Phase III Randomized Double-Blind Study of Durvalumab with Chemoradiation in Locally Advanced Unresectable Esophageal Squamous Cell Carcinoma

The primary objective of this study is to evaluate the **efficacy** of durvalumab in combination with definitive chemoradiation therapy (**dCRT**) compared to placebo plus dCRT in terms of progression-free survival (**PFS**) using blinded independent central review (**BICR**) assessments according to RECIST 1.1 criteria in patients with locally advanced, unresectable esophageal squamous cell carcinoma (**ESCC**) with PD-L1 tumor area positivity (TAP) ≥1%. This is clinically relevant as it aims to determine whether the addition of durvalumab can improve PFS, a critical endpoint in cancer treatment, indicating the time during which a patient's disease does not worsen.

Secondary objectives include: - Assessing the efficacy of durvalumab plus dCRT compared to placebo plus dCRT in terms of overall survival (**OS**), 24-month progression-free survival rate (**APF24**), objective response rate (**ORR**), duration of response (**DoR**), disease control rate (**DCR**), time to progression (**TTP**), second progression-free survival (**PFS2**), and 36-month overall survival rate (**OS36**) in all randomized patients and specifically in those with PD-L1 TAP ≥1% tumors. - Evaluating patient-reported symptoms, functioning, and health-related quality of life (**HRQoL**) using patient-reported outcome measures. - Assessing the pharmacokinetics (**PK**) of durvalumab when combined with dCRT. - Investigating the immunogenicity of durvalumab and its combination with dCRT in all randomized patients.

The clinical trial involves a total of **475 participants** diagnosed with **locally advanced unresectable esophageal squamous cell carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are in generally good health as indicated by an ECOG performance status of 0 or 1. Participants were selected based on their histologically or cytologically confirmed diagnosis of esophageal squamous cell carcinoma, with locally advanced disease classified as Stage II-IVA, and deemed unsuitable for surgical intervention. The trial includes individuals who have at least one evaluable lesion per RECIST 1.1 criteria and have provided tumor tissue for PD-L1 expression analysis. Participants are required to have adequate organ and marrow function and a life expectancy of more than three months. The trial population also includes vulnerable groups, although specific lifestyle considerations such as diet or physical activity are not detailed in the available data.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled, multi-center study designed to evaluate the efficacy of **durvalumab** in combination with definitive chemoradiation therapy (dCRT) in patients with locally advanced, unresectable esophageal squamous cell carcinoma. The primary objective is to assess progression-free survival (PFS) using blinded independent central review (BICR) assessments according to RECIST 1.1 in patients with PD-L1 TAP≥1% tumors. Secondary endpoints include overall survival (OS), objective response rate (ORR), and duration of response (DoR) among others. The trial is expected to commence recruitment on March 14, 2024, and conclude by November 30, 2026.

Participants will be randomly assigned to receive either durvalumab or a placebo, both administered concurrently with dCRT. The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of esophageal squamous cell carcinoma, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted according to RECIST 1.1 guidelines. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.

The expected duration of participant involvement is up to 24 months, contingent upon individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Capecitabine Accord** is provided in two dosages: 500 mg and 150 mg film-coated tablets. The active substance is **capecitabine**, a chemical compound classified under ATC code L01BC06. The tablets are administered orally. The specific dosage and frequency of administration are determined based on the trial protocol, with a maximum treatment period not specified in the data provided.

**Mycophenolate Mofetil Accord** is administered as 250 mg hard capsules. The active substance, **mycophenolate mofetil**, is a chemical compound with ATC code L04AA06. The route of administration is oral, and the dosing schedule is determined by the trial protocol, with no maximum treatment period specified in the data.

**Cisplatin** is provided as a 1 mg/ml concentrate for solution for infusion. The active substance is **cisplatin**, a chemical compound under ATC code L01XA01. This medication is administered via intravenous infusion, with the dosing schedule and maximum treatment period determined by the trial protocol.

**Fluorouracil** is administered as a 50 mg/ml solution for injection. The active substance is **fluorouracil**, classified under ATC code L01BC02. The route of administration is intravenous injection, with the dosing schedule and maximum treatment period specified by the trial protocol.

The trial also includes a **placebo** formulated as 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, and 0.02% (w/v) polysorbate 80, with a pH of 6.0. The placebo is used as a comparator treatment in the study, with the administration route and schedule determined by the trial protocol.

**IMFINZI** (durvalumab) is provided as a 50 mg/mL concentrate for solution for infusion. The active substance is **durvalumab**, a protein-based compound. It is administered intravenously, with a maximum daily dose of 1500 mg and a maximum treatment period of 24 weeks, as specified in the trial protocol.

**Inflectra** is administered as a 100 mg powder for concentrate for solution for infusion. The active substance is **infliximab**, a protein-based compound. The route of administration is intravenous, with the dosing schedule and maximum treatment period determined by the trial protocol.

The efficacy of the clinical trial will be assessed by evaluating the **progression-free survival (PFS)** using blinded independent central review (BICR) assessments according to RECIST 1.1 criteria in patients with PD-L1 TAP≥1% tumors. This primary endpoint will provide a measure of the time during and after the treatment that a patient lives with the disease without it getting worse. Secondary endpoints include PFS in all randomized patients, overall survival (OS), OS at 36 months (OS36), second progression-free survival (PFS2), and additional parameters such as objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and time to progression (TTP) as assessed by BICR in all randomized patients and in patients with PD-L1 TAP≥1% tumors. Furthermore, time to deterioration and change from baseline in symptoms, functioning, and health-related quality of life (HRQoL) will be measured using the EORTC QLQ-C30 and QLQ-OES18 questionnaires. The concentration of durvalumab in blood and the presence of anti-drug antibodies (ADA) will also be evaluated in all randomized patients.