Cisplatin, Nab-paclitaxel, Nivolumab With Radiotherapy After Resection of Non-Metastatic Muscle Invasive Bladder Cancer

Inclusion Criteria:

1. 18 years old or older

2. Histologic diagnosis of predominantly urothelial carcinoma of the bladder. Focaldifferentiation allowed other than small cell histology.

3. Stage T2-T3 N0M0 (AJCC-TNM version 6) based on trans-urethral resection of bladdertumor (TURBT), CT or MRI imaging, +/- bimanual examination under anaesthesia.

4. FDG-PET within 6 weeks from the start of treatments, showing no evidence of lymphnodes or metastatic disease.

5. Attempt of complete trans urethral resection of bladder tumour (TURBT) within 56days (8 weeks) prior to the start of chemoradiotherapy. If TURBT was performed > 8weeks prior but a recent cystoscopy shows no residual disease, then a repeat TURBTis not necessary.

6. Life expectancy greater than 6 months

7. Eastern Cooperative Oncology Group (ECOG) performance status of 1 or better

8. Another primary cancer is allowed only if treated with curative intent at least 3years prior to enrolment without evidence of recurrence or if the untreated canceris clinically indolent (e.g., lower risk prostate cancer).

9. Patients must be considered able to tolerate systemic chemotherapy combined withpelvic intensity-modulated radiation therapy (IMRT) by the joint agreement of theparticipating radiation oncologist and medical oncologist.

10. Able and willing to give written informed consent.

11. For women of childbearing potential (WOCBP), study participants must use acontraceptive method that is highly effective (with a failure rate of < 1% per year)for at least 5 months after the last dose of study intervention. Men receiving anystudy drug and who are sexually active with WOCBP will be instructed to adhere tocontraception for a period of 6 months after the last dose of chemotherapy withcisplatin or nab-paclitaxel. The investigator or a designated associate is requested to advise the subject how toachieve an adequate birth control. Adequate contraception is defined in the study asany medically recommend method (or combination of methods) as per standard of care.Acceptable methods are oral contraceptives, hormonal implants, hormonal patches,IDU, Diaphragm with spermicides, cervical cape with spermicide, and condom withspermicide.

12. Adequate bone-marrow, liver, and renal function as assessed by the followinglaboratory requirements conducted within 7 days of starting the study treatment:

13. Total bilirubin ≤1∙5 × the upper limit of normal (ULN).

14. Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN forpatients with liver involvement of their cancer).

15. International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1∙5 ×ULN. Subjects who are therapeutically treated with an agent such as warfarin orheparin will be allowed to participate if no prior evidence of an underlyingabnormality in coagulation parameters exists. Close monitoring with at least weeklyevaluations will be performed until INR and PTT are stable based on a pre-dosemeasurement as defined by the local standard of care.

16. Platelet count ≥100 000/mm3, haemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3.

17. Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvementof their cancer).

18. Creatinine clearance greater than 40 ml/min as evaluated by Cockcroft-Gault formula.

Exclusion Criteria:

1. Prior systemic therapy for other urothelial tumours.

2. Prior RT to the pelvis

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 enrolment.

4. Malignancies other than urothelial cancer within 3 years prior to Cycle 1, Day 1:

5. Patients with localized lower risk prostate cancer (defined as Stage ≤T2b,Gleason score ≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL [ifmeasured]) treated with radical prostatectomy and without prostate-specificantigen (PSA) recurrence are eligible.

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

7. 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 allthe following criteria:

8. Malignancy treated with expected curative intent (such as adequately treatedcarcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductalcarcinoma in situ of the breast treated surgically with curative intent) Noevidence of recurrence or metastasis by follow-up imaging and anydisease-specific tumor markers.

9. Pre-existing medical conditions precluding treatment (e.g., previous history ofimmune-related adverse reactions, pneumonitis, colitis, etc.)

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

11. History of autoimmune disease, including, but not limited to, myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history ofautoimmune-related hypothyroidism on a stable dose of thyroid replacement hormonemay be eligible for this study. Patients with controlled Type I diabetes mellitus ona stable dose of insulin regimen may be eligible for this study.

12. Active tuberculosis

13. For women of childbearing potential (WOCBP), study participants must use acontraceptive method that is highly effective (with a failure rate of < 1% per year)for at least 5 months after the last dose of study intervention. Men receiving anystudy drug and who are sexually active with WOCBP will be instructed to adhere tocontraception for a period of 6 months after the last dose of chemotherapy withcisplatin or nab-paclitaxel. Acceptable methods are oral contraceptives, hormonal implants, hormonal patches,IDU, Diaphragm with spermicides, cervical cape with spermicide, and condom withspermicide.

14. Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),anti-PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BBligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), oranti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (includingipilimumab or any other antibody or drug specifically targeting T-cellco-stimulation or checkpoint pathways).

15. 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.

16. Active autoimmune disease that has required systemic treatment in past 2 years.

17. Received or will receive a live vaccine within 4 weeks prior to first dose of studydrug except for vaccine against SARS-CoViD2. Influenza vaccination should be givenduring influenza season only (approximately October through May in the NorthernHemisphere and approximately April through September in the Southern Hemisphere).Patients must agree not to receive live, attenuated influenza vaccine (e.g.,FluMist®) within 28 days prior to randomization, during treatment or within 5 monthsfollowing the last dose of nivolumab.

18. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of activepneumonitis on screening chest CT scan History of radiation pneumonitis in theradiation field (fibrosis) is permitted.

19. Active infection requiring IV systemic therapy.

20. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day

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

22. Significant cardiovascular disease, such as New York Heart Association cardiacdisease (Class II or greater), myocardial infarction within the previous 3 months,unstable arrhythmias, or unstable angina. Patients with known coronary arterydisease, congestive heart failure not meeting the above criteria, or leftventricular ejection fraction < 50% must be on a stable medical regimen that isoptimized in the opinion of the treating physician, in consultation with acardiologist if appropriate.

23. Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1,Day 1, or anticipation of need for a major surgical procedure during the course ofthe study

24. Prior allogeneic stem cell or solid organ transplant

25. 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.

26. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

27. Patients with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)

28. Not willing or unable to sign a consent form.