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Squamous Cell Carcinoma of the Head and NeckPhase 3XXL_2022-01NCT05930938

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

A Phase 3 study testing Xevinapant, cetuximab and IMRT in people with Squamous Cell Carcinoma of the Head and Neck, run by Groupe Oncologie Radiotherapie Tete et Cou at 1 site in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 79 years
What is being tested?
Xevinapant, cetuximab and IMRT
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
19 participants
Where
1 siteFrance
Study dates
12 Dec 2023to 30 Sep 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 79 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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:
  • 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. The contraception, barrier, and pregnancy testing requirements are below:
  • -A female participant: i. Is not a WOCBP, no need serum pregnancy test or contraceptive method ii. If WOCBP, she must agree to use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, as described in section 3.3 from Inform Consent Form (ICF) to at least 6 months after the last dose of cetuximab or 3 months after the last dose of xevinapant/placebo, whichever is the latest. WOCBP must not agree to donate eggs (ova, oocytes) for reproduction during this period. Female participants using hormonal contraception must also use a barrier contraception method (preferably male condom) due to potential risk of CYP3A4 induction by xevinapant which may reduce hormonal contraception efficacy.
  • Note: The investigator evaluates the effectiveness of the contraceptive method in relationship to the date of randomization. The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
  • -A male participant must agree to the following from ICF signature to at least 6 months after the last dose of cetuximab or 3 months after the last dose of xevinapant/placebo, whichever is the latest: i. To refrain from donating fresh unwashed semen. If not done previously, cryopreservation of sperm prior to receiving study treatments is advised to male patients with a desire to have children.
  • Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use condom and spermicide. Because male condom and spermicide is not a highly effective contraception method, it is required that female partners of a male study participant use a highly effective contraceptive method (with a failure rate of < 1% per year, as described in section 3.3).
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the inform consent form and this protocol.

Who cannot join

  • 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.
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  • 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.
  • Known left ventricular ejection fraction < 50%, left ventricular hypertrophy, ventricular arrhythmias, bradycardia (heart rate < 50 bpm).
  • History of myocardial infarction, or severe/unstable angina, within 6 months prior to randomization.
  • New York Heart Association Class > 2 congestive heart failure.
  • Congenital long QT syndrome.
  • Family history of long QT syndrome.
  • Symptomatic pulmonary embolism within 6 months prior to randomization.
  • Ongoing or known history of transient ischemic attacks or stroke within 6 months prior to randomization.
  • QTc using Fridericia's formula (QTcF) interval > 450 ms for males and > 470 ms for females.
  • 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).
  • Current alcohol and/or drug abuse that puts at risk the compliance to the study procedures in the opinion of the Investigator.
  • Prior definitive or adjuvant RT and/or radical surgery to the head and neck region which may jeopardize the primary tumor irradiation plan in the opinion of the Investigator, or any other prior systemic treatment for SCCHN, including investigational agents.
  • Use within 14 days prior to randomization or requirement for ongoing treatment with any drug(s) on the prohibited medication list (see section 4.5.2 of the protocol).
  • Treatment with an investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment.
  • Any concomitant medication known to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication within 7 days prior to start of treatment.
  • Concurrent use of anticancer therapy.
  • Previous treatment with or hypersensitivity to cetuximab or other eGFR targeting agents or to monoclonal antibodies.
  • Major surgical intervention within 4 weeks prior to the first dose of study intervention. Biopsy(s) to establish the diagnosis for SCCHN is permitted.
  • Prior organ transplantation, including allogeneic stem cell transplantation.
  • Participation in any clinical interventional study within 28 days prior to screening or during participation in this study.
  • Known allergy to xevinapant, cetuximab, monoclonal antibodies, or any excipient known to be present in xevinapant formulation.
  • Pregnant or nursing (lactating) women.
  • Patient under guardianship, curatorship or deprived of liberty

Trial locations and contacts

1 site in 1 country.

France1 site

  • Hôpital Nord Franche Compté

    Montbéliard, 25200

Other trials in France

About this study

Official title: 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 LA SCCHN, Unfit for High-dose Cisplatin

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.

Read the detailed description

CT-RT and especially cisplatin-RT is a well-established and the most commonly used SoC for patients with LA SCCHN15. However, a large proportion of patients with LA SCCHN are not suitable for high dose platin based CT-RT for several reasons (age, medical/general conditions and or comorbidities…).

Based on recent GORTEC study, the proportion of patients unfit for receiving high-dose of cisplatin was 43% among 707 patients randomized19. In the corresponding cohort of the REACH study, the characteristics of the population (same population to be included in the XXL study) were fragile patients, unfit for high-dose cisplatin, with heavy alcohol and tobacco consumption, numerous comorbidities and a median age 67 years. In this population, there was a trend in the triplet combination of cetuximab-avelumab-RT towards improving PFS, but the triplet was also associated with increased death without previous cancer progression in the first 6 months after RT. In the control arm, the doublet of cetuximab-RT regimen was better tolerated with no excess of death. Same good tolerance was also observed with doublet treatments in both arms of the PembroRad trial (NCT02707588).

The addition of xevinapant to cetuximab is combining two complementary radiosensitizing effects that could ultimately improve the tumor control when compared to cetuximab alone. However, it is

Being tested
Xevinapant, Placebo, cetuximab, IMRT
Medical subject headings
Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • XevinapantDrug

    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

  • PlaceboDrug

    Xevinapant without active substance

  • cetuximabDrug

    cetuximab

  • IMRTRadiation

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

Study groups in NCT05930938
Study groupRoleWhat they receive
Placebo-RT-cetuximabPlacebo comparator3 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
Receives: Drug: Placebo; Drug: cetuximab; Radiation: IMRT
Xevinapant-RT-cetuximabExperimental3 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)
Receives: Drug: Xevinapant; Drug: cetuximab; Radiation: IMRT

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: through study completion, an average of 1 year"

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jul 2023
  2. Study start12 Dec 2023
  3. Primary completion30 Sep 2024
  4. Study completion30 Sep 2024

Why it stopped: toxicity

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Participants who meet the study criteria will be randomly assigned in a 1:1 ratio using minimization to Arm A or arm B
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05930938
Sponsor's protocol ID
2022-502584-38-00
Acronym
XXL_2022-01
Status last verified
May 2025
First submitted
23 Jun 2023
Last updated
9 May 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Xevinapant, cetuximab and IMRT in people with Squamous Cell Carcinoma of the Head and Neck, run by Groupe Oncologie Radiotherapie Tete et Cou at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 40 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: toxicity). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression free survival (time frame: through study completion, an average of 1 year"). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05930938.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2025.

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