Active, not recruiting
Phase 1
Zanubrutinib, Obinutuzumab and Lenalidomide in Newly Diagnosed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
Condition(s) studied
Chronic Lymphocytic LeukemiaSmall Lymphocytic LymphomaNewly Diagnosed
Investigational drug(s) / intervention(s)
ZanubrutinibLenalidomideObinutuzumab
Zanubrutinib: 160mg bid/d, from C1 to CR and MRD-negative or C24
Lenalidomide: From C3 dose escalation, all 3 dose groups climbed from 5 mg/d to 10 mg/d, 15 mg/d, and 20 mg/d respectively, Taking 21 days of medication and 7 days of rest, 1 cycle every 28 days to CR and MRD-negative or C24
Obinutuzumab: 1000 mg C1, d1/d8/15; 1000 mg C2-6, d1
Study summary
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.
Eligibility
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;
Primary outcome measure(s)
- Maximum Tolerated Dose (MTD) of lenalidomide in combination regimens were determined in newly diagnosed CLL/SLL patients, — From the date of first dose of study drugs until RP2D was determined(Approximately 4 months)]
- The incidence, nature and severity of adverse events (AE) were determined according to NCI-CTCAE v5.0 evaluation criteria — From first dose to 30 days after the last dose of Zanubrutinib or lenalidomide or Obinutuzumab
Trial sites (1)
| Facility | City | Region | Status |
| Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College |
Tianjin |
Tianjin Municipality |
|
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