Phase 3 Randomized Study of Sonrotoclax and Zanubrutinib Versus Venetoclax and Obinutuzumab in Untreated Chronic Lymphocytic Leukemia

The primary objective of this Phase 3, open-label, randomized study is to compare the **efficacy** of two treatment regimens in patients with previously untreated **Chronic Lymphocytic Leukemia**. Specifically, the study aims to evaluate the progression-free survival (PFS) between Arm A, which consists of sonrotoclax plus zanubrutinib, and Arm B, which includes venetoclax plus obinutuzumab. This comparison is clinically relevant as it seeks to determine the more effective treatment option in delaying disease progression, thereby potentially improving patient outcomes.

Secondary objectives include:

• Comparing the rate of complete response (CR/CRi) among patients enrolled in Arm A versus Arm B.
• Comparing the rate of overall survival (OS) among patients enrolled in Arm A versus Arm B.

The clinical trial involves a total of **466 participants** diagnosed with **Previously Untreated Chronic Lymphocytic Leukemia**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on a confirmed diagnosis of chronic lymphocytic leukemia (CLL) requiring treatment, as defined by specific clinical criteria such as progressive bone marrow failure, splenomegaly, lymphadenopathy, lymphocytosis, extranodal involvement, or constitutional symptoms. The trial does not include a vulnerable population. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants have not received prior treatment for CLL, aligning with the study's focus on previously untreated cases.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of Sonrotoclax (BGB-11417) in combination with Zanubrutinib (BGB-3111) compared to Venetoclax plus Obinutuzumab in patients with previously untreated **chronic lymphocytic leukemia** (CLL). The primary objective is to compare progression-free survival (PFS) between the two treatment arms, as determined by an independent review committee (IRC). Secondary endpoints include overall complete response rate and overall survival. The trial is expected to commence recruitment on May 11, 2024, and conclude by August 31, 2032.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years) and a confirmed diagnosis of CLL requiring treatment. Following randomization, participants will receive their assigned treatment and attend regular follow-up visits to monitor efficacy and safety outcomes. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity. The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of 420 days for the Sonrotoclax and Zanubrutinib arm and 336 days for the Venetoclax and Obinutuzumab arm.

Participants may be withdrawn from the study early due to reasons such as disease progression, adverse events, or withdrawal of consent. The study will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants. The trial will utilize oral administration for most investigational products, with Obinutuzumab being administered as a concentrate for solution for infusion. The study aims to provide valuable insights into the comparative efficacy of these treatment regimens in managing previously untreated CLL.

The clinical trial involves the administration of **Zanubrutinib**, a chemical compound provided in **capsule** form. The maximum daily dose is 320 mg, with a total maximum dose of 134,400 mg over a treatment period of 420 days. The route of administration is **oral**, and the medication is identified by the sponsor product code BGB-3111. Compliance with the dosing schedule is monitored throughout the trial.

**BGB-11417** is another experimental medication used in the trial, available as a **film-coated tablet**. The active substance is a complex chemical compound, and the maximum daily dose is 320 mg, with a total maximum dose of 91,826 mg over a treatment period of 336 days. This medication is also administered **orally**. The sponsor product code for BGB-11417 is consistent across multiple entries, indicating its role as a test medication in the study.

**Gazyvaro**, containing the active substance **Obinutuzumab**, is used as a comparator treatment. It is provided as a **concentrate for solution for infusion**. The maximum daily dose is 1,000 mg, with a total maximum dose of 8,000 mg over a 21-day treatment period. The route of administration is via **infusion**, and it is classified as a protein-based medication. This treatment is used to compare efficacy against the experimental medications.

**Venclyxto**, with the active substance **Venetoclax**, is also used as a comparator treatment in the trial. It is available in **film-coated tablet** form, with a maximum daily dose of 400 mg and a total maximum dose of 117,390 mg over a 45-day treatment period. The administration route is **oral**. This medication serves as a standard-of-care therapy in the study, providing a benchmark for evaluating the efficacy of the experimental treatments.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)**, which is defined as the time from the date of enrollment to the date of first confirmed disease progression or death due to any cause, as determined by an independent review committee (IRC). Additionally, the rate of **undetectable minimal residual disease (uMRD)** at a sensitivity of less than 10^-4 will be measured at the first post-treatment follow-up visit using next-generation sequencing (NGS) with clonoSEQ technology.

Secondary efficacy endpoints include the overall complete response rate (CRR), which is the proportion of patients achieving the best response of complete response (CR) or complete response with incomplete marrow recovery (CRi), as determined by the IRC. Overall survival (OS) will also be assessed, defined as the time from the date of enrollment to the date of death from any cause.