A double-blind randomized, Phase III study of radiotherapy combined with cetuXimab + Xevinapant compared to radiotherapy combined with cetuximab (Standard of care) + placebo in patients with Locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN), unfit for high-dose cisplatin (XXL study)
- Trial ID
- 2022-502584-38-00
- Protocol
- GORTEC-2022-01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III study is to demonstrate an improvement in **progression-free survival** (PFS) as evaluated by an independent review committee (IRC) with the combination of xevinapant, cetuximab, and radiotherapy (RT) compared to placebo, cetuximab, and RT in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who are unfit for high-dose cisplatin. This is clinically relevant as PFS is a critical endpoint in cancer trials, indicating the length of time during and after treatment that a patient lives with the disease without it worsening.
Secondary objectives include:
- To demonstrate improvement in overall survival (OS) with xevinapant-cetuximab-RT compared to placebo-cetuximab-RT.
- To demonstrate improvement in PFS as evaluated by local investigators with xevinapant-cetuximab-RT compared to placebo-cetuximab-RT.
- To evaluate the treatment compliance of xevinapant-cetuximab-RT compared to placebo-cetuximab-RT.
- To evaluate the safety and tolerability of xevinapant-cetuximab-RT compared to placebo-cetuximab-RT.
Participants
The clinical trial involves participants diagnosed with **locally advanced squamous cell carcinoma of the head and neck**. The study population includes both male and female subjects aged between 18 and 79 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have a histologically confirmed diagnosis of previously untreated locally advanced squamous cell carcinoma of the head and neck, specifically at sites such as the oral cavity, hypopharynx, and larynx. The trial excludes individuals eligible for high-dose cisplatin treatment. Participants must have adequate hematologic, renal, and hepatic function. The sponsor has not provided the total number of participants involved in the trial. Lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants are capable of giving informed consent and agree to use appropriate contraception if applicable.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled Phase III study to evaluate the efficacy of combining **radiotherapy** with **cetuximab** and **xevinapant** compared to radiotherapy with cetuximab and a placebo in patients with **locally advanced squamous cell carcinoma of the head and neck**. The primary objective is to demonstrate an improvement in progression-free survival (PFS) as assessed by an independent review committee. The trial is expected to run from September 2023 to September 2030, with the estimated duration of participant involvement being up to 18 months, depending on the treatment arm.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific medical conditions. Following randomization, participants will receive either the investigational treatment or the standard of care with placebo. Regular follow-up visits will be scheduled to monitor treatment compliance, assess adverse events, and evaluate disease progression. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.
The trial includes specific conditions for early termination, such as the occurrence of severe adverse events or significant protocol deviations. Participants will be closely monitored throughout the study to ensure safety and adherence to the protocol. The trial's primary endpoint is PFS, while secondary endpoints include overall survival, compliance with treatment regimens, and the occurrence of adverse events. The study aims to provide valuable insights into the potential benefits of xevinapant in combination with cetuximab and radiotherapy for this patient population.
Treatment
The clinical trial involves the administration of **xevinapant**, an experimental medication formulated as an **oral solution**. Xevinapant is a chemical antagonist of inhibitor of apoptosis proteins, provided by Merck Healthcare KGaA. The maximum daily dose of xevinapant is 200 mg, with a total maximum dose of 16,800 mg over a treatment period of up to 18 weeks. The medication can be administered orally, via a nasogastric tube, or through a percutaneous endoscopic gastrostomy tube. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to xevinapant, the study includes the administration of **Erbitux** (cetuximab), a standard-of-care therapy. Erbitux is provided as a **solution for infusion** and is manufactured by Merck Europe B.V. The active substance, cetuximab, is a protein-based therapeutic agent. The maximum daily dose is 400 mg/m², with a total maximum dose of 2,650 mg/m² over a treatment period of up to 10 weeks. Erbitux is administered via intravenous infusion, and dosing will be conducted in accordance with established protocols for cetuximab administration.
The trial also incorporates a **placebo** control, referred to as the xevinapant placebo. This placebo is used to maintain the double-blind nature of the study, ensuring unbiased assessment of the experimental treatment's efficacy. The placebo is designed to mimic the administration route and appearance of the xevinapant oral solution, although it contains no active pharmaceutical ingredients. Compliance with placebo administration will be monitored similarly to the active treatments.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, as evaluated by an independent review committee (IRC). PFS is defined as the time from randomization to the first occurrence of any of the following events: death from any cause, disease progression, primary treatment failure before achieving a complete response, or any radiological or clinical relapse after achieving a complete response. Secondary endpoints include Overall Survival (OS), which is defined as the time from the date of randomization to the date of death, with patients last known to be alive censored at the date of last contact. Additionally, progression-free survival will also be assessed by investigator evaluation.
Compliance with treatment protocols will be monitored and reported, including details on radiotherapy (tumor dose, number of fractions, duration, and major deviations), xevinapant/placebo, and cetuximab (number of cycles, dose, duration, dose intensity, and relative dose intensity). Treatment interruptions, reductions, discontinuations, and their reasons will also be documented. The occurrence of adverse events (AEs) and treatment-related AEs will be recorded as part of the efficacy assessment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 [AJCC]/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 [AJCC]/TNM Staging System, 8th Ed.) or • HPV-positive and smokers > 20 PY and must have according to the American Joint Committee on Cancer [AJCC]/TNM Staging System, 8th Ed: o T3 N1-3 o T4 and any N
- 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 • If > 70 years, unfit according to G8 questionnaire (Score ≤ 14)
- Adequate hematologic, renal and hepatic function as indicated by (using CTCAE v5.0): • Absolute neutrophil count ≥ 1500 /mm3 • Platelets ≥ 100 000 /mm3 • Hemoglobin ≥ 9.0 g/dL (blood transfusions during Screening are not permitted) • White blood cells ≥ 3 000/mm3 • AST and ALT ≤ 3 × ULN • eGFR ≥ 30 mL/min /1.73 m² (using the CKD-EPI creatinine formula) • 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)
- The Investigator confirms that the participant agrees to use appropriate contraception and barriers methods, if applicable
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the inform consent form and this protocol
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.
- 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 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
- Hypertension uncontrolled by medication (i.e. systolic blood pressure > 150 mmHg and diastolic blood pressure > 90 mmHg).
- Symptomatic pulmonary disease requiring continuous or intermittent oxygen supply.
- History of another malignancy within the last 3 years prior to randomization, with the exception of completely resected non-melanoma cell skin cancer outside the head and neck area or completely resected stage I breast cancer, or completely resected in-situ non-muscular invasive bladder, cervix and/or uterine carcinomas.
- Non compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 15 Sept 2023 | 377 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
xevinapant | Test | ORAL SOLUTION | ORAL, NASOGASTRIC TUBE OR PERCUTANEOUS ENDOSCOPIC GASTROSTOMY TUBE USE | 200 | 18 | PRD10233281 |
Erbitux 5 mg/mL solution for infusion | Other | SOLUTION FOR INFUSION | IV INFUSION | 400 | 10 | PRD327539 |
xevinapant placebo | Placebo | N/A | — | — | — | N/A |