Company withdrew interest

This is a phase III randomized blind placebo-controlled study, designed to show the superiority of the experimental arm to the control arm.

After surgery and checking eligibility criteria, patients will be randomized between the control and the experimental arms with a 1:1 ratio (randomization will take place at a maximum 4 weeks after surgery):

• Experimental Arm: Durvalumab (one dose) before chemoradiotherapy (CRT) and for 6 months every 4 weeks (Q4W) after CRT
• Control Arm: placebo (one dose) before CRT and for 6 months Q4W after CRT Radiotherapy planning will take place after randomization. The primary endpoint of this trial is disease free survival (DFS), measured from the date of randomization to the date of first occurrence of any loco-regional recurrence, metastatic progression, or death due to any cause.

Inclusion Criteria:

• Patients with squamous cell carcinoma of the oral cavity (excluding lip), larynx, hypopharynx or p16-negative oropharynx (p16 determined locally)
• Surgical treatment no more than 4 weeks prior randomization (which may include revisions, secondary flaps etc., VACs) with completed wound healing no later than 4 weeks after the initial procedure
• At high risk of locoregional recurrence based on extranodal extension (ENE) and/or R1 resection margin < 1 mm, as documented in the pathology report of surgery.
• With postoperative pathology stage III or IV or stage II but with positive margins (based on AJCC 8th edition)
• Availability of FFPE tumor tissue block from the resection specimen
• Availability of operative and pathology report and preoperative diagnostic images for retrospective review
• ECOG Performance status 0-1
• Age ≥ 18 years
• Adequate bone marrow, liver and renal functions within 7 days from randomization
• Audiogram must be within normal range
• Chemoradiation planned to start within maximum of 2 weeks from randomization. Whenever indicated, dental extraction should be carried out at least 10 days before the start of CRT.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients within 72 hours prior to randomization.
• Patients of childbearing / reproductive potential must agree to use highly effective methods of contraception based on the Clinical trials Facilitation Group (CFTG) guidance from randomization up to 90 days after the last dose of Durvalumab/placebo (Appendix I) or 6 months after the last CRT, whichever is longer.
• Female subjects who are breast feeding should discontinue nursing prior to randomization to 90 days after the last dose of Durvalumab.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with CRT or Durvalumab may be included only after consultation with the clinical research physician
• Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

Exclusion Criteria:

• Evidence of distant metastases before and after surgery
• Any evidence of early locoregional recurrence after surgery
• Any prior treatment with chemotherapy, radiotherapy or cetuximab
• Any previous treatment with a PD1 or PD-L1 inhibitor, including Durvalumab, a CTLA-4 inhibitor including tremelimumab or other checkpoint inhibitors or other immunotherapy during the last 12 months
• Any contraindication to cisplatin and radiotherapy
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Body weight \