Phase 3 Randomized, Double-Blind Study of Pembrolizumab with Gemcitabine/Cisplatin vs. Placebo with Gemcitabine/Cisplatin in Advanced Biliary Tract Carcinoma

The primary objective of this Phase 3 randomized, double-blind study is to compare **overall survival** (OS) between the combination of pembrolizumab plus gemcitabine/cisplatin and placebo plus gemcitabine/cisplatin in participants with advanced and/or unresectable **biliary tract carcinoma**. This objective is clinically relevant as it aims to determine the efficacy of pembrolizumab in extending the lifespan of patients with this aggressive cancer type, potentially offering a new therapeutic option.

Secondary objectives include: - Comparing **progression-free survival** (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), as assessed by Blinded Independent Central Review (BICR), between the two treatment groups. - Comparing **objective response rate** (ORR) per RECIST 1.1, as assessed by BICR, between the treatment groups. - Evaluating the **duration of response** (DOR) per RECIST 1.1, as assessed by BICR. - Evaluating the **safety and tolerability** profile of pembrolizumab plus gemcitabine/cisplatin.

The clinical trial involves a total of **844 participants** diagnosed with **Biliary Tract Carcinoma**, specifically advanced (metastatic) and/or unresectable (locally advanced) forms, including intra- or extrahepatic cholangiocarcinoma or gallbladder cancer. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The selection process for the trial population ensures that participants have a measurable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and a life expectancy of greater than 3 months. Participants are required to have adequate organ function and must be able to provide either archival tumor tissue samples or newly obtained core or excisional biopsies of a tumor lesion. Individuals with a history of hepatitis B or C are eligible if they meet the study criteria. The trial also includes vulnerable populations, although specific lifestyle considerations such as diet, physical activity, or habits are not detailed in the provided data.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and safety of **pembrolizumab** in combination with **gemcitabine** and **cisplatin** compared to a placebo combined with gemcitabine and cisplatin in participants with advanced and/or unresectable **biliary tract carcinoma**. The primary objective is to compare overall survival between the two groups. Secondary endpoints include progression-free survival, objective response rate, duration of response, and the incidence of adverse events. The trial is expected to run from September 2019 to February 2025, with participant involvement lasting up to 156 weeks, depending on individual response and tolerance to the treatment.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of advanced biliary tract cancer, measurable disease, and adequate organ function. Following randomization, participants will receive treatment via **intravenous infusion** and attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and evaluations by a blinded independent central review. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants with a history of hepatitis B or C may be included if they meet specific criteria. The trial is not classified as low intervention and is conducted under a Phase III framework to confirm the safety and efficacy of the treatment regimen in the target population.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is a **concentrate for solution for infusion**. This experimental medication is administered via **intravenous infusion**. The dosage is set at a maximum of 200 mg per day, with a total maximum dose of 10,400 mg over a treatment period of up to 156 weeks. Pembrolizumab is a biological product, specifically a protein of other origin, and is provided by Merck Sharp & Dohme B.V. It is used in combination with other treatments to evaluate its efficacy in participants with advanced and/or unresectable biliary tract carcinoma.

The trial also includes a **placebo** comparator, referred to as Placebo to MK-3475. The placebo is designed to match the experimental treatment in appearance and administration route, ensuring the study remains double-blind. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the efficacy of pembrolizumab when combined with standard chemotherapy.

In addition to pembrolizumab, the study employs **cisplatin** as a standard-of-care chemotherapy agent. Cisplatin is administered as a **PHF00230MIG** formulation via **intravenous infusion**. The dosing regimen allows for a maximum daily dose of 25 mg/m², with a total maximum dose of 400 mg/m² over a treatment period of 24 weeks. Cisplatin is a chemical compound used in the treatment of various cancers, including biliary tract carcinoma.

Another chemotherapy agent used in the trial is **gemcitabine**, also administered in a **PHF00230MIG** formulation through **intravenous infusion**. The maximum daily dose for gemcitabine is 1000 mg/m², with a total maximum dose of 35,000 mg/m² over a treatment period of 105 weeks. Gemcitabine is a chemical compound that is commonly used in combination with cisplatin for the treatment of biliary tract carcinoma.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The combination of pembrolizumab with gemcitabine and cisplatin is compared against the placebo with gemcitabine and cisplatin to evaluate overall survival outcomes in the study population.

The efficacy of the clinical trial will be assessed by comparing the **Overall Survival (OS)** between the treatment group receiving pembrolizumab plus gemcitabine/cisplatin and the control group receiving placebo plus gemcitabine/cisplatin. This primary endpoint will provide a direct measure of the treatment's impact on survival in participants with advanced and/or unresectable biliary tract carcinoma. Secondary endpoints include **Progression-free Survival (PFS)**, **Objective Response Rate (ORR)**, and **Duration of Response (DOR)**, all evaluated per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and assessed by Blinded Independent Central Review (BICR). Additionally, the trial will monitor the number of participants experiencing adverse events and those who discontinue the study intervention due to adverse events.