Zanubrutinib Followed Zanubrutinib Plus FCR / BR in Newly Diagnosed Symptomatic CLL/SLL

Study Overview
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Brief Summary
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This study aims to evaluate the long-term efficacy of BTK inhibitor Zanubrutinib monotherapy , sequential Zanubrutinib combined (Fludarabine, cyclophosphamide and rituximab /bendamustine and rituximab)FCR/BR regimen by a limited period of treatment for the newly diagnosed Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The investigators propose this combination will improve the MRD negative rate of patients with CR/CRi after treatment was significantly higher than that of FCR chemotherapy can be a time-limited regimen which will reduce the life-time therapy and benefit the patients.

Detailed Description
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The investigators designed timed FCR/BR treatment for BTK inhibitor Zanubrutinib monotherapy after continuous remission, which shortened the treatment time, deepened the depth of remission, and enabled some patients to achieve deep remission (MRD negative), and realized long-term survival after drug withdrawal. Treatment regimens: Zanubrutinib monotherapy for 12 months followed by 4 courses of immunochemotherapy with FCR or BR. Cohort 1 was designed to apply FCR for patients aged 65 years or younger who could tolerate FCR. Cohort 2 was designed to apply BR in patients older than 65 years or unable to tolerate FCR.

Official Title
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A Phase 2 Clinical Trial to Evaluate the Efficacy of Zanubrutinib Followed Zanubrutinib Plus FCR (Fludarabine Cyclophosphamide and Rituximab) / BR(Bendamustine and Rituximab) in Newly Diagnosed Symptomatic CLL/SLL (STOP Trial)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Newly Diagnosed

Intervention / Treatment
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* Drug: Zanubrutinib, Fludarabine, cyclophosphamide and rituximab
* Drug: Zanubrutinib, bendamustine, rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. 18 Years and older (Adult, Older Adult) 2. Age >65 years or age ≤65 years with creatinine clearance of 30-69 mL/min or patients with a cumulative Disease Rating Scale (CIRS-G) score greater than 6 point were enrolled in cohort 2 , other patients were enrolled in cohort 1. 3. Confirmed diagnosis of CLL or SLL that meets the 2008 IWCLL criteria 4. The patients are untreated or without prior systemic therapy for disease, the specific conditions are as follows: a) Prior treatment with a fludarabine or treatment with bendamustine or rituximab regimen b) Not treated with Chlorambucil, or treated with Chlorambucil for less than 4 weeks (alone or in combination with adrenal glucocorticoid) c) If the above treatment has been applied, it is necessary to stop treatment for 2 weeks before joining the group for treatment 5. Treatment indications for CLL mainly include (meeting at least one of the following conditions): a) Evidence of progressive bone marrow failure presenting as progressive decrease in hemoglobin and/or platelets b) Splenomegaly (e.g., >6cm below the left costal margin) or progressive or symptomatic splenomegaly c) giant lymph node enlargement (longest diameter >10cm) or progressive or symptomatic lymph node enlargement d) Progressive lymphocytosis, such as lymphocytosis >50% within 2 months, or lymphocyte multiplication time (LDT) <6 months. When the initial lymphocyte was <30×109/L, LDT alone could not be used as a treatment indication e) Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) do not respond well to corticosteroids or other standard treatments f) Symptoms associated with at least one of the following diseases: ①≥10% weight loss with no apparent cause in the previous 6 months; ② Severe fatigue (such as ECOG physical state ≥2 points; Unable to carry out regular activities); ③ No evidence of infection, body temperature >38℃, ≥2 weeks; (4) No evidence of infection, night sweats >1 month 6. ECOG performance status of 0, 1, or 2 7. The main organ functions met the following criteria within 7 days before treatment: Blood routine examination criteria: platelet ≥30×10^9/L; Biochemical tests should meet the following criteria: Total bilirubin (TBIL) ≤1.5 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase AST≤2.5*ULN; Creatinine clearance rate ≥ 30mL /min; Cardiac Doppler ultrasonography: Left ventricular ejection fraction (LVEF)≥ the lower limit of normal (50%). 8. Both men and women of reproductive age agreed to use reliable contraception throughout the study period and for up to four weeks after the end of treatment 9. Life expectancy ≥ 6 months 10. Patients voluntarily participated in the study and signed informed consent Exclusion Criteria: 1. Have been diagnosed or treated for malignancies other than CLL (including active CNS lymphoma) within the past year 2. Clinical evidence suggests that Richter's transformation occurs 3. Non-lymphoma-related liver and kidney function impairment: ALT > 3 times the upper limit of normal value, AST > 3 times the upper limit of normal value, TBIL > 2 times the upper limit of normal value, serum creatinine clearance <30ml/min 4. Other serious medical conditions, such as uncontrolled diabetes, gastric ulcers, and other serious heart and lung diseases, may affect this study. The right to make judgments belongs to the researcher 5. Diagnosed human immunodeficiency virus (HIV) infection or active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics. (Note: Active HBV infection was defined as a.HBV DNA quantification ≥2000 IU/ mL; b. ALT≥2 times normal upper limit; c. To exclude hepatitis caused by other causes, such as the disease itself or drugs, the three conditions must be met simultaneously. Patients with active HBV infection at initial diagnosis and non-active HBV infection after anti-HBV treatment can be included in this study on the premise of adequate anti-HBV treatment.) 6. Clinical manifestations of central nervous dysfunction or CNS invasion 7. Patients who have had major surgery (excluding lymph node biopsy) within the past 14 days or who are expected to require major surgery as part of their treatment 8.Unable to swallow capsules or malabsorption syndrome, disease that significantly affects gastrointestinal function, previous gastrectomy or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction 9. Requires ongoing treatment with any medication which is a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor or strong CYP3A inducer 10. Females who are currently pregnant or breastfeeding, or at a childbearing age who are not using contraception 11. Clinically significant cardiovascular abnormalities (NYHA classification: III/IV) (Annex 3), patients with myocardial infarction, malignant arrhythmia (including QTC≥480ms), unsatisfactory blood pressure control with antihypertensive drugs (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥100 mmHg), and uncontrolled angina pectoris within 6 months before enrollment 12. Persistent uncontrolled bleeding 13. A history of life-threatening haemorrhage, especially from irreversible causes 14. High doses of several anticoagulants are required and cannot be stopped for a short time 15. evere allergy to the active ingredient or any excipients of the product

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZFCR regimen<br>Patients aged 65 years or younger who can tolerate FCR： Patients in this group will receive zanubrutinib monotherapy for 12 months, then receive 4 cycles of zanubrutinib, fludarabine, cyclophosphamide and rituximab(ZFCR). Efficacy evaluation and MRD test of peripheral blood and bone marrow were performed at the 17th cycle after 16 cycles to obtain study end point data. Patients with CR/CRi and MRD negative could stop taking zanubrutinib, and other patients could stop taking zanubrutinib or continue treatment. Follow-up and efficacy assessment were conducted every three months. | Drug: Zanubrutinib, Fludarabine, cyclophosphamide and rituximab<br>* Patients aged 65 years or younger who can tolerate FCR.<br>* Other names: ZFCR regimen;|
| Experimental: ZBR regimen<br>For patients older than 65 years or who cannot tolerate FCR regimens: Patients in this group will receive zanubrutinib monotherapy for 12 months, then receive 4 cycles of bendamostine and rituximab(BR). Efficacy evaluation and MRD test of peripheral blood and bone marrow were performed at the 17th cycle after 16 cycles to obtain study end point data. Patients with CR/CRi and MRD negative could stop taking zanubrutinib and other patients could stop taking zanubrutinib or continue treatment. | Drug: Zanubrutinib, bendamustine, rituximab<br>* For patients older than 65 years or who cannot tolerate FCR regimens.<br>* Other names: ZBR regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD negative rate of CR patients | The negative MRD rate of patients with CR at the end of 16 cycles of treatment | up to the end of 16 cycles of treatment (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate(ORR) | Defined as the proportion of patients whose BICR was assessed for CR, CRi, or PR according to IWCLL 2018 criteria at or before initiation of subsequent antitumor therapy. | up to the end of 16 cycles of treatment (each cycle is 28 days) | 
| Complete response (CR) | Defined as the percentage of subjects who achieved CR after treatment in the conformance population and the intentionality treatment population. | up to the end of 16 cycles of treatment (each cycle is 28 days) | 
| Duration of tumor remission(DOR) | Defined as the time interval between the first documented remission of disease and the first documented evidence of PD for patients in the intentional-treatment population (ITT). Exit with no progress or no recorded time of disease progression, with the date of the last examination as the end date. | up to 5 years | 
| time to next treatment(TTNT) | Patients in the treatment-intentionality population (ITT) were defined from the beginning of first-line treatment to the beginning of back-line treatment or the time of death. | up to 5 years | 
| Progress-free survival(PFS) | the time from treatment initiation until disease progression or death, If there was no progress at the time of withdrawal or the time of disease progression was not recorded, the end date was the date of the last examination. | up to 5 years | 
| The time at which the median MRD turned positive | It was defined as the time for the median peripheral and/or bone marrow MRD to become positive in patients with CR/CRi and MRD negative in bone marrow and peripheral blood after the 16th cycle of treatment. | up to 5 years | 
| overall survival | Defined as the time interval from enrollment to death for patients in the treatment-intentionality population (ITT). If the patient remains alive or if it is not known whether the patient is alive or dead, the date of death will be adopted at the most recent point in time when the patient is known to be alive. | up to 5 years | 
| Safety of treatment regimens | Defined as treatment-related toxicity | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic lymphocytic leukemia, Small Lymphocytic Lymphoma, newly diagnosed, Zanubrutinib