Atezolizumab Plus One-year BCG Bladder Instillation in BCG-naive High-risk Non-muscle Invasive Bladder Cancer Patients

Inclusion Criteria:

1. Signed informed consent form after the last endoscopic surgery (TURBT)

2. Adult man and women ( age ≥18 years)

3. Any high risk non muscle invasive urothelial carcinoma histologically confirmed (mixed histology tumors allowed if urothelial carcinoma histology is predominant)defined on the TURBT as any of the following :

• T1 tumor and/or

• High grade (WHO 2004) and/or

• Grade 3 (WHO1973) and/or

• Carcinoma in situ (CIS)

4. Tumor tissue available from the surgery for central confirmation of the diagnosisand analysis the expression of PD-L1

5. At least one additional (second) resection of the primary tumor has been performedin any of the following cases [without upstaging towards Muscle Invasive BladderCancer (EAU guidelines, 2017)] :

• T1 tumors at physician's discretion,

• incomplete initial TURB,

• no muscle in the specimen (can be omitted if TaLG/G1 tumors or primary CIS onlywas found)

6. Absence of metastasis in pelvis, abdomen, or chest, as confirmed by a negativebaseline computed tomography (CT) or magnetic resonance imaging (MRI) scan no morethan 90 days prior to the first study treatment

7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

8. Life expectancy ≥12 weeks

9. Systolic blood pressure (BP) <160 mmHg and diastolic BP <95 mmHg, as documentedwithin 7 days prior to the first study treatment (hypertension allowed provided itis controlled)

10. Adequate hematologic and end-organ function, as defined by the following laboratoryresults obtained within 7 days prior to the first study treatment:

• absolute neutrophil count (ANC) ≥1500 cells/μL

• white blood cell (WBC) counts >2500/μL

• Lymphocyte count ≥300/μL

• Platelet count ≥100,000/μL

• Hemoglobin ≥9.0 g/dL

• aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), andalkaline phosphatase ≤2.5 × the upper limit of normal (ULN)

• Serum bilirubin ≤1.0 × ULN Patients with known Gilbert disease who have serumbilirubin level ≤3 × ULN may be enrolled.

• Partial thromboplastin time (PTT)/Prothrombin Time (PT) ≤1.5 × ULN orinternational normalized ratio (INR) <1.7 × ULN

• Calculated creatinine clearance ≥20 mL/min (Cockcroft-Gault formula)

11. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods that result in a failure rateof <1% per year during the treatment period and for at least 5 months after the lastdose of atezolizumab

12. Patients affiliated to the social security system

13. Patient is willing and able to comply with the protocol for the duration of thetrial including undergoing treatment and scheduled visits, and examinationsincluding follow-up.

Exclusion Criteria:

1. Patient having received previous BCG therapy for bladder cancer

2. Any approved anti-cancer therapy, including systemic chemotherapy, or hormonaltherapy within 3 weeks prior to initiation of study treatment. Hormone-replacementtherapy or oral contraceptives are allowed

3. Treatment with any other investigational agent or participation in another clinicaltrial with therapeutic intent within 28 days or five half-lives of the drug,whichever is longer, prior to day 1 of study treatment

4. Malignancies other than urothelial cancer within 5 years prior to Day 1 of cycle 1of treatment except the following:

• Patients with localized low risk prostate cancer (defined as Stage ≤T2b,Gleason score ≤7, and PSA at prostate cancer diagnosis ≤20 ng/mL [if measured])treated with curative intent (radiotherapy and/or prostatectomy) and withoutprostate-specific antigen (PSA) recurrence are eligible.

• Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤7 and PSA ≤10 ng/mL) who are treatment-naive and undergoing activesurveillance are eligible.

• Patients with malignancies of a negligible risk of metastasis or death (e.g.,risk of metastasis or death <5% at 5 years) are eligible provided they meet allof the following criteria: malignancy treated with expected curative intent (such as adequately treated carcinoma in situ of the cervix, basal or squamouscell skin cancer, or ductal carcinoma in situ treated surgically with curativeintent) and no evidence of recurrence or metastasis by follow-up imaging andany disease-specific tumor markers.

5. Pregnancy or breastfeeding

6. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

7. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cellsor any component of the atezolizumab formulation

8. History of autoimmune disease or history of immunosuppression, or conditionsassociated with congenital or acquired immune deficiency , including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren'ssyndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, orglomerulonephritis (see Appendix 6 for a more comprehensive list of autoimmunediseases)

• Patients with a history of autoimmune-related hypothyroidism/hyperthyroidism ona stable dose of thyroid replacement hormone may be eligible for this study.

• Patients with controlled Type I diabetes mellitus on a stable dose of insulinregimen may be eligible for this study.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, orevidence of active pneumonitis on screening chest CT scan may be eligible.

• History of radiation pneumonitis in the radiation field (fibrosis) ispermitted.

9. Serum albumin <2.5 g/dL

10. Known HIV infection

11. Patients with active hepatitis B virus (HBV; chronic or acute; defined as having apositive hepatitis B surface antigen (HBsAg) test prior the randomisation) orhepatitis C.

• Patients with past HBV infection or resolved HBV infection (defined as thepresence of hepatitis B core antibody (HBc Ab) and absence of HBsAg) areeligible. HBV DNA must be obtained in these patients prior to randomisation.

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction is negative for HCV RNA.

12. Known active tuberculosis

13. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limitedto hospitalization for complications of infection, bacteremia, or severe pneumonia

14. Signs or symptoms of urinary infection and/or other signs and symptoms > grade 1 (NCI CTCAE v5.0) within 2 weeks prior to Cycle 1, Day 1

• Patients receiving therapeutic oral or IV antibiotics within 2 weeks prior toCycle 1, Day 1 are not eligible

• Patients receiving prophylactic antibiotics (e.g., for prevention of a urinarytract infection or to prevent chronic obstructive pulmonary diseaseexacerbation) are eligible.

15. Significant cardiovascular disease, such as New York Heart Association cardiacdisease (Class II or greater), myocardial infarction within the previous 3 monthsbefore Cycle1, Day 1, unstable arrhythmias, or unstable angina.

• Patients with known coronary artery disease, congestive heart failure notmeeting the above criteria, or left ventricular ejection fraction <50% must beon a stable medical regimen that is optimized in the opinion of the treatingphysician, in consultation with a cardiologist if appropriate.

16. Major surgical procedure other than for diagnosis within 4 weeks prior to Cycle 1,Day 1 or anticipation of need for a major surgical procedure during the course ofthe study

17. Prior allogeneic stem cell or solid organ transplant

18. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 oranticipation if such a live, attenuated vaccine will be required during the study

• Influenza vaccination should be given during influenza season only (approximately October through May in the Northern Hemisphere and approximatelyApril through September in the Southern Hemisphere). Patients must agree not toreceive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeksprior to Cycle 1, Day 1, at randomization, during treatment or within 5 monthsfollowing the last dose of atezolizumab (for patients randomized toatezolizumab).

19. Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplications

20. Prior treatment with CD137 agonists or immune checkpoint-blockade therapies,including anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

21. Treatment with systemic immunostimulatory agents (including but not limited tointerferons, interleukin 2 (IL-2)) within 6 weeks or five half-lives of the drug,whichever is shorter, prior to Cycle 1, Day 1

22. Treatment with systemic corticosteroids or other systemic immunosuppressivemedications (including but not limited to prednisone, dexamethasone,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosisfactor (anti-TNF) agents) within 2 weeks prior to Cycle 1, Day 1, or anticipatedrequirement for systemic immunosuppressive medications during the trial

• Patients who have received acute, low-dose, systemic immunosuppressantmedications (e.g., a one-time dose of dexamethasone for nausea, multiple dosesfor contrast allergy) may be enrolled in the study.

• The use of inhaled or low-dose (e.g., ≤10 mg/day prednisone) corticosteroidsfor chronic obstructive pulmonary disease (COPD) or asthma, mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) and low-dose corticosteroidsfor patients with orthostatic hypotension or adrenocortical insufficiency isallowed.

23. Person deprived of their liberty or under protective custody or guardianship