Trial Title:
Zanubrutinib, Obinutuzumab and Lenalidomide in Newly Diagnosed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
NCT ID:
NCT06547944
Condition:
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Newly Diagnosed
Conditions: Official terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lenalidomide
Obinutuzumab
Zanubrutinib
Conditions: Keywords:
Zanubrutinib
Lenalidomide
Obinutuzumab
newly diagnosed CLL/SLL
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Zanubrutinib
Description:
160mg bid/d, from C1 to CR and MRD-negative or C24
Arm group label:
ZGR regimen
Intervention type:
Drug
Intervention name:
Lenalidomide
Description:
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
Arm group label:
ZGR regimen
Intervention type:
Drug
Intervention name:
Obinutuzumab
Description:
1000 mg C1, d1/d8/15; 1000 mg C2-6, d1
Arm group label:
ZGR regimen
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.
Detailed description:
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.
Criteria for eligibility:
Criteria:
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;
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Sciences & Peking Union Medical College
Address:
City:
Tianjin
Country:
China
Start date:
January 1, 2024
Completion date:
December 1, 2026
Lead sponsor:
Agency:
Institute of Hematology & Blood Diseases Hospital, China
Agency class:
Other
Source:
Institute of Hematology & Blood Diseases Hospital, China
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06547944
