Phase III Randomized, Double-Blind, Placebo-Controlled Study of Durvalumab with Gemcitabine and Cisplatin in First-Line Advanced Biliary Tract Cancer

The primary objective of this study is to assess the **efficacy** of Arm A compared to Arm B in terms of overall survival (OS) in patients with first-line advanced biliary tract cancers (BTC). This is clinically relevant as OS is a critical endpoint in evaluating the effectiveness of cancer treatments, providing a direct measure of the treatment's impact on patient survival.

Secondary objectives include:

• Further assessing the efficacy of Arm A compared to Arm B in terms of progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) using investigator assessments.
• Summarizing the efficacy of Arm A compared to Arm B in terms of ORR and DoR using blinded independent central review (BICR) assessments.
• Assessing disease-related symptoms, impacts, and health-related quality of life (HRQoL) in patients treated with Arm A compared to Arm B.
• Evaluating the efficacy of Arm A compared to Arm B by PD-L1 expression.
• Assessing the pharmacokinetics (PK) of durvalumab when used in combination with gemcitabine/cisplatin.
• Investigating the immunogenicity of durvalumab.

The clinical trial involves a total of **685 participants** diagnosed with **advanced biliary tract cancers (BTC)**, including cholangiocarcinoma and gallbladder carcinoma. 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 unresectable advanced or metastatic biliary tract cancer, and a **WHO/ECOG performance status** of 0 or 1. The trial excludes vulnerable populations and focuses on individuals who have not received prior treatment for unresectable or metastatic disease at initial diagnosis, or those with recurrent disease more than six months post-curative surgery or adjuvant therapy. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled, multi-regional, international study designed to evaluate the efficacy of **durvalumab** in combination with **gemcitabine** plus **cisplatin** compared to a placebo in combination with gemcitabine plus cisplatin for patients with first-line advanced biliary tract cancers. The primary objective is to assess overall survival, while secondary endpoints include progression-free survival, objective response rate, and duration of response according to RECIST 1.1 using both investigator and BICR assessments. The trial is expected to commence recruitment on April 5, 2024, and conclude by March 31, 2025, with a maximum treatment period of 99 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed, unresectable advanced or metastatic biliary tract cancer, and a WHO/ECOG performance status of 0 or 1. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments including serum concentration of durvalumab and presence of anti-drug antibodies. The end-of-study visit will evaluate the overall outcomes and any adverse events. Participant involvement is expected to last up to 99 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Durvalumab**, marketed as IMFINZI, is a **concentrate for solution for infusion**. It is administered intravenously at a maximum daily dose of 1500 mg. The treatment period is set for a maximum of 99 weeks. Durvalumab is a protein-based therapeutic agent, specifically classified under the ATC code L01XC28. It is provided by AstraZeneca AB and is used in combination with other agents in the study.

**Gemcitabine** is utilized as a comparator treatment in the trial. It is provided in the form of a **powder for solution for infusion** and is administered intravenously. The maximum treatment period for gemcitabine is also 99 weeks. This chemical-based agent is used in combination with other treatments to evaluate its efficacy in the study.

**Cisplatin** is another comparator treatment used in the trial. It is available as a **concentrate for solution for infusion** and is administered intravenously. Like gemcitabine, the maximum treatment period for cisplatin is 99 weeks. Cisplatin is a chemical-based agent and is used in combination with other treatments to assess its effectiveness in the study.

**Mycophenolate mofetil** is included as an auxiliary treatment in the trial. It is provided in the form of **hard capsules** and is administered orally. The maximum treatment period for mycophenolate mofetil is 99 weeks. This chemical-based immunosuppressive agent is used to support the primary treatment regimen.

**Infliximab** is also used as an auxiliary treatment in the trial. It is available as a **powder for concentrate for solution for infusion** and is administered intravenously. The maximum treatment period for infliximab is 99 weeks. Infliximab is a protein-based therapeutic agent used to complement the primary treatment regimen.

The efficacy of the clinical trial will be assessed by comparing the **overall survival (OS)** of patients in Arm A, receiving Durvalumab in combination with Gemcitabine plus Cisplatin, to those in Arm B, receiving a placebo in combination with Gemcitabine plus Cisplatin. The primary endpoint is overall survival, which will be measured to determine the efficacy of the treatment regimen in patients with first-line advanced biliary tract cancers.

Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) according to RECIST 1.1, using both Investigator and BICR assessments. Additionally, the study will evaluate the global health status and quality of life using the EORTC QLQ-C30 and QLQ-BIL21 questionnaires, which assess various symptoms and impacts on physical function. The association of PD-L1 expression levels with PFS, ORR, DoR, disease control rate (DCR), and OS will also be analyzed. Furthermore, the serum concentration of Durvalumab and the presence of anti-drug antibodies (ADAs) will be measured to provide additional insights into the treatment's efficacy and safety profile.