Efficacy and Safety Comparison of Venetoclax and Obinutuzumab Versus FCR/BR in Fit Patients with Untreated Chronic Lymphocytic Leukemia Without DEL(17P) or TP53 Mutation

The primary objective of this study is to evaluate the **efficacy** of venetoclax in combination with obinutuzumab (VEN + G) compared with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) in patients with previously untreated **Chronic Lymphocytic Leukemia (CLL)** without del(17p) or TP53 mutation. The assessment is based on the minimal residual disease (MRD) response rate. This is clinically relevant as achieving a lower MRD is associated with improved long-term outcomes in CLL treatment.

Secondary objectives include: - Evaluating the efficacy of VEN + G compared with FCR/BR based on progression-free survival, MRD response rate in peripheral blood and bone marrow, overall response rate, duration of objective response, best response achieved, event-free survival, overall survival, tumor lysis syndrome risk reduction rate, and reduction in mandatory hospitalizations. - Evaluating the safety of VEN + G compared with FCR/BR based on the nature, frequency, and severity of adverse events, changes in vital signs, physical findings, clinical laboratory test results, and premature withdrawals. - Comparing disease and treatment-related symptoms and evaluating changes in physical functioning, role functioning, and global health status/quality of life following treatment with the combination of VEN + G compared with FCR/BR.

The clinical trial involves a total of **45 participants** diagnosed with **Chronic Lymphocytic Leukemia (CLL)**. The study population includes both male and female subjects aged 18 years or older, who have not previously received treatment for CLL. Participants were selected based on specific health criteria, including a cumulative illness rating scale score of 6 or less and a creatinine clearance of 70 mL/min or higher, as calculated by the Standard Cockcroft and Gault Formula. Hematology values must be within defined limits unless cytopenia is attributed to the underlying disease. Adequate liver function is required, with total bilirubin, aspartate aminotransferase, and alanine transaminase levels not exceeding twice the institutional upper limit of normal, unless directly related to CLL. The trial does not exclude vulnerable populations, and participants must have a life expectancy greater than six months. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, open-label, multicenter Phase III study to evaluate the efficacy and safety of a combined regimen of **venetoclax** and **obinutuzumab** compared to fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) in patients with previously untreated **Chronic Lymphocytic Leukemia (CLL)** without DEL(17P) or TP53 mutation. The trial aims to assess the minimal residual disease (MRD) response rate as the primary endpoint, with secondary endpoints including progression-free survival, overall survival, and the nature and frequency of adverse events. The trial is expected to last until July 31, 2026, with recruitment having started on March 16, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented CLL, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including MRD response rates in peripheral blood and bone marrow, as well as overall response rates. The end-of-study visit will evaluate the long-term outcomes and any adverse events experienced during the trial.

The expected length of participant involvement is up to 48 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable insights into the treatment of CLL.

The clinical trial involves the administration of several **experimental medications** and **comparator treatments** to evaluate their efficacy and safety in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) without DEL(17P) or TP53 Mutation. The primary experimental medication is **venetoclax**, marketed under the names Venclexta and Venclyxto, which is provided in the form of a film-coated tablet. Venetoclax is administered orally with a maximum daily dose of 400 mg and a maximum total dose of 117.39 g over a treatment period of up to 48 weeks. The medication is a small molecule developed by AbbVie, Inc.

Another key component of the experimental regimen is **obinutuzumab**, marketed as Gazyvaro, which is a concentrate for solution for infusion. Obinutuzumab is administered via intravenous infusion with a maximum daily dose of 1000 mg and a total dose of 9 g over a 24-week period. This protein-based medication is produced by Roche Registration GmbH and is designated as an orphan drug for this trial.

The comparator treatments include a regimen of **fludarabine phosphate**, **cyclophosphamide monohydrate**, and **rituximab**. Fludarabine phosphate is available as a solution for injection or infusion, with a maximum daily dose of 25 mg/m² and a total dose of 450 mg/m² over 24 weeks. It is manufactured by Ebewe Pharma and Sandoz Pharmaceuticals D.D. Cyclophosphamide monohydrate, marketed as Endoxan, is also administered via intravenous infusion with a maximum daily dose of 250 mg/m² and a total dose of 4500 mg/m² over the same period. This chemical-based medication is produced by Baxter Oncology GmbH.

**Rituximab**, marketed as MabThera, is provided as a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 500 mg/m² and a total dose of 2875 mg/m² over 24 weeks. This protein-based medication is developed by Roche Registration GmbH.

Additionally, the trial includes the use of **bendamustine hydrochloride**, marketed as Levact and Bendamustin cell pharm, which is available as a solution for infusion. Bendamustine is administered intravenously with a maximum daily dose of 90 mg/m² and a total dose of 1080 mg/m² over 24 weeks. This chemical-based medication is produced by Pharmaand GmbH and Stadapharm GmbH.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to compare the efficacy of the venetoclax and obinutuzumab combination against the standard-of-care regimens, focusing on the minimal residual disease response rate as the primary outcome measure.

The efficacy of the clinical trial will be assessed primarily through the **minimal residual disease (MRD) response rate**. This will be measured in peripheral blood (PB) using next-generation sequencing (NGS) at Month 15. Secondary endpoints include a variety of measures such as progression-free survival, MRD response rates in both PB and bone marrow (BM) at the end of treatment response visit, and overall response rate (ORR) which encompasses complete remission (CR), complete remission with incomplete blood count recovery (CRi), and partial response (PR) at the Month 15 assessment. Additional secondary endpoints include complete response rate, best response up to and including the Month 15 assessment, duration of objective response, event-free survival, and overall survival.

Further assessments will focus on the reduction of tumor lysis syndrome risk and mandatory hospitalizations during venetoclax ramp-up in Arm A. Changes in vital signs, physical findings, and clinical laboratory test results during and following study treatment will also be monitored. Patient-reported outcomes will be evaluated using the MDASI-CLL and EORTC QLQ-C30 instruments to measure changes in disease and treatment-related symptoms, physical functioning, role functioning, and health-related quality of life. The nature, frequency, and severity of adverse events and serious adverse events will be documented throughout the trial.