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1. Locoregional event-free survival (LREFS) (Time Frame - 5 years after first patient in): To demonstrate superior efficacy in terms of locoregional event-free survival of xevinapant vs placebo when added to radical radiotherapy in older patients with LA-HNSCC.
Secondary outcome:
1. Response to treatment by RECIST 1.1 (Time Frame - 5 years after first patient in): To estimate the added value of xevinapant over RT alone in terms of response to treatment.
2. Progression Free Survival as assessed by the local investigator (Time Frame - 5 years after first patient in): To estimate the added value of xevinapant over RT alone in PFS.
3. Overall Survival (Time Frame - 5 years after first patient in): To estimate the added value of xevinapant over RT alone in OS.
4. Safety according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting (Time Frame - 5 years after first patient in): To evaluate the frequency and severity of toxicities according to CTCAE v5.0 in the two arms.
5. HRQOL as assessed by global health/QoL and physical functioning scales at week 20 (Fatigue scale from the Quality of Life Core-30 (QLQ-C30) and pain in the head and neck scale from Item List-225 (IL225)). (Time Frame - 5 years after first patient in): To assess non-inferiority of xevinapant arm 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.
The questionnaires employ 50 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall HRQoL. For functional and global HRQoL scales, higher scores represent a better level of functioning and are converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represents more severe symptoms.
Experimental: Radiotherapy + Xevinapant 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per 21-day cycle) + IMRT followed by 3 cycles of xevinapant in monotherapy (200 mg/day from Day 1 to 14, per 21-day cycle)
Placebo Comparator: Radiotherapy + Placebo 3 cycles of placebo (from Day 1 to 14, per 21-day cycle) + IMRT followed by 3 cycles of placebo in monotherapy (from Day 1 to 14, per 21-day cycle).