Phase III Randomized Trial of Radiotherapy with Cisplatin Versus Radiotherapy Alone in Sinus and Salivary Gland Tumors

The primary objective of this Phase III randomized trial is to compare **progression-free survival (PFS)** between two treatment arms: radiotherapy (RT) only versus radiotherapy combined with chemotherapy (RT-CT) as adjuvant therapy in surgical patients with resected tumors of sinuses or salivary glands. This comparison is clinically relevant as it aims to determine the efficacy of adding chemotherapy to radiotherapy in improving PFS, which is a critical endpoint in assessing the effectiveness of cancer treatments.

Secondary objectives include:

• Comparing the two treatment arms in operated patients in terms of overall survival (OS), quality of life (QoL), time to locoregional progression, time to distant progression, severe acute toxicity (grade ≥ 3 occurring during treatment and within the following 6 months), and severe late toxicity (grade ≥ 3 occurring from 6 months after the end of radiotherapy treatment).
• Evaluating major and minor prognostic factors such as T, R1 margins, high-grade histological subtypes according to REFCOR, N+ with/without capsular rupture, perineural sheathing, and vascular emboli.
• Comparing the oncological efficacy (PFS, OS, time to progression) between the two arms in non-operated patients and studying whether the effect of adding chemotherapy is similar in operated and non-operated patients.
• Evaluating the specific toxicity of proton therapy associated with cisplatin.
• Analyzing the oncological results by type of histology, including adenoid cystic carcinoma, intestinal type carcinoma, and high-grade salivary gland tumors.

The clinical trial involves a study population comprising both **male** and **female** participants aged 18 years and older. The participants are individuals diagnosed with resected or non-operable tumors of the sinuses or salivary glands, including carcinomas of the major salivary glands and malignant tumors of the sinuses. The trial does not include a vulnerable population. Participants were selected based on specific criteria, including a performance index according to the World Health Organization (WHO) criteria ranging from 0 to 2. For those aged 70 years and above, a G8 questionnaire score greater than 14 is required, with no falls noted in the previous 12 months or a geriatric assessment compatible with chemotherapy administration. The estimated life expectancy of participants is required to be six months or more. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **Phase III** randomized, double-blind, controlled study designed to compare the efficacy of concomitant administration of radiotherapy with **cisplatin** versus radiotherapy alone in the treatment of tumors of the sinuses and salivary glands. The primary objective is to evaluate progression-free survival between the two treatment arms. Secondary endpoints include overall survival, quality of life, time to locoregional and distant progression, and rates of acute and late toxicities of grade ≥ 3. The trial is expected to commence recruitment on July 12, 2024, and conclude by May 31, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥ 18 years), performance index according to WHO criteria (0 to 2), and estimated life expectancy of at least 6 months. The inclusion criteria also specify the types of tumors eligible for the study, including resected or unresectable tumors of the sinuses or salivary glands, and carcinomas of the major salivary glands. Exclusion criteria are not specified in the provided data.

Following the screening visit, participants will be randomized into one of the two treatment arms. Regular follow-up visits will be scheduled to monitor treatment response, manage any adverse events, and assess progression-free survival. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. The expected length of participant involvement is up to 43 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events or disease progression that necessitates withdrawal from the trial.

The clinical trial involves the administration of **Cisplatin**, a cytostatic antineoplastic agent, as part of the experimental treatment regimen. The investigational product is formulated as a **concentrate for solution for infusion**, with a concentration of 1 mg/ml. The active substance, **cisplatin**, is of chemical origin and is classified under the ATC code L01XA01. The pharmaceutical form is specifically designed for intravenous infusion, ensuring direct delivery into the bloodstream. The dosing regimen for cisplatin is calculated based on body surface area, with a maximum daily dose of 100 mg/m² and a cumulative maximum dose of 300 mg/m² over the treatment period. The maximum treatment duration is set at 43 days. The administration of cisplatin is intended to be concomitant with radiotherapy, as part of the trial's objective to compare progression-free survival between the two treatment arms: radiotherapy alone versus radiotherapy combined with cisplatin.

In addition to the experimental treatment, the study includes a comparator arm where participants receive standard-of-care radiotherapy without the addition of cisplatin. This arm serves as a control to evaluate the efficacy of the combined treatment approach. The trial does not utilize a placebo, as the comparator is an established treatment modality for the targeted conditions, namely tumors of the sinuses and salivary glands. Compliance with the dosing schedule and administration protocol is monitored throughout the study to ensure adherence and to accurately assess the outcomes related to the investigational treatment.

Efficacy in this Phase III clinical trial will be assessed by comparing **progression-free survival (PFS)** between two treatment arms: radiotherapy (RT) only versus radiotherapy combined with cisplatin (RT-CT) as adjuvant therapy in surgical patients with tumors of the sinuses or salivary glands. The primary endpoint for evaluating efficacy is progression-free survival. Secondary endpoints include overall survival, quality of life, time to locoregional progression, time to distance progression, rate of acute toxicity grade ≥ 3, rate of late toxicities of grade ≥ 3, and prognostic criteria. These parameters will be measured and collected at specified intervals throughout the trial duration, with the final analysis conducted at the end of the treatment period. The trial is designed to provide a comprehensive assessment of the therapeutic benefits and safety profile of the combined treatment regimen compared to radiotherapy alone.