Phase III Study on Laryngeal Preservation in Locally Advanced Squamous Cell Carcinomas of the Larynx or Hypopharynx: Comparing Induction Chemotherapy with Cisplatin, 5-Fluorouracil, and Docetaxel Followed by Radiotherapy Versus Concomitant Radiotherapy with Cisplatin.

The primary objective of this Phase III trial is to compare **survival** without laryngeal or pharyngoesophageal dysfunction in patients with locally advanced **squamous cell carcinomas** of the larynx or hypopharynx. This is achieved by evaluating two treatment regimens: triple therapy with induction chemotherapy using cisplatin, 5-fluorouracil, and docetaxel (TPF) followed by external radiotherapy, versus the concomitant combination of external radiotherapy and cisplatin. The clinical relevance of this objective lies in determining the most effective treatment strategy for preserving laryngeal function while managing advanced laryngeal or hypopharyngeal cancer.

Secondary objectives include evaluating overall survival, locoregional control, survival without recurrence, incidence and survival of distant metastases, survival without laryngeal or pharyngoesophageal dysfunction assessed with dynamic swallowing videocopy or VHI/DHI, laryngeal preservation, response rate to induction chemotherapy, acute and late toxicity, feasibility and morbidity of salvage surgery, and quality of laryngeal and pharyngoesophageal function. These objectives aim to provide a comprehensive assessment of the treatment's impact on patient outcomes and quality of life.

The clinical trial involves participants diagnosed with **squamous cell carcinomas** of the larynx or hypopharynx, specifically in a locally advanced stage. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants are required to be in good general health, as indicated by a performance status of 0 or 1. The trial does not include a vulnerable population. The selection criteria for the trial population are based on specific medical conditions and health status, ensuring that participants have not been previously treated for the condition and have no distant metastasis. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of induction chemotherapy followed by radiotherapy compared to concomitant chemotherapy and radiotherapy in patients with locally advanced **squamous cell carcinomas of the larynx or hypopharynx**. The trial aims to compare survival without laryngeal or pharyngoesophageal dysfunction, utilizing a combination of **cisplatin**, **fluorouracil**, and **docetaxel**. The study is expected to commence recruitment on June 26, 2024, and conclude by December 31, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven squamous cell carcinoma, absence of distant metastasis, and a performance status of 0 or 1. Following successful screening, participants will be randomized to receive either the induction chemotherapy regimen followed by radiotherapy or the concomitant chemotherapy and radiotherapy regimen. The trial will include regular follow-up visits to monitor treatment response, assess any adverse events, and evaluate the primary endpoint of survival with preservation of laryngeal and pharyngoesophageal function. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 9 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial will also assess secondary endpoints such as overall survival, locoregional control, and the incidence of metastases, providing comprehensive data on the efficacy and safety of the treatment regimens under investigation.

The clinical trial involves the administration of several **antineoplastic agents**. The first experimental medication is **Docetaxel Accord**, a concentrate for solution for infusion, with a concentration of 20 mg/1 ml. The active substance is **docetaxel**, a chemical compound classified under the ATC code L01CD02. The pharmaceutical form is a solution for infusion, administered via the **intravenous route**. The maximum daily dose is 75 mg/m², with a total maximum dose of 225 mg/m² over a treatment period of up to 9 weeks. This medication is not a pediatric formulation and is used as part of the trial's test treatment.

The second medication is **Fluorouracil 50 mg/ml Solution for Injection or Infusion**, containing the active substance **fluorouracil**. It is a cytostatic antineoplastic agent of the antimetabolite class, specifically an antipyrimidine, with the ATC code L01BC02. The solution can be administered either as an injection or infusion, also via the **intravenous route**. The maximum daily dose is 750 mg/m², with a total maximum dose of 2250 mg/m², administered over a period of up to 9 weeks. This medication is also not formulated for pediatric use and serves as a test treatment in the trial.

The third medication is **CISPLATINE ACCORD 1 mg/ml**, a solution to be diluted for infusion, with the active substance **cisplatin**. It is a cytostatic antineoplastic agent, classified under the ATC code L01XA01. The solution is administered as an infusion, with a maximum daily dose of 100 mg/m² and a total maximum dose of 300 mg/m² over a treatment period of up to 6 weeks. This medication is not a pediatric formulation and is used as a comparator treatment in the trial.

The fourth medication is **Cisplatin 1 mg/ml concentrate for solution for infusion**, also containing the active substance **cisplatin**. It is administered via the **intravenous route** as a solution for infusion. The maximum daily dose is 75 mg/m², with a total maximum dose of 225 mg/m² over a treatment period of up to 9 weeks. This medication is not formulated for pediatric use and is part of the test treatment in the trial.

All medications are chemically derived and are administered under strict compliance monitoring to ensure adherence to the dosing schedules. The trial aims to compare the efficacy of these treatments in preserving laryngeal function in patients, with a focus on survival without laryngeal or pharyngoesophageal dysfunction.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is **survival with preservation of laryngeal and pharyngoesophageal function**. This will be evaluated by considering events such as death, total laryngectomy, tracheotomy at 24 months, gastric tube at 24 months, and local recurrence not accessible to salvage treatment. The causes of death will be specified to provide a comprehensive understanding of the outcomes.

Secondary endpoints include overall survival, survival without recurrence, locoregional control, metastasis-free survival, and incidence of metastases. Additionally, the trial will assess survival with preservation of laryngeal and pharyngoesophageal function using dynamic swallowing videoscopy, laryngeal preservation, and response rate to induction chemotherapy. The toxicity of the treatments will be distinguished between acute and late toxicities. Feasibility and morbidity of salvage surgery will be evaluated by the number of recurrences successfully treated and the description of operative consequences. The quality of laryngeal and pharyngoesophageal function will be assessed using a qualitative scale, focusing on voice, swallowing, and respiration both at rest and during exertion. The quality of rehabilitation for laryngectomized patients will also be analyzed.