Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, CLL, SLL, relapsed, refractory
Brief summary
This study is designed to compare the overall response rate of zanubrutinib versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
Detailed description
This is a global, Phase 3, randomized study of zanubrutinib versus ibrutinib in 652 participants with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The primary efficacy endpoint is overall response rate determined by investigator assessment. Participants were randomized in a 1:1 manner to either zanubrutinib or ibrutinib. Treatment with zanubrutinib and ibrutinib was open label.
Interventions
DRUGZanubrutinib
160 mg orally twice daily
DRUGIbrutinib
Ibrutinib 420 mg orally once daily
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. Confirmed diagnosis of CLL or SLL that meets the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria 2. CLL/SLL requiring treatment per 2008 IWCLL criteria 3. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL 4. Measurable disease by computerized tomography (CT)/magnetic resonance imaging (MRI) 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 6. Life expectancy ≥ 6 months 7. Adequate bone marrow function 8. Adequate renal and hepatic function Key
Exclusion criteria
1. Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation 2. Clinically significant cardiovascular disease. 3. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, non-muscle-invasive bladder cancer, carcinoma in situ of the cervix or breast 4. History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention 5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug 6. Severe or debilitating pulmonary disease 7. Active fungal, bacterial, and/or viral infection requiring systemic therapy 8. Known central nervous system involvement by leukemia or lymphoma 9. Known infection with HIV or active viral hepatitis B or C infection 10. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C 11. Major surgery within 4 weeks of the first dose of study drug 12. Prior treatment with a (Burton's Kinase) BTK inhibitor 13. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1 14. Pregnant or lactating women 15. Vaccination with a live vaccine within 35 days prior to the first dose of study drug 16. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug 17. Concurrent participation in another therapeutic clinical trial NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Assessed by the Investigator | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) per investigator assessment. Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL. |
| ORR Assessed by the Independent Review Committee (IRC) | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) assessed by a blinded independent review committee. Overall response was assessed by the IRC for the purpose of regulatory filing with the Food and Drug Administration (FDA). Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Atrial Fibrillation or Atrial Flutter | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | Participants were considered as having an atrial fibrillation/flutter event if they had a treatment-emergent AE of either atrial fibrillation or atrial flutter. |
| Duration of Response Assessed by the Independent Review Committee | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by independent central review. Median DOR was estimated using the Kaplan-Meier method. |
| Duration of Response (DOR) Assessed by the Investigator | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by investigator assessment. Median DOR was estimated using the Kaplan-Meier method. |
| Time to Treatment Failure | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | Time to treatment failure is defined as the time from randomization to discontinuation of study drug due to any reason. Median time to treatment failure was estimated by the Kaplan-Meier method. |
| Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or a complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis assessed by the blinded IRC. Disease response was assessed per iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and per Lugano classification for participants with SLL. |
| Progression-free Survival (PFS) Assessed by the Investigator | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. |
| Overall Survival (OS) | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | Overall survival is defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. |
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Baseline and Weeks 24 and 48 | The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life. |
| Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Baseline and Weeks 24 and 48 | The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Lower scores in symptom scales indicate better quality of life. |
| Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS) | Baseline and Weeks 24 and 48 | The EQ-5D-5L VAS measures a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes. |
| Number of Participants With Treatment-emergent Adverse Events (TEAE) | From first dose of study drug up to 30 days after last dose, up to the end of study data cutoff (28 February 2024); median (range) time on treatment was 41.2 (0.4-59.1) months in the zanubrutinib arm and 37.8 (0.1-60.4) months in the ibrutinib arm. | An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization * Resulted in disability/incapacity * Resulted in a congenital anomaly/birth defect * Was considered a significant medical AE by the investigator based on medical judgment |
| Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis as assessed by the investigator. Disease response was assessed according to the iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and in accordance with Lugano classification for participants with SLL. Partial response with lymphocytosis: blood lymphocytes decreased \< 50% or increased from baseline, and otherwise meeting criteria for PR. |
| Progression-free Survival Assessed by the Independent Review Committee | From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months). | PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. |
Countries
Australia, Belgium, China, Czechia, France, Germany, Italy, Netherlands, New Zealand, Poland, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 113 study centers in 15 countries (Australia, Belgium, China, the Czech Republic, France, Germany, Italy, the Netherlands, New Zealand, Poland, Spain, Sweden, Turkey, the United Kingdom, and the United States).
Pre-assignment details
Participants were randomly assigned to one of two treatment groups. Randomization was stratified according to age (\< 65 versus ≥ 65 years), geographic region (China vs non-China), refractory status (yes or no), and chromosome 17p deletion or TP53 mutation status (present or absent).
Participants by arm
| Arm | Count |
|---|---|
| Zanubrutinib Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy. | 327 |
| Ibrutinib Participants received ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy. | 325 |
| Total | 652 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 69 | 83 |
| Overall Study | Lost to Follow-up | 6 | 2 |
| Overall Study | Miscellaneous | 5 | 1 |
| Overall Study | Physician Decision | 1 | 12 |
| Overall Study | Sponsor Ended Study | 225 | 200 |
| Overall Study | Withdrawal by Subject | 21 | 27 |
Baseline characteristics
| Characteristic | Zanubrutinib | Ibrutinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 201 Participants | 200 Participants | 401 Participants |
| Age, Categorical Between 18 and 65 years | 126 Participants | 125 Participants | 251 Participants |
| Age, Continuous | 67.0 years | 68.0 years | 67.0 years |
| Chromosome 17p Deletion (del[17p]) and TP53 Mutation Status Del(17p) and/or TP53 mutation | 75 Participants | 75 Participants | 150 Participants |
| Chromosome 17p Deletion (del[17p]) and TP53 Mutation Status Missing | 1 Participants | 0 Participants | 1 Participants |
| Chromosome 17p Deletion (del[17p]) and TP53 Mutation Status Neither Del(17p) nor TP53 mutation | 251 Participants | 250 Participants | 501 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 13 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 309 Participants | 298 Participants | 607 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 14 Participants | 25 Participants |
| Geographic Region Asia | 49 Participants | 45 Participants | 94 Participants |
| Geographic Region Australia/New Zealand | 28 Participants | 30 Participants | 58 Participants |
| Geographic Region Europe | 198 Participants | 191 Participants | 389 Participants |
| Geographic Region North America | 52 Participants | 59 Participants | 111 Participants |
| Race/Ethnicity, Customized Asian | 47 Participants | 44 Participants | 91 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown/Not Reported | 9 Participants | 12 Participants | 21 Participants |
| Race/Ethnicity, Customized White | 261 Participants | 265 Participants | 526 Participants |
| Sex: Female, Male Female | 114 Participants | 93 Participants | 207 Participants |
| Sex: Female, Male Male | 213 Participants | 232 Participants | 445 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 69 / 327 | 83 / 325 |
| other Total, other adverse events | 310 / 324 | 314 / 324 |
| serious Total, serious adverse events | 172 / 324 | 196 / 324 |
Outcome results
Primary
ORR Assessed by the Independent Review Committee (IRC)
ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) assessed by a blinded independent review committee. Overall response was assessed by the IRC for the purpose of regulatory filing with the Food and Drug Administration (FDA). Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | ORR Assessed by the Independent Review Committee (IRC) | 86.2 percentage of participants |
| Ibrutinib | ORR Assessed by the Independent Review Committee (IRC) | 75.7 percentage of participants |
p-value: <0.000195% CI: [1.05, 1.22]Stratified Wald test
p-value: 0.0007Cochran-Mantel-Haenszel
Primary
Overall Response Rate (ORR) Assessed by the Investigator
ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) per investigator assessment. Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: Intent To Treat (ITT) Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Overall Response Rate (ORR) Assessed by the Investigator | 83.5 percentage of participants |
| Ibrutinib | Overall Response Rate (ORR) Assessed by the Investigator | 74.2 percentage of participants |
p-value: <0.000195% CI: [1.04, 1.22]Stratified Wald test
p-value: 0.0035Cochran-Mantel-Haenszel
Secondary
Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea
The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Lower scores in symptom scales indicate better quality of life.
Time frame: Baseline and Weeks 24 and 48
Population: Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Diarrhoea Symptom Scale at Week 48 | -3.23 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Fatigue Symptom Scale at Week 48 | -11.13 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Nausea and Vomiting Symptom Scale at Week 24 | -1.21 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Nausea and Vomiting Symptom Scale at Week 48 | -0.92 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Pain Symptom Scale at Week 24 | -5.06 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Pain Symptom Scale at Week 48 | -5.18 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Fatigue Symptom Scale at Week 24 | -12.54 score on a scale |
| Zanubrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Diarrhoea Symptom Scale at Week 24 | -2.11 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Pain Symptom Scale at Week 48 | -2.75 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Diarrhoea Symptom Scale at Week 24 | -0.52 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Fatigue Symptom Scale at Week 48 | -10.78 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Diarrhoea Symptom Scale at Week 48 | -1.38 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Nausea and Vomiting Symptom Scale at Week 24 | -0.92 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Fatigue Symptom Scale at Week 24 | -10.63 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Nausea and Vomiting Symptom Scale at Week 48 | -0.40 score on a scale |
| Ibrutinib | Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea | Pain Symptom Scale at Week 24 | -3.63 score on a scale |
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Fatigue Symptom Scale at Week 24.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.177895% CI: [-4.7, 0.87]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Fatigue Symptom Scale at Week 48.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.817495% CI: [-3.32, 2.62]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Nausea and Vomiting Symptom Scale at Week 24.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.629495% CI: [-1.48, 0.89]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Nausea and Vomiting Symptom Scale at Week 48.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.493395% CI: [-1.99, 0.96]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Pain Symptom Scale at Week 24.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.364395% CI: [-4.51, 1.66]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Pain Symptom Scale at Week 48.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.136395% CI: [-5.62, 0.77]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Diarrhoea Symptom Scale at Week 24.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.200195% CI: [-4.01, 0.84]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Diarrhoea Symptom Scale at Week 48.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.112195% CI: [-4.12, 0.43]Mixed model for repeated measures (MMRM)
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores
The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life.
Time frame: Baseline and Weeks 24 and 48
Population: Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Zanubrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | GHS/QoL Scale at Week 24 | 8.18 score on a scale |
| Zanubrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Physical Functioning Scale at Week 24 | 6.55 score on a scale |
| Zanubrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Physical Functioning Scale at Week 48 | 5.46 score on a scale |
| Zanubrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Role Functioning Scale at Week 24 | 6.95 score on a scale |
| Zanubrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | GHS/QoL Scale at Week 48 | 7.28 score on a scale |
| Zanubrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Role Functioning Scale at Week 48 | 6.81 score on a scale |
| Ibrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | GHS/QoL Scale at Week 48 | 5.93 score on a scale |
| Ibrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Physical Functioning Scale at Week 48 | 4.31 score on a scale |
| Ibrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Role Functioning Scale at Week 48 | 5.01 score on a scale |
| Ibrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | GHS/QoL Scale at Week 24 | 5.18 score on a scale |
| Ibrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Physical Functioning Scale at Week 24 | 4.73 score on a scale |
| Ibrutinib | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores | Role Functioning Scale at Week 24 | 6.32 score on a scale |
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 GHS/QOL at Week 24. A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.033895% CI: [0.23, 5.77]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 GHS/QOL at Week 48. A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.330495% CI: [-1.37, 4.06]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale at Week 24.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.118995% CI: [-0.47, 4.12]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Physical Functioning Scale at Week 48.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.327495% CI: [-1.15, 3.44]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Role Functioning Scale at Week 24.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.682195% CI: [-2.4, 3.66]Mixed model for repeated measures (MMRM)
Comparison: Analysis of Change from Baseline in EORTC QLQ-C30 Role Functioning Scale at Week 48.~A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.p-value: 0.270195% CI: [-1.4, 5]Mixed model for repeated measures (MMRM)
Secondary
Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS)
The EQ-5D-5L VAS measures a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes.
Time frame: Baseline and Weeks 24 and 48
Population: Participants in the ITT Analysis Set who completed the EQ-5D-5L VAS at Baseline; participants with available data at baseline and the relevant post-baseline visit are included in the analysis at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zanubrutinib | Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS) | Week 24 | 7.92 score on a scale | Standard Deviation 18.245 |
| Zanubrutinib | Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS) | Week 48 | 7.75 score on a scale | Standard Deviation 18.806 |
| Ibrutinib | Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS) | Week 24 | 3.44 score on a scale | Standard Deviation 16.972 |
| Ibrutinib | Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS) | Week 48 | 3.92 score on a scale | Standard Deviation 16.778 |
Secondary
Duration of Response Assessed by the Independent Review Committee
DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by independent central review. Median DOR was estimated using the Kaplan-Meier method.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: Participants in the ITT Analysis Set with an objective response assessed by the IRC
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Duration of Response Assessed by the Independent Review Committee | NA months |
| Ibrutinib | Duration of Response Assessed by the Independent Review Committee | 33.9 months |
Secondary
Duration of Response (DOR) Assessed by the Investigator
DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by investigator assessment. Median DOR was estimated using the Kaplan-Meier method.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: Participants in the ITT Analysis Set with an objective response as assessed by the investigator
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Duration of Response (DOR) Assessed by the Investigator | NA months |
| Ibrutinib | Duration of Response (DOR) Assessed by the Investigator | 33.9 months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAE)
An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization * Resulted in disability/incapacity * Resulted in a congenital anomaly/birth defect * Was considered a significant medical AE by the investigator based on medical judgment
Time frame: From first dose of study drug up to 30 days after last dose, up to the end of study data cutoff (28 February 2024); median (range) time on treatment was 41.2 (0.4-59.1) months in the zanubrutinib arm and 37.8 (0.1-60.4) months in the ibrutinib arm.
Population: The Safety Analysis Set includes all participants who received any dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zanubrutinib | Number of Participants With Treatment-emergent Adverse Events (TEAE) | Any TEAE | 322 Participants |
| Zanubrutinib | Number of Participants With Treatment-emergent Adverse Events (TEAE) | Serious adverse events | 172 Participants |
| Ibrutinib | Number of Participants With Treatment-emergent Adverse Events (TEAE) | Any TEAE | 323 Participants |
| Ibrutinib | Number of Participants With Treatment-emergent Adverse Events (TEAE) | Serious adverse events | 196 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Overall Survival (OS) | NA months |
| Ibrutinib | Overall Survival (OS) | NA months |
95% CI: [0.51, 1.11]
Secondary
Percentage of Participants With Atrial Fibrillation or Atrial Flutter
Participants were considered as having an atrial fibrillation/flutter event if they had a treatment-emergent AE of either atrial fibrillation or atrial flutter.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: The Safety Analysis Set includes all participants who received any dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Percentage of Participants With Atrial Fibrillation or Atrial Flutter | 5.2 percentage of participants |
| Ibrutinib | Percentage of Participants With Atrial Fibrillation or Atrial Flutter | 13.3 percentage of participants |
p-value: 0.000495% CI: [-12.4, -3.6]Chi-squared
Secondary
Progression-free Survival Assessed by the Independent Review Committee
PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: Intent To Treat Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Progression-free Survival Assessed by the Independent Review Committee | NA months |
| Ibrutinib | Progression-free Survival Assessed by the Independent Review Committee | 35.0 months |
p-value: <0.000195% CI: [0.49, 0.86]Stratified Wald test
p-value: 0.0024Stratified Log-rank test
Secondary
Progression-free Survival (PFS) Assessed by the Investigator
PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Progression-free Survival (PFS) Assessed by the Investigator | NA months |
| Ibrutinib | Progression-free Survival (PFS) Assessed by the Investigator | 34.2 months |
p-value: <0.000195% CI: [0.49, 0.86]Stratified Wald test
p-value: 0.0024Stratified Log-rank test
Secondary
Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee
The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or a complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis assessed by the blinded IRC. Disease response was assessed per iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and per Lugano classification for participants with SLL.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee | 91.7 percentage of participants |
| Ibrutinib | Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee | 83.1 percentage of participants |
Secondary
Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator
The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis as assessed by the investigator. Disease response was assessed according to the iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and in accordance with Lugano classification for participants with SLL. Partial response with lymphocytosis: blood lymphocytes decreased \< 50% or increased from baseline, and otherwise meeting criteria for PR.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zanubrutinib | Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator | 89.9 percentage of participants |
| Ibrutinib | Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator | 82.5 percentage of participants |
Secondary
Time to Treatment Failure
Time to treatment failure is defined as the time from randomization to discontinuation of study drug due to any reason. Median time to treatment failure was estimated by the Kaplan-Meier method.
Time frame: From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zanubrutinib | Time to Treatment Failure | NA months |
| Ibrutinib | Time to Treatment Failure | NA months |
95% CI: [0.41, 0.72]