Phase III Randomized Double-Blind Study of Rilvegostomig Plus Chemotherapy in Adjuvant Treatment of Resected Biliary Tract Adenocarcinoma

The primary objective of this Phase III, randomized, double-blind, placebo-controlled, multicenter study is to demonstrate the superiority of **rilvegostomig** in combination with chemotherapy over placebo combined with chemotherapy. This is assessed by evaluating the recurrence-free survival (RFS) in participants with biliary tract cancer (BTC) following resection with curative intent. The clinical relevance of this objective lies in potentially improving the management of BTC by delaying cancer recurrence, thereby enhancing patient outcomes.

Secondary objectives include demonstrating the superiority of rilvegostomig in combination with chemotherapy relative to placebo in combination with chemotherapy by assessing overall survival (OS) in participants with BTC after resection with curative intent. This objective is crucial for understanding the long-term benefits of the treatment regimen on patient survival.

The clinical trial involves a total of **667 participants** diagnosed with **adenocarcinoma of the biliary tract**, including intrahepatic or extrahepatic cholangiocarcinoma and muscle invasive gallbladder cancer. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of adenocarcinoma of the biliary tract following macroscopically complete resection, and a confirmed disease-free status by imaging within 28 days prior to randomization. The trial includes individuals with an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The population also includes a vulnerable group, although specific lifestyle considerations such as diet or physical activity are not detailed. The selection process ensures that participants are randomized within 12 weeks post-resection, with adequate healing and removal of drains, and a tumor sample collected at surgical resection is provided.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled, multicenter, global study designed to evaluate the efficacy and safety of **rilvegostomig** in combination with chemotherapy as an adjuvant treatment following resection of biliary tract cancer. The trial aims to demonstrate the superiority of rilvegostomig plus chemotherapy over placebo plus chemotherapy by assessing recurrence-free survival (RFS) in participants with adenocarcinoma of the biliary tract after resection with curative intent. The study is expected to commence recruitment on April 15, 2024, and conclude by September 30, 2030.

Participants will be involved in the study for a maximum treatment period of 12 months. The trial includes several key visits: an inclusion (screening) visit, where eligibility is confirmed based on criteria such as histologically confirmed adenocarcinoma and disease-free status by imaging; randomization within 12 weeks post-resection; and follow-up visits to monitor treatment response and safety. The end-of-study visit will assess the primary and secondary endpoints, including overall survival and patient-reported tolerability. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdrawal of consent.

The trial involves the administration of rilvegostomig via **intravenous use** and chemotherapy agents such as **gemcitabine**, **capecitabine**, and **cisplatin**. The chemotherapy regimen is tailored to each participant, with specific dosing and administration routes, including oral and intravenous, as per the study protocol. The trial's primary endpoint is the comparison of RFS between the treatment arms, while secondary endpoints include overall survival, progression-free survival following recurrence, and patient-reported outcomes. The study is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure participant safety and data integrity.

**Rilvegostomig** is the primary investigational drug in this clinical trial. It is administered as a **solution for infusion** and is classified as a bispecific IgG1 monoclonal antibody targeting PDCD1 and TIGIT. The maximum daily dose is 750 mg, with a total maximum dose of 13,500 mg over a treatment period of up to 12 months. The administration route is **intravenous use**. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Gemcitabine** is used as part of the chemotherapy regimen in this study. It is provided in the form of a **powder for solution for infusion**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 16,000 mg/m² over a 6-month period. The drug is administered via **intravenous use**. Compliance is monitored through infusion records and participant logs.

**Capecitabine** is another chemotherapy agent used in the trial, available as a **film-coated tablet**. The maximum daily dose is 2500 mg/m², with a total maximum dose of 280,000 mg/m² over 6 months. It is administered **orally**. Participant adherence is tracked through pill counts and diary entries.

**Tegafur** is included in the chemotherapy regimen and is provided as a **hard capsule**. The maximum daily dose is 120 mg, with a total maximum dose of 13,440 mg over 6 months. The administration route is **oral**. Compliance is monitored through capsule counts and participant diaries.

**Cisplatin** is administered as a **concentrate for solution for infusion**. The maximum daily dose is 25 mg/m², with a total maximum dose of 400 mg/m² over a 6-month period. The route of administration is **intravenous use**. Compliance is ensured through infusion records.

**Sodium Chloride** and **Glucose** are used as auxiliary treatments in the trial, both provided as **solutions for infusion**. They are administered via **intravenous use** as needed, with no specified maximum daily or total dose. These solutions are used to maintain hydration and electrolyte balance during the trial.

**Infliximab** is included as an auxiliary treatment, provided as a **powder for concentrate for solution for infusion**. It is administered **orally**, with no specified maximum daily or total dose. Its role is supportive, and compliance is monitored through administration records.

**Mycophenolate Mofetil** is also used as an auxiliary treatment, available as a **hard capsule**. It is administered **orally**, with no specified maximum daily or total dose. Compliance is tracked through capsule counts and participant logs.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **Recurrence Free Survival (RFS)**, comparing Arm A (rilvegostomig + chemotherapy) with Arm B (placebo + chemotherapy) in participants with biliary tract cancer (BTC) after resection with curative intent. Secondary endpoints include **Overall Survival (OS)**, **Patient-reported tolerability**, and **Progression Free Survival (PFS)** following recurrence, also comparing Arm A with Arm B. These efficacy parameters will be measured and collected at specified intervals throughout the trial duration, with the final analysis conducted at the end of the study period. The trial is designed to demonstrate the superiority of the investigational treatment over the placebo in terms of these clinical outcomes.