Efficacy and Safety of Acalabrutinib with Venetoclax and Obinutuzumab Versus Chemoimmunotherapy in Untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation

The primary objective of this study is to evaluate the **efficacy** of the combination of acalabrutinib and venetoclax (AV; Arm A) compared with chemoimmunotherapy, specifically fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR; Arm C), in subjects with previously untreated **Chronic Lymphocytic Leukemia** without del(17p) or TP53 mutation. This evaluation is clinically relevant as it aims to determine if the AV combination offers a more effective treatment option compared to the standard chemoimmunotherapy regimens, potentially improving patient outcomes in this specific leukemia population.

Secondary objectives include:

• Evaluating the efficacy of AV (Arm A) in comparison with chemoimmunotherapy (FCR/BR [Arm C]).
• Assessing the efficacy of acalabrutinib/venetoclax/obinutuzumab (AVG; Arm B) versus FCR/BR (Arm C).
• Comparing the efficacy of AV (Arm A) versus FCR/BR (Arm C) and AVG (Arm B) versus FCR/BR (Arm C).

The clinical trial involves a total of **578 participants** diagnosed with **previously untreated Chronic Lymphocytic Leukemia** without del(17p) or TP53 mutation. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 2. Participants were selected based on specific diagnostic criteria for CLL, including the presence of monoclonal B-cells and active disease requiring treatment. The trial population was chosen to ensure adequate bone marrow function and specific laboratory parameters, such as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, total bilirubin, and estimated creatinine clearance. The study also considers vulnerable populations, although specific lifestyle factors such as diet and physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, multicenter, open-label, Phase 3 study to evaluate the efficacy and safety of **acalabrutinib** in combination with **venetoclax**, with and without **obinutuzumab**, compared to the investigator's choice of chemoimmunotherapy in subjects with previously untreated **chronic lymphocytic leukemia** (CLL) without del(17p) or TP53 mutation. The trial aims to assess progression-free survival as the primary endpoint, with secondary endpoints including overall response rate, duration of response, and overall survival. The study is expected to commence recruitment on May 17, 2024, and conclude by November 30, 2025.

Participants will be involved in the trial for a maximum treatment period of up to 56 weeks, depending on the treatment arm. The trial includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age, performance status, and laboratory parameters. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Early termination from the study may occur due to disease progression, unacceptable toxicity, or withdrawal of consent. The trial involves the administration of investigational products via oral and intravenous routes, with specific dosing regimens tailored to each treatment arm. The study will be conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

**Obinutuzumab** is administered as a **solution for infusion** and is a humanized and glycoengineered monoclonal antibody. It is delivered via **intravenous use** with a maximum daily dose of 1000 mg. The treatment period for obinutuzumab is up to 24 months. This medication is utilized in the study as part of the experimental treatment arm.

**Venetoclax** is provided in the form of a **film-coated tablet** and is classified as a chemical substance. It is administered **orally** with a maximum daily dose of 400 mg. The treatment duration for venetoclax can extend up to 48 months. Venetoclax is used in both the experimental and comparator arms of the study.

**Bendamustine** is available as a **powder for concentrate for solution for infusion** and is a chemical compound. It is administered via **intravenous use** with a maximum daily dose of 90 mg/m². The treatment period for bendamustine is up to 24 months. This medication is part of the comparator treatment arm.

**Fludarabine** is provided as a **concentrate for solution for infusion** and is administered via **intravenous use**. It is a chemical substance with a maximum daily dose of 25 mg/m². The treatment duration for fludarabine is up to 24 months, and it is used in the comparator arm of the study.

**Acalabrutinib** is administered in the form of a **hard capsule** and is a chemical compound. It is taken **orally** with a maximum daily dose of 200 mg. The treatment period for acalabrutinib can last up to 56 months. This medication is part of the experimental treatment arm and is modified for clinical trials by being packed in HDPE bottles instead of blister packs.

**Cyclophosphamide** is available as a **powder for solution for injection/infusion** and is a chemical substance. It is administered via **intravenous use** with a maximum daily dose of 250 mg/m². The treatment duration for cyclophosphamide is up to 24 months, and it is used in the comparator arm of the study.

**Rituximab** is provided as a **concentrate for solution for infusion** and is a chimeric/murine/human monoclonal antibody. It is administered via **intravenous use** with a maximum daily dose of 375 mg/m². The treatment period for rituximab is up to 24 months, and it is part of the comparator treatment arm.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to the first occurrence of disease progression or death from any cause, as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria. Secondary endpoints include PFS as determined by investigator assessment, Event-Free Survival (EFS), Overall Response Rate (ORR), Duration of Objective Response (DOR), Time to Next Therapy (TTNT), Minimal Residual Disease (MRD) negativity rate, and Overall Survival (OS).

These efficacy parameters will be measured and collected at various timepoints throughout the trial. MRD negativity rate will be specifically measured in the peripheral blood by flow cytometry at the start of Cycle 9 in Arm A, the start of Cycle 10 in Arm B, and 12 weeks after the start of Cycle 6 in Arm C. The analysis of these endpoints will involve both IRC and investigator assessments to ensure comprehensive evaluation of the treatment's efficacy.