N-[4-({[(1R,4R)-4-HYDROXY-4-METHYLCYCLOHEXYL]METHYL}AMINO)-3- NITROBENZENE-1-SULFONYL]-4-(2-{(2S)-2-[2-(PROPAN-2-YL)PHENYL]PYRROLIDIN1-YL}-7-AZASPIRO[3.5]NONAN-7-YL)-2-[(1H-PYRROLO[2,3-B]PYRIDIN-5- YL)OXY]BENZAMIDE for Chronic lymphocytic leukemia

Inclusion criteria

• {"criterion_text":"- 1.\tConfirmed diagnosis of CLL that meets the iwCLL criteria: a.\tClonal, 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.\tClonal B-cells ≥ 5 x 109/L in peripheral blood at any timepoint since the initial diagnosis. c.\tAbsence of t(11:14) in FISH\n- 2.\tCLL requiring treatment as defined by ≥ 1 of the following criteria: a.\tEvidence 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.\tMassive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. c.\tMassive (ie, ≥ 10 cm in longest diameter [LDi]), progressive, or symptomatic lymphadenopathy. d.\tProgressive 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.\tSymptomatic or functional extranodal involvement (eg, skin, kidney, lung, and spine). f.\tDisease-related symptoms as defined by any of the following: \tUnintentional weight loss ≥ 10% within the previous 6 months. \tFevers ≥ 100.5°F or ≥ 38.0°C for 2 or more weeks without evidence of infection. \tNight sweats for ≥ 1 month without evidence of infection. \tSignificant 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.\n- 3.\tECOG Performance Status of 0, 1, or 2.\n- 4.\tMeasurable disease by CT/MRI. Measurable disease is defined as ≥ 1 lymph node ≥ 1.5 cm in LDi and measurable in 2 perpendicular diameters.\n- 5.\tAdequate marrow function as defined by: a.\tAbsolute 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.\tPlatelet 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.\tHemoglobin > 75 g/L (may be posttransfusion).\n- 6.\tAdequate 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).\n- 7.\tAdequate 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\n- 8.\tLife expectancy > 6 months.\n- 9.\tAdult 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.\n- 10.\tFemale 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: \t≥ 7 days after the last dose of sonrotoclax, \t≥ 30 days after the last dose of zanubrutinib or venetoclax, \t≥ 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.\n- 11.\tNonsterile 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: \t≥ 7 days after the last dose of sonrotoclax, \t≥ 30 days after the last dose of zanubrutinib or venetoclax, \t≥ 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

• {"criterion_text":"- 1.\tPrevious 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).\n- 2.\tKnown prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation).\n- 3.\tKnown CNS involvement.\n- 4.\tPatients with a history of confirmed progressive multifocal leukoencephalopathy.\n- 5.\tSevere or debilitating pulmonary disease, defined as chronic supplementation of oxygen and/or respiratory failure requiring assisted ventilation.\n- 6.\tClinically significant cardiovascular disease including the following: a.\tMyocardial infarction within 6 months before screening. b.\tUnstable angina within 3 months before screening. c.\tNew York Heart Association class III or IV congestive heart failure. d.\tHistory of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes). e.\tQTcF > 480 milliseconds based on Fridericia’s formula. \tNOTE: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility. f.\tHistory of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. g.\tUncontrolled 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.\n- 7.\tUncontrolled autoimmune hemolytic anemia or immune thrombocytopenia requiring treatment.\n- 8.\tHistory 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.\tMalignancies surgically treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and randomization. b.\tAdequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease. c.\tAdequately treated cervical carcinoma in situ without evidence of disease. d.\tLocalized prostate cancer with Gleason score ≤ 6.\n- 9.\tUse of investigational agents within the last 4 weeks before screening.\n- 10.\tActive fungal, bacterial, and/or viral infection requiring systemic therapy.\n- 11.\tHistory or known hypersensitivity to zanubrutinib, sonrotoclax, acalabrutinib, venetoclax, or any of its excipients (eg, trehalose), xanthine oxidase inhibitors, or rasburicase.\n- 12.\tHistory 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.\n- 13.\tFemale patients who are pregnant or are breastfeeding.\n- 14.\tVaccination with a live vaccine within 28 days before enrollment and randomization\n- 15.\tPatients 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.\n- 16.\tPositive HIV serology (HIVAb) status or serologic status reflecting active hepatitis B or C infection as follows: a.\tPresence of HBsAg. b.\tPatients 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.\tPatients 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.\n- 17.\tRequires the use of warfarin, marcumar, phenprocoumon, or vitamin K antagonist.\n- 18.\tReceiving 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.\n- 19.\tConsumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days before the first dose of study treatment.\n- 20.\tUnable 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.\n- 21.\tAt time of enrollment, receiving systemic corticosteroids unless administered for adrenal replacement.\n- 22.\tMajor surgery within 4 weeks of the first dose of study treatment."}

Primary endpoints

• {"endpoint_text":"- \tPFS, defined as time from the date of randomization to the date of disease progression as determined by IRC or death due to any cause, whichever occurs first.","definition_or_measurement_approach":"PFS measured from date of randomization to date of disease progression as determined by the Independent Review Committee (IRC) or death from any cause, whichever occurs first."}

Secondary endpoints

• {"endpoint_text":"- \tuMRD4 rate defined as the proportion of patients that achieved uMRD4 measured in both PB and BMA at the PTFU1 Visit based on next-generation sequencing (NGS [clonoSEQ])","definition_or_measurement_approach":"Proportion achieving undetectable MRD at sensitivity <10^-4 measured in peripheral blood (PB) and bone marrow aspirate (BMA) at the PTFU1 visit using NGS (clonoSEQ)."}
• {"endpoint_text":"- \tPFS as determined by IRC in high-risk patients that have unmutated IGHV and/or TP53 aberrations (del(17p) present and/or TP53 mutated)","definition_or_measurement_approach":"Progression-free survival assessed by IRC in the subset of high-risk patients defined by unmutated IGHV and/or TP53 aberrations (del(17p) and/or TP53 mutation)."}
• {"endpoint_text":"- \tOS, defined as time from the date of randomization to the date of death due to any cause","definition_or_measurement_approach":"Overall survival measured from randomization to death from any cause."}
• {"endpoint_text":"- \tORR defined as the proportion of patients with a CR, CRi, nodular partial response (nPR), or partial response (PR) per the IRC assessment","definition_or_measurement_approach":"Overall response rate determined by IRC as proportion with CR, CRi, nPR or PR per IRC assessment."}
• {"endpoint_text":"- \tuMRD5 rate defined as the proportion of patients that achieved uMRD5 measured in both PB and BMA at the PTFU1 Visit based on NGS (clonoSEQ)","definition_or_measurement_approach":"Proportion achieving undetectable MRD at sensitivity <10^-5 measured in PB and BMA at PTFU1 by NGS (clonoSEQ)."}
• {"endpoint_text":"- \tAdverse events (AEs), adverse events of clinical interest (AECIs), serious adverse events (SAEs), changes from baseline in clinical laboratory tests, physical examinations, and vital signs","definition_or_measurement_approach":"Safety outcomes include collection and reporting of AEs, AECIs, SAEs, and changes from baseline in labs, physical exams and vital signs per protocol."}
• {"endpoint_text":"- \tPFS determined by investigator assessment","definition_or_measurement_approach":"Investigator-assessed progression-free survival measured from randomization to progression or death as assessed by site investigator."}
• {"endpoint_text":"- \tOverall CRR determined by IRC and by investigator assessment.","definition_or_measurement_approach":"Complete response rate (CRR) evaluated by IRC and investigator assessments."}
• {"endpoint_text":"- \tORR determined by investigator assessment","definition_or_measurement_approach":"Overall response rate per investigator assessment (CR/CRi/nPR/PR)."}
• {"endpoint_text":"- \tDuration of response (DOR; determined by both IRC and investigator assessment) defined as the time from first qualifying response (CR, CRi, nPR, or PR) until disease progression or death","definition_or_measurement_approach":"Time from first qualifying response to disease progression or death, evaluated by IRC and investigator."}
• {"endpoint_text":"- \tTime to next treatment (TTNT) defined as the time from randomization to the start of next treatment for CLL","definition_or_measurement_approach":"Time from randomization until initiation of subsequent therapy for CLL."}
• {"endpoint_text":"- \tPatient-reported symptoms of global health status (GHS), role functioning, and physical functioning, symptom burden, and physical condition/fatigue measured by European Organization for Research and Treatment of Cancer quality of life questionnaire EORTC IL-409","definition_or_measurement_approach":"PROs collected using EORTC IL-409 (and other linked questionnaires such as EQ-5D-5L and PGI-S) measuring global health status, role and physical functioning, symptom burden and fatigue."}

Sweden

Earliest CTIS Part Ii Submission Date

16-03-2026

Latest Decision Or Authorization Date

22-04-2026

Processing Time Days

37

Number Of Sites

1

Number Of Participants

5

Czechia

Earliest CTIS Part Ii Submission Date

09-04-2026

Latest Decision Or Authorization Date

21-04-2026

Processing Time Days

12

Number Of Sites

6

Number Of Participants

30

Germany

Earliest CTIS Part Ii Submission Date

30-03-2026

Latest Decision Or Authorization Date

21-04-2026

Processing Time Days

22

Number Of Sites

6

Number Of Participants

25

Romania

Earliest CTIS Part Ii Submission Date

24-03-2026

Latest Decision Or Authorization Date

24-04-2026

Processing Time Days

31

Number Of Sites

3

Number Of Participants

9

Spain

Earliest CTIS Part Ii Submission Date

08-04-2026

Latest Decision Or Authorization Date

24-04-2026

Processing Time Days

16

Number Of Sites

4

Number Of Participants

12

Netherlands

Earliest CTIS Part Ii Submission Date

31-03-2026

Latest Decision Or Authorization Date

21-04-2026

Processing Time Days

21

Number Of Sites

3

Number Of Participants

8

Poland

Earliest CTIS Part Ii Submission Date

02-04-2026

Latest Decision Or Authorization Date

23-04-2026

Processing Time Days

21

Number Of Sites

6

Number Of Participants

40

Italy

Earliest CTIS Part Ii Submission Date

12-01-2026

Latest Decision Or Authorization Date

27-04-2026

Processing Time Days

105

Number Of Sites

6

Number Of Participants

25

France

Earliest CTIS Part Ii Submission Date

08-04-2026

Latest Decision Or Authorization Date

27-04-2026

Processing Time Days

19

Number Of Sites

7

Number Of Participants

32

Primary sponsor

Full Name

BeOne Medicines I GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

WCG Clinical Inc.

Responsibilities

Distribute BeiGene Safety Information (e.g. DSUR/SUSAR) to site

Name

4g Clinical LLC

Responsibilities

sponsorDuties code: 3

Name

Scout Clinical

Responsibilities

Process Payments to patients for travel expenses

Name

Medidata Solutions Inc.

Responsibilities

sponsorDuties codes: 7 (technology platform/vendor responsibilities as listed)

Third parties

• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"sponsorDuties codes: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Adaptive Biotechnologies Corp.","duties_or_roles":"MRD NGS","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"Distribute BeiGene Safety Information (e.g. DSUR/SUSAR)","organisation_type":"Pharmaceutical company"}
• {"country":"China","full_name":"Beigene (Beijing) Biotechnology Co. Ltd.","duties_or_roles":"PD testing","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Early Development Laboratories Inc.","duties_or_roles":"Blood biomarker:CGRP testing","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Predicine Inc.","duties_or_roles":"TP53 and other CLL driver mutations/Gene alteration profile, GAP","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"MLL Dx GmbH","duties_or_roles":"CLL Diagnosis Flow/Complex karyotype","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Process Payments to patients for travel expenses","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Iqvia Laboratories Limited","duties_or_roles":"Blood biomarker:Immune cell profiling +PD assay","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Central imaging","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"LabPMM GmbH","duties_or_roles":"IGHV mutation","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Laboratory Corporation Of America Holdings","duties_or_roles":"Central pathology testing for all ex-china regions, t(11,14) FISH for APAC, NA, Brazil，EMEA","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"China","full_name":"Sequanta Technologies Co. Ltd.","duties_or_roles":"RNA extracted from blood and BMA samples","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Central lab for EU region CLL FISH, HBV DNA / HCV RNA, PK, MRD NGS and others biomarker samples for processing, storage and shipment.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Beone Medicines USA Inc.","duties_or_roles":"PD testing","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"sponsorDuties code: 3","organisation_type":"Non-Pharmaceutical company"}