Zanubrutinib Induction Followed by Delayed Fixed-Duration Combination With Sonrotoclax for CLL/SLL：Stop Trial 2.0 (ZS)

A Single-arm, Multicenter, Prospective Phase II Clinical Trial of Delayed Fixed-duration Combination With Sotoraclax Following Zanubrutinib Induction in Patients With CLL/SLL: Stop Trial 2.0

The goal of this clinical trial is to learn if zanubrutinib induction followed by delayed fixed-duration combination with sonrotoclax works to treat previously untreated Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL). It will also learn about the safety of this combination regimen. The main questions it aims to answer are:Does this combination therapy achieve undetectable minimal residual disease (uMRD) in participants?What medical problems (adverse events) do participants have when taking zanubrutinib and sonrotoclax?Researchers will conduct a single-arm study to systematically evaluate the MRD clearance, efficacy, safety, and immune-related functions of this specific treatment sequence.Participants will:Low-risk group (without 17p deletion/TP53 mutation): Take zanubrutinib monotherapy for 12 cycles, followed by combination zanubrutinib + sonrotoclax for 12 cycles, then discontinue treatment for observation.High-risk group (with 17p deletion/TP53 mutation): Follow the same initial regimen (12 cycles monotherapy + 12 cycles combination), followed by zanubrutinib monotherapy maintenance until disease progression.Visit the clinic periodically for MRD assessment (via flow cytometry), efficacy evaluation (CT/PET-CT, lab tests), and safety checks (physical exam, blood tests, ECG).Undergo immune function evaluation via peripheral blood samples to assess changes in T-cell counts and subsets.

Study Overview

• Status: Not yet recruiting
• Conditions: CLL / SLL
• Intervention / Treatment: Drug: 12 cycles of zanubrutinib followed by 12 cycles of zanubrutinib in combination with sonrotoclax; Drug: zanubrutinib maintenance until disease progression

Detailed Description

This exploratory Phase II single-arm clinical trial is designed to evaluate the efficacy, safety, and immune reconstitution effects of a novel delayed fixed-duration BTK inhibitor (BTKi) induction followed by BCL-2 inhibitor combination regimen in previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients, with risk-stratified post-treatment management based on TP53/del(17p) status.Scientific RationaleCLL/SLL is a mature B-cell clonal proliferative neoplasm, where traditional chemoimmunotherapy has limited efficacy and high toxicity in high-risk populations with del(17p)/TP53 mutations. The current treatment paradigm has shifted to targeted therapies, with BTKi + BCL-2i combination as a first-line strategy. However, existing BCL-2i-based fixed-duration regimens have a grade ≥3 treatment-emergent adverse event (TEAE) incidence of 45%-80%, primarily hematological toxicities and infections. Prior clinical evidence shows that 12 cycles of BTKi monotherapy induction before combination therapy (the "brake" regimen) reduces infection risk compared to alternating chemoimmunotherapy + BTKi regimens, and 12 months of BTKi monotherapy increases T-cell receptor diversity, correlating with better clinical response and lower infection rates in relapsed/refractory CLL. This supports that extending BTKi induction before fixed-duration BCL-2i combination may optimize immune reconstitution, improving safety and long-term disease control.The study uses two investigational agents: zanubrutinib, a next-generation highly selective BTKi with higher BTK target selectivity and fewer off-target effects (e.g., lower cardiovascular adverse event risk vs. first-generation ibrutinib) compared to ibrutinib, approved in China for relapsed/refractory CLL/SLL and mantle cell lymphoma (MCL); and sonrotoclax, a highly selective BCL-2 inhibitor that restores mitochondrial apoptosis in CLL cells, with monotherapy showing 80.5% ORR and 26.8% CR/CRi rate in BTKi-pretreated high-risk relapsed/refractory CLL, and zanubrutinib + sonrotoclax combination achieving 92% 48-week uMRD rate and 100% 30-month PFS rate in treatment-naïve CLL/SLL. Study Design and PopulationThe study will consecutively enroll approximately 60 treatment-naïve CLL/SLL subjects meeting the 2025 Chinese CLL/SLL Diagnosis and Treatment Guidelines criteria, stratified into two groups:High-risk group (n=20): With 17p deletion (del17p) and/or TP53 mutationLow-risk group (n=40): Without del17p and/or TP53 mutationLow-risk group: Discontinue all treatment and enter observational follow-upHigh-risk group: Receive zanubrutinib monotherapy maintenance until disease progressionThis protocol is designed to systematically evaluate whether the delayed BCL-2i combination after extended BTKi induction improves MRD clearance, reduces toxicity, and optimizes long-term outcomes in treatment-naïve CLL/SLL, with tailored post-treatment management for high-risk populations to address their higher relapse risk.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shuhua Yi, Doctor; Phone Number: （+86）15900265415; Email: yishuhua@ihcams.ac.cn
• Study Contact Backup: Name: Tingyu Wang, Doctor; Email: wangtingyu@ihcams.ac.cn

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China
      • Shenzhen Second People's Hospital
      • Contact: xiaoqing li; Phone Number: （+86）18620385718; Email: 18620385718@163.com
  • Henan
    • Zhengzhou, Henan, China
      • Henan Cancer Hospital
      • Contact: keshu zhou; Phone Number: （+86）13674902391; Email: dr_zkshu23810@163.com
  • Hunan
    • Changsha, Hunan, China
      • The Second Xiangya Hospital of Central South University
      • Contact: hongling peng; Phone Number: （+86）18900766137; Email: 577769365@qq.com
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Jiangsu Province Hospital
      • Contact: huayuan zhu; Phone Number: （+86）13813810650; Email: huayuan.zhu@hotmail.com
  • Jiangxi
    • Nanchang, Jiangxi, China
      • The First Affiliated Hospital of Nanchang University
      • Contact: fei li; Phone Number: （+86）13970038386; Email: yx021021@sina.com
  • Shandong
    • Jinan, Shandong, China
      • Qilu Hospital of Shandong University
      • Contact: jingjing ye; Phone Number: （+86）18560086995; Email: yejingjing@sdu.edu.cn
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300000
      • Blood Disease Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, CAMS)
      • Contact: Shuhua Yi, Doctor; Phone Number: （+86）15900265415; Email: yishuhua@ihcams.ac.cn
      • Contact: Tingyu Wang, Doctor; Email: wangtingyu@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged ≥18 years, no restriction on gender.
2. Newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) consistent with the Chinese Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (2025 Edition).

3. Meet at least one of the following indications for CLL treatment:

   1. Evidence of progressive bone marrow failure manifested by progressive reduction in hemoglobin and/or platelet counts.
   2. Massive splenomegaly (spleen palpable >6 cm below the left costal margin) or symptomatic splenomegaly.
   3. Bulky lymphadenopathy (maximum diameter >10 cm) or symptomatic lymphadenopathy.
   4. Progressive lymphocytosis: ≥50% increase in lymphocyte count within 2 months, or lymphocyte doubling time (LDT) <6 months. LDT alone shall not serve as an indication for treatment if the baseline lymphocyte count is <30×10⁹/L.
   5. Symptomatic organ dysfunction caused by CLL/SLL (involving skin, kidney, lung, spine and other organs).
   6. Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) with inadequate response to corticosteroid therapy.

   7. At least one of the following disease-related B symptoms:

      • Unintentional weight loss ≥10% within the preceding 6 months without identifiable cause; ② Severe fatigue (ECOG performance status ≥2, inability to perform routine daily activities);

        ③ Unexplained fever >38.0 °C lasting ≥2 weeks without confirmed infection;

        ④ Unexplained night sweats persisting for more than 1 month without confirmed infection.

4. ECOG performance status ≤2.

5. Major organ function meets the following criteria within 7 days prior to treatment initiation:

   ￮ Hematology: platelet count ≥30×10⁹/L;

   ￮ Biochemistry: total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN; creatinine clearance ≥30 mL/min;

   ￮ Cardiac Doppler echocardiography: left ventricular ejection fraction (LVEF) ≥lower limit of normal (50%).

6. Male and female participants agree to use effective contraception throughout the study period and for a minimum of 4 weeks after treatment completion.
7. Estimated life expectancy ≥6 months.
8. The patient voluntarily participates in the trial and signs the written informed consent form.

Exclusion Criteria:

• 1. Previously received any systemic anti-tumor therapy for CLL/SLL. 2. Pathologically confirmed transformation to Richter's syndrome via biopsy. 3. Severe non-lymphoma-related hepatic or renal impairment defined as: ALT/AST >3×ULN or TBIL >2×ULN; creatinine clearance <30 mL/min or serum creatinine >2×ULN.

  4. Significant pre-existing renal, neurological, psychiatric, pulmonary, endocrine, metabolic, immune, cardiovascular or hepatic disease judged by the investigator to compromise trial participation.

  5. Other uncontrolled clinically significant medical conditions including but not limited to:

  a. Uncontrolled systemic infection (viral, bacterial, fungal); positive hepatitis B surface antigen with HBV-DNA >1000 IU/mL; positive anti-HCV antibody or detectable HCV-RNA; positive anti-HIV antibody.

  b. Active uncontrolled autoimmune diseases other than autoimmune cytopenias. 6. Clinical signs of central nervous system (CNS) dysfunction or documented CNS infiltration by disease.

  7. Received major surgery (excluding lymph node biopsy) within 14 days prior to enrollment or scheduled to undergo major surgery during trial treatment.

  8. Inability to swallow capsules, malabsorption syndrome, or severe gastrointestinal disorders including prior gastrectomy, small bowel resection, symptomatic inflammatory bowel disease, ulcerative colitis, partial or complete intestinal obstruction.

  9. Concurrent use of strong CYP3A inhibitors or inducers during study drug initiation and dose titration period.

  10. Pregnant or breastfeeding females; females of childbearing potential without reliable contraceptive measures.

  11. Clinically significant cardiovascular disease (NYHA cardiac functional class III/IV); history of myocardial infarction, malignant arrhythmia (including QTc ≥480 ms), inadequately controlled hypertension (systolic BP ≥150 mmHg, diastolic BP ≥100 mmHg) or unstable angina within 6 months before enrollment.

  12. Coagulopathy-related exclusion: long-term treatment with multiple high-dose anticoagulants with no possibility of short-term discontinuation; persistent uncontrolled active bleeding; or prior life-threatening irreversible bleeding events.

  13. History of severe hypersensitivity to any active ingredient or excipient of the investigational product.

  14. Systemic disorders that may impair patient compliance with trial requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-risk group（Without del17p and/or TP53 mutation）; 12 cycles of zanubrutinib monotherapy induction → 12 cycles of zanubrutinib combined with sonrotoclax → discontinuation of study drugs followed by regular follow-up	Drug: 12 cycles of zanubrutinib followed by 12 cycles of zanubrutinib in combination with sonrotoclax; 12 cycles of zanubrutinib monotherapy induction → 12 cycles of zanubrutinib combined with sonrotoclax → discontinuation of study drugs followed by regular follow-up Zanubrutinib Dosage The total daily oral dose is 320 mg. The dosing schedule is 160 mg (2 × 80 mg capsules) twice daily, Sonrotoclax Dose Escalation Schedule Cycle 13 Week 1 (C13W1): Days 1-3: 1 mg daily (1 × 1 mg tablet); Days 4-7: 2 mg daily (2 × 1 mg tablets) Cycle 13 Week 2 (C13W2): Days 1-3: 5 mg daily (1 × 5 mg tablet); Days 4-7: 10 mg daily (2 × 5 mg tablets) Cycle 13 Week 3 (C13W3): Days 1-3: 20 mg daily (1 × 20 mg tablet); Days 4-7: 40 mg daily (2 × 20 mg tablets) Cycle 13 Week 4 (C13W4): Days 1-3: 80 mg daily (1 × 80 mg tablet); Days 4-7: 160 mg daily (2 × 80 mg tablets) Cycle 14 Week 1 (C14W1) and all subsequent cycles: 320 mg daily (4 × 80 mg tablets)
Experimental: High-risk group(With del17p and/or TP53 mutation); 12 cycles of zanubrutinib followed by 12 cycles of zanubrutinib in combination with sonrotoclax, then zanubrutinib maintenance monotherapy until disease progression or intolerable toxicity occurs.	Drug: 12 cycles of zanubrutinib followed by 12 cycles of zanubrutinib in combination with sonrotoclax; 12 cycles of zanubrutinib monotherapy induction → 12 cycles of zanubrutinib combined with sonrotoclax → discontinuation of study drugs followed by regular follow-up Zanubrutinib Dosage The total daily oral dose is 320 mg. The dosing schedule is 160 mg (2 × 80 mg capsules) twice daily, Sonrotoclax Dose Escalation Schedule Cycle 13 Week 1 (C13W1): Days 1-3: 1 mg daily (1 × 1 mg tablet); Days 4-7: 2 mg daily (2 × 1 mg tablets) Cycle 13 Week 2 (C13W2): Days 1-3: 5 mg daily (1 × 5 mg tablet); Days 4-7: 10 mg daily (2 × 5 mg tablets) Cycle 13 Week 3 (C13W3): Days 1-3: 20 mg daily (1 × 20 mg tablet); Days 4-7: 40 mg daily (2 × 20 mg tablets) Cycle 13 Week 4 (C13W4): Days 1-3: 80 mg daily (1 × 80 mg tablet); Days 4-7: 160 mg daily (2 × 80 mg tablets) Cycle 14 Week 1 (C14W1) and all subsequent cycles: 320 mg daily (4 × 80 mg tablets); Drug: zanubrutinib maintenance until disease progression; Continuous zanubrutinib monotherapy until disease progression or intolerable toxicity occurs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
uMRD rate	Proportion of patients achieving undetectable minimal residual disease (uMRD, defined as MRD <10-⁴, fewer than 1 CLL cell per 10,000 leukocytes)	At the end of 12 cycles (each cycle is 28 days) of combination therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	The proportion of patients who achieve a Complete Response (CR) and a Partial Response (PR) according to standardized criteria	At the end of 12 cycles (each cycle is 28 days) of combination therapy
Complete Response Rate	The percentage of patients who meet the stringent criteria for Complete Remission	At the end of 12 cycles (each cycle is 28 days) of combination therapy
Duration of Response	The time from the first documented objective response (CR or PR) until disease progression (PD) or death from any cause.	up to 8 years
Progression-Free Survival	The time from treatment initiation (or randomization) to disease progression or death	up to 8 years
Overall Survival	The time from treatment initiation (or randomization) to death from any cause	up to 8 years

Collaborators and Investigators

• Sponsor: Yi Shuhua
• Collaborators: BeOne Medicines
• Investigators: Principal Investigator: Shuhua Yi, Docter, Blood Disease Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, CAMS)

Publications and helpful links

General Publications

• Hugosson J, Mansson M, Wallstrom J, Axcrona U, Carlsson SV, Egevad L, Geterud K, Khatami A, Kohestani K, Pihl CG, Socratous A, Stranne J, Godtman RA, Hellstrom M; GOTEBORG-2 Trial Investigators. Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only. N Engl J Med. 2022 Dec 8;387(23):2126-2137. doi: 10.1056/NEJMoa2209454.
• Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Koppler H, Kiehl M, Sokler M, Schlag R, Vehling-Kaiser U, Kochling G, Ploger C, Gregor M, Plesner T, Trneny M, Fischer K, Dohner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Bottcher S, Hallek M; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1. Epub 2016 May 20.
• Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984 Nov 30;226(4678):1097-9. doi: 10.1126/science.6093263.
• Venditti A, Piciocchi A, Candoni A, Melillo L, Calafiore V, Cairoli R, de Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Mazza P, Martelli MP, Cuneo A, Albano F, Fabbiano F, Tafuri A, Chierichini A, Tieghi A, Fracchiolla NS, Capelli D, Foa R, Alati C, La Sala E, Fazi P, Vignetti M, Maurillo L, Buccisano F, Del Principe MI, Irno-Consalvo M, Ottone T, Lavorgna S, Voso MT, Lo-Coco F, Arcese W, Amadori S. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia. Blood. 2019 Sep 19;134(12):935-945. doi: 10.1182/blood.2018886960. Epub 2019 Aug 8.
• Bischler T, Hsieh PK, Resch M, Liu Q, Tan HS, Foley PL, Hartleib A, Sharma CM, Belasco JG. Identification of the RNA Pyrophosphohydrolase RppH of Helicobacter pylori and Global Analysis of Its RNA Targets. J Biol Chem. 2017 Feb 3;292(5):1934-1950. doi: 10.1074/jbc.M116.761171. Epub 2016 Dec 14.
• Chriskos P, Frantzidis CA, Plomariti CS, Papanastasiou E, Pataka A, Kourtidou-Papadeli C, Bamidis PD. SmartHypnos: An Android application for low-cost sleep self-monitoring and personalized recommendation generation. Comput Biol Med. 2025 Jan;184:109306. doi: 10.1016/j.compbiomed.2024.109306. Epub 2024 Nov 14.
• Laurencin CT, Walker JM. A Pandemic on a Pandemic: Racism and COVID-19 in Blacks. Cell Syst. 2020 Jul 22;11(1):9-10. doi: 10.1016/j.cels.2020.07.002. Epub 2020 Jul 22.
• Jana A, Baruah M, Munan S, Samanta A. ICT based water-soluble fluorescent probe for discriminating mono and dicarbonyl species and analysis in foods. Chem Commun (Camb). 2021 Jun 29;57(52):6380-6383. doi: 10.1039/d1cc02600c.
• Zakir M, Thomas D, Adams R, Farnell D, Claydon N. A Systematic Review and Meta-Analysis of the Clinical Outcomes for Adjunctive Physical, Chemical, and Biological Treatment of Dental Implants With Peri-Implantitis. J Oral Implantol. 2023 Apr 1;49(2):168-178. doi: 10.1563/aaid-joi-D-21-00204.
• Duncanson G. Evolve to thrive. Vet Rec. 2019 May 4;184(18):560. doi: 10.1136/vr.l1956. No abstract available.
• Tam CS, Allan JN, Siddiqi T, Kipps TJ, Jacobs R, Opat S, Barr PM, Tedeschi A, Trentin L, Bannerji R, Jackson S, Kuss BJ, Moreno C, Szafer-Glusman E, Russell K, Zhou C, Ninomoto J, Dean JP, Wierda WG, Ghia P. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood. 2022 Jun 2;139(22):3278-3289. doi: 10.1182/blood.2021014488.
• Eichhorst B, Ghia P, Niemann CU, Kater AP, Gregor M, Hallek M, Jerkeman M, Buske C; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. ESMO Clinical Practice Guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukaemia. Ann Oncol. 2024 Sep;35(9):762-768. doi: 10.1016/j.annonc.2024.06.016. Epub 2024 Jul 3. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): June 8, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): August 1, 2034

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Chronic Lymphocytic Leukemia; Zanubrutinib; Sonrotoclax
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell
• Other Study ID Numbers: IIT2026068

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: only IPD used in the results publication
• IPD Sharing Time Frame: June 2026-January 2030
• IPD Sharing Access Criteria: Researchers who are interested in the study can obtain the above information by sending an email to my mailbox
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No