Study Comparing RT With Cetuximab + Xevinapant to RT With Cetuximab-placebo in Patients With Head and Neck Cancer

NCT05930938 | Terminated Phase 3 DMC

• 1 other identifier: 2022-502584-38-00
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

Xevinapant is an antagonist of inhibitor of apoptosis proteins (IAPs) that has been shown both chemo-, radiosensitizing, and immunomodulatory activities in nonclinical in vitro and in vivo squamous cell carcinoma of the head and neck (SCCHN) models. In previously untreated patients with non-resected locally advanced SCCHN, the addition of xevinapant recently showed a significant improvement of progression-free survival (PFS), overall survival (OS) and loco-regional control at 3 years after completing treatment. Thus, the purpose of this Phase III study is to demonstrate the superior efficacy to the xevinapant when it is administered in combination with radiotherapy (RT)+cetuximab compared to radiotherapy+cetuximab (SoC) + placebo in previously untreated participants with LA-SCCHN, ineligible for high-dose cisplatin defined as ≥ 200 mg/m² (projective total cumulative dose) throughout the course of the radiotherapy.

Conditions

Squamous Cell Carcinoma of the Head and Neck

Outcome Measures

Primary Outcomes (1)

• Progression free survival

  PFS as assessed by independent review committee (IRC) defined as the time from randomization to the first occurrence of any of the following events: death from any cause, disease progression (PD), primary treatment failure before achieving a complete response (CR) or any radiological or clinical relapse after achieving a CR.

  through study completion, an average of 1 year"

Study Arms (2)

Placebo-RT-cetuximab

PLACEBO COMPARATOR

3 cycles of placebo (matching oral solution from Day 1 to 14, per 3-week cycle) + IMRT (69.96 Gy in 33 fractions, 2.12 Gy/fraction) + cetuximab (loading dose of 400 mg/m² IV on Day -7, followed by weekly dose of 250 mg/m² IV until the end of the RT), followed

Drug: Placebo; Drug: cetuximab; Radiation: IMRT

Xevinapant-RT-cetuximab

EXPERIMENTAL

3 cycles of xevinapant (oral solution 200 mg/day from Day 1 to 14, per 3-week cycle) + IMRT (69.96 Gy in 33 fractions, 2.12 Gy/fraction) + cetuximab (loading dose of 400 mg/m² IV on Day -7, followed by weekly dose of 250 mg/m² IV until the end of the RT), followed by 3 cycles of monotherapy of xevinapant (200 mg/day from Day 1 to 14, per 3-week cycle)

Drug: Xevinapant; Drug: cetuximab; Radiation: IMRT

Interventions

Xevinapant DRUG

Xevinapant is a multi-IAP antagonist that blocks the activity of several IAPs including X-linked IAP (XIAP), cellular inhibitor of apoptosis proteins (cIAP) 1, cIAP2 and ML-IAP

Xevinapant-RT-cetuximab

Placebo DRUG

Xevinapant without active substance

Placebo-RT-cetuximab

cetuximab DRUG

cetuximab

Placebo-RT-cetuximab; Xevinapant-RT-cetuximab

IMRT RADIATION

IMRT (69.96 Gy in 33 fractions, 2.12 Gy/fraction)

Placebo-RT-cetuximab; Xevinapant-RT-cetuximab

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or Female ≥ 18 years (or based on the country legal age limit for adults on day of signing the Informed Consent Form, ICF) and \< 80 years
• ECOG PS 0-1
• Histologically confirmed diagnosis in previously untreated LA-SCCHN participant (Stage III, IVA or IVB according to the American Joint Committee on Cancer-TNM Staging System, 8th Ed.) of at least one of the following sites: oral cavity, hypopharynx and larynx. OPC participants are also eligible but their primary tumor must be:
• HPV-negative (Stage III, IVA or IVB according to the American Joint Committee on Cancer/TNM Staging System, 8th Ed.) or
• HPV-positive and smokers \> 20 PY and must have according to the American Joint Committee on Cancer/TNM Staging System, 8th Ed:
• T3 N1-3
• T4 and any N Note: HPV status is determined by p16 expression using IHC (pathological report should be available).
• Note: Patient with primary tumor of unknown primary site are not eligible.
• Able to swallow liquids or have an adequately functioning feeding tube, gastrostomy or jejunostomy placed.
• Patients must be ineligible to receive high-dose cisplatin defined as ≥ 200 mg/m² (projected total cumulative dose throughout the course of the RT). Ineligibility is defined as at least one of the following criteria:
• eGFR \< 60 mL/min /1.73 m² (using the CKD-EPI creatinine formula)
• History of hearing loss, defined as either:
• i. Existing need of a hearing aid and/or ii. Clinically relevant hearing loss by clinical assessment including tinnitus ≥ Grade 2. Note: In case of doubt, an audiogram should be requested to guide the Investigator
• Peripheral neuropathy ≥ Grade 2
• Cardiac function not compatible with hyperhydration

You may not qualify if:

• 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.
• Metastatic disease (according to AJCC/TNM, 8th ed.).
• Primary tumor of nasopharyngeal, paranasal sinuses, salivary, thyroid or parathyroid gland, skin or unknown primary site.
• Known history of infection with human immunodeficiency virus (HIV). If unknown history of HIV, an HIV screening test is to be performed and participants with positive serology for HIV-1/2 must be excluded.
• Known chronically active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. If unknown status, HBV and HCV tests (see section 6.1.2) are to be performed and participants with positive serology must be excluded:
• HBV screening tests: both HBV Ag and Anti-HepB core IgG.
• HCV screening tests: both HCV-antibody and positive viral load HCV-RNA by PCR. Note: Positive serology is defined as the presence of hepatitis B core antibody \[anti-HBc\] and/or presence of HBsAg and/or the presence of HCV antibody and/or positive for HCV RNA by PCR.
• Other infections (viral \[including COVID-19\] and/or mycotic) requiring systemic treatment.
• Ongoing uncontrolled infection requiring intravenous antibiotic therapy within 7 days prior to randomization.
• Known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal surgery that may limit oral absorption.
• 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.
• 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 randomization.
• Active uncontrolled inflammatory disease (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, severe extensive psoriasis, and other autoimmune diseases) requiring ongoing treatment with anti-TNF medication.
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• Ongoing or history of uncontrolled or symptomatic ischemic myocardiopathy within 6 months prior to randomization.

Sponsors & Collaborators

• Groupe Oncologie Radiotherapie Tete et Cou: lead

Study Sites (1)

Hôpital Nord Franche Compté

Montbéliard, 25200, France

Location

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

Cetuximab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants who meet the study criteria will be randomly assigned in a 1:1 ratio using minimization to Arm A or arm B

Study Record Dates

• First Submitted: June 23, 2023
• First Posted: July 5, 2023
• Study Start: December 12, 2023
• Primary Completion: September 30, 2024
• Study Completion: September 30, 2024
• Last Updated: May 9, 2025

Record last verified: 2025-05

Locations

FR (1)