Phase III Evaluation of Xevinapant and Radiotherapy Versus Placebo and Radiotherapy in High-Risk Resected Squamous Cell Carcinoma of the Head and Neck

The primary objective of this Phase III study is to evaluate the efficacy and safety of **xevinapant** in combination with radiotherapy compared to placebo with radiotherapy in improving **disease-free survival** (DFS) in participants with resected squamous cell carcinoma of the head and neck. These participants are at high risk for relapse and are ineligible for high-dose cisplatin therapy. The clinical relevance of this study lies in its potential to offer an alternative treatment option for this specific patient population, which could lead to improved DFS outcomes and potentially reduce the risk of cancer recurrence.

The clinical trial involves a total of **386 participants** diagnosed with resected **squamous cell carcinoma of the head and neck**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on their ability to tolerate standard of care IMRT treatment and their Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2. The trial includes individuals who have undergone surgery with curative intent for squamous cell carcinoma at specific primary sites, such as the oral cavity, oropharynx, hypopharynx, or larynx, within 4 to 10 weeks prior to the start of treatment. Participants must have no residual disease as confirmed by imaging and are at high risk of relapse. The trial population also includes individuals unfit for high-dose cisplatin due to specific health criteria, such as renal function or hearing impairment. Both genders are represented, and the study includes a vulnerable population. Participants are required to have adequate hematologic, renal, and hepatic function as per protocol specifications. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized, double-blind, placebo-controlled** Phase III study designed to evaluate the efficacy and safety of **xevinapant** in combination with radiotherapy compared to placebo and radiotherapy. The primary objective is to demonstrate an improvement in disease-free survival in participants with resected squamous cell carcinoma of the head and neck, who are at high risk for relapse and ineligible for high-dose cisplatin. The trial is expected to run until February 28, 2030, with recruitment having commenced on August 31, 2022.

Participants will be randomly assigned to one of two arms: one receiving xevinapant and radiotherapy, and the other receiving a placebo and radiotherapy. The study will involve multiple visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as Eastern Cooperative Oncology Group Performance Status, histologically confirmed squamous cell carcinoma, and adequate organ function. Participants must have undergone surgery with curative intent 4 to 10 weeks prior to the start of treatment and must be unfit for high-dose cisplatin due to specific health criteria.

Following the screening, participants will attend regular follow-up visits to monitor their health status, treatment adherence, and any adverse effects. These visits will include assessments such as imaging studies to confirm the absence of residual disease and evaluations of hematologic, renal, and hepatic function. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes related to disease-free survival.

The expected length of participant involvement is up to 18 months, corresponding to the maximum treatment period with xevinapant. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any protocol deviations that compromise the integrity of the trial. The study is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the administration of **xevinapant**, an experimental medication, in the form of an **oral solution**. Xevinapant is chemically synthesized and is also known by its alternative name, Debio 1143. The active substance, xevinapant, is administered orally with a maximum daily dose of 200 mg and a total maximum dose of 3600 mg over the treatment period. The treatment duration is set for a maximum of 18 weeks. The pharmaceutical formulation is provided by Merck Healthcare KGaA, and the medication is intended for use in participants with resected squamous cell carcinoma of the head and neck, who are at high risk for relapse and ineligible for high-dose cisplatin. The administration schedule and participant compliance are monitored throughout the study to ensure adherence to the dosing regimen.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the experimental medication in appearance and administration route but does not contain the active substance. The placebo is administered in the same manner as xevinapant, ensuring that neither the participants nor the investigators are aware of the treatment allocation, thereby maintaining the study's blinding integrity. The use of a placebo allows for the assessment of xevinapant's efficacy and safety in improving disease-free survival when combined with radiotherapy, compared to the placebo and radiotherapy combination.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **Disease-Free Survival (DFS)**. This endpoint is defined as the time from randomization to the first occurrence of local or regional recurrence, distant metastasis, or death from any cause. The trial is designed as a randomized, double-blind, placebo-controlled, 2-arm Phase III study. Participants will receive either xevinapant in combination with radiotherapy or a placebo with radiotherapy. The study aims to demonstrate an improvement in DFS with xevinapant compared to placebo when added to radiotherapy, irrespective of subsequent anticancer therapy.