Phase 1-2 Study Investigating Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Various Combinations of BGB-A425 and LBL-007 with Tislelizumab in Patients with Advanced Solid Tumors

The primary objective of this study is to evaluate the **safety** and tolerability of BGB-A425 in combination with tislelizumab in patients with advanced solid tumors during Phase 1 (Dose Escalation). This includes determining the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended Phase 2 dose (RP2D) of BGB-A425 in combination with tislelizumab. In Phase 2 (Safety Lead-in), the study aims to assess the safety and tolerability of BGB-A425 in combination with LBL-007 and tislelizumab, or LBL-007 in combination with tislelizumab, and to determine the MTD or MAD and RP2D for these combinations. Additionally, Phase 2 (Dose Expansion) focuses on evaluating the antitumor activity based on the objective response rate (ORR) of various combinations of BGB-A425 and LBL-007 with tislelizumab in selected tumor types. These objectives are clinically relevant as they aim to establish the safety profile and optimal dosing of these novel therapeutic combinations, which could potentially improve treatment outcomes for patients with advanced solid tumors.

Secondary objectives include:

• Phase 1 (Dose Escalation): Assessing the preliminary antitumor activity, characterizing the pharmacokinetics (PK), and assessing host immunogenicity of BGB-A425 in combination with tislelizumab.
• Phase 2 (Safety Lead-in): Evaluating the preliminary antitumor activity, characterizing the PK, and assessing host immunogenicity of BGB-A425, LBL-007, and tislelizumab in combination treatments.
• Phase 2 (Dose Expansion): Evaluating antitumor activity using other secondary efficacy endpoints, further characterizing the safety and tolerability, characterizing the PK, and further assessing host immunogenicity of BGB-A425 and LBL-007 in combination with tislelizumab.

The clinical trial involves a total of **310 participants** diagnosed with advanced solid tumors, specifically **Head and Neck Squamous Cell Cancer**, **Renal Cell Carcinoma**, and **Non-Small Cell Lung Cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their diagnosis of histologically or cytologically confirmed advanced, metastatic, or unresectable solid tumors, and they have previously received standard systemic therapy or have no available or tolerated treatment options. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ function is a prerequisite for participation. The trial population also includes vulnerable groups, ensuring a comprehensive assessment of the investigational treatments across diverse demographics. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and preliminary antitumor activity of various combinations of BGB-A425, LBL-007, and **tislelizumab** in patients with advanced solid tumors, including head and neck squamous cell cancer, renal cell carcinoma, and non-small cell lung cancer. This study is structured as a Phase 1-2 trial, incorporating a randomized, double-blind, and controlled methodology. The trial is expected to commence on December 1, 2022, and conclude by December 29, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 and adequate organ function. The trial is divided into three phases: Phase 1 (Dose Escalation), Phase 2 (Safety Lead-in), and Phase 2 (Dose Expansion). Each phase involves specific objectives, including determining the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended Phase 2 dose (RP2D) for the drug combinations. Follow-up visits will be conducted to monitor adverse events (AEs), serious AEs (SAEs), and laboratory abnormalities, as well as to evaluate pharmacokinetic parameters and immunogenic responses.

The expected length of participant involvement varies depending on the phase and individual response to treatment. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities (DLTs) or any adverse events that compromise patient safety. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data for analysis. Throughout the trial, the safety and efficacy of the drug combinations will be rigorously monitored to ensure the well-being of participants and the integrity of the study results.

The clinical trial involves the administration of **BGB-A425**, an investigational medication with the active substance **surzebiclimab**. This product is provided in the form of an **infusion** and is administered via **intravenous infusion**. The pharmaceutical form is specifically designed for infusion, and the product is not a pediatric formulation. The administration schedule and dosage are determined based on the phase of the trial, with the primary objective being to assess safety, tolerability, and to establish the maximum tolerated dose (MTD) or maximum administered dose (MAD) for further phases.

Another investigational product used in this trial is **LBL-007**, which contains the active substance **LBL-007**. It is supplied as a **concentrate for solution for infusion** and is also administered through **intravenous infusion**. This product is similarly not intended for pediatric use. The trial aims to evaluate the safety and tolerability of LBL-007 in combination with other investigational drugs, as well as to determine the recommended dose for expansion in subsequent phases.

**Tislelizumab** is the third investigational medication involved in the study, with the active substance **tislelizumab**. It is provided as a **concentrate for solution for infusion** and administered via **intravenous infusion**. Like the other investigational products, it is not a pediatric formulation. The trial's objectives include assessing the antitumor activity of tislelizumab in combination with other investigational drugs, focusing on objective response rates in selected tumor types.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The investigational products are all developed by BeiGene and are classified as proteins of other origin. The trial is structured to progress through different phases, each with specific objectives related to safety, tolerability, and efficacy.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Phase 1 (Dose Escalation) and Phase 2 (Safety Lead-in) include the evaluation of **adverse events (AEs)** and serious AEs (SAEs), characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy, as well as laboratory abnormalities. The maximum tolerated dose (MTD) or maximum administered dose (MAD) will be determined, and the recommended Phase 2 dose (RP2D) will be established based on these findings. For Phase 2 (Dose Expansion), the primary endpoint is the objective response rate (ORR) as determined from investigator-derived tumor assessments per RECIST v1.1.

Secondary endpoints include efficacy evaluations such as ORR, duration of response (DOR), and disease control rate (DCR), also determined from tumor assessments per RECIST v1.1. Pharmacokinetic (PK) parameters will be measured, including maximum observed plasma concentration (Cmax), minimum observed plasma concentration (Cmin), time to maximum plasma concentration (Tmax), half-life (t1/2), and area under the concentration-time curve from zero to 21 days (AUC0-21d) for BGB-A425 and LBL-007, with Cmax and Cmin for tislelizumab. Immunogenicity will be assessed by summarizing the number and percentage of patients who develop detectable antidrug antibodies (ADAs) to BGB-A425, LBL-007, and tislelizumab. In Phase 2 (Dose Expansion), progression-free survival (PFS), DOR, and DCR will be further evaluated, alongside safety and tolerability through monitoring of AEs and SAEs, physical examinations, electrocardiograms (ECGs), and laboratory assessments as needed.