration of Response (DOR) | HCL | NA Months |
Secondary
Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 86.0 nanograms/milliliter | Geometric Coefficient of Variation 46.6 |
| Part 1: 80 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 125 nanograms/milliliter | Geometric Coefficient of Variation 77.6 |
| Part 1: 160 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 397 nanograms/milliliter | Geometric Coefficient of Variation 76.1 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 304 nanograms/milliliter | Geometric Coefficient of Variation 63.8 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 566 nanograms/milliliter | Geometric Coefficient of Variation 65.6 |
Secondary
Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib
Time frame: Week 2 Day 1 pre-dose and 24 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 75.7 nanograms/milliliter | Geometric Coefficient of Variation 36.2 |
| Part 1: 80 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 169 nanograms/milliliter | Geometric Coefficient of Variation 50 |
| Part 1: 160 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 387 nanograms/milliliter | Geometric Coefficient of Variation 60.7 |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 299 nanograms/milliliter | Geometric Coefficient of Variation 56.1 |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) After Administration of Zanubrutinib | 533 nanograms/milliliter | Geometric Coefficient of Variation 55 |
Secondary
Part 1 and Part 2: Overall Response Rate (ORR)
ORR is defined as the percentage of participants with partial or complete response (CR), as assessed by the investigator. For CLL/SLL, ORR includes partial response (PR) with lymphocytosis (PR-L) or better (includes PR-L, PR, nodular PR or nPR and CR with incomplete marrow recovery or CRi) and for MW, ORR includes minor response or better. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time frame: Up to 6 years and 7 months
Population: Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | MCL | 82.5 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | FL | 36.4 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | RT | 61.5 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | CLL/SLL | 95.2 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | WM | 95.9 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | MZL | 85.0 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | DLBCL | 42.2 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Response Rate (ORR) | HCL | 58.3 Percentage of participants |
Secondary
Part 1 and Part 2: Overall Survival (OS)
OS is defined as the time from the date of the first dose to death due to any cause. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time frame: Up to 6 years and 7 months
Population: Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | FL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | CLL/SLL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | WM | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | MCL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | MZL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | DLBCL | 14.7 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | RT | 29.3 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Overall Survival (OS) | HCL | NA Months |
Secondary
Part 1 and Part 2: Partial Response (PR) or Better
PR or better is defined as the percentage of participants who achieve a partial response or better, as assessed by the investigator. For CLL/SLL, includes PR, nPR, CRi, CR and for WM includes PR, VGPR, and CR. Efficacy results are reported for the B-cell malignancy subtypes chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Waldenström macroglobulinemia (WM).
Time frame: Up to 6 years and 7 months
Population: Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Partial Response (PR) or Better | CLL/SLL | 92.0 Percentage of participants |
| Part 1: 40 mg QD | Part 1 and Part 2: Partial Response (PR) or Better | WM | 82.2 Percentage of participants |
Secondary
Part 1 and Part 2: Progression-free Survival (PFS)
PFS is defined as the time from the first dose date of study drug to the date of the earliest occurrence of progressive disease or death due to any cause, whichever occurs first. Efficacy results are reported for each of the B-cell malignancy subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Richter's Transformation (RT), and Hairy cell leukemia (HCL).
Time frame: Up to 6 years and 7 months
Population: Efficacy Evaluable Set consists of all participants who received at least one dose of zanubrutinib; for WM, participants also must have a baseline IgM (or M-protein) ≥ 5 g/L and no prior exposure to a BTK inhibitor.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | CLL/SLL | 61.4 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | WM | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | MCL | 27.6 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | MZL | NA Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | FL | 10.4 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | DLBCL | 4.1 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | RT | 17.3 Months |
| Part 1: 40 mg QD | Part 1 and Part 2: Progression-free Survival (PFS) | HCL | NA Months |
Secondary
Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib
Time frame: Week 2 Day 1 pre-dose and 24 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |
| Part 1: 80 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.50 Hours |
| Part 1: 160 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |
Secondary
Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib
Time frame: Week 1 Day 1 pre-dose, 0.5, 1, 2, 3, 4, and 8 hours
Population: The PK analysis set included all participants for whom valid zanubrutinib PK parameters could be estimated, shown as overall number analyzed. Only participants with available data per dose were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: 40 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 1.00 Hours |
| Part 1: 80 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |
| Part 1: 160 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 1.92 Hours |
| Parts 1 and 2: 160 mg BID | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |
| Parts 1 and 2: 320 mg QD | Part 1 and Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Zanubrutinib | 2.00 Hours |