NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab and Tremelimumab in Muscle-invasive Urothelial Carcinoma

Inclusion Criteria: 1. Written informed consent and any locally required authorization (e.g., EU Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations 2. Age ≥18 years at time of study entry 3. Histologically confirmed MIUC (also termed TCC) of the bladder. Patients with mixed histologies are required to have a dominant transitional cell pattern (urothelial carcinoma must be \> 50%) 4. Localized MIUC of the bladder with clinical stage T2-T4a and ≤N1 disease ( the single lymph node must be \< 15 mm (short axis) on imaging 5. Patients with urothelial carcinoma of the prostatic urethra 6. Bodyweight \>45kg 7. Patients eligible for cisplatin-based neoadjuvant chemotherapy, including: * Creatinine clearance (CL) \>60 mL/min based on the Modification of Diet in Renal Disease Study (MDRD) formula * Cardiac left ventricular ejection fraction (LVEF) ≥50% 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. Absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Patients with clinical stage N1 disease are eligible if the single lymph node measures ≤2 cm in greatest dimension. 10. Adequate organ and marrow function as defined below (obtained within 14 days prior to the first study treatment): * Hemoglobin ≥10.0 g/dL (patients may be transfused to meet this criterion) * Absolute neutrophil count (ANC) ≥1500 cells/μL (without G-CSF support within 2 weeks prior to Cycle 1, Day 1) * WBC counts \>2500/µL * Platelet count ≥100,000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1) * Serum bilirubin ≤1.0 x institutional upper limit of normal (ULN). Patients with known Gilbert disease who have serum bilirubin level ≤3 x ULN may be enrolled. * AST, ALT, and alkaline dehydrogenase ≤2.5 x ULN * Partial thromboplastin time/prothrombin time (PTT/PT) ≤1.5 x ULN or international normalized ratio (INR) \<1.7 x ULN 11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) * Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 12. Women of childbearing potential and non-sterilized males who are sexually active with a female partner of childbearing potential must be willing to use contraceptive methods during the treatment period and for at least 6 months after the last dose of treatment 13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: 1. Urothelial carcinoma of the upper tract 2. Any approved anti-cancer therapy for urothelial carcinoma, including chemotherapy, or immunotherapy prior to initiation of study treatment. Of note, previous intravesical BCG injections are allowed if administered for non-muscle invasive urothelial carcinoma 3. Primary chemoradiation for bladder preservation for urothelial carcinoma of the bladder 4. Impaired renal function (glomerular filtration rate \[GFR\]\<60 mL/min); GFR should be assessed by calculation from serum/plasma creatinine (MDRD formula) 5. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal 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 6. Grade 2 or greater hearing loss that contraindicates cisplatin use. Threshold shift of \>25 decibel averaged at 2 contiguous test frequencies in least one ear. Exception: Patients with Grade 2 hearing loss diagnosed on the audiogram that are asymptomatic (no complain of hearing loss and no tinnitus) can be enrolled in the study. 7. Grade 2 or greater peripheral neuropathy 8. Oral anticoagulation treatment (vitamin K antagonist should be replaced by low-molecular-weight heparin). 9. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug 10. 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 11. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable 12. Major surgical procedure (as defined by the Investigator) other than for diagnosis within 28 days prior to Cycle 1 13. History of prior organ transplantation, including stem cell allografting 14. 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 antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and type I diabetes mellitus on stable dose of insulin may be eligible for this study 15. All micropapillary and plasmacytic forms, with or without squamous cell adenocarcinoma 16. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia 17. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 18. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 19. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina 20. History of another primary malignancy within 3 years prior to Cycle 1, Day 1, except for: Localized low-risk prostate cancer (defined as Stage ≤T2b, Gleason score ≤7, and prostate-specific antigen \[PSA\] at prostate cancer diagnosis ≤20 ng/mL \[if measured\]) treated with curative intent and without PSA recurrence Low-risk prostate cancer (defined as Stage T1/T2a, Gleason score \<7, and PSA ≤10 ng/mL) who are treatment-naive and undergoing active surveillance Patients with malignancies of a risk of metastasis/death (e.g., risk of metastasis or death \<5% at 5 years) are eligible after investigator's approval if they meet both of the following criteria: Malignancy treated with expected curative intent, and no evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers 21. History of leptomeningeal carcinomatosis 22. History of idiopathic pulmonary fibrosis, organizing pneumonia 23. Serum albumin \<25 g/L 24. LVEF \<50% 25. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 electrocardiograms (ECGs) within 15 minutes at 5 minutes apart 26. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if PCR is negative for HCV RNA 27. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 28. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and for up to 30 days after the last dose of study treatment 29. 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 monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy 30. Known allergy or hypersensitivity to chimeric or humanized antibodies or fusion proteins, or to any of the study drugs or study drug excipients 31. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment 32. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the Investigator, makes the patient unsuitable for participation in the study Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3 If a patient withdraws from participation in the study, then his or her enrollment/randomization code cannot be reused. Withdrawn patients will not be replaced.