Evaluation of Venetoclax, Delayed Rituximab, and Ibrutinib for Achieving Undetectable Minimal Residual Disease in Treatment-Naïve Chronic Lymphocytic Leukemia

The primary objective of this study is to evaluate the **effectiveness** of a sequential combination therapy consisting of venetoclax, delayed rituximab, and ibrutinib in achieving undetectable minimal residual disease (uMRD, <10^-4) in the bone marrow of treatment-naïve patients with **chronic lymphocytic leukemia** (CLL). This is assessed using 6-color cytofluorimetry to determine the best response at any time during treatment, up to three months after the completion of the combined therapy. Achieving uMRD is clinically significant as it is associated with improved patient outcomes and prolonged remission in CLL.

The clinical trial involves participants diagnosed with **Previously Untreated Chronic Lymphocytic Leukemia** (CLL). The study population includes both male and female subjects aged between 18 and 65 years, who have not received prior therapy for CLL. Participants are required to have active CLL/SLL necessitating treatment as per iwCLL 2018 criteria and must demonstrate appropriate medullary function, with specific thresholds for absolute neutrophil count, platelet count, and hemoglobin levels. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the effectiveness of a sequential combination therapy involving **venetoclax**, delayed rituximab, and ibrutinib in patients with previously untreated chronic lymphocytic leukemia (CLL). The trial follows a **randomized**, **double-blind**, and **controlled** design to ensure the reliability and validity of the results. The primary objective is to assess the achievement of undetectable minimal residual disease (uMRD) using 6-color cytofluorimetry in bone marrow as the best response at any time during treatment, up to three months after the completion of the combined therapy. The trial is expected to run until January 31, 2027, with recruitment having commenced on January 31, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to <65 years), active CLL requiring treatment, and appropriate medullary function. Following the screening, participants will be randomized to receive the investigational treatment. Regular follow-up visits will be scheduled to monitor the participants' response to the treatment and to assess safety and efficacy endpoints. The end-of-study visit will occur three months after the completion of the therapy, where the final assessment of uMRD will be conducted.

The expected length of participant involvement in the trial is up to 24 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial is conducted in accordance with ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **venetoclax**, a chemical compound with the active substance name **VENETOCLAX**. It is also known by its synonyms, ABT-199 and GDC-0199. The pharmaceutical form of venetoclax is designated as PHF00082MIG, and it is administered orally. The maximum daily dose of venetoclax is 400 mg, with a total maximum dose amounting to 260,190 µg. The treatment period for venetoclax extends up to 24 months. The administration of venetoclax is monitored to ensure participant compliance with the dosing schedule.

In addition to venetoclax, the study includes the administration of delayed rituximab and ibrutinib as part of the treatment regimen. These non-experimental treatments are used in combination with venetoclax to evaluate their effectiveness in achieving undetectable minimal residual disease (uMRD) in treatment-naïve patients with chronic lymphocytic leukemia (CLL). The dosing schedules and administration routes for rituximab and ibrutinib are consistent with standard-of-care practices, and participant compliance is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint of **undetectable minimal residual disease (uMRD)**, defined as less than 10^-4, using 6-color cytofluorimetry in bone marrow (BM). This endpoint will be measured as the best response at any time during treatment, up to three months after the completion of the combined therapy involving venetoclax, delayed rituximab, and ibrutinib. The trial aims to determine the effectiveness of this sequential combination in treatment-naïve patients with chronic lymphocytic leukemia (CLL). The assessment of uMRD will be conducted using a validated laboratory method, ensuring accurate and reliable measurement of the disease state. The schedule for measuring this endpoint is designed to capture the best response during the treatment period and shortly after its completion, providing a comprehensive evaluation of the therapy's efficacy.