Comparing 3 vs 6 Cycles of Platinum-based Chemotherapy Prior to Maintenance Avelumab in Advanced Urothelial Cancer

Inclusion Criteria:

1. Willing and able to provide written informed consent.

2. Ability to comply with the protocol, including but not limited to, the repeatedcompletion of the EORTC QLQ-C30 questionnaires.

3. Age ≥ 18 years.

4. Histologically confirmed, unresectable locally advanced or metastatic urothelialcarcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patientswith squamous or sarcomatoid differentiation or mixed cell types are eligible but acomponent of urothelial cancer is required.

5. Measurable disease by RECIST v1.1.

6. Eligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. The followingcriteria are established for the use of carboplatin (patients not fulfilling thefollowing carboplatin criteria should be considered for gemcitabine/ cisplatin):

7. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula or bylocal accepted standards). Subjects with a GFR ≥50 mL/min and no othercisplatin ineligibility criteria may be considered cisplatin-eligible based onthe investigator's clinical judgement.

8. ECOG or WHO performance status of 2.

9. NCI CTCAE Grade ≥2 audiometric hearing loss.

10. NYHA Class III heart failure.

11. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.

12. Adequate haematologic and organ function as defined below:

13. Negative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for femalepatients of childbearing potential only.

14. Agreement to use adequate contraceptive measures

Exclusion Criteria:

1. Prior treatment with a PD-(L)-1 inhibitor for any advanced malignancy.Treatment with PD-(L)-1 inhibitors in the neoadjuvant or adjuvant setting forUC are permitted.

2. Prior systemic therapy for locally advanced or metastatic urothelial carcinomawith the following exceptions: a platinum containing regimen (cisplatin orcarboplatin) in the neoadjuvant or adjuvant setting if more than 6 months sincelast cycle have occurred. Patients who received adjuvant or neoadjuvant immunetherapy for muscle invasive or non-muscle invasive disease are eligible.

3. Pregnant and lactating female patients. 4. Known history of active CNSmetastases. Patients with treated CNS metastases are permitted on the study ifall of the following are true: 5. Prior allogeneic stem cell or solid organtransplantation. 6. Administration of a live, attenuated vaccine within 4 weeksprior to enrolment or anticipation that such a live, attenuated vaccine will berequired during the study.

4. Treatment with systemic immunostimulatory agents (including but not limited tointerferons or interleukin [IL]-2) within 4 weeks or five half-lives of thedrug, whichever is shorter, prior to enrolment (see section 11.26).

5. Concurrent treatment with any other investigational agent or participation inanother clinical trial with therapeutic intent within 4 weeks prior toenrolment.

6. Evidence of significant uncontrolled concomitant disease that could affectcompliance with the protocol or interpretation of results, includingsignificant liver disease (such as cirrhosis, uncontrolled major seizuredisorder, or superior vena cava syndrome).

7. Malignancies other than urothelial carcinoma within 3 years prior to Cycle 1,Day 1, with the exception of those with a negligible risk of metastasis ordeath and treated with expected curative outcome (such as adequately treatedcarcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductalcarcinoma in situ treated surgically with curative intent) or localizedprostate cancer treated with curative intent and absence of prostate-specificantigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 andPSA < 10 ng/mL undergoing active surveillance and treatment naive). .

8. Significant cardiovascular disease, such as New York Heart Association cardiacdisease (Class II or greater), myocardial infarction or cerebral vascularaccident/stroke within 6 months prior to enrolment, unstable arrhythmias, orunstable angina.

9. Radiotherapy within 2 weeks prior to C1D1. Patients must have recoveredadequately from toxicities resulting from the intervention prior to startingstudy treatment.

10. Major surgery (defined as requiring general anaesthesia and >24-hour inpatienthospitalization) within 4 weeks prior to randomisation. Patients must haverecovered adequately from complications from the intervention prior to startingstudy treatment.

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

12. Active hepatitis infection (defined as having a positive hepatitis B surfaceantigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitisB virus (HBV) infection or resolved HBV infection (defined as having a negativeHBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc]antibody test) are eligible.

13. Positive HIV test. 17. Active tuberculosis. 18. Active autoimmune diseaseincluding but not limited to myasthenia gravis, myositis, autoimmune hepatitis,systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome, Wegener'sgranulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiplesclerosis, vasculitis, or glomerulonephritis.

14. History of autoimmune-related hypothyroidism, unless on a stable dose ofthyroid replacement hormone.

15. History of severe allergic, anaphylactic, or other hypersensitivity reactionsto chimeric or humanized antibodies.

16. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinesehamster ovary cells or any component of avelumab.

17. Active infection requiring systemic therapy. 23. Persisting toxicity related toprior therapy (NCI CTCAE Grade > 1); however, alopecia, sensory neuropathyGrade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based oninvestigator's judgment are acceptable.

18. Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or studyresults 25. Participants with previous or known history of allergic reaction tocisplatin, gemcitabine, carboplatin or other platinum containing compounds, orany component of the chemotherapy formulations.

19. Patients with bleeding tumours 27. Any other contraindication for gemcitabine/cisplatin or gemcitabine/carboplatin treatment as per SmPC.