Phase II Study of Acalabrutinib and Venetoclax in Patients with Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following First-Line BTKi and BCL2 Inhibitor Therapy

The primary objective of this study is to evaluate the efficacy of second-line treatment with acalabrutinib and venetoclax in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have experienced relapse following initial therapy with a covalent Bruton’s tyrosine kinase inhibitor and a BCL2 inhibitor. Efficacy is measured via the overall response rate. Secondary objectives include the assessment of:

• Progression-free survival
• Duration of response
• Event-free survival
• Time to next treatment
• Overall survival
• Undetectable minimal residual disease
• Safety and tolerability

This study involves 17 participants diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma. The study population includes both male and female individuals within the specified age ranges. Participants must have a diagnosis confirmed according to the International Workshop on Chronic Lymphocytic Leukemia guidelines. Eligible individuals are those who have undergone first-line treatment consisting of a fixed duration covalent Bruton’s tyrosine kinase inhibitor plus B-cell leukemia/lymphoma-2 inhibitor therapy, achieving at least a partial remission, with a minimum of 2 years elapsed since the conclusion of said treatment. Required clinical data includes immunoglobulin heavy chain status, 17p deletion, and tumor protein 53 mutation status. Additionally, participants must possess an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and demonstrate adequate organ function and bone marrow function.

This Phase II clinical trial is designed to evaluate the efficacy and safety of second-line treatment using acalabrutinib and venetoclax in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma. The study focuses on determining the overall response rate after patients have undergone prior first-line therapy involving a covalent BTK inhibitor and a BCL2 inhibitor. The research methodology involves assessing primary efficacy endpoints after the completion of Cycle 14, alongside secondary measures including progression-free survival, duration of response, event-free survival, time to next treatment, and overall survival. Additionally, the rate of undetectable minimal residual disease in peripheral blood will be monitored. The clinical investigation includes a screening phase to verify IGHV status, 17p deletion, and TP53 mutation, followed by treatment and subsequent follow-up assessments. Participation in the study is estimated to occur within a recruitment and observation period extending through May 2028. Early termination of an individual's involvement may occur based on safety profiles, including adverse events, or changes in clinical status.

The investigational treatment involves acalabrutinib administered as 200 mg of film-coated tablets via the oral route. This substance is utilized as part of a combination regimen for participants with chronic lymphocytic leukemia or small lymphocytic lymphoma.

The investigational treatment also includes venetoclax, which is provided in various strengths of film-coated tablets, including 10 mg, 50 mg, and 100 mg. The administered dose is 400 mg per oral administration.

The efficacy of the treatment in participants with chronic lymphocytic leukemia or small lymphocytic lymphoma will be evaluated through several parameters. The primary endpoint is the overall response rate, defined as the proportion of participants achieving a best response of complete remission, complete remission with incomplete bone marrow recovery, nodular partial remission, or partial remission according to the International Workshop on Chronic Lymphocytic Leukemia criteria. This primary assessment is planned for the timepoint following the completion of Cycle 14.

Secondary efficacy endpoints include:

• Progression-free survival, measured as the time from the first dose until disease progression or death from any cause.
• Duration of response, measured as the time from the first documented response until documented progression or death.
• Event-free survival, measured as the time from the first dose until disease progression, initiation of subsequent therapy, or death.
• Time to next treatment, measured as the time from the first dose to the initiation of subsequent therapy or death.
• Overall survival, measured as the time from the first dose until death from any cause, with a 5-year landmark estimate.
• The rate of undetectable minimal residual disease in peripheral blood, determined by a clonoSEQ® assay to identify fewer than 1 CLL cell per 100,000 leukocytes. This is assessed at 3 months after the last treatment dose.