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

2026年6月28日 更新者：Yi Shuhua

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.

調査の概要

状態

まだ募集していません

条件

介入・治療

詳細な説明

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.

研究の種類

介入

入学 (推定)

60

段階

  • フェーズ2

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究連絡先

研究連絡先のバックアップ

研究場所

  • 中国
    • Guangdong
      • Shenzhen、Guangdong、中国
        • Shenzhen Second People's Hospital
        • コンタクト：
    • Henan
      • Zhengzhou、Henan、中国
        • Henan Cancer Hospital
        • コンタクト：
    • Hunan
      • Changsha、Hunan、中国
        • The Second Xiangya Hospital of Central South University
        • コンタクト：
          • hongling peng
          • 電話番号：（+86）18900766137
          • メール：577769365@qq.com
    • Jiangsu
      • Nanjing、Jiangsu、中国
        • Jiangsu Province Hospital
        • コンタクト：
    • Jiangxi
      • Nanchang、Jiangxi、中国
        • The First Affiliated Hospital of Nanchang University
        • コンタクト：
    • Shandong
      • Jinan、Shandong、中国
        • Qilu Hospital of Shandong University
        • コンタクト：
    • Tianjin Municipality
      • Tianjin、Tianjin Municipality、中国、300000
        • Blood Disease Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, CAMS)
        • コンタクト：
        • コンタクト：

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

  • 大人
  • 高齢者

健康ボランティアの受け入れ

いいえ

説明

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.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：非ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：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
薬：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)
実験的：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.
薬：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)

薬：zanubrutinib maintenance until disease progression
Continuous zanubrutinib monotherapy until disease progression or intolerable toxicity occurs.

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
uMRD rate
時間枠：At the end of 12 cycles (each cycle is 28 days) of combination therapy
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

二次結果の測定

結果測定
メジャーの説明
時間枠
Objective Response Rate
時間枠：At the end of 12 cycles (each cycle is 28 days) of combination therapy
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
時間枠：At the end of 12 cycles (each cycle is 28 days) of combination therapy
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
時間枠：up to 8 years
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
時間枠：up to 8 years
The time from treatment initiation (or randomization) to disease progression or death
up to 8 years
Overall Survival
時間枠：up to 8 years
The time from treatment initiation (or randomization) to death from any cause
up to 8 years

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Yi Shuhua

協力者

BeOne Medicines

捜査官

  • 主任研究者：Shuhua Yi, Docter、Blood Disease Hospital of Chinese Academy of Medical Sciences (Institute of Hematology, CAMS)

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (推定)

2026年6月8日

一次修了 (推定)

2029年12月31日

研究の完了 (推定)

2034年8月1日

試験登録日

最初に提出

2026年6月2日

QC基準を満たした最初の提出物

2026年6月28日

最初の投稿 (実際)

2026年7月2日

学習記録の更新

投稿された最後の更新 (実際)

2026年7月2日

QC基準を満たした最後の更新が送信されました

2026年6月28日

最終確認日

2026年6月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • IIT2026068

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

はい

IPD プランの説明

only IPD used in the results publication

IPD 共有時間枠

June 2026-January 2030

IPD 共有アクセス基準

Researchers who are interested in the study can obtain the above information by sending an email to my mailbox

IPD 共有サポート情報タイプ

  • STUDY_PROTOCOL
  • ICF

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