Single-Dose Intravesical Chemotherapy After Diagnostic URS

Study period This study will include a screening period, a treatment and disease assessment period, safety follow-up visits and a 5-year survival follow-up period to begin immediately after the treatment.

Screening period: The period up to 28 days prior to intervention during which the screening procedures occur.

Treatment and disease assessment period: The period starting the day of diagnostic URS (Day 0) during which patients receive their assigned treatment (Day 0 to day 1) and disease assessments are performed. All patients must follow the disease assessment schedule, which includes disease assessments at screening and every 3 months (±1 week) from the date of intervention until 24 months from the date of randomization, and then every 6 months for up to 5 years. The treatment and disease assessment period will end at the time of intravesical recurrence, death, or MINERVA-CTU decision to terminate the trial early.

Safety follow-up visits: Every patient in this study will be assessed for the occurrence of adverse events (AEs) and serious adverse events from the time of signed informed consent until 90 days after the administration of SI. All patients who receive SI will have safety visits 4, 8, and 12 weeks following administration of SI. Safety assessments include targeted physical examination, complications according to Dindo-Clavien classification and patient-reported outcomes (PRO) assessments.

Survival follow-up period: Patients will be followed up at in-clinic site visits, by telephone contact, or by contact with the patient's current physician for up to 5 years from the date of randomized into this study.

Objectives Primary objective Efficacy of a SI in the prophylaxis of intravesical recurrence after diagnostic URS for UTUC

Secondary objectives

• Time to intravesical recurrence
• 5-years intravesical recurrence rates
• Incidence of high-grade BCa recurrence
• Incidence and gravity of adverse events (AEs) due to the SI
• To collect and store blood, urine and tissue samples according to each country's local and ethical procedures for identifying candidate markers that may correlate with likelihood of clinical benefit (optional)
• To collect and store DNA according to each country's local and ethical procedures for future exploratory research into somatic mutations and genes/genetic variations that may influence oncologic outcomes, to study treatments and susceptibility to disease (optional)
• To assess disease-related symptoms and HRQoL in patients with UTUC treated with SI compared those undergoing observation
• To assess patient-reported treatment tolerability directly using specific PRO-CTCAE symptoms

Target study population The study population includes patients 18 years of age or older with a primary diagnosis of UTUC, scheduled for diagnostic URS

Duration of treatment Patients randomized to the interventional arm will receive a SI within 24h after diagnostic URS. In case of multiple diagnostic URS during the follow-up (including 2nd look for incomplete ablation, non-diagnostic first URS or UTUC recurrence) patients randomized to the interventional arm will receive a SI after each diagnostic URS for 2 years after the day of first diagnostic URS.

Follow-up of subjects post discontinuation of study treatment Patients who have discontinued study treatment due to toxicity, symptomatic deterioration, intravesical recurrence or investigator's decision will be followed up for survival until 5 years from the date of diagnostic URS.

Survival All randomized patients, regardless of disease status, will be followed up for survival until 5 years from the date of diagnostic URS.

Investigational product, dosage, and mode of administration Patients randomized to the interventional arm will receive a SI. The chemotherapy will be at investigator's discretion and institutional availability.

The selected chemotherapy must be approved by the MINERVA-CTU in discussion with the local investigator.

Statistical methods This study will randomize 394 patients globally. Patients will be randomized 1:1 to SI or observation.

Randomization will be stratified by the following factors:

1. Center
2. EAU UTUC risk stratification