A Trial Evaluating the Addition of Nivolumab to Cisplatin-RT for Treatment of Cancers of the Head and Neck

This open-label, randomized, controlled, multicenter phase III study will include 680 patients who have been operated for their LA SCCHN and exhibiting extra capsular extension (ECE) and/or positive margins (high risk). Subjects will be randomized (1:1) to receive post-operative concomitant cisplatin-RT with or without nivolumab.

The study is designed with the general objective of demonstrating that treatment with nivolumab in combination with 3 cycles of cisplatin during RT is more efficient and not more toxic than the SOC 3 cycles of cisplatin during RT.

Stratification will be based on the P16 status (immunohistochemistry assay on surgical sample). Two classes: Oropharyngeal Cancer (OPC) p16 positive versus OPC p16 negative or not OPC.

Inclusion criteria

• Age > 18 and < 75 years
• Performance Status (PS) ECOG 0-1 (Appendix 2)
• Written informed consent
• Recording of alcohol consumption and smoking history
• Histologically proven squamous cell carcinoma of the head and neck from one or more of the following primary sites: oral cavity, oropharynx, hypopharynx or larynx
• Squamous cell carcinoma of the head and neck treated by primary surgery
• Histopathological classification: pStage III or IV. However, Oropharyngeal Cancer pStage II p16 positive with pT3N1 or pT4N1 and tobacco consumption ≥20 packs/year are eligible. (American Joint Committee on Cancer 8th edition)
• Subject must have complete macroscopic resection.
• Subject must be free of disease
• Recovery from the surgical procedure allowing for cisplatin-Radiotherapy
• Radiotherapy planned to start within 4 to 9 weeks after surgery. However, a maximum of 1 additional week could be considered in case of delay due to healing or logistical problem
• Patient/tumor carrying a high risk of relapse with:

• Extra-capsular extension (ECE),
• Multiple peri-neural invasion
• Multiple nodal extension without ECE (≥ 4 nodes)
• Positive margins (R1 or close margin ≤ 1 mm) R1 is microscopic residual disease and close margin is R0 with a minimum margin ≤ 1 mm in any direction.
• Adequate tumor specimen from archived or resected tissue available for PD-L1, TILs and immune landscape and other biomarker evaluation
• For oropharyngeal tumor, known p16 status (by IHC)
• Patient's ability to receive cisplatin 100 mg/m2 for 3 cycles:

• Creatinine Cclearance (CrCl) ≥ 60 mL/min (measured or calculated by Cockcroft and Gault method) or estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73m2 (determined by CKDEPI or MDRD method). The highest value should be considered if both are assessed.
• Absolute neutrophil count ≥1 500/mm3, platelets ≥100 000/mm3, haemoglobin ≥ 9 g/dL, aspartate transaminase (AST) and alanine transaminase (ALT) less than 2.5 times the upper limit of the normal range (ULN), total bilirubin ≤ 1.5 mg/dL(except Gilbert Syndrom: < 3.0 mg/dL).
• Peripheral neuropathy ≤ grade 1
• No hearing loss (assessed clinically and confirmed by audiogram if doubtful)
• Cardiac function compatible with hyperhydration
• No administration of prophylactic phenytoin
• Patients aged 71-74 years,must be fit according to geriatric evaluation

Exclusion criteria

• Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers
• Squamous cell carcinoma involving cervical neck nodes with unknown primary site
• Metastatic disease
• Incomplete macroscopic resection (R2), as stated in the surgical report
• Known active viral infection Human Immunodeficiency Virus (HIV), Hepatitis B/C) or known history of positive test for HIV, active autoimmune disease and/or an active immunodeficiency or ongoing immunosuppressive therapy
• Active Central Nervous System disease
• Interstitial lung disease
• Active infection
• Any prior treatment for the current head and neck cancer other than primary surgery. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, induction chemotherapy, prior RT, or use of any investigational agent
• Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol
• Concomitant treatment with any drug on the prohibited medication list such as live vaccines. Live vaccines administered more than 30 days before study entry are permitted
• History of other malignancy within the last 3 years (exception of in situ carcinoma, thyroid papillary carcinoma, skin carcinomas, localized prostate carcinoma Gleason 6 and in situ breast carcinoma)
• Pregnant, 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 5 months after the last dose of nivolumab
• Male patients who are unwilling or unable to use contraception methods for the duration of the study and for at least 6 months after the last dose of cisplatin.
• Severe acute or chronic medical conditions including colitis, pneumonitis, pulmonary fibrosis, laboratory abnormalities or other 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
• Known hypersensitivity to study drugs
• Prior organ transplantation including allogenic stem-cell transplantation
• 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
• Concurrent enrolment in another clinical trial using an investigational anti-cancer treatment within 28 days prior to the first dose of study treatment
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Any psychiatric condition (including active suicidal ideation), or psychological, or familial, or sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Individuals deprived of liberty or placed under the authority of a tutor.