Zanubrutinib, Obinutuzumab and Lenalidomide in Newly Diagnosed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

A Phase 1b Clinical Study of Lenalidomide in Combination With Zanubrutinib and Obinutuzumab (ZGR) in the Treatment of Newly Diagnosed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) With Therapeutic Indications

The ZGR regimen limited-course regimen was designed to combine three targeted agents, zanubrutinib, obinutuzumab (a third-generation CD20 monoclonal antibody), and lenalidomide, to deepen the depth of remission in patients with new-diagnosis CLL/SLL, with a view to achieving the goal of discontinuation of the drug and long-term remission after discontinuation of the drug, and prolonging the PFS, and at the same time, the regimen no longer includes cytotoxic chemotherapeutic agents, such as fludarabine and cyclophosphamide, which improves the CLL/ SLL patients' treatment tolerance, and can eliminate the treatment limitation for elderly or poorly tolerated CLL/SLL patients.

BTK inhibitor monotherapy for CLL/SLL can obtain 80-90% ORR and give patients long-term survival, but most patients only obtain PR efficacy, even after up to 7-8 years of continuous treatment, the proportion of patients with CR can only be improved from less than 10% to about 30%, and it is very difficult for any patient to achieve MRD negativity, so it is determined that the mode of treatment of BTK inhibitor monotherapy is long-term continuous administration for tumor control. In order to change this pattern of long-term continuous treatment, and to shorten the long-term continuous treatment to a limited cycle of treatment, it is necessary to deepen the depth of remission by combining the treatment with other mechanisms of drugs, or even to achieve MRD-negativity in order to realize the discontinuation of the drug.

Lenalidomide is an oral immunomodulatory drug with direct antitumor effects and indirect antitumor effects by acting on a variety of immune cells in the tumor microenvironment. Lenalidomide alone, in combination with CD20 monoclonal antibody (rituximab), or (and) BTK inhibitors for the treatment of R/R CLL/SLL has shown therapeutic responses, with the best response to triple therapy of lenalidomide in combination with rituximab and BTK inhibitors. combination therapy showed the best response.

The ZGR limited-course regimen that combines zanubrutinib, obinutuzumab, and lenalidomide in the treatment of patients with primary diagnosis of CLL/SLL, which can deepen the depth of remission, with a view to achieving the goal of discontinuation of the drug and long-term remission after discontinuation of the drug, and prolonging the PFS, and at the same time, the regimen are removed cytotoxic chemotherapeutic agents, such as fludarabine, to increase the tolerance of the treatment in patients with CLL/SLL, and can eliminate the need for treatment of elderly or poorly tolerated patients with CLL/SLL. treatment limitations in poorly tolerated CLL/SLL patients.

Inclusion Criteria:

• 1） Patients were not categorized by gender ，Age ≥18;

• 2） Confirmed diagnosis of CLL or SLL;

• 3）Patients must be untreated, or not undergoing standardized treatment for the first time, under the following conditions:

• a) Not treated with fludarabine-containing or bendamustine-containing or rituximab-containing regimens;

• b) Have not been treated with the application of chlorambucil, or have applied chlorambucil for less than 4 weeks (alone or in combination with adrenal glucocorticoids);

• (c) If the above treatment has been applied, it must be stopped for 2 weeks before enrollment in the group to start the treatment.

• 4） Indications for treatment of CLL/SLL include, inter alia (at least one of the following conditions is met)

  1. Evidence of progressive bone marrow failure: as evidenced by progressive decrease in hemoglobin and/or platelets;
  2. Giant spleen (e.g., >6 cm below the left costal margin) or symptomatic splenomegaly;
  3. Giant lymph node enlargement (e.g., longest diameter >10 cm) or symptomatic lymph node enlargement;
  4. Progressive lymphocytosis, e.g., >50% lymphocytosis within 2 months, or lymphocyte doubling time (LDT) <6 months. When initial lymphocytes are <30 x 10^9/L, LDT alone cannot be used as a therapeutic indication;
  5. CLL/SLL resulting in symptomatic organ dysfunction (e.g., skin, kidney, lung, spine, etc.)
  6. Autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) that does not respond well to corticosteroids or other standard therapy;
  7. Presence of at least one of the following disease-related symptoms: i) weight loss ≥10% without apparent cause within the previous 6 months; ii) severe fatigue (e.g., ECOG physical status ≥2; inability to perform routine activities); iii) temperature >38°C for ≥2 weeks without evidence of infection; iv) nocturnal night sweats for >1 month without evidence of infection;

• 5） ECOG≤2

• 6) Major organ function within 7 days prior to treatment, meet the following criteria: routine blood test criteria: platelets ≥30×10^9/L; biochemical tests need to 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 ≥ 30 ml/min; and cardiac Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ low limit of normal (50%);

• 7) Male and female patients of childbearing age agree to use reliable contraception throughout the study period and for 4 weeks after the end of study treatment;

• 8) Patients need to have an expected survival of ≥ 6 months;

• 9) Patients need to voluntarily participate in this study by signing an informed consent form.

Exclusion Criteria:

• Patients who met any of the following criteria were excluded from the study:
• (1) Malignancies other than CLL/SLL (including active CNS lymphoma) have been diagnosed or treated within the past year;
• (2) There has been clinical evidence of Richter transformation;
• (3) Non-lymphoma-related hepatic and renal impairment: alanine aminotransferase (ALT) > 3 times the upper limit of normal, alanine transaminase (AST) > 3 times the upper limit of normal, total bilirubin (TBIL) > 2 times the upper limit of normal, and serum creatinine clearance < 30 ml/min;
• (4) Other serious medical disorders that would interfere with the study (e.g., uncontrolled diabetes mellitus, gastric ulcers, grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, other serious cardiorespiratory diseases, etc.). The judgmental decision is vested in the investigator;
• (5) Patient who had infected with Human Immunodeficiency Virus (HIV) or active Hepatitis B Virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics;
• (6) Clinically manifested CNS dysfunction or invasion of the center;
• (7) Patients who have undergone a major surgical procedure (excluding lymph node biopsy) within the last 14 days or who require a major surgical procedure in anticipation of treatment;
• (8) Inability to swallow capsules or suffering from malabsorption syndromes, disorders significantly affecting gastrointestinal function, having undergone gastric or small bowel resection, symptomatic inflammatory bowel disease or ulcerative colitis, and partial or complete intestinal obstruction.
• (9) Requires treatment with potent cytochrome P450 (CYP) 3A inhibitors;
• (10) Pregnant or lactating women of childbearing age who are not using contraception;
• (11) Patients with clinically significant cardiovascular abnormalities (New York Heart Association (NYHA) classification: III/IV), myocardial infarction within 6 months prior to enrollment, malignant arrhythmias (including QTC ≥ 480 ms), poorly controlled blood pressure (systolic ≥ 150 mmHg, diastolic ≥ 100 mmHg) despite the use of antihypertensive medications, and uncontrolled angina;
• (12) Persistent uncontrolled bleeding;
• (13) History of life-threatening hemorrhage, especially from irreversible causes;
• (14) Need for high doses of several anticoagulants that cannot be briefly discontinued;
• (15) Thrombotic events within three months of treatment initiation;
• (16) Patients with severe hypersensitivity to the active ingredient of the study drug or to any of its excipients;