Phase 3 Randomized Study of Sonrotoclax and Zanubrutinib Versus Placebo and Zanubrutinib in Relapsed/Refractory Mantle Cell Lymphoma

The primary objective of this study is to demonstrate the superiority of **sonrotoclax** plus **zanubrutinib** over placebo plus zanubrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL), as measured by progression-free survival (PFS) determined by a blinded independent review committee (BIRC). This is clinically relevant as improving PFS can indicate a delay in disease progression, which is crucial for patients with R/R MCL, a condition known for its aggressive nature and limited treatment options.

Secondary objectives include:

• Comparing the efficacy of sonrotoclax plus zanubrutinib with that of placebo plus zanubrutinib as measured by overall survival (OS).
• Evaluating efficacy through various measures: progression-free survival (PFS) determined by the investigator, overall response rate (ORR) and complete response rate (CRR) as determined by BIRC and investigator assessment per Lugano 2014 criteria, duration of response (DOR), and time to first response.
• Evaluating patient-reported disease and treatment symptoms.
• Assessing safety and tolerability.

The clinical trial involves a total of **160 participants** diagnosed with **relapsed or refractory mantle cell lymphoma (R/R MCL)**. 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 histologically confirmed diagnosis of mantle cell lymphoma, having received 1 to 5 prior lines of systemic therapy, and possessing measurable disease. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, indicating a general health status that allows for daily activities with minimal restrictions. Adequate organ function is also a requirement for participation. The study includes individuals from vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of a combination therapy in patients with **relapsed or refractory mantle cell lymphoma**. The trial aims to demonstrate the superiority of the investigational combination therapy over a placebo-controlled regimen, with the primary endpoint being progression-free survival as assessed by a blinded independent review committee. Secondary endpoints include overall survival, overall response rate, duration of response, and patient-reported outcomes, among others.

The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of mantle cell lymphoma, previous treatment history, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment.

Participants are expected to be involved in the study for a maximum treatment period of 60 days, with the overall trial duration estimated to extend until August 2032. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The investigational products, administered orally, include **zanubrutinib** in capsule form and a film-coated tablet of the investigational compound, with a placebo used for control purposes. The trial is not categorized as low intervention and does not include pediatric subjects.

The clinical trial involves the administration of **Zanubrutinib**, a small molecule investigational drug, in the form of a capsule. The active substance, **zanubrutinib**, is chemically derived and manufactured by BeiGene. The maximum daily dose of Zanubrutinib is 320 mg, with a total maximum dose of 584 g over a treatment period of 60 days. The route of administration is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Another investigational drug used in the trial is **BGB-11417**, also a small molecule, provided as a film-coated tablet. The active substance is a complex chemical compound, specifically N-[4-({[(1R,4R)-4-hydroxy-4-methylcyclohexyl]methyl}amino)-3-nitrobenzene-1-sulfonyl]-4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide, also produced by BeiGene. The maximum daily dose for BGB-11417 is 320 mg, with a total maximum dose of 215.9 g over a 23-day treatment period. This medication is administered orally and is not intended for pediatric use. Participant compliance is closely monitored to ensure the integrity of the trial data.

The study also includes a **placebo** for BGB-11417, which serves as a comparator in the trial. The placebo is designed to mimic the appearance of the BGB-11417 film-coated tablet but contains no active pharmaceutical ingredient. The placebo is administered orally, following the same schedule as the active comparator, to maintain the double-blind nature of the study. Compliance with placebo administration is similarly monitored to ensure consistency across the study arms.

Efficacy in this clinical trial will be assessed primarily through **progression-free survival (PFS)**, as evaluated by a blinded independent review committee (BIRC). PFS is defined as the time from randomization to the date of disease progression or death, whichever occurs first. Secondary efficacy endpoints include overall survival (OS), overall response rate (ORR), duration of response (DOR), complete response rate (CRR), time to first response, and time to initiation of new anticancer therapy. These parameters will be determined by both BIRC and investigators, with ORR and CRR assessed per the Lugano 2014 criteria.

Patient-reported outcomes will be measured using the European Organisation of Research and Treatment of Cancer-Quality of Life Questionnaire Non-Hodgkin Lymphoma High Grade Module 29 (EORTC-QLQ-NHL-HG29) and the Core 30 (EORTC-QLQ-C30) to evaluate symptom burden, physical condition, fatigue, global health status, and physical function. The incidence and severity of treatment-emergent adverse events (TEAEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.