Phase III Xevinapant (Debio 1143) and Radiotherapy in Resected LA SCCHN High Risk, Cisplatin-ineligible Participants (XRAY VISION)

Prior treatment

• Participant with incomplete surgery
• Prior definitive, neoadjuvant, concurrent or adjuvant (C)RT to the head and neck region which may jeopardize the primary tumor irradiation plan,or any other prior SCCHN systemic treatment, including investigational agents
• Participation in any interventional clinical study within 28 days prior to screening or during participation in this study

Other illness

• Any condition, including any uncontrolled disease state other than SCCHN that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation
• Known allergy to Xevinapant (Debio 1143) or any excipient known to be present in Xevinapant (Debio 1143) or in the placebo formulation
• Participants with recurrent or metastatic disease

Other

• Primary tumor of nasopharyngeal, paranasal sinuses, nasal cavity, salivary, thyroid or parathyroid gland, skin or unknown primary site
• Known contraindication to undergoing positron emission tomography with 18F-FDG-PET-CT scans, or both contrast-enhanced MRI and contrast enhanced CT scans
• Other protocol-defined exclusion criteria could apply

• Participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 and able to tolerate standard of care IMRT treatment according to Investigator assessment
• Participants with histologically confirmed squamous cell carcinoma with one of the following primary sites: oral cavity, oropharynx, hypopharynx or larynx. Participants have received surgery with curative intent on these sites in the past 4 to 10 weeks before start of treatment (Cycle 1 Day 1)
• Oropharynx (OPC) participants must have known human papillomavirus (HPV) status as determined by p16 expression using immunohistochemistry ICH)
• Participants with no residual disease by computed tomography (CT) or magnetic resonance imaging (MRI) and have a high risk of relapse with 1 or 2 of the following criteria, confirmed by local histopathology:
• nodal extra-capsular extension (ECE) and positive resection margins (R1 or close margin less than or equal to (<=) 1 millimeter (mm)
• Are unfit to receive high-dose cisplatin by meeting one or more of the following criteria: estimated glomerular filtration rate (eGFR) < 60 milliliter per minute per 1.73 meter square (mL/min /1.73 m^2);History of hearing impairment, defined as Grade >= 2 audiometric hearing loss or tinnitus Grade >=2. An audiogram is not required if one of the other criteria meets unfitness to receive high-dose cisplatin; Peripheral neuropathy > = Grade 2 and if >= 70 years, unfit according to G8 questionnaire (Score <= 14) or ineligible for cisplatin treatment due to age limit according to national guidelines.
• "Participants with adequate hematologic, renal and hepatic function as defined in the protocol"
• Other protocol-defined inclusion criteria could apply