DURvalumab in Combination With S-488210/S-488211 vAccine in Non-muscle Invasive Bladder CancEr

Inclusion Criteria:

1. Histologically proven high risk non-muscle invasive bladder cancer (NMIBC)

2. Adequate archival tissue sample available for histological assessment (date sampletaken must be within 6 months of planned start of treatment)

3. Predominant histologic component (> 50%) must be urothelial (transitional cell)carcinoma

4. Bacillus Calmette-Guerin (BCG) unresponsive disease or are intolerant of BCG therapy

5. Refused or deemed clinically inappropriate for radical cystectomy

6. ≥18 years of age

7. Body weight >30 kg

8. World Health Organisation (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 nomuscle invasive disease in the resected specimens (muscle must be present inthe tumour 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 (≥150,000 per mm3)

• Platelet count ≥100 x 10^9/L (≥100,000 per mm3)

• International Normalised Ratio (INR) ≤1.5 and Activated Partial ThromoplastinTime (APTT) ≤1.5 x Upper Limit Normal (ULN). NB: This applies only to patientswho are not receiving therapeutic anticoagulation; patients receivingtherapeutic 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)

• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤2.5 x ULN

12. Adequate renal function: Measured creatinine clearance ≥40 mL/min or calculatedcreatinine clearance ≥40 mL/min using Cockcroft-Gault formula or by 24-hour urinecollection for determination of creatinine clearance

13. Life expectancy of ≥6 months

14. Willing and able to give informed consent (which includes compliance with therequirements and restrictions listed in the patient information sheet (PIS) and inthis protocol). NB: Consent must be obtained from the patient/legal representativeprior to performing any protocol-related procedures, including screeningevaluations.

15. Patients of child-bearing potential and male patients with female partners ofchild-bearing potential must agree to use highly effective contraception methodsfrom date of consent, which must be continued for up to 90 days after last treatmentadministration.

16. Female patients must not be pregnant. There should be sufficient evidence ofpost-menopausal status or a negative serum pregnancy test for pre-menopausal femalepatients.

17. Willingness and ability to comply with scheduled visits, treatment plan, laboratorytests and any other study procedures.

Exclusion Criteria:

1. Any history of autoimmune or inflammatory disease including (any patients with ahistory of an autoimmune condition but without active disease in the last 5 yearsmay be included only after consultation with the CI/TMG):

• Inflammatory bowel disease (e.g. colitis or Crohn's disease)

• Diverticulitis (with the exception of diverticulosis)

• Systemic lupus erythematous (SLE)

• Sarcoidosis syndrome

• Wegener syndrome (granulomatosis with polyangitis, Grave's disease, rheumatoidarthritis, hypophysitis, uveitis, etc.)

2. Patients with prior allogeneic stem cell or solid organ transplantation

3. Patients who have had prior treatment with anti- PD-1, PD-L1 or CTLA-4 monoclonalantibody or other novel immune-oncology agent(s)

4. Active invasive malignancy in the previous 2 years excluding non-melanoma skincancer

5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenicorganizing pneumonia) or evidence of active pneumonitis on screening chest CT scan (history of radiation pneumonitis in the radiation field is permitted)

6. Patients with interstitial lung disease that is symptomatic or may interfere withthe detection or management of suspected drug-related pulmonary toxicity

7. QTcF value of >470 ms. If prolonged, this should be confirmed by 2 further ECGs eachseparated by at least 5 minutes.

8. Patients with the following 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 CTCAE Grade ≥2 from previous anti-cancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria. Patients with any irreversible toxicity not reasonably expected to beexacerbated by treatment with durvalumab may be included only after consultationwith the CI/TMG

10. Receipt of last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrinetherapy, targeted therapy, biologic therapy, embolisation, monoclonal antibodies)within 30 days prior to first dose of trial treatment. NB: If sufficient washouttime has not occurred due to the schedule or pharmacokinetic (PK) properties of anagent, a longer washout period will be required, as agreed by the Trial ManagementGroup (TMG) and/or Chief Investigator (CI).

11. Treatment with any experimental drug within 30 days or 5 half-lives (whichever islonger) 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 aninterventional study

13. Any evidence of severe or uncontrolled systemic diseases or laboratory finding thatin the view of the investigator makes it undesirable for the patient to participatein the trial

14. Received therapeutic oral antibiotics that cannot be discontinued at least 14 daysprior to starting treatment or received intravenous (IV) antibiotics within 14 daysprior to registration. NB: Patients receiving prophylactic antibiotics (e.g. forprevention of a urinary tract infection or COPD) are eligible

15. Any psychiatric or other disorder (e.g. brain metastases) that impacts the patientsability to give informed consent or comply with trial treatment and activities

16. History of leptomeningeal carcinomatosis

17. Active infection of tuberculosis (TB) (clinically evaluated in accordance with localguidelines, e.g. clinical history, examination and radiographic findings with orwithout TB testing as clinically indicated)

18. Patients must not have had systemic corticosteroid therapy (>10 mg dailyprednisolone equivalent) within 14 days prior to registration or concomitant use ofother immunosuppressive medications. NB: The use of inhaled corticosteroids,physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency)and mineralocorticoids (e.g. fludrocortisone) are allowed

19. Administration of a live, attenuated vaccine within 4 weeks prior to planned startof treatment or anticipation that such a live, attenuated vaccine will be requiredduring the study

20. Evidence of significant uncontrolled concomitant disease that could substantiallyincrease the risk of incurring adverse events (AEs), affect compliance with theprotocol or interpretation of results, including significant liver disease (such ascirrhosis), uncontrolled hypertension, serious chronic gastrointestinal conditionsassociated with diarrhoea and uncontrolled major seizure disorder

21. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of trial treatment. This does not include rigid cystoscopy andbiopsies

22. Significant cardiovascular disease, such as:

• New York Heart Association cardiac disease (Class II or greater)

• Myocardial infarction within 3 months prior to registration

• Unstable arrhythmias

• Unstable angina

23. Patients with uncontrolled Type 1 diabetes mellitus. Patients controlled on a stableinsulin regimen are eligible

24. Patients with uncontrolled adrenal insufficiency

25. Patients with active hepatitis infection (defined as having a positive hepatitis Bsurface antigen [HBsAg] test at screening) or hepatitis C. Patients with pasthepatitis B virus (HBV) infection or resolved HBV infection (defined as having anegative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc]antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibodyare eligible only if polymerase chain reaction (PCR) is negative for HCV RNA

26. Known active primary immune deficiency, including but not limited to, uncontrolledhuman immunodeficiency virus (HIV) (detectable viral load) or acquiredimmunodeficiency syndrome (AIDS)-related illness

27. Women who are pregnant or breast feeding. Female or male patient of reproductivepotential who is not willing to employ highly effective birth control from screeningto 90 days after the last dose of trial treatment.

28. Known allergy or hypersensitivity to any of the investigational products or theirexcipients

29. Prior enrolment to, or treatment in a previous durvalumab clinical study, regardlessof treatment arm assignment

30. Patients must not donate blood while participating in this study and for at least 90days following the last dose of trial treatment