A phase Ib/II study to assess the safety and activity of DURvalumab (MEDI4736) in combination with S-488210/S-488211 vAccine in Non-muscle invasive bladder CancEr

1. Histologically proven high-risk non-muscle invasive bladder cancer (high-risk tumours include any of the following features: T1 lesions, high-grade disease, tumours larger than 3 cm, multiple or recurrent lesions, and CIS). 2. Adequate archival tissue sample available for histological assessment. 3. Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma. 4. BCG unresponsive disease (persistent high-risk NMIBC or recurrence of high-risk NMIBC after disease-free period at 6 months despite receiving adequate course of BCG). 5. Refused or deemed clinically inappropriate for radical cystectomy. 6. > = 18 years of age. 7. Body weight > 30 kg. 8.WHO performance status 0-1. 9. Must have undergone each of the following procedures within 8 weeks of registration: • Complete excision of all papillary disease (T1/TaHG) and demonstration of no muscle invasive disease in the resected specimen (muscle must be present in the tumour tissue sample); • Bladder ‘Mapping biopsies’ taken; • CT of the chest; • CT urogram or MRI of the abdomen and pelvis (if CT is not possible). 10. Adequate haematological status: • Haemoglobin > = 9.0 g/dL; • Absolute neutrophil count > = 1.5 x 10^9/L; • Platelet count > = 100 x 10^9/L; • INR and APTT < = 1.5 x ULN. NB: This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. 11. Adequate liver function: • Total bilirubin < = 1.5 X ULN (< 3.0 x ULN for patients with Gilbert’s syndrome); • AST or ALT < = 2.5 x ULN. 12. Adequate renal function (measured creatinine clearance or calculated creatinine clearance using Cockcroft-Gault formula of > = 40 mL/min, or by 24-hour urine collection for determination of creatinine clearance). 13. Life expectancy of > = 6 months. 14. Willing and able to give informed consent (which includes compliance with the requirements and restrictions listed in the patient information sheet and in the protocol). 15. Patients of child-bearing potential and male patients with female partners of child-bearing potential must agree to use highly effective contraception methods from date of consent, which must be continued for up to 90 days after last treatment administration. 16. Female patients must not be pregnant. There should be sufficient evidence of post-menopausal status or a negative serum pregnancy test for pre-menopausal female patients. 17. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and any other study procedures.

1. Any history of autoimmune or inflammatory disease including: inflammatory bowel disease, diverticulitis, SLE, sarcoidosis syndrome, wegener syndrome. Exceptions: thyroid disease on stable treatment, any chronic skin condition that does not require systemic corticosteroid therapy. Patients with a history of an autoimmune condition but without active disease in the last 5 years may be included after consultation with the CI/TMG. 2. Prior allogeneic stem cell or solid organ transplantation. 3. Prior treatment with anti- PD-1, PD-L1 or CTLA-4 monoclonal antibody or other novel immune-oncology agent(s). 4. Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer. 5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest CT scan. 6. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. 7. QTcF value of > 470 ms. If prolonged, should be confirmed by 2 further ECGs each at least 5 minutes apart. 8. Patients with risk factors for bowel perforation: history of acute diverticulitis or intra-abdominal abcess in the last 3 years, history of mechanical GI obstruction or abdominal carcinomatosis. 9. Any unresolved toxicity Grade > = 2 from previous anti-cancer therapy with the exception of alopecia, vitiligo and laboratory values defined in the inclusion criteria. Patients with any irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the CI/TMG. 10. Receipt of last dose of anti-cancer therapy within 30 days prior to first dose of trial treatment. 11. Treatment with any experimental drug within 30 days or 5 half-lives (whichever is longer) of the first dose of trial treatment. 12. Concurrent enrolment in another clinical study, unless it is an observational/ non-interventional clinical study or during the follow-up period of an interventional study. 13. Any evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial. 14. Received therapeutic oral antibiotics that cannot be discontinued at least 14 days prior to starting treatment or received IV antibiotics within 14 days prior to registration. 15. Any psychiatric or other disorder that impacts the ability to give informed consent or comply with trial treatment and activities. 16. History of leptomeningeal carcinomatosis. 17. Active infection of TB (clinically evaluated in accordance with local guidelines). 18. Patients must not have had systemic corticosteroid therapy (> 10 mg daily prednisone equivalent) within 14 days prior to registration or concomitant use of other immunosuppressive medications. 19. Administration of a live, attenuated vaccine within 4 weeks prior to planned start of treatment or anticipation that such a live, attenuated vaccine will be required during the study. 20. Evidence of significant uncontrolled concomitant disease that could substantially increase the risk of incurring AEs, affect compliance with the protocol or interpretation of results, including significant liver disease, uncontrolled hypertension, serious chronic GI conditions associated with diarrhoea and uncontrolled major seizure disorder. 21. Major surgical procedure within 28 days prior to first dose of treatment. 22. Significant cardiovascular disease (as outlined in the protocol). 23. Uncontrolled Type 1 diabetes (eligible if controlled on a stable insulin regimen). 24. Uncontrolled adrenal insufficiency. 25. Active hepatitis infection or hepatitis C (HCV). Patients with past hepatitis B virus infection or resolved infection are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 26. Known active primary immune deficiency, including uncontrolled HIV (detectable viral load) or AIDS-related illness. 27. Women who are pregnant or breast feeding. 28. Known allergy or hypersensitivity to any of the IMPs or their excipients. 29. Prior randomisation to, or treatment in a previous durvalumab clinical study. 30. Must not donate blood while participating in this study and for at least 90 days following the last dose of trial treatment.