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
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.
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.
Inclusion Criteria:
Aged ≥18 years, no restriction on gender.
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).
Meet at least one of the following indications for CLL treatment:
Evidence of progressive bone marrow failure manifested by progressive reduction in hemoglobin and/or platelet counts.
Massive splenomegaly (spleen palpable >6 cm below the left costal margin) or symptomatic splenomegaly.
Bulky lymphadenopathy (maximum diameter >10 cm) or symptomatic lymphadenopathy.
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.
Symptomatic organ dysfunction caused by CLL/SLL (involving skin, kidney, lung, spine and other organs).
Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) with inadequate response to corticosteroid therapy.
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.
ECOG performance status ≤2.
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%).
Male and female participants agree to use effective contraception throughout the study period and for a minimum of 4 weeks after treatment completion.
Estimated life expectancy ≥6 months.
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.
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