Phase 3 Randomized Study of Zanubrutinib vs. Bendamustine and Rituximab in Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

The primary objective of this study is to compare the **efficacy** between treatment groups in Cohort 1, as measured by **progression-free survival** determined by independent central review. This is clinically relevant as progression-free survival is a critical endpoint in assessing the effectiveness of treatments for **Chronic Lymphocytic Leukemia** or **Small Lymphocytic Lymphoma**, providing insights into how long patients remain free from disease progression under different therapeutic regimens.

Secondary objectives include:

• Comparing efficacy between Arms A and B, measured by overall response rate, duration of response, overall survival, progression-free survival, and patient-reported outcomes.
• Comparing efficacy between Arms A and B in pooled Cohort 1/1a patients from Chinese sites, measured by progression-free survival, overall response rate, and duration of response.
• Evaluating efficacy in Cohort 2 (patients with del17p) for Arm C, measured by overall response rate, progression-free survival, and duration of response.
• Evaluating efficacy in Cohort 3 for Arm D, measured by overall response rate, progression-free survival, duration of response, and assessing undetectable minimal residual disease at 10^-4 sensitivity at various timepoints.
• Comparing safety between the treatment groups in Cohort 1 and in pooled Cohort 1/1a patients from Chinese sites.
• Summarizing safety in Cohort 2 (Arm C) and Cohort 3 (Arm D).
• Evaluating pharmacokinetics of **zanubrutinib** in Arms A and C, and pharmacokinetics of zanubrutinib and **venetoclax** in Arm D.

The clinical trial involves a total of **342 participants** diagnosed with **untreated Chronic Lymphocytic Leukemia (CLL)** or **Small Lymphocytic Lymphoma (SLL)**. The study population includes both male and female subjects, with an age range primarily encompassing individuals aged 18 years and older. Participants were selected based on specific criteria, including unsuitability for treatment with FCR due to age (≥ 65 years) or other health factors such as a Cumulative Illness Rating Scale (CIRS) score greater than 6, creatinine clearance below 70 mL/min, or a history of serious infections. The trial also requires participants to have a confirmed diagnosis of CD20-positive CLL or SLL, measurable disease by CT/MRI, and an ECOG performance status of 0, 1, or 2. Lifestyle considerations such as the ability to comply with study requirements and the use of effective contraception for females of childbearing potential are also noted. The trial includes a vulnerable population, ensuring that all participants have a life expectancy of at least 6 months and adequate organ and bone marrow function.

The clinical trial is a Phase 3, open-label, randomized study designed to evaluate the efficacy of **zanubrutinib** compared to bendamustine plus **rituximab** in patients with previously untreated **chronic lymphocytic leukemia** (CLL) or small lymphocytic lymphoma (SLL). The primary objective is to compare progression-free survival (PFS) between treatment groups, as determined by independent central review. The trial is expected to conclude by May 31, 2026, with recruitment having commenced on September 19, 2017.

Participants will be randomly assigned to receive either zanubrutinib or the combination of bendamustine and rituximab. The study is not blinded, allowing both participants and investigators to know the treatment assignments. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The expected duration of participant involvement varies, with a maximum treatment period of 103 weeks for zanubrutinib and 6 weeks for bendamustine plus rituximab.

Inclusion criteria require participants to have a confirmed diagnosis of CD20-positive CLL or SLL, measurable disease, and an ECOG performance status of 0, 1, or 2. Participants must also have adequate bone marrow and organ function. Exclusion criteria are not specified in the provided data. Participants may be withdrawn from the study early due to disease progression, unacceptable toxicity, or withdrawal of consent.

The primary endpoint is PFS in patients without del17p, assessed using the iwCLL guidelines with modifications for treatment-related lymphocytosis. Secondary endpoints include overall response rate (ORR), overall survival (OS), duration of response, and patient-reported outcomes (PROs). Safety parameters, including adverse events and clinical laboratory tests, will be monitored throughout the study. The trial will also assess pharmacokinetic parameters of zanubrutinib, such as apparent clearance and area under the curve (AUC).

The clinical trial involves the administration of several treatments, including **Venclyxto** 100 mg film-coated tablets. This medication contains the active substance **venetoclax**, a chemical compound, and is manufactured by AbbVie Deutschland GmbH & Co. KG. The pharmaceutical form is a film-coated tablet, intended for **oral use**. The maximum daily dose is 400 mg, with a total dose amount of 260.19 mg over a treatment period of up to 24 weeks. Compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

Another treatment used in the trial is **MabThera** 500 mg concentrate for solution for infusion, which contains the active substance **rituximab**. This protein-based medication is produced by Roche Registration GmbH and is administered via **intravenous use**. The maximum daily dose is 500 mg/m², with a total dose amount of 2875 mg/m² over a treatment period of up to 6 weeks. Rituximab targets the CD20 antigen on B-cells, and participant compliance is monitored through infusion records.

The experimental medication **Zanubrutinib** is also included in the trial. It is a potent, specific, and irreversible BTK inhibitor, provided in capsule form for **oral use**. Manufactured by BeiGene, the maximum daily dose is 320 mg, with a total dose amount of 320 mg over a treatment period of up to 103 weeks. Compliance is assessed through pill counts and patient diaries to ensure accurate dosing.

Additionally, **Venclyxto** 50 mg film-coated tablets are used, containing the same active substance, **venetoclax**, as the 100 mg formulation. This product is also manufactured by AbbVie Deutschland GmbH & Co. KG and is administered **orally**. The dosing schedule and compliance monitoring are consistent with the 100 mg formulation, with a maximum daily dose of 400 mg and a total dose amount of 260.19 mg over 24 weeks.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)** in Cohort 1, which includes patients without del17p. This will be determined by central review using the iwCLL guidelines, with modifications for treatment-related lymphocytosis in patients with Chronic Lymphocytic Leukemia (CLL) and the Revised Criteria for Response for Malignant Lymphoma in patients with Small Lymphocytic Lymphoma (SLL). PFS is defined as the time from randomization to disease progression or death.

Secondary endpoints include the **overall response rate (ORR)** in Cohort 1, defined as the proportion of patients achieving a complete response, complete response with incomplete bone marrow recovery, partial response, or partial response with lymphocytosis. This will be determined by independent central review and investigator assessment. Additionally, **overall survival (OS)** in Cohort 1 will be measured as the time from randomization to death from any cause. The **duration of response** will also be evaluated, defined as the time from the first meeting of response criteria to disease progression or death, assessed by central review and investigator assessment using the iwCLL criteria and the Lugano Classification for NHL.

Patient-reported outcomes (PROs) will be measured using the European Quality of Life 5 Dimensions 5 Levels Health Questionnaire (EQ-5D-5L) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Safety parameters, including adverse events (AEs), serious adverse events (SAEs), clinical laboratory tests, physical examination, and vital signs, will also be monitored. Pharmacokinetic parameters of zanubrutinib, such as apparent clearance from plasma (CL/F) and area under the curve (AUC) from time 0 to 12 hours postdose (AUC0-12), will be assessed for Arms A, C, and D.