A randomised Phase II study comparing three vs six cycles of platinum-based chemotherapy prior to maintenance avelumab in advanced urothelial cancer (DISCUS)
Bladder cancer
Eligible patients will be randomised in a 1:1 ratio using the minimisation method to receive either: Arm A: three cycles of Q3W gemcitabine (1000 mg/m²) + carboplatin (AUC 4.5 or 5, as per local practice) / cisplatin (70 mg/m²) followed by maintenance avelumab (800 mg Q2W) Arm B: six cycles of Q3W gemcitabine (1000 mg/m²) + carboplatin (AUC 4.5 or 5) / cisplatin (70 mg/m²) followed by maintenance avelumab (800 mg Q2W). Maintenance avelumab treatment will be given up to a maximum of 2 years from the end of chemotherapy in both arms. Following the end of study treatment, patients will attend safety follow up visits at 30 and 90 days post the last dose. Patients will then enter a follow-up phase during which they will be contacted 12 weekly to collect survival and disease status data. The follow-up duration will be until the end of avelumab treatment or for 2 years from completion of chemotherapy, whichever is longer. Patients will have a variety of assessments as part of standard of care treatment, including: medical history, physical examination, ECG, haematology, biochemistry, urinalysis, and tumour assessments. Quality of life will be assessed using patient-reported outcomes from the EORTC-QLQ-C30 questionnaire collected at various timepoints throughout the study.
1. Willing and able to provide written informed consent 2. Ability to comply with the protocol, including but not limited to, the repeated completion of the EORTC QLQ-C30 questionnaires 3. Age ≥18 years 4. Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Patients with squamous or sarcomatoid differentiation or mixed cell types are eligible but a component of urothelial cancer is required. 5. Measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 6. Eligible for gemcitabine/cisplatin or gemcitabine/carboplatin 7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2 8. Adequate haematologic and organ function 9. Negative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential only 10. Agreement to use adequate contraceptive measures
1. Prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC 2. Prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions: a platinum-containing regimen (cisplatin or carboplatin) in the neoadjuvant or adjuvant setting if more than 6 months since the last cycle have occurred. 3. Pregnant and lactating female patients 4. Known history of active CNS metastases 5. Prior allogeneic stem cell or solid organ transplantation 6. Oral or IV steroids for 14 days prior to C1D1 7. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study 8. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment 9. Concurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment 10. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, 11. Malignancies other than urothelial carcinoma of the bladder within 3 years prior to Cycle 1, Day 1 12. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebral vascular accident/stroke within 6 months prior to enrolment, unstable arrhythmias, or unstable angina 13. Radiotherapy within 2 weeks prior to C1D1 14. Major surgery (defined as requiring general anaesthesia and >24-hour inpatient hospitalization) within 4 weeks prior to randomisation. Patients must have recovered adequately from complications from the intervention prior to starting study treatment. 15. History of idiopathic pulmonary fibrosis (including pneumonitis),drug-induced pneumonitis, organizing pneumonia (i.