CompARE: Escalating Treatment of Intermediate and High-risk Oropharyngeal Cancer (OPC)

Inclusion Criteria:

1. Oropharyngeal squamous cell carcinoma (OPSCC) in base of tongue and tonsil with aMultidisciplinary Team (MDT) recommendation for treatment with definitive concurrentchemoradiotherapy

2. All OPC T4 or N3 (HPV+ and HPV-) OR all HPV -ve (negative) OPC T1-T4, N1-N3 or T3-4,N0 OR HPV +ve (positive) OPC T1-T4 with N2b-N3 nodes AND who are smokers ≥ 10 packyears current or previous smoking history

3. Minimum life expectancy of 3 months

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

5. Adequate renal function, glomerular filtration rate (GFR) >50ml/min calculated usingCockcroft-Gault formula

6. Adequate bone marrow function (absolute neutrophil count (ANC) ≥1.5 x 109/L,haemoglobin ≥9.0g/dL and platelets ≥100 x 109/L)

7. Adequate liver function i.e. plasma bilirubin ≤1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤2.5 x ULN

8. Prothrombin time (PT) ≤1.5 x ULN or International Normalised Ratio (INR) ≤1. 5

9. Magnesium ≥ lower limit of normal

10. No cancers in previous 5 years, except basal cell carcinoma of skin and cervicalintra-epithelial neoplasia (CIN)

11. Aged 18-70

12. Written informed consent given for the trial

13. Surgically resectable disease if being randomised to all four arms

14. Females must either be of non-reproductive potential (i.e. post-menopausal byhistory: ≥55 years old and no menses for ≥1 year without an alternative medicalcause; or history of hysterectomy, or history of bilateral tubal ligation or historyof bilateral oophorectomy) or must have a negative serum pregnancy test upon studyentry

15. Willingness to comply with the protocol for the duration of the study, includingundergoing treatment and scheduled visits and examinations including follow up

Exclusion Criteria:

1. All T1-T2,N0 OPC (HPV +ve or HPV-ve)

2. HPV positive patients who are: T1-T3, N0-N2c non-smokers T1-T3, N0-N2c smokers with ≤10 pack years or T1-T2, N0-N2asmokers with ≥10 pack years

3. Unfit for chemoradiotherapy regimens

4. Creatinine Clearance <50ml/min

5. Treatment with any of the following, prior to randomisation:

6. Any Investigational Medicinal Products (IMP) within 30 days

7. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks

8. Major surgery within 4 weeks

9. History of allergic reactions to any of the IMPs and excipients used in this trial

10. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis,active bleeding diatheses including any subject known to have evidence of acute orchronic hepatitis B, hepatitis C, Human Immunodeficiency Virus (HIV), or psychiatricillness/social situations that would limit compliance with study requirements orcompromise the ability of the subject to give written informed consent

11. Women who are pregnant or breast-feeding. Women of child- bearing potential musthave a negative pregnancy test performed within 7 days prior to randomisation

12. Men or women who are not prepared to practise methods of contraception of provenefficacy during treatment and for 6 months following the end of treatment

13. Any condition that, in the opinion of the Investigator, would interfere withevaluation of study treatment or interpretation of patient safety or study results Additional Exclusion Criteria for Arm 5 only:

14. Any previous treatment with PD-L or PD-L1 inhibitor, including durvalumab

15. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids orsystemic corticosteroids at physiological doses, which are not to exceed 10 mg/dayof prednisone, or an equivalent corticosteroid dose

16. Active or prior documented autoimmune or inflammatory disorders includinginflammatory bowel disease e.g. colitis or Crohn's disease, diverticulitis (with theexception of diverticulosis), celiac disease, systemic lupus erythematosus,Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves'disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptionsto this criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

14. Patients with an active non-infectious pneumonitis

15. History of primary immunodeficiency

16. History of allogeneic organ transplant

17. Known history of previous clinical diagnosis of tuberculosis

18. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. Inactivated viruses, such as those in the influenzavaccine, are permitted