Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
zanubrutinib, BTK inhibitor, bendamustine, rituximab, venetoclax, BGB-3111, Phase 3
Brief summary
To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as measured by progression free survival assess by Independent Central Review.
Detailed description
This is a global phase 3, open label, randomized study of zanubrutinib versus bendamustine plus rituximab (B+R) in participants with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), including participants without del(17p) \[Cohort 1\] and participants with del(17p) \[Cohort 2 and Cohort 3\]. Participants in Cohort 1 are randomized 1:1 to zanubrutinib (Arm A) or bendamustine plus rituximab (Arm B). Randomization will be stratified by age, Binet stage, immunoglobulin variable region heavy chain (IGHV) mutational status, and geographic region. Participants in Cohort 2 will receive treatment with zanubrutinib. Participants in Cohort 3 will receive treatment with zanubrutinib and venetoclax.
Interventions
DRUGZanubrutinib
Administered as two 80-milligram (mg) capsules by mouth twice a day (160 mg twice a day)
DRUGBendamustine
Administered intravenously (IV) at a dose of 90 mg/m\^2/day on the first 2 days of each cycle for 6 cycles.
DRUGRituximab
Administered intravenously (IV) at a dose of 375 mg/m\^2 on day 0 of cycle 1, and at a dose of 500 mg/m\^2 on day 1 of cycles 2 to 6
DRUGVenetoclax
400 mg tablets administered 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: * Unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) * Confirmed diagnosis of CD20-positive CLL or SLL, requiring treatment * Measurable disease by imaging * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 * Life expectancy ≥ 6 months * Adequate bone marrow function * Adequate renal and hepatic function Key
Exclusion criteria
* Previous systemic treatment for CLL/SLL * Requires ongoing need for corticosteroid treatment * Known prolymphocytic leukemia or history of or suspected Richter's transformation. * Clinically significant cardiovascular disease * 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 of breast, or localized Gleason score 6 prostate cancer * History of severe bleeding disorder * History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug * Severe or debilitating pulmonary disease * Inability to swallow capsules or disease affecting gastrointestinal function * Active infection requiring systemic treatment * Known central nervous system involvement by leukemia or lymphoma * Underlying medical condition that will render the administration of study drug hazardous or obscure interpretation of toxicity or AEs * Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C infection * Major surgery ≤ 4 weeks prior to start of study treatment * Pregnant or nursing females * Vaccination with live vaccine within 35 days prior to the first dose of study drug. * Ongoing alcohol or drug addiction * Known hypersensitivity to zanubrutinib, bendamustine, rituximab, or venetoclax (as applicable) or any other ingredients of the study drugs * Requires ongoing treatment with strong cytochrome P450 (CYP3A) inhibitor or inducer * Concurrent participation in another therapeutic clinical study NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR) | Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021) | PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the ICR per 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with small lymphocytic lymphoma (SLL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR | Up to 5 years | ORR in Cohort 1 is defined as the percentage of participants who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by the ICR. |
| Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups | Up to 5 years | — |
| Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR | Up to 5 years | OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason. |
| Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR | Up to 5 years | Duration of response in Cohort 1 determined using the iwCLL criteria with modification for treatment related lymphocytosis (in participants with CLL) and the Lugano Classification for non-Hodgkin lymphoma (NHL; in participants with SLL), is defined as the time from the date that criteria for response (ie, partial response with lymphocytosis \[PR-L\] or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first. |
| Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups | Up to 5 years | — |
| Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) | Up to 5 years | PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the investigator per iwCLL guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL. |
| Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA) | Up to 5 years | — |
| Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire | Up to 5 years | — |
| Cohort 1: Patient-reported Outcomes as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Questionnaire. | Up to 5 years | — |
| Cohort 2: Overall Response Rate (ORR) | Up to 5 years | — |
| Cohort 2: Progression-free Survival (PFS) | Up to 5 years | — |
| Cohort 2: Duration of Response (DOR) | Up to 5 years | — |
| Cohort 3: Overall Response Rate (ORR) | Up to 5 years | — |
| Cohort 3: Progression-free Survival (PFS) | Up to 5 years | — |
| Cohort 3: Duration of Response (DOR) | Up to 5 years | — |
| Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4) | Up to 5 years | — |
| Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to 5 years | — |
| Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F | Predose up to 12 hours postdose | — |
| Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) | Predose up to 12 hours postdose | — |
| Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib | Predose up to 12 hours postdose | — |
Countries
Australia, Austria, Belgium, China, Czechia, France, Italy, New Zealand, Poland, Russia, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORStudy Director
BeiGene
Participant flow
Recruitment details
Available data are presented as of the primary analysis data cut-off date of 07MAY2021; as of the data cut-off date, all cohorts were ongoing.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Bendamustine + Rituximab Without Del(17p) Bendamustine + Rituximab in participants with CLL without del(17p); bendamustine 90 milligrams (mg)/m\^2/day administered intravenously (IV) on the first 2 days of each cycle for 6 cycles; rituximab 375 mg/m\^2 for Cycle 1 and 500 mg/m\^2 for Cycles 2 to 6 (each cycle is 28 days) | 238 |
| Cohort 1: Zanubrutinib Without Del(17p) Zanubrutinib in participants with CLL without del(17p); 160 mg administered twice a day orally until unacceptable toxicity or disease progression | 241 |
| Cohort 2: Zanubrutinib With Del(17p) Zanubrutinib in participants with CLL with del(17p); 160 mg administered twice a day orally until unacceptable toxicity or disease progression | 111 |
| Total | 590 |
Baseline characteristics
| Characteristic | Cohort 2: Zanubrutinib With Del(17p) | Total | Cohort 1: Bendamustine + Rituximab Without Del(17p) | Cohort 1: Zanubrutinib Without Del(17p) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 95 Participants | 483 Participants | 192 Participants | 196 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 107 Participants | 46 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 10 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 99 Participants | 528 Participants | 211 Participants | 218 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 52 Participants | 23 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 14 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 1 Participants | 4 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 38 Participants | 22 Participants | 11 Participants |
| Race (NIH/OMB) White | 105 Participants | 532 Participants | 206 Participants | 221 Participants |
| Sex: Female, Male Female | 32 Participants | 213 Participants | 94 Participants | 87 Participants |
| Sex: Female, Male Male | 79 Participants | 377 Participants | 144 Participants | 154 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 238 | 16 / 241 | 8 / 111 |
| other Total, other adverse events | 214 / 227 | 208 / 240 | 104 / 111 |
| serious Total, serious adverse events | 113 / 227 | 88 / 240 | 45 / 111 |
Outcome results
Primary
Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR)
PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the ICR per 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with small lymphocytic lymphoma (SLL).
Time frame: Up to approximately 3 years and 7 months (as of cut-off date of 07MAY2021)
Population: ITT analysis set included all enrolled participants who were assigned to a treatment group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Bendamustine + Rituximab Without Del(17p) | Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR) | 33.7 Months |
| Cohort 1: Zanubrutinib Without Del(17p) | Cohort 1: Progression-free Survival (PFS) as Determined by Independent Central Review (ICR) | NA Months |
p-value: <0.000195% CI: [0.28, 0.63]Log Rank
Secondary
Apparent Rate of Clearance of Zanubrutinib From Plasma (CL/F)CL/F
Time frame: Predose up to 12 hours postdose
Secondary
Cohort 1: Duration of Response (DOR) Between Treatment Groups as Determined by the ICR
Duration of response in Cohort 1 determined using the iwCLL criteria with modification for treatment related lymphocytosis (in participants with CLL) and the Lugano Classification for non-Hodgkin lymphoma (NHL; in participants with SLL), is defined as the time from the date that criteria for response (ie, partial response with lymphocytosis \[PR-L\] or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first.
Time frame: Up to 5 years
Secondary
Cohort 1: Overall Response Rate (ORR) Between Treatment Groups as Determined by ICR
ORR in Cohort 1 is defined as the percentage of participants who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by the ICR.
Time frame: Up to 5 years
Secondary
Cohort 1: Overall Survival (OS) Between Treatment Groups as Determined by the ICR
OS in Cohort 1 is defined as the time from randomization to the date of death due to any reason.
Time frame: Up to 5 years
Secondary
Cohort 1: Patient-reported Outcomes as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Questionnaire.
Time frame: Up to 5 years
Secondary
Cohort 1: Patient-reported Outcomes as Assessed by the (European Quality Of Life 5D 5L) EQ-5D-5L Questionnaire
Time frame: Up to 5 years
Secondary
Cohort 1: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
PFS is defined as the time from randomization until first documentation of progression or death from any cause, whichever occurs first, as assessed by the investigator per iwCLL guidelines with modifications for treatment-related lymphocytosis in participants with CLL and the Revised Criteria for Response for Malignant Lymphoma in participants with SLL.
Time frame: Up to 5 years
Secondary
Cohort 1 Zanubrutinib Only Arms: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12)
Time frame: Predose up to 12 hours postdose
Secondary
Cohort 2: Duration of Response (DOR)
Time frame: Up to 5 years
Secondary
Cohort 2: Overall Response Rate (ORR)
Time frame: Up to 5 years
Secondary
Cohort 2: Progression-free Survival (PFS)
Time frame: Up to 5 years
Secondary
Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib
Time frame: Predose up to 12 hours postdose
Secondary
Cohort 3: Area-Under-Curve From Time 0 to 12 Hours Postdose (AUC0-12) of Zanubrutinib
Time frame: Predose up to 12 hours postdose
Secondary
Cohort 3: Duration of Response (DOR)
Time frame: Up to 5 years
Secondary
Cohort 3: Overall Response Rate (ORR)
Time frame: Up to 5 years
Secondary
Cohort 3: Progression-free Survival (PFS)
Time frame: Up to 5 years
Secondary
Cohort 3: Rate of Undetectable Minimal Residual Disease (MRD4)
Time frame: Up to 5 years
Secondary
Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Up to 5 years
Secondary
Pooled Cohort 1/1a: Duration of Response (DOR) Between Treatment Groups
Time frame: Up to 5 years
Secondary
Pooled Cohort 1/1a: Overall Response Rate (ORR) Between Treatment Groups
Time frame: Up to 5 years
Secondary
Pooled Cohort 1/1a: Progression-free Survival (PFS) Between Treatment Groups Determined by Investigator Assessment (IA)
Time frame: Up to 5 years