Zanubrutinib With Obinutuzumab in Untreated Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
NCT Number: NCT06544785
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Chronic Lymphocytic Leukemia|Small Lymphocytic Lymphoma
Interventions: DRUG: Zanubrutinib Oral Product|DRUG: Obinutuzumab
Sponsor: PETHEMA Foundation
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 106
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-09-30
Completion Date: 2032-05-31

Summary:
The goal of this phase II randomized open label study is to compare the rate of complete remission (CR) with undetectable minimal residual disease (uMRD) obtained with zanubrutinib in combination with obinutuzumab with two different schedules of administration of obinutuzumab (starting obinutuzumab at cycle 2 or 12 months) in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). There is scarce information about which is the most appropriate schedule of combining the BTKi and the anti-CD20 monoclonal antibody, and whether treatment can be safely stopped in those patients attaining deep responses (CR with uMRD) remains to be determined.

Response will be assessed after 20 cycles of treatment for the primary objective of the study. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first.

Primary Outcome Measures: Rate of Complete Remission (CR) with undetectable Measurable Residual Disease (uMRD)., To compare the rates of complete remission (CR) with undetectable minimal residual disease (uMRD, assessed by flow cytometry in bone marrow with a value \<10-4 \[0.01%\] tumour cells for being considered as negative) between both arms A and B.

Response will be assessed after 20 cycles of treatment for the primary outcome measure. Patients attaining uMRD will stop treatment with zanubrutinib, whereas the rest of patients will continue on treatment with zanubrutinib until progression, unacceptable toxicity, or trial completion, whichever comes first. Patients who achieve an uMRD in bone marrow beyond C20, will also be allowed to stop the treatment.

The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects., 7.5 Years
Secondary Outcome Measures: Overall response rate (ORR), Includes the following categories: Complete Remission (CR); CR with incomplete marrow recovery (CRi); Partial Remission (PR), and partial response with lymphocytosis.

The IWCLL guidelines (Hallek, 2018) will be used to measure response in CLL subjects.

Overall response assessment will include evaluation of physical exams, recording of symptoms, and haematological evaluations. OR will be assessed on Day 1 Cycle 2, on Day 1 of Cycles 3 to 12, and on Day 1 of Cycles 13, 15, 17, 19, 21, and 23, and then every 3 cycles to disease progression or study closure., 7.5 Years|Measurable Residual Disease (MRD) analysis, In cycle 20, MRD should be analysed in peripheral blood and in the bone marrow by flow-cytometry. Patients with uMRD should be followed every 6 months during 24 months and then every 12 months for MRD by peripheral blood flow cytometry. Patients with detectable MRD and without lymphocytosis (lymphocyte count \< 4.0 X 109/L) should be followed every 6 months for MRD by peripheral blood flow cytometry during 24 months and then every 12 months. In addition, a further bone marrow MRD assessment should be performed at any time during follow-up when the patient has cleared MRD from the peripheral blood. MRD will also be evaluated in PB by flow-cytometry at cycle 9 in arm A (2 cycles after finalizing obinutuzumab)., 7.5 Years|Progression-Free Survival (PFS), Defined as the time from randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death by any cause, whichever occurs first., 7.5 Years|Overall Survival (OS), Defined as the time from the date of first dose of study drug to the date of the subject's death. If the subject is alive or the vital status is unknown, then the subject's data will be censored at the date the subject was last known to be alive.

After progression, patients will be followed every 6 months to assess survival status and the start of subsequent cancer therapies until death, patient withdrawal, loss to follow-up, or study termination, whichever comes first., 7.5 Years|Immunological recovery, Serum quantitative immunoglobulin (IgG, IgM, IgA) levels will be evaluated by local laboratory at screening, on Day 1 of every odd cycle from Cycles 3 through 12, on Day 1 of every odd cycle (for Cycles 13, 15, 17, 19, 21 and 23), and then every 3 cycles until progression or study closure. The units if measure for the immunoglobulin levels determinations of will be g/L for all 3 Ig types., 7.5 Years|Adverse Events (AE), Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with the treatment.

Type, rate and severity of AEs and relationship of AEs to zanubrutinib or the combination of zanubrutinib and obinutuzumab, including the assessment of infusion related reactions (IRR) and tumour lysis syndrome (TLS) will be recorded. The rate and severity of IRR and TLS will be analyzed also according to the two different schedules of administration of obinutuzumab (arm A and arm B)., 7.5 Years