discontinuation of all ongoing studies involving xevinapant

This is a multicenter, randomized, placebo-controlled, triple blind, phase II study to determine the efficacy and safety of xevinapant with radiotherapy in older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) of oral cavity, oropharynx, hypopharynx, or larynx.

Upon confirmation of eligibility, subjects will be enrolled and randomized in a 1:1 ratio to:

• Arm A: 3 cycles of xevinapant (200 mg/day from Day 1 to 14, per cycle) + intensive modulated radiotherapy (IMRT) followed by 3 cycles of xevinapant in monotherapy phase (200 mg/day from Day 1 to 14, per cycle)
• Arm B: 3 cycles of placebo (from Day 1 to 14, per cycle) + IMRT followed by 3 cycles of placebo in monotherapy phase (from Day 1 to 14, per cycle).

Patients will be stratified by institution, disease location/p16 status (p16 positive oropharyngeal cancer, versus others), G8 score. Three strata for the G8 will be used (>14, versus 11-14 versus <11).

Patients will undergo imaging in week 20 and upon clinical suspicion of progression/recurrence. Clinical examination will take place every 12 weeks in the first 3 years.

Main Inclusion Criteria:

• Age ≥ 70 years.
• Pathologically proven new diagnosis of HNSCC of oral cavity, oropharynx, hypopharynx and larynx tumor.
• cT3-4 cN0 cM0 or cT1-4 cN1-3 cM0 except for T1-2N1 p16 positive oropharyngeal cancer (AJCC 8th edition).
• HPV status using p16 immunohistochemistry (IHC) available for oropharyngeal squamous cell carcinoma.
• Measurable disease per RECIST 1.1.
• Eastern Coperative Oncology Group Performance Status (ECOG PS) ≤ 1.
• Intention to treat with curative intent primary radiotherapy alone.
• Able to swallow liquids or has an adequately functioning feeding tube, gastrostomy or jejunostomy placed.
• Adequate hematologic, renal, and hepatic function as indicated by:
• Creatinine clearance ≥ 30 mL/min, measured with the Cockroft and Gault formula.
• Absolute neutrophil count ≥ 1 500 cells/μL.
• Platelets ≥ 100 000 cells/μL.
• Hemoglobin ≥ 9.0 g/dL or ≥5.6 mmol/L (blood transfusions during screening are permitted).
• AST and ALT ≤ 3.0 × upper limit of normal (ULN).
• Total bilirubin ≤ 1.5 × ULN (up to 2.0 × ULN is allowed if the direct bilirubin level is normal and the elevation is limited to indirect bilirubin).
• Written informed consent must be signed according to ICH/GCP, and national/local regulations.

Main Exclusion Criteria:

• Unknown primary, primary nasopharynx and paranasal sinus.
• Two primaries.
• Any previous or current treatment for invasive head and neck cancer, including induction chemotherapy, surgery, concomitant chemotherapy and cetuximab.
• Gastrointestinal disorders that could affect drug absorption.
• Another malignancy in the previous 3 years with exception of curatively treated disease with no evidence of recurrence.
• Known allergy to xevinapant or any excipient known to be present in active or placebo formulation.
• Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 red blood cell transfusions or 4 units of packed red blood cells within 4 weeks prior to enrolment
• Non-Decompensated or symptomatic liver cirrhosis (Child-Pugh score: B or C).
• Impaired cardiovascular function or clinically significant cardiovascular diseases
• Any uncontrolled, intercurrent illness or clinical situation that would in the judgment of investigator, limit compliance with study requirements. This includes but is not limited to uncontrolled active infections, defined as any infection requiring IV antibiotics within 7 days prior to enrolment.