Clinical Study of Orelabrutinib Combined With BG Regimen First-line Treatment of CLL/SLL

Study Overview
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Brief Summary
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This study aims to investigate the treatment of navie CLL/SLL with orelabrutinib, bendamustine and obinutuzumab . The primary endpoint is the rate of CR and uMRD, and the second endpoints are survival time (OS and PFS) and toxicities.

Official Title
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Exploratory Clinical Study of Orelabrutinib in Combination With BG Regimen in Patients With Naive and Unfit CLL/SLL Without 17p- or TP53 Mutations

Conditions
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CLL/SLL

Intervention / Treatment
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* Drug: Orelabrutinib and BG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 65 years of age and older or between 18 and 65 years of age with severe illness (non-CLL/SLL associated CIRS ≥ 6); ECOG performance status (PS) level 0 2； Expected survival is not less than 12 weeks; Chronic lymphocytic leukemia/small lymphocytic lymphoma diagnosed by flow cytometry or histopathology according to IWCLL2008 criteria, and CD20 positive; Meet at least 1 indication for treatment according to IWCLL2008 criteria or Chinese CLL/SLL guidelines 2022 Enhanced computed tomography/magnetic resonance imaging (CT/MRI) to detect measurable lesions: at least one lymph node with a maximum axis of more than 1.5 cm and one measurable vertical dimension; for patients with chronic lymphocytic leukemia, only peripheral circulating lymphocyte count must be > 5000/μL (or 5×10^9/L); Have not received systematic treatment for CLL/SLL in the past; The main organs are functioning normally, the following criteria are met: Routine blood test standards should meet: Absolute neutrophil (ANC) ≥1.0×109/L, platelet (PLT) ≥30×109/L; unless bone marrow and hematopoietic insufficiency is confirmed to be due to CLL/SLL Biochemical examination should meet the following standards: TBIL<2.0× ULN, CLL/SLL liver involvement or confirmed Gilbert syndrome (normal direct bilirubin), total bilirubia ≤ 3 times ULN; ALT and AST <2.5×ULN (ALT and AST <5×ULN for CLL/SLL liver involvement); Endogenous creatinine clearance ≥ 30 ml/min (Cockcroft-Gault formula). Women of childbearing age must have taken reliable contraceptive measures or have taken a pregnancy test (serum or urine) within 7 days prior to enrollment, have a negative result, and be willing to use appropriate methods of contraception during the trial and 8 weeks after the last administration of the test drug. For men, consent to appropriate methods of contraception or surgical sterilization during the trial and 8 weeks after the last administration of the test drug must be agreed; Subjects voluntarily join the study, sign the informed consent form, have good compliance, and cooperate with follow-up. Exclusion Criteria: Patients with 17P- chromosome abnormalities or TP53 mutations; Current or previous biopsy pathology confirms conversion to Richter's syndrome; Have active and uncontrolled autoimmune cytopenias, including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura; Patients with central nervous system invasion; Glucocorticoid therapy (at a dose equal to or greater than 20 mg/day of prednisone or equivalent) within 14 days prior to the first dose, excluding inhalation, topical medication, intra-articular medication, and prophylaxis before or after iodine contrast use; After discussion with the team leader, higher doses, longer steroid therapy may be allowed in the following cases: treatment of autoimmune hemolysis or autoimmune thrombocytopenia associated with CLL/SLL disease; Acute exacerbations due to short-term (within 14 days) use of inactive infections for diseases not associated with CLL/SLL (e.g., arthritis, asthma), including steroid dose adjustment required for adrenal insufficiency; Previous or concurrent uncured malignant tumors, except cured basal cell carcinoma of the skin, carcinoma in situ of the cervix and superficial bladder cancer; Suffering from the following cardiovascular diseases: grade II or above myocardial ischemia or myocardial infarction, poorly controlled arrhythmias (including QTc interval QTc >480ms); According to NYHA standards, grade III. IV. cardiac insufficiency, or cardiac ultrasound showed left ventricular ejection fraction (LVEF) < 50%; Coagulation dysfunction (INR>1.5 or prothrombin time (PT) >ULN+4 seconds or APTT >1.5 ULN), bleeding tendency or receiving thrombolysis or anticoagulation therapy; Arteriovenous thrombotic events that occurred within 12 months before enrollment, such as cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc.; Known hereditary or acquired bleeding and thrombosis (such as hemophilia, coagulation dysfunction, thrombocytopenia, hypersplenism, etc.); Have undergone major surgical procedures or developed severe traumatic injuries, fractures or ulcers within 4 weeks of enrollment; Factors that significantly affect the absorption of oral drugs, such as inability to swallow, chronic diarrhea and intestinal obstruction; Active infection requiring antimicrobial therapy (such as antibacterial drugs and antiviral drugs, excluding chronic hepatitis B anti-hepatitis B treatment and antifungal treatment); Active hepatitis B (HBV DNA≥2000 IU/mL or 10000 copy number/mL) or hepatitis C (positive for hepatitis C antibodies and HCV RNA above the lower limit of the assay); Those who have a history of psychotropic substance abuse and cannot quit or have mental disorders; Have participated in clinical trials of other antitumor drugs within 4 weeks before enrollment; Those who have received strong CYP3A4 inhibitor therapy within 7 days before enrollment, or received strong CYP3A4 inducer therapy within 12 days before participating in the study; Pregnant or lactating women; Patients of childbearing potential who are unwilling or unable to use effective contraception; 19. Other circumstances that may affect the conduct of clinical research and the determination of research results as determined by the investigator.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OBG<br> | Drug: Orelabrutinib and BG<br>* Drug: Orelabrutinib Orelabrutinib 200mg, po, qd，C2-C7. Twenty-eight days for a cycle. Drug: BG Bendamustin 70mg/m2, IV, d2&d3 inC1, and then d1&d2 inC2-6.Twenty-eight days for a cycle. Obintuzumab 100mg IV, d1, 900mg d2, 1000mg d8&d15 in C1, and then 1000mg/m2 IV, d1 in C2-6. Twenty-eight days for a cycle.<br>* Other names: OBG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of CR and uMRD | The proportion of patients with CR and undetectable peripheral blood/bone marrow minimal residual disease in the end of combination therapy. Patients with CRi are counted as CR. | Approximately 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of CR/CRu and uMRD | The proportion of patients with CR/CRu and undetectable peripheral blood/bone marrow minimal residual disease in the end of combination therapy. Patients with CRi are counted as CR. CRu is defined as a large spleen size of 16cm or less, and the rest of the indicators meet CR/CRi standards. | Approximately 2 years. | 
| The Rate of uMRD | According to the detection of Shihe Gene [igNGS kit], no residual leukemia cells were detected in a million peripheral blood or bone marrow cells. | Approximately 2 years. | 
| PFS（progression-free survival） | Progression-free survival (PFS) is defined as the time from the date of first administration to the date of first disease progression or death from any cause, whichever occurs first. | Up to 8 years. | 
| OS（overall survival） | Overall survival (OS) refers to the time from receiving the first dose to death from any cause. | Up to 10 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Orelabrutinib, bendamustine, obintuzumab