LYSARI – LYmphocyte-Sparing And Radio-Immunotherapy in Head and neck carcinoma - A multicenter, randomised 2*2 factorial design comparing standard to reduced-target volume radiotherapy with or without all-trans retinoic acid (ATRA) in patients with lateralised oropharyngeal, laryngeal and hypopharyngeal squamous cell carcinoma.

Prior treatment

• E10. Patient with infectious diseases: - severe infection within 4 weeks prior to randomisation, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, - active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening), - active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA at screening, - HIV infection, - active tuberculosis.
• E14. Patient with ongoing or expected need for concomitant treatment with vitamin A, tetracyclines, other retinoids, anti-fibrinolytic agent, and strong inducers or inhibitors of CYP3A4.
• E5. Patient with any previous anti-cancer therapy for HNSCC (all prior treatments are forbidden: chemotherapy, radiotherapy, targeted therapy, immunotherapy or any other therapy approved or experimental).
• E6. Patient with malignancies other than HNSCC within 3 years prior to randomisation with the exception of adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localised prostate cancer treated surgically with curative intent.
• E7. Patient with ongoing or anticipation of need for systemic immunosuppressive medication (including, but not limited to, glucocorticoids, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents); with the exceptions of intranasal, inhaled or topical corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
• E9. Patient with concurrent treatment with any other anti-cancer treatment, approved or investigational agent or participation in another clinical trial with therapeutic intent.

Other illness

• E11. Patient with any psychological, cognitive, familial, sociological or geographical condition potentially hampering compliance with the study protocol, completion of patient reported measures and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• E12. Patient with known hypersensitivity to tretinoin, other retinoids, soya, peanut or to any of the excipients of vesanoid listed in section 6.3.
• E13. Patient with known malabsorption syndrome and/or unable to swallow oral medication.
• E2. Patients with T1-N0 (p16-), T1-N1 (p16-), T1-N0 (p16+), T4 (p16- and p16+), bilateral lymph nodes or nodal disease more than 6 cm (p16- and p16+).

Other

• E1. Patient with primary tumor crossing the midline or patients with bilateral primary tumors.
• E15. Pregnant or lactating woman.
• E3. Patients with unknown primary tumor size as per TNM i.e. T0-N1 to T0-N3, p16- or p16+.
• E4. Patients with contralateral FDG-PET/CT nodal uptake.
• E8. Patient with ongoing or anticipation of need for systemic immunostimulatory agents (including, but not limited to, interferons and IL-2).

• I1. Male or female patients aged ≥ 18 years old at time of inform consent signature
• I9 Fertile men must agree to use an effective method of contraception during the study and for up to 1 month after the end of study treatments.
• I11. Patients must be covered by a medical insurance in country where applicable.
• I10. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed and should be able and willing to comply with study visits and procedures as per protocol.
• I2. Patients with primary head and neck tumour up to, but not crossing the midline, previously untreated with histologically-confirmed squamous cell carcinoma of: 1) the oropharynx p16-, larynx or hypopharynx : T1/N2a-N2b, T2/N0-N2b, T3/N0-N2b (UICC 8th Ed.), or 2) the oropharynx p16+ : T1/N1 (multiple nodes), T2-T3/N0-N1 (UICC 8th Ed.)
• I3. Patients with lymph node staging assessed by a FDG-PET/CT with no contralateral nodal uptake
• I4. Patients amenable to treatment with RT or concomitant chemo-radiotherapy.as decided by the treating physician as a function of tumor stage, tumor location, performance of the patients
• I5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• I6. Adequate hematologic and end-organ function, defined by the following laboratory test results obtained within 7 days prior to randomisation : 1) Hematological (without transfusion within 2 weeks) - Neutrophils count > 1,5x10.9 /L - Platelets count > 75x10.9/L - WBC≥ 3.0x10.9/L 2) Hepatic function - o Total Bilirubin < 1.5 × ULN (except for Gilbert's syndrome which will allow bilirubin ≤ 3 ULN), - Alanine aminotransferase (ALT) ≤ 2.5×ULN - Aspartate aminotransferase (AST) ≤ 2.5×ULN - Albumin >3.0g/dL 3) Renal function - Serum creatinine < 1.5xULN
• I7. QTcF ≤450ms for men and 470ms for women, from 3 electrocardiograms on screening ECG, within 7 days prior randomisation
• I8. Women patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test within 7 days prior randomisation, and agrees to use adequate contraception for up to 1 month after the end of study treatments.