A Study of Xevinapant (Debio 1143) in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Participants With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy (TrilynX)

Study Overview
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Brief Summary
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The primary objective of the study is to demonstrate superior efficacy of Xevinapant (Debio 1143) vs placebo when added to chemoradiotherapy (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).

Official Title
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A Randomized, Double-Blind Placebo-Controlled, Phase 3 Study of Debio 1143 in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy (TrilynX)

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Xevinapant (Debio 1143)
* Drug: Cisplatin
* Radiation: Intensity Modulation Radiation Therapy (IMRT)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 Histologically confirmed diagnosis of previously untreated Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-SCCHN) participant (stage III, IVa or IVb according to the American Joint Committee on Cancer(AJCC))/Classification of malignant tumors: T=size of the primary tumor, N=regional lymph node involvement, M=distant metastasis (TNM) Staging System, 8th Edition.) suitable for definitive ChemoRadiotherapy (CRT), of at least one of the following sites: oropharynx, hypopharynx and larynx For OroPharyngeal Cancer (OPC) participants, primary tumors must be human papillomavirus (HPV)-negative as determined by p16 expression using immunohistochemistry Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan (CT-scan) or magnetic resonance imaging (MRI), based on Response evaluation criteria in solid tumors (RECIST) version 1.1 Peripheral neuropathy less than (<) grade 2 Adequate hematologic, renal and hepatic function Other protocol defined inclusion criteria may apply Exclusion Criteria: Primary tumor of nasopharynx, paranasal sinuses, nasal or oral cavity, salivary, thyroid or parathyroid gland pathologies, skin or unknown primary site Metastatic disease (stage IVc as per AJCC/TNM, 8th Ed.) Prior definitive or adjuvant Radiotherapy (RT) and/or radical surgery to the head and neck region which may jeopardize the primary tumor irradiation plan, or any other prior SCCHN systemic treatment, including investigational agents Documented weight loss of >10% during the last 4 weeks prior to randomization (unless adequate measures are undertaken for nutritional support), OR plasmatic albumin < 3.0 g/dL. No albumin transfusions are allowed within 2 weeks before randomization Known allergy to Xevinapant (Debio 1143), cisplatin, carboplatin, other platinum-based agent or any excipient known to be present in any of these products or in the placebo formulation other protocol defined exclusion criteria may 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: Xevinapant (Debio 1143)<br>Participants will receive: Concomitant chemo-radiation therapy period (Cycles 1-3): Radiotherapy Cisplatin Xevinapant (Debio 1143) Monotherapy period (Cycles 4-6): • Xevinapant (Debio 1143) | Drug: Xevinapant (Debio 1143)<br>* Xevinapant (Debio 1143) administrated as oral solution from Day 1 to 14, every 21-day cycle.<br>Drug: Cisplatin<br>* Cisplatin administered as an IV infusion every 3 weeks (Q3W).<br>Radiation: Intensity Modulation Radiation Therapy (IMRT)<br>* 70 Gy given in 35 fractions over 7 weeks.<br>|
| Active Comparator: Placebo<br>Participants will receive: Concomitant chemo-radiation therapy period (Cycles 1-3): Radiotherapy Cisplatin Matched placebo Monotherapy period (Cycles 4-6): • Matched placebo | Drug: Cisplatin<br>* Cisplatin administered as an IV infusion every 3 weeks (Q3W).<br>Radiation: Intensity Modulation Radiation Therapy (IMRT)<br>* 70 Gy given in 35 fractions over 7 weeks.<br>Drug: Placebo<br>* Matched placebo administrated as oral solution from Day 1 to 14, every 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) | EFS is the time from the date of randomization to the date of first record of disease progression or death. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is the time from randomization to death due to any cause. | Up to 5 years | 
| Progression-Free Survival (PFS) | PFS is the time from randomization to the earliest between PFS event or End of Study (EOS) | Up to 5 years | 
| Locoregional Control (LRC) |  | From randomization to the earliest between PFS event (progression at the site of the primary tumor or the locoregional lymph nodes) or EOS (Up to 5 years) | 
| Objective Response Rate (ORR) | ORR defined as proportion of participants with complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by Blinded Independent Review Committee (BIRC). | Up to 5 years | 
| Complete Response Rate (CRR) | CRR defined as proportion of participants with complete response (CR) as assessed by Blinded Independent Review Committee (BIRC). | Up to 5 years | 
| Duration of Response (DOR) | Duration of response (DoR) defined as the time from the first evidence of response (partial or complete, as assessed by the BIRC according to RECIST v1.1) to the first occurrence of progression (radiological or clinical, as assessed by the BIRC) or death from any cause. | Up to 5 years | 
| Number of Participants with Radical Salvage Surgery |  | Up to 5 years | 
| Time to Subsequent Systemic Cancer Treatments |  | Up to 5 years | 
| Safety and Tolerability as assessed by incidence and severity of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Changes in Laboratory Values, Vital Signs, Electrocardiogram (ECGs) and Extent of Exposure |  | From signed informed consent to EOS (within 6.8 years) | 
| Changes from Baseline in Global Health Status/Quality of Life (GHS/QoL) and Fatigue Symptom | Change from baseline in GHS/QoL and Fatigue Symptom using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) | Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (Up to 5 years) | 
| Changes from Baseline in Swallowing and Pain Symptoms | Change from baseline in swallowing, and pain symptoms using the EORTC Head and Neck Questionnaire (EORTC QLQ-H&N35) | Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (Up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TrilynX