Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma MedDRA version: 21.0 Level: LLT Classification code 10003946 Term: B-Lymphocytic, CLL (Kiel Classification) System Organ Class: 100000004864 MedDRA version: 21.1 Level: LLT Classification code 10041152 Term: Small lymphocytic lymphoma, consistent with CLL (Working Formulation) System Organ Class: 100000004864
Conditions
Sponsors
BeiGene, Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Patients must be unsuitable for treatment with FCR defined as: = 65 years of age at the time of informed consent, OR 18 - 64 years of age and have one or more of the following factors: a. Cumulative Illness Rating Scale (CIRS) score > 6. A CIRS is not required, it may be used to meet this inclusion requirement. b. Creatinine clearance 1.5 cm in longest diameter and measurable in 2 perpendicular diameters. 4. CLL/SLL requiring treatment 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 6. Life expectancy = 6 months 7. Adequate bone marrow function 8. Patient must have adequate organ function 9. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for = 90 days after the last dose of zanubrutinib, = 30 days after the last dose of venetoclax,3 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer. 10. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for = 90 days after the last dose of zanubrutinib or 3 months after the last dose of bendamustine whichever is longer. 11. Ability to provide written informed consent and can understand and comply with the requirements of the study 12. Must have FISH results from the study-specified central laboratory confirming the presence or absence of del17p.a. For Arm D only: Patients must have a central laboratory FISH test for del17p performed. A patient with a result other than “with del17p” may be eligible for enrollment into the del17p-positive subset only if the patient has a pathogenic TP53 variant previously documented per local laboratory test meeting the criteria specified in Appendix 18. Approval for enrollment by the medical monitor is required. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 185 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 555
Exclusion criteria
Exclusion criteria: 1. Previous systemic treatment for CLL/SLL 2. Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids must be fully tapered off/stopped at least 5 days before day of first study drug. 3. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation 4. Clinically significant cardiovascular disease 5. 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, or localized Gleason score 6 prostate cancer. 6. History of severe bleeding disorder 7. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug 8. Severe or debilitating pulmonary disease 9. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 10. Active fungal, bacterial and/or viral infection requiring systemic therapy 11. Known central nervous system involvement by leukemia or lymphoma 12. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs 13. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection 14. Major surgery within 4 weeks of the first dose of study drug 15. Pregnant or lactating women 16. Vaccination with a live vaccine within 35 days prior to the first dose of study drug 17. Ongoing alcohol or drug addiction 18. Hypersensitivity to zanubrutinib, bendamustine, rituximab or venetoclax (as applicable) or any of the other ingredients of the applicable study drugs 19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer 20. Concurrent participation in another therapeutic clinical study. 21. Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura). 22. Arm D only: requires ongoing treatment with warfarin or warfarin derivatives.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare efficacy between treatment groups in Cohort 1, as measured by progression-free survival determined by independent central review;Secondary Objective: Compare efficacy between Arms A and B, measured by: - Overall response rate (ORR) and Duration of Response (DOR), Overall survival (OS), Progression-free survival (PFS), Patient-reported outcomes Compare efficacy between Arms A and B in pooled Cohort 1/1a patients from Chinese sites, measured by: - PFS, ORR, DOR To evaluate efficacy in Cohort 2 (patients with del17p) for Arm C, measured by: - ORR, PFS, DOR To evaluate efficacy in Cohort 3 for Arm D, measured by: - ORR, PFS, DOR, Assess undetectable minimal residual disease at 10^-4 sensitivity at various timepoints Compare safety between the treatment groups in Cohort 1 Compare safety between the treatment groups in pooled Cohort 1/1a patients from Chinese sites Summarize safety in Cohort 2 (Arm C), Cohort 3 (Arm D) Evaluate zanubrutinib pharmacokinetics in Arms A and C Evaluate pharmacokinetics of zanubrutinib and venetoclax (Arm D);Primary end point(s): The primary endpoint is PFS in Cohort 1 (patients without del17p) determined by independent central review using the iwCLL guidelines with modification for treatment-related lymphocytosis in patients with CLL and the Revised Criteria for Response for Malignant Lymphoma in patients with SLL, and defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first.;Timepoint(s) of evaluation of this end point: 1 interim analysis of progression-free survival by independent central review in Cohort 1, performed when approximately 86 events (73% of the target number of events at final analysis) from the Arms A and B are observed. It is estimated that it will take approximately 33 months to observe 86 events. The final analysis of progression-free survival will take place after 118 events are observed in Cohort 1, which is estimated as a | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • ORR in Cohort 1 defined as the proportion of patients who achieve a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis, determined by independent central review and by investigator assessment • OS in Cohort 1 defined as the time from randomization to the date of death due to any reason • Duration of response in Cohort 1 determined by independent central review and by investigator assessment using the iwCLL criteria with modification for treatment-related lymphocytosis (in patients with CLL) and the Lugano Classification for NHL (in patients with SLL), and defined as the time from the date that criteria for response (i.e. PRL or better) are first met to the date that disease progression is objectively documented or death, whichever occurs first • PFS in Cohort 1 determined by investigator assessment • PROs in Cohort 1 measured by the European Quality of Life 5 Dimensions 5 Levels Health Questionnaire (EQ-5D-5L) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) • PFS in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment • ORR in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment • Duration of response in pooled Cohort 1/1a patients from Chinese sites determined by independent central review and by investigator assessment • ORR in Cohort 2 (patients with del17p), Arm C, determined by independent central review and investigator review • PFS in Cohort 2 (Arm C), determined by independent central review and investigator review • Duration of response in Cohort 2 (Arm C), determined by independent central review and investigator review • ORR in Cohort 3, Arm D, determined by investigator review • PFS in Cohort 3 (Arm D), determined by investigator review • Duration of r | — |
Countries
Australia, Austria, Belgium, China, Czechia, Czech Republic, France, Germany, Hungary, Italy, New Zealand, Poland, Russian Federation, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
Public ContactUS
BeiGene, Ltd.
Outcome results
None listed