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

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

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.

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:

  1. 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

  2. Biochemical examination should meet the following standards:

     1. TBIL<2.0× ULN, CLL/SLL liver involvement or confirmed Gilbert syndrome (normal direct bilirubin), total bilirubia ≤ 3 times ULN;
     2. ALT and AST <2.5×ULN (ALT and AST <5×ULN for CLL/SLL liver involvement);
     3. 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:

  1. treatment of autoimmune hemolysis or autoimmune thrombocytopenia associated with CLL/SLL disease;
  2. 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.