A Phase II, Open-Label, Multi-Drug, Multi-Center, Master Protocol to Evaluate the Efficacy and Safety of Novel Immunomodulators as Monotherapy and in Combination with Anticancer Agents in Participants with Advanced Hepatobiliary Cancer (GEMINI-Hepatobiliary)

The primary objective of this study is to assess the **efficacy** and safety of novel immunomodulators, either as monotherapy or in combination with other anticancer agents, in participants with advanced hepatobiliary cancer. The efficacy will be evaluated by measuring the Objective Response Rate (ORR) for sub-study 1 in hepatocellular carcinoma (HCC) and Progression-free Survival (PFS) for sub-study 2 in biliary tract cancer (BTC). This is clinically relevant as it aims to determine the potential of these novel treatments to improve patient outcomes in these challenging cancer types.

Secondary objectives include: - Further assessing the efficacy of these immunomodulators by evaluating Duration of Response (DoR), Disease Control Rate (DCR) at 12 and 24 weeks, PFS, and Overall Survival (OS) in participants with specified advanced solid tumors. - Assessing the pharmacokinetics (PK) of the immunomodulators. - Evaluating the immunogenicity of the immunomodulators, both alone and in combination with other anticancer drugs.

The clinical trial involves a total of **220 participants** diagnosed with **Advanced Hepatobiliary Cancer**. The study population includes both male and female subjects aged 18 years and older, with a focus on individuals who have confirmed locally advanced or metastatic solid tumors. Participants were selected based on their ability to provide a signed informed consent form and demonstrate adequate organ and bone marrow function. The trial includes individuals with a life expectancy of at least 12 weeks and at least one measurable lesion not previously irradiated, as per RECIST 1.1 criteria. The study population is characterized by a willingness to provide an adequate tumor sample for research purposes. The trial does not specify particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, although specific details are not provided by the sponsor.

The clinical trial is designed as a **Phase II**, open-label, multi-drug, multi-center study to evaluate the efficacy and safety of novel immunomodulators, both as monotherapy and in combination with anticancer agents, in participants with advanced hepatobiliary cancer. The trial employs a master protocol approach, allowing for the assessment of multiple therapeutic agents within a single overarching study framework. The trial is expected to run from April 2023 to November 2026, with the primary objective of assessing the **Objective Response Rate (ORR)** for sub-study 1 and **Progression-Free Survival (PFS)** for sub-study 2, as determined by the investigator at local sites per RECIST 1.1 criteria. Secondary endpoints include Duration of Response (DOR), Disease Control Rate (DCR), Overall Survival (OS), and pharmacokinetic parameters of the novel immunomodulators.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, tumor histopathology, and organ function. The trial includes regular follow-up visits to monitor treatment efficacy and safety, with assessments of adverse events, serious adverse events, and any adverse events leading to treatment discontinuation. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes and any long-term effects. The expected duration of participant involvement is up to 12 months, with conditions for early termination including significant adverse events or disease progression.

The trial involves the administration of various investigational products, including **gemcitabine**, **bevacizumab**, **cisplatin**, and other agents, delivered primarily via intravenous infusion. The study is not limited to a single therapeutic approach, allowing for flexibility in treatment regimens based on individual participant needs and responses. The trial's design ensures rigorous monitoring and data collection to support the evaluation of both efficacy and safety, contributing valuable insights into the treatment of advanced hepatobiliary cancer.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Gemcitabine**, marketed as Gemcitabina Accord, is provided as a 100 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 1000 mg/m². The treatment period extends up to 12 months. This formulation is chemically derived and is used in combination with other anticancer agents.

**Bevacizumab**, known commercially as Avastin, is a 25 mg/ml concentrate for solution for infusion. It is administered via intravenous infusion with a maximum daily dose of 2250 mg and a total dose limit of 40500 mg over a 12-month period. Bevacizumab is a protein-based treatment and serves as a comparator in the study.

**Cisplatin** is available in multiple formulations, including Cisplatino Accord Healthcare Italia and Cisplatin NeoCorp, both at 1 mg/ml concentration for solution for infusion. The administration route is intravenous, with a maximum daily dose of 25 mg/m². The treatment duration is up to 12 months. Cisplatin is chemically synthesized and is used as a standard-of-care therapy in the trial.

**Rilvegostomig**, identified by the sponsor product code AZD2936, is a solution for infusion administered intravenously. The maximum daily dose is 750 mg, with a total dose limit of 13500 mg over a 12-month period. This protein-based treatment is a novel immunomodulator under investigation in the trial.

**Volrustomig**, also known as MEDI5752, is another investigational protein-based solution for infusion. It is administered intravenously, with dosing parameters yet to be fully established. The treatment period is set for up to 12 months.

**Lenvatinib**, marketed as LENVIMA, is provided in 4 mg hard capsules for oral use. The maximum daily dose is 12 mg, with a total dose limit of 4380 mg over a 12-month period. Lenvatinib is chemically derived and serves as a comparator treatment in the study.

**Mycophenolate Mofetil** is available as 500 mg film-coated tablets for oral administration. The maximum daily dose is 2000 mg, with a total dose limit of 730000 mg over a 12-month period. This chemical compound is used as a standard-of-care therapy in the trial.

**Infliximab**, marketed as Remsima, is a 120 mg solution for injection in a pre-filled pen. It is administered intravenously with a maximum daily dose of 5 mg/kg and a total dose limit of 2250 mg over a 6-month period. Infliximab is a protein-based treatment used as a comparator in the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy and safety of these treatments in participants with advanced hepatobiliary cancer.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** for sub-study 1 and **Progression-Free Survival (PFS)** for sub-study 2, as determined by the Investigator at the local site using RECIST 1.1 criteria. Additionally, the incidence of adverse events (AEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and AEs leading to discontinuation of treatment will be monitored.

Secondary endpoints will further evaluate efficacy through the **Duration of Response (DOR)**, **Disease Control Rate (DCR)** at 12 and 24 weeks, and **Overall Survival (OS)**, all assessed per RECIST 1.1 based on Investigator assessment. The trial will also measure serum concentrations of novel immunomodulators and derived pharmacokinetic (PK) parameters, as well as the incidences of anti-drug antibodies (ADAs) against these immunomodulators in serum.