| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Squamous cell carcinoma, previously untreated
Stage III, stage IVa (i.e. operable, but not operated) or IVb (non resectable)
Oral cavity, oropharynx, hypopharynx or larynx
|
Carcinome épidermoïde jamais traité
Stade III, stade IVa (i.e. opérable, mais non opéré) ou IVb (non résécable)
Cavité orale, oropharynx, hypopharynx ou larynx
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally advanced squamous cell carcinoma of the head and neck |
| Carcinome épidermoïde localement avancé de la tête et du cou |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate that treatment with avelumab in combination with cetuximab-RT is superior to SOC Cisplatin-RT and/or to SOC cetuximab-RT alone in terms of PFS in front-line patients with locally advanced SCCHN. Each cohort will be analyzed separately. |
| Démontrer que le traitement par avelumab en combinaison avec le cetuximab et la radiothérapie (RT) est supérieur aux traitements standards cisplatine-RT et/ou cetuximab-RT seuls, en termes de survie sans progression chez les patients ayant un carcinome épidermoïde localement avancé de la tête et du cou. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the overall safety and tolerability profile of avelumab in combination with cetuximab-RT as compared to SOC cisplatin-RT or cetuximab-RT alone.
To evaluate the effect of avelumab in combination with cetuximab-RT compared to SOC CT-RT or cetuximab-RT alone on health-related quality of life.
To evaluate candidate immune-related predictive biomarkers of sensitivity or insensitivity to treatment with avelumab in pre-treatment tumor samples and in blood (levels of cells, DNA, RNA, or proteins that may be related to antitumor immune response and/or disease progression) and to explore potential correlations between treatment outcome and the immune landscape / TCR sequencing / antitumor cellular responses
|
Comparer la survie globale (SG), le contrôle locorégional, les métastases à distance entre les bras.
Evaluer la tolérance globale et les profils de toxicité de l’avelumab en combinaison avec le cetuximab-RT comparés aux traitements standards.
Evaluer l’effet de l’avelumab en combinaison avec le cetuximab-RT comparé aux traitements standards sur la qualité de vie.
Evaluer des biomarqueurs prédictifs de sensibilité ou insensibilité à l’avelumab liés à l’immunité (sur des échantillons tumoraux avant traitement, sang) et explorer les corrélations potentielles entre résultats des traitements et l’environnement immunitaire/ séquençage TCR/ réponses cellulaires antitumorales
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age > 18 years and ≤ 80 years.
2. Performance Status ECOG 0-1
3. Histologically confirmed squamous cell carcinoma, previously untreated
4. Stage III, stage IVa (i.e. operable, but not operated) or IVb (non resectable)
5. Oral cavity, oropharynx, hypopharynx or larynx
6. Availability of pre-treatment tumour tissue sample (for PD -L1 expression, TILs and immune lanscape)
7. Documentation of p16 disease (HPV status for oropharyngeal tumor)
8. Recording of alcohol consumption and smoking history
9. Determination of the patient’s ability to receive cisplatin 100 mg/m2 for 3 cycles (fit / unfit)*
10. Written informed consent
* Criteria for determining if a patient is fit for receiving high dose cisplatin :
- Calculated creatinine clearance ≥ 50 mL/min as determined by the CKD-EPI method
- Absolute neutrophil count ≥1 500/μL, platelets ≥100 000/μL, haemoglobin ≥ 10 g/dL, aspartate (AST) and alanine transaminase (ALT) less than 2 times the upper limit of the normal range (ULN), total bilirubin ≤ 1.5 mg/dL, serum albumin > 35 g/L.
- Peripheral neuropathy < grade 2
- No sensorineural hearing loss ≥ grade 2 (confirmed by audiogram)
- Cardiac function compatible with hyperhydration with no significant heart disease
|
1. Age > 18 ans et ≤ 80 ans.
2. Performance Status ECOG 0-1
3. Carcinome épidermoïde jamais traité
4. Stade III, stade IVa (i.e. opérable, mais non opéré) ou IVb (non résécable)
5. Cavité orale, oropharynx, hypopharynx ou larynx
6. Disponibilité d’échantillon de tissu tumoral avant le début de traitement (pour recherche des expressions p16 & PD -L1, TILs et environnement immun)
7. Enregistrement de l’intoxication alcoolique et tabagique
8. Détermination de la capacité du patient à recevoir 3 cycles de cisplatine à 100 mg/m2 (éligible / non éligible)*
9. Consentement éclairé écrit
* Critères de détermination de la capacité du patient à recevoir de fortes doses de cisplatine :
- Clairance à la créatinine calculée ≥ 50 mL/min (méthode modifiée de Cockcroft and Gault ou par méthode EDTA),
- Polynucléaires Neutrophiles ≥1 500/μL, plaquettes ≥100 000/μL, hémoglobine ≥ 10 g/dL, SGOT (ASAT) SGPT (ALAT) < 2 limite supérieure de la normale (LSN), bilirubine totale ≤ 1.5 mg/dL, albumine sérique > 35 g/L.
- Neuropathie périphérique < grade 2
- Absence de perte d’audition neurosensorielle ≥ grade 2 (confirmée par audiogramme)
- Fonction cardiaque compatible avec une hyperhydration et absence de maladie cardiaque significative
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|
| E.4 | Principal exclusion criteria |
1. Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers
2. Squamous cell carcinoma involving cervical neck nodes with unknown primary site
3. Metastatic disease (stage IVc)
4. Active viral infection (HIV, Hepatitis B/C)
5. Active autoimmune disease
6. Active immunodeficiency or ongoing immunosuppressive therapy
7. Active CNS disease
8. Interstitial lung disease
9. Active infection
10. Any prior or current treatment for invasive head and neck cancer. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, induction chemotherapy, prior surgical resection or RT, or use of any investigational agent
11. Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol
12. Concomitant treatment with any drug on the prohibited medication list such as live vaccines (for details, see the protocol)
13. History of other malignancy within the last 3 years (exception of in situ carcinoma, skin carcinomas,thyroid papillary carcinoma, localized prostate carcinoma Gleason 6 and in situ breast carcinoma)
14. If Pregnant patients, breastfeeding patients, and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in the protocol for the duration of the study and for at least 6 months after the last dose of cisplatin and 60 days after the last dose of avelumab
15. Significant disease which, in the judgment of the investigator, as a result of the medical interview, physical examinations, or screening investigations would make the patient inappropriate for entry into the trial
16. Known hypersensitivity reaction to study drugs
17. Any social, personal, medical and/or psychologic factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent
18. Prior organ transplantation including allogenic stem-cell transplantation
19. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
20. Persisting toxicity related to prior therapy or pre-existing conditions (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable
21. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
22. Concurrent enrolment in another clinical trial using an investigational anti-cancer treatment within 28 days prior to the first dose of study treatment |
1. Tumeur du nasopharynx, des sinus, de la cavité nasale ou cancer de la thyroïde
2. Atteinte ganglionnaire cervicale sans primitif connu
3. Maladie métastatique (stade IVc)
4. Infection virale (VIH, Hépatites B/C)
5. Maladie autoimmune
6. Immunodéficience ou thérapie immunosuppressive
7. Maladie active du SNC
8. Maladie interstitielle pulmonaire
9. Infection active
10. Traitement antérieur ou actuel pour cancer de la tête et du cou. Ceci inclut les traitements suivants : inhibiteurs de la tyrosine kinase, tout anticorps monoclonal, la chimiothérapie d’induction, radiothérapie ou chirurgie antérieure, utilisation d’un traitement en cours d’investigation… (liste non exhaustive)
11. Traitement concomitant avec tout autre traitement anticancéreux systémique non spécifié dans le protocole
12. Traitement concomitant avec un traitement interdit mentionné dans le protocole tel que les vaccins vivants
13. Antécédent d’autre cancer dans les 3 dernières années (à l’exception des carcinomes in situ, carcinomes cutanés basocellulaires,carcinomes papillaires de la thyroïde, cancer de la prostate localisé Gleason 6 et les cancers du sein in situ)
14. Femme enceinte, allaitante, et patiente en âge de procréer refusant ou ne pouvant utiliser 2 méthodes de contraception efficaces comme définies dans le protocole pendant toute la durée de l’étude et au moins 6 mois après la dernière dose de cisplatine et 60 jours après la dernière dose d’avelumab.
15. Toute maladie significative qui pourrait, selon l’investigateur à la vue des résultats de l’interrogatoire médical, de l’examen physique et des examens du bilan d’inclusion, contre indiquer l’inclusion du patient dans l’étude
16. Réaction connue d’hypersensibilité à l’un des traitements de l’étude
17. Présence de facteurs d’ordre social, médical et/ou psychologique susceptibles de compromettre l’adhésion du patient au protocole et/ou au suivi et/ou à la signature du consentement
18. Antécédent de transplantation d’organe, y compris greffe de cellules souches allogéniques.
19. Maladie cardiovasculaire cliniquement significative (i.e., active): accident vasculaire cérébral (< 6 mois de l’inclusion), infarctus du myocarde (< 6 mois de l’inclusion), angor instable, insuffisance cardiaque congestive (≥ Classe II de la classification NYHA New York Heart Association), ou arythmie cardiaque grave nécessitant un traitement médicamenteux
20. Toxicité persistante liée à un traitement antérieur ou à des affections préexistantes (NCI CTCAE v. 4.03 Grade> 1); Cependant, une alopécie, une neuropathie sensorielle de grade ≤ 2 ou tout toxicité de grade ≤ 2 ne constituant pas un risque pour la sécurité du patient selon l’investigateur, sont acceptables.
21. Autres affections sévères aiguës ou chroniques y compris la colite, la maladie inflammatoire de l'intestin, la pneumonie, la fibrose pulmonaire ou les affections psychiatriques (y compris une tentative ou un comportement suicidaire au cours de la dernière année); les anomalies biologiques qui pourraient s’aggraver du fait de la participation à l'étude ou à l’administration du traitement à l’étude ou qui pourraient interférer avec l'interprétation des résultats de l'étude et, selon le jugement de l'investigateur, rendrait le patient inapproprié pour l'entrée dans cette étude.
22.Inclusion dans une autre étude clinique utilisant un traitement anti-cancéreux expérimental dans les 28 jours avant la première dose du traitement à l’étude |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Between randomization and the first event among progression (per modified Response Evaluation Criteria in Solid Tumors version (v)1.1 and death, whatever the cause of death |
|
| E.5.2 | Secondary end point(s) |
Overall survival
Cumulative incidence of locoregional failure, cumulative incidence of distant metastatic failure by Investigator assessment and cumulative incidence of death without previous progression
Safety: Acute adverse events and laboratory abnormalities as graded by National Cancer Institute Common Terminology Criteria for Adverse Events , v4.03. Incidence of delayed toxicity
Patient-Reported Outcomes: Health related quality of life assessed by EORTC QLQ-C30 and H&N35 questionnaires
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival
Cumulative incidence of locoregional failure, cumulative incidence of distant metastatic failure by Investigator assessment and cumulative incidence of death without previous progression
Safety: Acute adverse events and laboratory abnormalities as graded by National Cancer Institute Common Terminology Criteria for Adverse Events , v4.03. Incidence of delayed toxicity
Patient-Reported Outcomes: Health related quality of life assessed by EORTC QLQ-C30 and H&N35 questionnaires
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Cetuximab cisplatin radiotherapy |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 32 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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