DISCUS: A Randomised Phase II Study Comparing 3 vs 6 Cycles of Platinum-based Chemotherapy Prior to Maintenance Avelumab in Advanced Urothelial Cancer

Prior treatment

• Prior treatment with a PD-(L)-1 inhibitor for any advanced malignancy. Treatment with PD-(L)-1 inhibitors in the neoadjuvant or adjuvant setting for UC are permitted.
• 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 or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).
• 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.
• Radiotherapy within 2 weeks prior to C1D1. Patients must have recovered adequately from toxicities resulting from the intervention prior to starting study treatment.
• 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.
• 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 last cycle have occurred. Patients who received adjuvant or neoadjuvant immune therapy for muscle invasive or non-muscle invasive disease are eligible.
• Persisting toxicity related to prior therapy (NCI CTCAE Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable.
• Participants with previous or known history of allergic reaction to cisplatin, gemcitabine, carboplatin or other platinum containing compounds, or any component of the chemotherapy formulations.
• Known history of active CNS metastases. Patients with treated CNS metastases are permitted on the study if all of the following are true: a. CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b. the subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks prior to C1D1 (if requiring steroid treatment); c. subject does not have leptomeningeal disease.
• Prior allogeneic stem cell or solid organ transplantation.
• 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.
• 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 (see section 11.26).
• Concurrent treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment.
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).

Other illness

• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
• Active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
• Positive HIV test.
• Active tuberculosis.
• Active 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.
• History of autoimmune-related hypothyroidism, unless on a stable dose of thyroid replacement hormone.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of avelumab.
• Active infection requiring systemic therapy.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
• Patients with bleeding tumours

Other

• Any other contraindication for gemcitabine/ cisplatin or gemcitabine/carboplatin treatment as per SmPC.
  • France Specific Criteria: 28. Person deprived of their liberty or under protective custody or guardianship.
• Pregnant and lactating female patients.

• Willing and able to provide written informed consent.
• Agreement to use adequate contraceptive measures (Refer to section 11.30 for full details).
  • FRANCE SPECIFIC CRITERIA: 11. Patients affiliated to the social security system.
• Ability to comply with the protocol, including but not limited to, the repeated completion of the EORTC QLQ-C30 questionnaires.
• Age ≥ 18 years.
• 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.
• Measurable disease by RECIST v1.1.
• Eligible for gemcitabine/ cisplatin or gemcitabine/carboplatin. Patients meeting any of the following criteria or considered ineligible for cisplatin as per investigator discretion, should be considered for gemcitabine/carboplatin (as per local standard practice): a. GFR <60 mL/min (measured by the Cockcroft-Gault formula or by local accepted standards). Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement. Subjects are required to have a GFR ≥30 mL/min (measured by the Cockcroft-Gault formula or by local accepted standards) to receive carboplatin. b. ECOG or WHO performance status of 2. c. NCI CTCAE Grade ≥2 audiometric hearing loss. d. NYHA Class III heart failure.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2.
• Adequate haematologic and organ function as defined below: a. Haemoglobin ≥ 9.0g/dL b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500/µL) without growth factor support c. Platelet count ≥ 100 x 109 /L (≥100,000/µL) d. Total serum bilirubin ≤1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology], who will be allowed only in consultation with their physician. e. Serum transaminases (AST/ALT) ≤2.5 x the institutional ULN with the following exception in patients with documented liver metastases: AST and/or ALT ≤5 × ULN f. GFR ≥30mL/min measured by Cockcroft-Gault formula, or locally accepted standards.
• Negative serum or urine pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential only. Non-childbearing potential is defined as either: a. Postmenopausal ≥ 50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR b. Documented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR c. <50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels within local institution postmenopausal ranges