EORTC 2120-HNCG: Radiotherapy plus xevinapant or placebo in older patients with locally advanced head and neck squamous cell carcinoma: a randomized phase II study (Ravina)

The primary objective of this study is to assess the benefit of adding **xevinapant** to radiotherapy (RT) in terms of duration of locoregional event-free survival (LREFS) in older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This is clinically relevant as it aims to improve the management and outcomes of a population with limited treatment options due to age-related factors.

Secondary objectives include:

• Estimating the added value of xevinapant over RT alone in terms of response to treatment according to RECIST.
• Estimating the added value of xevinapant over RT alone in progression-free survival (PFS).
• Estimating the added value of xevinapant over RT alone in overall survival (OS).
• Evaluating the frequency and severity of toxicities according to CTCAE v5.0 in the two arms.
• Assessing the non-inferiority of xevinapant compared to placebo in terms of health-related quality of life (HRQoL) as assessed by the EORTC QLQ-C30 global health/QoL and physical functioning scales, including additional insights from the fatigue scale and pain in the head and neck scale.

The clinical trial involves a total of **19 participants** diagnosed with **squamous cell carcinoma of the head and neck**. The study population includes both male and female subjects aged **70 years and older**, with a focus on assessing the benefit of adding xevinapant to radiotherapy in terms of locoregional event-free survival. Participants were selected based on specific inclusion criteria, including a pathologically proven new diagnosis of head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx, with measurable disease per RECIST 1.1 and an ECOG performance status of 0 or 1. The trial does not involve a vulnerable population. Participants are required to have adequate hematologic, renal, and hepatic function, and must be able to swallow liquids or have a functioning feeding tube. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **xevinapant** in combination with radiotherapy compared to a placebo in older patients with locally advanced **squamous cell carcinoma of the head and neck**. This is a randomized, double-blind, controlled phase II study. The trial aims to assess the benefit of adding xevinapant to radiotherapy in terms of locoregional event-free survival (LREFS). The study is expected to run until June 2030, with recruitment starting in September 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and health status. Following successful screening, participants will be randomized to receive either xevinapant or a placebo, both administered as an oral solution. The trial includes regular follow-up visits to monitor treatment response, safety, and any adverse events. The primary endpoint is LREFS, with secondary endpoints including response to treatment, progression-free survival, overall survival, and patient-reported health-related quality of life (HRQoL).

The expected duration of participant involvement is up to 18 months, with conditions for early termination including significant adverse events or disease progression. Participants will have an end-of-study visit to assess final outcomes and gather data on long-term effects. The trial is conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study period.

The clinical trial involves the administration of **xevinapant**, an experimental medication, in the form of an **oral solution**. Xevinapant is an antagonist of Inhibitor of Apoptosis Proteins (IAP) and is chemically synthesized. The active substance, xevinapant, is also known by the synonyms Debio 1143 and AT-406. The medication is provided by Merck Healthcare KGaA. Participants will receive a maximum daily dose of 200 mg, with a total maximum dose of 16,800 mg over a treatment period of 18 weeks. The route of administration is oral, and compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **placebo** group, where participants will receive a placebo matching the xevinapant oral solution. The placebo is designed to mimic the experimental medication in appearance and administration route, ensuring blinding of the study. The placebo will be administered with the same frequency and dosing schedule as the xevinapant group to maintain consistency across the trial arms. Participant adherence to the placebo regimen will be monitored similarly to those receiving the active treatment.

Efficacy in this clinical trial will be assessed primarily through the measurement of **locoregional event-free survival (LREFS)**. This primary endpoint will be evaluated by the local investigator and is defined by the absence of locoregional progression, recurrence of locoregional disease, the emergence of new squamous cell carcinoma (SCC) of the head and neck within the radiation field, and death from any cause. Secondary endpoints include response to treatment as per RECIST 1.1 criteria, progression-free survival, overall survival, and safety, which will be monitored according to the CTCAE Version 5.0 for toxicity and serious adverse event reporting. Additionally, patient-reported health-related quality of life (HRQoL) will be assessed using the EORTC QLQ-C30 scales at week 20, focusing on global health, physical functioning, fatigue, and pain in the head and neck. These assessments will provide comprehensive insights into the treatment effects on patients' quality of life and physical functioning.