Efficacy and Safety Evaluation of Venetoclax and Obinutuzumab Retreatment in Patients with Recurrent Chronic Lymphocytic Leukemia

The primary objective of this study is to assess the **efficacy** of Venetoclax-Obinutuzumab (VenG) retreatment in patients with recurring **chronic lymphocytic leukemia** (CLL) in Cohort 1. The clinical relevance of this objective lies in determining the overall response rate (ORR) achieved by all treated subjects in this cohort, as evaluated by their end-of-cycle treatment (EOCT) assessment plus three months. This evaluation is crucial for understanding the potential benefits of VenG retreatment in managing CLL recurrence.

Secondary objectives include:

• Quantifying the efficacy of VenG treatment in Cohort 1 via specified secondary endpoints.
• Not conducting any hypothesis testing framework or formal statistical comparisons during the study.
• Utilizing appropriate summaries, including descriptive statistics and confidence intervals (CIs), as the basis for analysis.
• Assessing the safety of retreatment with VenG.

The clinical trial involves a total of **31 participants** diagnosed with **chronic lymphocytic leukemia recurrent**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a documented diagnosis of CLL requiring retreatment and a history of completing a venetoclax plus anti-CD20 antibody regimen. The trial does not include vulnerable populations, and participants must not have active or uncontrolled autoimmune hemolytic anemia or immune thrombocytopenic purpura. Additionally, individuals with a transformation of CLL to aggressive non-Hodgkin lymphoma are excluded. The selection process ensures that participants have not received intervening treatments for CLL after their previous therapy and have not discontinued prior treatment due to disease progression. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **venetoclax** and **obinutuzumab** in patients with recurring **chronic lymphocytic leukemia** (CLL). This is a multicenter, open-label, Phase 2 study. The trial employs a non-randomized, controlled design, with participants receiving the investigational treatment in a structured manner. The study is expected to span approximately three years, with an estimated end date in February 2025.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on specific criteria, such as a documented diagnosis of CLL and previous treatment history. The inclusion visit will also involve obtaining informed consent. Following the inclusion visit, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments based on the 2018 International Workshop for Chronic Lymphocytic Leukemia criteria. The end-of-study visit will occur three months after the end of the treatment cycle, known as EOCT + 3, to evaluate the primary efficacy endpoint, which is the overall response rate.

The expected length of participant involvement in the study is determined by the treatment cycle, which may last up to 36 months, depending on the cohort. Participants may be subject to early termination from the study if they experience disease progression, adverse events that compromise safety, or if they withdraw consent. The study aims to provide valuable insights into the potential benefits of retreatment with venetoclax and obinutuzumab in this patient population.

The clinical trial involves the administration of **Venetoclax**, a small molecule Bcl-2 family protein inhibitor, which is provided in the form of a **film-coated tablet**. The active substance, venetoclax, is of chemical origin and is manufactured by AbbVie Deutschland GmbH & Co. KG. The maximum daily dose of venetoclax is 400 mg, with a total maximum dose of 400 mg per day. The treatment period for venetoclax is up to 12 months, and the medication is administered orally. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Additionally, the trial includes the use of **Gazyvaro**, which is a concentrate for solution for infusion containing the active substance **obinutuzumab**. Obinutuzumab is a protein of other origin, produced by Roche Registration GmbH. The pharmaceutical form is a solution for infusion, and it is administered via intravenous infusion. The maximum daily dose of Gazyvaro is 1000 mg, with a total maximum dose of 1000 mg per day. The treatment period for Gazyvaro extends up to 36 months. The administration schedule and participant compliance are closely monitored to ensure the integrity of the trial data.

The efficacy of the treatment in this clinical trial will be assessed primarily through the **overall response rate (ORR)** in patients with recurring Chronic Lymphocytic Leukemia (CLL). The primary efficacy endpoint is defined as the proportion of subjects achieving a best response of complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR), or partial response (PR) in Cohort 1. This assessment will be conducted by the investigator at the end of the treatment cycle (EOCT), specifically evaluated three months after the EOCT, which corresponds to Cycle 9.

Secondary efficacy endpoints include several parameters: the overall response of CR or CRi at the end of treatment assessment (EOT), time to response (TTR), duration of response (DOR), time to next treatment (TTNT) for CLL, progression-free survival (PFS), overall survival (OS), and the rate of undetectable minimal residual disease (uMRD) at both EOCT and EOT, measured in peripheral blood (PB). These assessments will be based on the 2018 International Workshop for Chronic Lymphocytic Leukemia criteria for tumor response.