Efficacy of Durvalumab with FOLFOX and IMRT in Localized Unresectable Esophageal Adenocarcinoma or Squamous Cell Carcinoma: A Phase II Randomized Trial

The primary objective of this study is to assess the efficacy of **durvalumab**, initially in combination with FOLFOX and IMRT 50 Gy, and subsequently as maintenance therapy, in treating patients with localized unresectable oesophageal cancer. The evaluation focuses on progression-free survival (PFS) as centrally reviewed (cPFS). This is clinically relevant as it aims to determine the potential of durvalumab to improve outcomes in patients with this challenging condition, where traditional surgical options are not viable.

Secondary objectives include:

• Assessing the efficacy in terms of local progression-free survival (PFS).
• Evaluating the efficacy in terms of overall survival.
• Evaluating the safety and tolerance of the study treatments.
• Assessing the quality of life of the patients.

The clinical trial involves participants diagnosed with **localized unresectable adenocarcinoma or squamous cell carcinoma of the oesophagus** who have not received prior chemotherapy, surgery, or radiotherapy. The study population includes both male and female subjects, aged 18 years and older, with a **WHO performance status** of less than 2, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have a body weight greater than 35 kg and a life expectancy of at least 12 weeks. The trial includes individuals who are part of a vulnerable population. Participants are required to have adequate biochemistry, haemostasis, and haematology laboratory data within seven days before randomization. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **durvalumab** in combination with FOLFOX and IMRT 50 Gy, followed by maintenance therapy, for patients with localized unresectable adenocarcinoma or squamous cell carcinoma of the oesophagus. This is a randomized, double-blind, controlled phase II trial. The trial is expected to run from May 2019 to April 2027, with the primary endpoint being progression-free survival (PFS) as assessed by a blinded independent centralized review. Secondary endpoints include overall survival, safety, and quality of life assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven carcinoma, adequate laboratory data, and a WHO performance status of less than 2. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events, with assessments including clinical examinations, ECGs, and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 12 months, depending on the treatment arm. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on the participant's best interest. Participants will receive **IMFINZI** 50 mg/mL concentrate for solution for infusion, **fluorouracil**, **folinic acid**, and **oxaliplatin** as part of the treatment regimen, with dosing and administration following the protocol guidelines.

The clinical trial involves the administration of **durvalumab**, marketed as IMFINZI, which is a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, with a concentration of 50 mg/mL. The active substance, durvalumab, is a protein of other origin, and the product is manufactured by AstraZeneca AB. The maximum daily dose is 1500 mg, with a total maximum dose of 18000 mg over a treatment period of up to 12 months. The administration route is intravenous infusion, and compliance with the dosing schedule is monitored throughout the trial.

**Fluorouracil** is used as a non-experimental treatment in this study. It is provided as a solution for infusion, with the active substance being of chemical origin. The maximum daily dose is 2000 mg/m², and the total maximum dose is 12000 mg/m² over a treatment period of up to 3 months. The administration is via intravenous infusion, and participant adherence to the dosing regimen is closely monitored.

**Folinic acid** is also included as a non-experimental treatment. It is administered as a solution for injection, with the active substance being chemically derived. The maximum daily dose is 200 mg/m², with a total maximum dose of 1200 mg/m² over a treatment period of up to 3 months. The route of administration is intravenous infusion, and compliance with the dosing schedule is ensured through regular monitoring.

**Oxaliplatin** is another non-experimental treatment used in the trial. It is available as a solution for infusion, with the active substance of chemical origin. The maximum daily dose is 85 mg/m², and the total maximum dose is 510 mg/m² over a treatment period of up to 3 months. The administration is conducted via intravenous infusion, and participant compliance is monitored to ensure adherence to the prescribed dosing schedule.

The efficacy of the treatment regimen in this clinical trial will be primarily assessed through the evaluation of **Progression-Free Survival (PFS)**. PFS is defined as the time from randomization until disease progression or death. This primary endpoint will be determined by a blinded independent centralized review, utilizing the RECIST criteria 1.1 to assess progression through imaging techniques such as TDM. Patients who are alive and without documented progression at the last follow-up will have their PFS data censored at that date or at the initiation of any new anticancer treatment.

Secondary efficacy endpoints include overall survival (OS), which is defined as the time from randomization to death from any cause. Patients who are still alive at the time of analysis will have their data censored at the last known date they were alive. Additionally, safety will be evaluated by monitoring adverse events (AEs) using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0). This will involve clinical examinations, vital signs, electrocardiograms (ECGs), and laboratory tests. Quality of life will also be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire, specifically the EORTC QLQ-C30 and the Oesophageal Cancer Module (Oes18).