A phase III randomized, open-label, multi-centre, global study of Durvalumab and Bacillus Calmette-Guerin (BCG) administered as combination therapy versus BCG alone in high-risk, BCG-naive non-muscle-invasive bladder cancer patients

1. Age >=18 years at the time of screening.
2. Written informed consent.
3. BCG-naïve (patients who have not received prior intravesical BCG or who
previously received but stopped BCG more than 3 years before study entry are
eligible).
4. Local histological confirmation (based on pathology report) of high-risk
transitional
cell carcinoma of the urothelium of the urinary bladder confined to the mucosa
or
submucosa. A high-risk tumor is defined as one of the following:
- T1 tumor
- High grade/G3 tumor
- CIS
- Multiple and recurrent and large (with diameter of largest tumor >=3 cm)
tumors (all conditions must be met in this point)
5. Complete resection of all Ta/T1 papillary disease prior to randomization,
with the TURBT removing high-risk NMIBC performed not more than 4 months before
randomization in the study. Patients with residual CIS after TURBT are eligible.
6. No prior radiotherapy for bladder cancer.
7. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 at screening.
8. Body weight >30 kg.
9. Must have a life expectancy of at least 12 weeks.
10. No prior exposure to immune-mediated therapy of cancer including, but not
limited
to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death
ligand 2 antibodies. Patients who have been treated with anticancer vaccines
will
be excluded.
11. Must be a candidate for BCG treatment.
12. Adequate organ and marrow function as defined below:
- Hemoglobin >=9.0 g/dL
- Absolute neutrophil count >=1.0 × 109/L
- Platelet count >=75 × 109/L
- Serum bilirubin <=1.5 × the upper limit of normal (ULN). This will not apply
to patients with confirmed Gilbert*s syndrome, who will be allowed in
consultation with their physician.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5 ×
ULN
- Measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL >40
mL/min as determined by Cockcroft-Gault (using actual body weight)
Males
Creatinine CL (mL/min) = Weight (kg) × (140 - Age) / 72 × serum creatinine
(mg/dL)
Females:
Creatinine CL (mL/min) = Weight (kg) × (140 - Age) × 0.85 / 72 × serum
creatinine (mg/dL)
13. Postmenopausal or negative pregnancy test.
14 . At screening, provision of a tumor biopsy that is formalin-fixed and
paraffin-embedded (FFPE) is mandatory. Tumor sample should be relevant to the
high-risk NMIBC which is the reason for inclusion in the study, preferably,
from TURBT removing this tumor.

1. Evidence of muscle-invasive, locally advanced, metastatic, and/or
extra-vesical bladder cancer (ie, T2, T3, T4, and / or stage IV).
2. Predominantly variant histology such as micropapillary, plasmocytoid,
nested, sarcomatoid, microcystic, squamous and adeno variants of urothelial
carcinoma representing more than 50% of tumor tissue or other than urothelial
tumors as assessed by pathology
3. Evidence of lymphovascular invasion of bladder tumor.
4. Immediate cystectomy is indicated.
5. Known or documented absolute and/or relative contraindication of adjuvant
intravesical BCG treatment.
6. Concurrent extravesical (ie, urethra, ureter, or renal pelvis),
non-muscle-invasive transitional cell carcinoma of the urothelium.
7. Involvement in the planning and/or conduct of the study.
8. Previous investigational product (IP) assignment in the present study.
9. Concurrent enrollment in another clinical study.
10. Participation in another clinical study with an IP during the last 28 days
or 5 half-lives of the respective Investigational Product, whichever is longer
prior to study enrollment.
11. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer
treatment. Chemotherapy for previous instances of NMIBC is acceptable.
Patients who have received a single instillation of Mitomycin C or equivalent
chemotherapy agent immediately after TURBT can be enrolled in the study.
12. Previous or concurrent treatment with potent systemic immunostimulatory
agents (i.e systemic use of interleukins, interferons, glatiramer or similar
agents).
13. Major surgical procedure within 28 days prior to randomization.
14. History of allogenic organ transplantation.
15. Active or prior documented autoimmune or inflammatory disorders,
diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener
syndrome.
16. Uncontrolled intercurrent illness, including but not limited to, ongoing or
active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious
chronic GI conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially
increase risk of incurring AEs, or compromise the ability of the patient to
give written informed consent.
17. History of another primary malignancy.
18. History of active primary immunodeficiency.
19. Intentionally Omitted.
20. Active infection including TB, hepatitis B, hepatitis C or HIV.
21. Current or prior use of immunosuppressive medication within 14 days before
the first dose of durvalumab.
22. Receipt of live attenuated vaccine within 90 days (approximately 5
half-lives) prior to the first dose of IP.
23. Female patients who are pregnant or breastfeeding or male or female
patients of
reproductive potential who are not willing to employ effective birth control
from
screening to 90 days after the last dose of durvalumab.
24. Known allergy or hypersensitivity to any of the study drugs or any of the
study
drug excipients.
25. Prior randomization or treatment in a previous durvalumab clinical study
regardless of treatment group assignment.
26. Signs or symptoms of localized bladder infection or urinary tract infection
within 2 weeks prior to the first dose of study treatment.
27. Treatment with therapeutic oral or IV antibiotics within 1 week prior to
the start of treatment with BCG..
28. Judgment by the Investigator that the patient is unsuitable to participate
in the study.