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

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the superior efficacy of Xevinapant (Debio 1143) versus placebo when added to radiotherapy in the treatment of high-risk participants with resected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) who are ineligible to receive cisplatin-based chemoradiation concurrently. Study details include: Study duration: Participants will be followed until the last on-study participant reaches his/her 60-month post-randomization visit, a decision to end the study has been triggered, or until premature discontinuation from study, whichever occurs first. Treatment duration: 18 weeks, consisting of six 3-week cycles. Health measurement/observation: Improved Disease-Free Survival. Visit frequency: Weekly visit during combination therapy period, once every 3 weeks during monotherapy period, and every 3, 4, or 6 months during the Disease-Free Survival Follow-up period in Year 1, 2 and 3, or 4 and 5 (with telephone contact in between), respectively, and every 3 months (telephone visits allowed) during the Overall Survival Follow-up period.

Official Title
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A Randomized, Double-blind, Placebo-controlled, 2-arm Phase III Study to Assess Efficacy and Safety of Xevinapant and Radiotherapy Compared to Placebo and Radiotherapy for Demonstrating Improvement of Disease-free Survival in Participants With Resected Squamous Cell Carcinoma of the Head and Neck, Who Are at High Risk for Relapse and Are Ineligible for High-dose Cisplatin (XRAY VISION)

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: Xevinapant (Debio 1143)
* Radiation: IMRT
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 renal, hematologic and hepatic function as defined in the protocol Other protocol-defined inclusion criteria could apply Exclusion Criteria: 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 Participants with incomplete surgery Participants with recurrent or metastatic disease Primary tumor of nasopharyngeal, paranasal sinuses, nasal cavity, salivary, thyroid or parathyroid gland, skin or unknown primary site 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 Known contraindication to undergoing positron emission tomography with 18F-FDG-PET-CT scans, or both contrast-enhanced MRI and contrast-enhanced CT scans Known allergy to Xevinapant (Debio 1143) or any excipient known to be present in Xevinapant (Debio 1143) or in the placebo formulation Other protocol-defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Xevinapant (Debio 1143) + IMRT<br> | Drug: Xevinapant (Debio 1143)<br>* Participants will receive 3 cycles of oral solution of Xevinapant (Debio 1143) at a dose of 200 milligrams per day (mg/day) once daily from Day 1 to 14, per 3-week cycle in combination with radiotherapy followed by 3 cycles of monotherapy of Xevinapant (Debio 1143) at a dose of 200 mg/day from Day 1 to 14, per 3-week cycle (Each cycle is of 3 weeks).<br>Radiation: IMRT<br>* Participants will receive 66 Gy of intensity modulated radiation therapy (IMRT) in 33 fractions, 2 Gy/fraction, 5 days/week.<br>|
| Placebo Comparator: Arm B: Placebo + IMRT<br> | Radiation: IMRT<br>* Participants will receive 66 Gy of intensity modulated radiation therapy (IMRT) in 33 fractions, 2 Gy/fraction, 5 days/week.<br>Drug: Placebo<br>* Participants will receive 3 cycles of oral solution of placebo matched to Xevinapant (Debio 1143) once daily from Day 1 to 14 per 3-week cycle in combination with radiotherapy followed by 3 cycles of monotherapy of placebo matched to Xevinapant (Debio 1143) from Day 1 to 14, per 3-week cycle (Each cycle is of 3 weeks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) |  | Time from randomization to the first occurrence of death from any cause or objective disease recurrence, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Time from randomization to death from any cause, assessed up to 5 years | 
| Time to Subsequent Cancer Treatments |  | Time from randomization to the start of first subsequent cancer treatment, assessed up to 5 years | 
| Number of Participants with Adverse Events (AEs) and Treatment-related AEs |  | Time from randomization until end of study (up to 5 years) | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Head and Neck Module (EORTC QLQ-HN35) Score |  | Baseline, Day 64 [at Week 10 (each cycle is 3 weeks)] and End of treatment Day 134 (at Week 20) | 
| Change from Baseline in European Organization for research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) Score |  | Baseline, Day 64 [at Week 10 (each cycle is 3 weeks)] and End of treatment Day 134 (at Week 20) | 
| Change from Baseline in EuroQOL 5 Dimension 5 Level Health-Related Quality of Life Measure Visual Analog Scale Score (EQ-5D-5L VAS) |  | Baseline, Day 64 [at Week 10 (each cycle is 3 weeks)] and End of treatment Day 134 (at Week 20) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Larynx, Unfit, Adjuvant radiotherapy (RT), Stage III, Stage IVA, Stage IVB, Oral cavity, Oropharynx, Hypopharynx