Phase 3 Study of BGB-11417 plus Zanubrutinib versus Venetoclax plus Acalabrutinib in Treatment-Naive Chronic Lymphocytic Leukemia
- Trial ID
- 2025-524366-21-00
- Protocol
- BGB-11417-304
- Sponsor
- BeOne Medicines I GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of sonrotoclax plus zanubrutinib versus venetoclax plus acalabrutinib in patients with previously untreated chronic lymphocytic leukemia, as evaluated by progression-free survival determined by an independent review committee. Secondary objectives include the comparison of overall survival, overall response rate, and progression-free survival in high-risk patient populations. Additionally, the study evaluates the rate of undetectable minimal residual disease at < 10⁻⁴ and < 10⁻⁵ sensitivity in both peripheral blood and bone marrow aspirate. The assessment of safety and changes in patient-reported outcomes, specifically regarding disease- and treatment-specific symptoms and functioning, are also conducted.
Participants
This study involves 314 participants diagnosed with treatment-naive chronic lymphocytic leukemia. The study population consists of male and female adults aged 18 years or older. Eligible participants must meet the iwCLL criteria, characterized by monoclonal B cells expressing CD5, CD19, CD20, and CD23, with a clonal B-cell count of ≥ 5 x 10^9/L and the absence of t(11:14) in FISH. Inclusion requires measurable disease via CT or MRI and a need for treatment based on parameters such as progressive marrow failure, symptomatic splenomegaly, progressive lymphadenopathy, or specific disease-related symptoms. Participants must possess an ECOG Performance Status of 0, 1, or 2, adequate marrow, liver, and renal function, and a life expectancy exceeding 6 months. Specific requirements regarding contraception are mandated for individuals of childbearing potential and nonsterile males. The primary objective is to evaluate progression-free survival as determined by an Independent Review Committee.
Plans and Procedures
This Phase 3, open-label, randomized study is designed to compare the efficacy of sonrotoclax plus zanubrutinib against venetoclax plus acalabrutinib in patients with previously untreated chronic lymphocytic leukemia. The primary endpoint is progression-free survival, as determined by an independent review committee. The study involves an initial screening period to confirm diagnosis according to iwCLL criteria and assess eligibility based on marrow function, organ function, and disease status. Following randomization, participants are assigned to receive the designated therapeutic combinations. The study includes follow-up assessments to evaluate secondary endpoints, such as overall survival, overall response rate, and measurable residual disease. The total study duration, including recruitment and follow-up, is estimated to span from March 2026 to March 2032. Early termination of participation may occur based on study protocol requirements or clinical conditions.
Treatment
The experimental treatment consists of BGB-11417, administered as a 320 mg film-coated tablet via the oral route. Another experimental agent is zanubrutinib, which is administered as a 320 mg capsule via the oral route.
The comparator treatments include venetoclax, provided as film-coated tablets for oral administration at a dosage of 400 mg, and acalabrutinib, administered as film-coated tablets at a dosage of 200 mg via the oral route.
Efficacy
The primary efficacy endpoint is progression-free survival (PFS), defined as the time from the date of randomization to the date of disease progression as determined by an Independent Review Committee (IRC) or death due to any cause, whichever occurs first. Secondary efficacy assessments include overall survival (OS), defined as the time from randomization to death from any cause, and the overall response rate (ORR), which represents the proportion of patients achieving a complete response (CR), complete response inadequate (CRi), nodular partial response (nPR), or partial response (PR) per IRC assessment. Additional measures include the overall CRR, ORR, and duration of response (DOR) as determined by both the IRC and investigator assessment. The time to next treatment (TTNT) for chronic lymphocytic leukemia is also evaluated from the date of randomization.
The assessment of minimal residual disease involves evaluating the uMRD4 rate and uMRD5 rate, defined as the proportion of patients achieving these states in both peripheral blood (PB) and bone marrow aspirate (BMA) at the PTFU1 Visit. These rates are measured using next-generation sequencing (NGS) via clonoSEQ. For high-risk patients characterized by unmutated IGHV and/or TP53 aberrations, such as TP53 mutation or del(17p), PFS will be assessed by the IRC. Patient-reported outcomes are collected using the European Organization for Research and Treatment of Cancer quality of life questionnaire EORTC IL-409 to evaluate global health status (GHS), role functioning, physical functioning, symptom burden, physical condition, and fatigue.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Confirmed diagnosis of CLL that meets the iwCLL criteria: a. Clonal, either kappa or lambda light chain restricted, monoclonal B cells that are co-expressing CD5 surface antigen together with B-cell antigens CD19, CD20, and CD23. b. Clonal B-cells ≥ 5 x 109/L in peripheral blood at any timepoint since the initial diagnosis. c. Absence of t(11:14) in FISH
- CLL requiring treatment as defined by ≥ 1 of the following criteria: a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Hemoglobin concentrations < 10 g/dL or platelet counts < 100 x 109 cells/L are generally regarded as indications for treatment. b. Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. c. Massive (ie, ≥ 10 cm in longest diameter [LDi]), progressive, or symptomatic lymphadenopathy. d. Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period, or lymphocyte doubling time (LDT) < 6 months. NOTE: LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts < 30 x 109 cells/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (eg, infections and steroid administration) should be excluded. e. Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, and spine). f. Disease-related symptoms as defined by any of the following: Unintentional weight loss ≥ 10% within the previous 6 months. Fevers ≥ 100.5°F or ≥ 38.0°C for 2 or more weeks without evidence of infection. Night sweats for ≥ 1 month without evidence of infection. Significant fatigue (ie, ECOG Performance Status score of 2 or worse; cannot work or unable to perform usual activities). NOTE: Patients with significant fatigue cannot have an ECOG score of 0.
- ECOG Performance Status of 0, 1, or 2.
- Measurable disease by CT/MRI. Measurable disease is defined as ≥ 1 lymph node ≥ 1.5 cm in LDi and measurable in 2 perpendicular diameters.
- Adequate marrow function as defined by: a. Absolute neutrophil count ≥ 1.0 x 109 cells/L with an exception for patients with bone marrow involvement, in which case, the absolute neutrophil count must be ≥ 0.75 x 109 cells/L (without growth factor support within the past 14 days). b. Platelet counts ≥ 50 x 109 cells/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL, platelet count should be ≥ 30 x 109 cells/L (without growth factor support or transfusion within the past 14 days). c. Hemoglobin > 75 g/L (may be posttransfusion).
- Adequate liver function as indicated by AST and ALT ≤ 2.5 x the institutional ULN value; serum total bilirubin ≤ 2.0 x ULN (unless documented Gilbert syndrome when serum total bilirubin ≤ 3.0 x ULN and conjugated bilirubin ≤ 1.5 x ULN).
- Adequate renal function defined as creatinine clearance ≥ 30 mL/min directly measured with a 24-hour urine collection or ≥ 30 mL/min calculated according to the BSA-adjusted CKD-EPI calculation
- Life expectancy > 6 months.
- Adult patient ≥ 18 years of age, inclusive, at the time of signing the ICF and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Prisoners, individuals institutionalized by regulatory or court order, and persons who may be dependent on the sponsor or an investigator are excluded from the study.
- Female patients of childbearing potential must be willing to use a highly effective method of birth control and refrain from egg donation for the duration of the study and for the following, whichever comes last: ≥ 7 days after the last dose of sonrotoclax, ≥ 30 days after the last dose of zanubrutinib or venetoclax, ≥ 7 days after the last dose of acalabrutinib. Female patients must also have a negative serum pregnancy test result ≤ 7 days before enrollment and randomization, as well as a negative highly sensitive urine or serum pregnancy test result within 24 hours prior to Day 1 of Cycle 1 dosing.
- Nonsterile male patients must be willing to use a highly effective method of birth control and must refrain from donating sperm for the duration of the study and for the following, whichever comes last: ≥ 7 days after the last dose of sonrotoclax, ≥ 30 days after the last dose of zanubrutinib or venetoclax, ≥ 7 days after the last dose of acalabrutinib A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. Males with known “low sperm counts” (consistent with “subfertility”) are not to be considered sterile for purposes of this study.
Exclusion Criteria
- Previous systemic treatment for CLL. (Note: Up to 4 doses of anti-CD-20 antibody specifically for autoimmune cytopenia is allowed; the last dose should be given ≥ 6 months before screening).
- Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation).
- Known CNS involvement.
- Patients with a history of confirmed progressive multifocal leukoencephalopathy.
- Severe or debilitating pulmonary disease, defined as chronic supplementation of oxygen and/or respiratory failure requiring assisted ventilation.
- Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening. b. Unstable angina within 3 months before screening. c. New York Heart Association class III or IV congestive heart failure. d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes). e. QTcF > 480 milliseconds based on Fridericia’s formula. NOTE: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility. f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening.
- Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment.
- History of prior malignancy, except for conditions as listed below and as long as patients have recovered from the acute side effects incurred because of previous therapy: a. Malignancies surgically treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and randomization. b. Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease. c. Adequately treated cervical carcinoma in situ without evidence of disease. d. Localized prostate cancer with Gleason score ≤ 6.
- Use of investigational agents within the last 4 weeks before screening.
- Active fungal, bacterial, and/or viral infection requiring systemic therapy.
- History or known hypersensitivity to zanubrutinib, sonrotoclax, acalabrutinib, venetoclax, or any of its excipients (eg, trehalose), xanthine oxidase inhibitors, or rasburicase.
- History of severe bleeding disorder, such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
- Female patients who are pregnant or are breastfeeding.
- Vaccination with a live vaccine within 28 days before enrollment and randomization
- Patients with underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study treatment, precludes the patient’s safe participation in the study or will affect the explanation of drug toxicity or AEs, or will result in insufficient or impaired compliance with study conduct.
- Positive HIV serology (HIVAb) status or serologic status reflecting active hepatitis B or C infection as follows: a. Presence of HBsAg. b. Patients with presence of HBcAb, in the absence of HBsAg, with detectable HBV DNA. NOTE: The limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL; Patients with presence of HBcAb but undetectable HBV DNA who are willing to undergo HBV DNA monitoring every 4 weeks for HBV reactivation are eligible. c. Patients with presence of HCV antibody and HCV RNA detectable NOTE: The limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL; Patients with presence of HCVAb and undetectable HCV RNA who are willing to undergo HCV RNA monitoring every 4 weeks for HCV reactivation are eligible.
- Requires the use of warfarin, marcumar, phenprocoumon, or vitamin K antagonist.
- Receiving treatment with any moderate or strong CYP3A4 inhibitor or strong CYP3A4 inducer (≤ 14 days or 5 half lives, whichever is shorter) before the first dose of study drug, or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a strong CYP3A inducer.
- Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days before the first dose of study treatment.
- Unable to swallow capsules or tablets or diseases significantly affecting GI 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.
- At time of enrollment, receiving systemic corticosteroids unless administered for adrenal replacement.
- Major surgery within 4 weeks of the first dose of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 31 Mar 2026 | 30 |
 France | Recruiting | 31 Mar 2026 | 32 |
 Germany | Recruiting | 31 Mar 2026 | 25 |
 Italy | Recruiting | 31 Mar 2026 | 25 |
 The Netherlands | Recruiting | 31 Mar 2026 | — |
 Poland | Recruiting | 31 Mar 2026 | 40 |
 Romania | Recruiting | 31 Mar 2026 | 9 |
 Spain | Recruiting | 31 Mar 2026 | 12 |
 Sweden | Recruiting | 31 Mar 2026 | 5 |
| Netherlands | — | — | 8 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venclyxto 50 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 400 | 56 | PRD6353826 |
BGB-11417 | Test | FILM-COATED TABLET | ORAL | 320 | 60 | PRD9450025 |
Venclyxto 10 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 400 | 56 | PRD6353818 |
BGB-11417 | Test | FILM-COATED TABLET | ORAL | 320 | 60 | PRD9450023 |
Zanubrutinib | Test | CAPSULE | ORAL | 320 | 60 | PRD4470763 |
Calquence 100 mg film-coated tablets | Comparator | FILM-COATED TABLET (TABLET). | ORAL | 200 | 56 | PRD10242587 |
BGB-11417 | Test | FILM-COATED TABLET | ORAL | 320 | 60 | PRD9450022 |
BGB-11417 | Test | FILM-COATED TABLET | ORAL | 320 | 420 | PRD9450024 |
Venclyxto 100 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 400 | 57 | PRD6353834 |