Phase II Multicenter Trial of Ibrutinib and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia with/without TP53 Aberrations

The primary objective of this study is to evaluate the **efficacy** of the combination therapy of ibrutinib and venetoclax in patients with relapsed or refractory **chronic lymphocytic leukemia** (RR-CLL). The focus is on the proportion of patients meeting the criteria for progression-free survival (PFS) at 12 months after cessation of therapy, specifically for those randomized to stop treatment (arm B of the study). This is clinically relevant as it assesses the potential of this treatment regimen to maintain disease control without continuous therapy, which could significantly impact patient quality of life and treatment strategies.

Secondary objectives include:

• Evaluation of efficacy in terms of minimal residual disease (MRD) at 12 months post-treatment cessation (month 27).
• Assessment of efficacy based on PFS according to IWCLL criteria.
• Determination of the time to and number of patients reinitiating treatment.
• Evaluation of time to treatment failure after reinitiated treatment.
• Measurement of time to next CLL treatment.
• Assessment of MRD after cycle 12 in peripheral blood (PB), at day 15 of cycle 15 in PB and bone marrow (BM), and at later time points in PB.
• Overall survival (OS) analysis.
• Evaluation of complete response (CR), partial response (PR), and stable disease (SD) after cycles 3, 9, 12, 15, and at months 27 and 51 (3 years post-treatment cessation).
• Duration of response assessment.
• Evaluation of safety concerning the type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to the study treatment.
• Evaluation of patient-related outcomes, measured in terms of health-related quality of life (QoL) using EORTC QLQ-C30 and QLQ-CLL16 questionnaires.

The clinical trial involves participants diagnosed with **chronic lymphocytic leukemia** (CLL) or small lymphocytic lymphoma (SLL) who have experienced a relapse or are refractory to previous treatments. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have adequate bone marrow and liver function, as well as a creatinine clearance of at least 30 ml/min. The trial includes individuals who are part of a vulnerable population, and all participants must provide written informed consent. The study does not specify the total number of participants, as the sponsor has not provided this information. Participants are expected to adhere to specific lifestyle considerations, including the use of effective birth control methods for those of reproductive potential and regular monitoring for hepatitis B and C. The trial population was selected based on their ability to meet these criteria and their willingness to comply with the study protocol.

The clinical trial is a prospective, multicenter, phase-II study designed to evaluate the efficacy of a combination therapy involving **ibrutinib** and **venetoclax** in patients with relapsed or refractory **chronic lymphocytic leukemia** (CLL). The trial employs a randomized, controlled design with a primary objective to assess the proportion of patients achieving progression-free survival (PFS) at 12 months after cessation of therapy. The study is expected to span approximately 10 years, with an estimated end date in March 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented relapsed/refractory CLL, adequate bone marrow and liver function, and a creatinine clearance of at least 30 ml/min. Following the screening, participants will be randomized into treatment arms and will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of minimal residual disease (MRD), overall survival, and quality of life, among other endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 27 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will utilize **Venclyxto** (venetoclax) in film-coated tablet form and **IMBRUVICA** (ibrutinib) in hard capsule form, both administered orally. The study aims to provide valuable insights into the treatment of CLL, particularly in patients with or without TP53 aberrations, and to explore the relationship between baseline markers and clinical outcomes.

The clinical trial involves the administration of **Venclyxto** (venetoclax) in various dosages as part of the treatment regimen. Venclyxto is available in film-coated tablet form and is administered orally. The trial includes three different dosages of Venclyxto: 10 mg, 50 mg, and 100 mg film-coated tablets. The maximum daily dose for Venclyxto is 400 mg, with a total maximum dose of 280,000 mg over a treatment period of up to 700 days. The active substance, venetoclax, is of chemical origin and is produced by AbbVie Deutschland GmbH & Co. KG. The administration of Venclyxto is monitored to ensure compliance with the dosing schedule.

In addition to Venclyxto, the trial also includes the administration of **IMBRUVICA** (ibrutinib), which is provided in the form of 140 mg hard capsules. IMBRUVICA is also administered orally, with a maximum daily dose of 420 mg and a total maximum dose of 317,520 mg over a treatment period of up to 756 days. The active substance, ibrutinib, is of chemical origin and is manufactured by Janssen-Cilag International NV. Participant compliance with the dosing schedule for IMBRUVICA is similarly monitored throughout the trial.

The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective of the trial is to evaluate the efficacy of the combination of ibrutinib and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (RR-CLL), with or without TP53 aberrations. The trial aims to assess the proportion of patients achieving progression-free survival at 12 months after stopping therapy.

The efficacy of the treatment regimen comprising **ibrutinib** and **venetoclax** will be assessed in a clinical trial involving patients with relapsed or refractory chronic lymphocytic leukemia (RR-CLL). The primary endpoint for evaluating efficacy is the proportion of patients achieving progression-free survival (PFS) at 12 months after stopping therapy. This assessment will be conducted for patients randomized to stop treatment, with reinitiated treatment due to minimal residual disease (MRD) positivity not considered as progression. Symptomatic CLL according to IWCLL criteria within 12 months after randomization, followed by reinitiation of treatment resulting in a response before or at 12 months, will also not be considered as progression.

Secondary endpoints include the evaluation of MRD at 12 months after stopping treatment, PFS across all study groups, time to and number of patients reinitiating treatment, time to treatment failure after reinitiated treatment, and time to next CLL treatment. Additional secondary endpoints involve MRD assessments after cycle 12, at day 15 of cycle 15, and at later time points, overall survival (OS), and response rates (complete response, partial response, stable disease) at specified cycles and months. The duration of response, safety parameters, and health-related quality of life will also be evaluated using EORTC QLQ-C30 and QLQ-CLL16 questionnaires.

Exploratory endpoints will investigate the relationship between various baseline markers and clinical outcomes, markers at the time of progression, and correlations between MRD in bone marrow and peripheral blood with PFS and OS. The trial is designed to provide comprehensive data on the efficacy of the treatment regimen, with assessments scheduled at specific time points throughout the study duration.