CLL (Chronic Lymphocytic Leukemia)
Conditions
Keywords
BCL2i, MRD
Brief summary
This study is a prospective, multicenter, open-label, single-arm phase II clinical trial evaluating the efficacy and safety of an MRD-guided, time-limited therapy with zanubrutinib combined with sonrotoclax in previously untreated high-risk CLL/SLL patients.
Interventions
DRUGZanubrutinib and sonrotoclax
Zanubrutinib: 160 mg BID, orally, administered until Cycle 15, 21, or 27, and thereafter until discontinuation criteria are met, disease progression, or unacceptable toxicity.(28d/cycle) Sonrotoclax: Starting from Day 1 of Cycle 3, a 4-week dose-escalation regimen is administered until the target dose of 320 mg QD is reached, then administered orally until Cycle 15, 21, or 27, and thereafter until discontinuation criteria are met, disease progression, or unacceptable toxicity. All patients must complete at least 12 cycles of combination therapy with zanubrutinib and sonrotoclax (C4-C15), with a maximum of 24 cycles of combination therapy (C4-C27). If uMRD6 is not achieved after 24 cycles of combination therapy, patients will receive zanubrutinib monotherapy as maintenance. For patients in whom assessment is feasible, treatment discontinuation may be considered upon achieving uMRD6 at any time point. Otherwise, treatment will be continued until disease progression.
Sponsors
The First Affiliated Hospital with Nanjing Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients must meet all of the following inclusion criteria to be enrolled in this study: Age between 18 and 75 years, inclusive. Diagnosis of CLL/SLL according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. Meeting iwCLL 2018 treatment indications and carrying at least one high-risk factor, including CLL-IPI high-risk/very high-risk, del(11q), del(17p)/TP53 mutation, unmutated IGHV, or complex karyotype. Measurable disease: presence of measurable lymphadenopathy by computed tomography (CT) scan. ECOG performance status of 0 to 2. Adequate major organ function meeting the following criteria: 1. Hematologic function: without transfusion or hematopoietic growth factor support for at least 7 days prior to enrollment (at least 14 days for pegylated G-CSF such as pegfilgrastim), and meeting the following criteria: absolute neutrophil count (ANC) \> 0.75 × 10⁹/L, platelet count (PLT) \> 30 × 10⁹/L, hemoglobin (Hb) \> 80 g/L. 2. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN). 3. Creatinine clearance (CrCl) ≥ 60 mL/min (estimated by Cockcroft-Gault formula). 4. Total bilirubin (TBIL) ≤ 1.5 × ULN (unless due to Gilbert's syndrome or other non-hepatic causes). 5. Coagulation function: prothrombin time (PT)/international normalized ratio (INR) \< 1.5 × ULN, activated partial thromboplastin time (APTT) \< 1.5 × ULN (exceptions may be considered on a case-by-case basis if clearly unrelated to coagulopathy or bleeding disorders). Life expectancy ≥ 6 months. Female subjects of non-childbearing potential (e.g., postmenopausal for ≥ 1 year with amenorrhea, history of hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) are eligible. Female subjects of childbearing potential must have a negative serum pregnancy test at enrollment. Able to understand and voluntarily sign a written informed consent form.
Exclusion criteria
* Patients meeting any of the following criteria will be excluded from this study: Any prior treatment for CLL or SLL (including but not limited to chemotherapy, targeted therapy, immunomodulatory therapy, radiotherapy, and/or monoclonal antibody therapy). History of other malignancies, unless: 1. The malignancy has been cured with no known active disease for at least 3 years prior to the first dose and is considered by the treating physician to carry a low risk of recurrence. 2. Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease. 3. Adequately treated carcinoma in situ with no evidence of disease. Known or suspected history of Richter's transformation. Uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. Subjects with a decline in hemoglobin level or platelet count due to autoimmune destruction within 4 weeks prior to first dose, or requiring \> 20 mg prednisone daily (or equivalent) to treat or control autoimmune disease. Use of \> 20 mg/day prednisone within 7 days prior to first dose of study drug (unless used for prophylaxis or treatment of allergic reactions, such as to contrast media). Known allergic reaction to any of the study drugs. Known hypersensitivity to xanthine oxidase inhibitors and/or rasburicase. Subjects with hypersensitivity to xanthine oxidase inhibitors who cannot receive rasburicase will be excluded. Receipt of a live attenuated vaccine within 4 weeks prior to first dose of study drug. Active infection requiring systemic therapy that is ongoing or completed within 14 days prior to first dose, or any uncontrolled active systemic infection. Known bleeding disorders (e.g., von Willebrand disease or hemophilia). History of stroke or intracranial hemorrhage within 6 months prior to enrollment. Known history of HIV infection, or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects who are positive for HBV core antibody, hepatitis B surface antigen (HBsAg), or HCV antibody must have a negative PCR result prior to enrollment. Subjects with a positive PCR result will be excluded. Major surgery within 4 weeks prior to first dose. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's judgment, could compromise the subject's safety or pose an undue risk to the study results. Current active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia, New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months. Inability to swallow capsules/tablets, or presence of malabsorption syndrome, disease significantly affecting gastrointestinal function, history of partial or total gastrectomy or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. Concurrent use of warfarin or other vitamin K antagonists. Requirement for treatment with strong cytochrome P450 (CYP) 3A inhibitors. Current active, clinically significant hepatic impairment meeting Child-Pugh Class B or C criteria. Female subjects who are lactating or pregnant. Unwilling or unable to participate in all required study assessments and procedures. Inability to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization for use of protected health information (in accordance with national and local privacy regulations).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| uMRD6 rate at Cycle 15 | At the end of Cycle 15 (each cycle is 28 days) | defined as the proportion of patients achieving undetectable minimal residual disease (MRD negativity, \<10-⁶) in peripheral blood as assessed by next-generation sequencing (NGS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| complete response (CR) rate | On Day 1 of Cycle 7, Day 1 of Cycle 19, Day 1 of Cycle 13, Day 1 of Cycle 16, Day 1 of Cycle 19, End of Treatment (each cycle is 28 days) | Overall response rate is the proportion of patients who achieve a complete response to treatment defined by the iwCLL. |
| 3-year Progression-free survival rate | From the first dose of treatment until the date of progression or date of death from any cause, whichever came first.assessed up to 3 years ( 36 month) . | PFS is defined as the time from the first dose of treatment to progression, or death due to any cause, whichever occurs first. For subjects without progression, relapse, or death at the time of analysis, EFS will be censored at the last assessment date. |
| 3-year Overall survival tare | lFrom the first dose of treatment until the date of death from any cause, whichever came first.assessed up to 3 years( 36 month) . | OS is defined as the time from the first dose of treatment to death due to any cause. Subjects who remain alive at the time of analysis will be censored at the last known alive date of the subject. |
| uMRD4 and uMRD6 rates of EOT | On Day 1 of Cycle 16, Day 1 of Cycle 19, Day 1 of Cycle 22, Day 1 of Cycle 25 (up to 25 cycles, each cycle is 28 days). | uMRD4 and uMRD6 rates assessed by flow cytometry and NGS after the actual end of combination therapy. |
| Number of participants with any adverse events (Safety assessed by NCI-CTC AE v5.0) | Safety was evaluated everyday during induction and maintenance therapy. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | All treatment-emergent AEs will be included in the analysis. For each AE, the number and percentage of subjects who experience at least one occurrence of the given event will be summarized. The number and percent of subjects with TEAEs will be summarized according to intensity (CTCAE, v5) for hematologic toxicity, and drug relationship, as well as categorized by system organ class and preferred term. Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those subjects who die, who discontinue treatment due to an AE, or who experience a severe AE or a SAE. |
Countries
China
Contacts
CONTACTHuayuan ZHU, MD, phD
Outcome results
None listed