Phase II Randomized Trial of Neo-adjuvant vs. Adjuvant Cisplatin-Based Chemotherapy in Upper Tract Urothelial Carcinoma with Gemcitabine

The primary objective of this study is to evaluate the proportion of patients with **Upper Tract Urothelial Carcinoma** (UTUC) who possess adequate renal function and are fit to receive either neo-adjuvant or adjuvant cisplatin-based chemotherapy. Additionally, the study aims to determine the proportion of patients randomized to either treatment who can successfully initiate and complete three courses of the planned chemotherapy regimen. The assessment of the administered versus planned dose of chemotherapy in these patients is also a key focus. This is clinically relevant as it helps to identify the feasibility and effectiveness of chemotherapy regimens in patients with UTUC, potentially guiding treatment decisions and improving patient outcomes.

Secondary objectives include:

• Assessing 1- and 2-year **Disease Free Survival** (DFS), **Overall Survival** (OS), and **Cancer-Specific Survival** (CSS) in patients across the study's three arms, analyzed both by intention to treat and per protocol.
• Evaluating the safety and tolerability of three courses of neo-adjuvant chemotherapy compared to three courses of adjuvant chemotherapy.
• Examining the histopathology in each patient group and the histological response in the neo-adjuvant patient group.

The clinical trial involves a total of **5 participants** diagnosed with **Upper Tract Urothelial Carcinoma**, specifically upper urinary tract transitional cell carcinoma. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their histologically-confirmed diagnosis of predominantly urothelial carcinoma of the upper urinary tract, with clinical staging of cT2-cT4 cN0-N1 M0 according to the TNM classification. The trial does not include a vulnerable population. Participants are required to have adequate organ system function, as defined by hematological results, and must not have evidence of distant metastasis as confirmed by CT scans and bone scans. Women of childbearing potential must have a negative serum pregnancy test and agree to use effective contraception. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the selection process or lifestyle factors.

The clinical trial is designed to evaluate the feasibility of **neo-adjuvant** versus **adjuvant chemotherapy** in patients with **Upper Tract Urothelial Carcinoma** (UTUC). This is a phase II, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial aims to assess the proportion of UTUC patients with adequate renal function who are fit to receive either neo- or adjuvant cisplatin-based chemotherapy. Additionally, it evaluates the ability of patients to start and complete three courses of the planned chemotherapy regimen and compares the administered versus planned doses.

The trial is expected to run from May 15, 2018, to December 31, 2025. Participants will be involved in the study for a maximum treatment period of nine months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment progress and side effects, and an end-of-study visit to assess overall outcomes. The inclusion criteria require participants to be 18 years or older, have a histologically confirmed diagnosis of UTUC, and meet specific health and safety standards, including adequate organ function and no evidence of distant metastasis. Women of childbearing potential must have a negative pregnancy test and agree to use effective contraception.

Participants may be terminated early from the study if they experience significant adverse effects, fail to comply with the study protocol, or withdraw consent. The primary endpoint is the proportion of patients able to complete the chemotherapy courses, while secondary endpoints include 1-, 2-, and 3-year disease-free survival, overall survival, and cancer-specific survival. The trial uses **gemcitabine** as part of the chemotherapy regimen, administered as a powder for solution for infusion, with a maximum daily dose of 1000 mg/m² and a total dose of 3000 mg/m². The study is not classified as low intervention and does not involve a pediatric formulation.

The clinical trial involves the administration of **GEMCITABINE**, an experimental medication used in the treatment of Upper Tract Urothelial Carcinoma (UTUC). **GEMCITABINE** is provided in the form of a **powder for solution for infusion**. The active substance, **gemcitabine**, is administered via **infusion**. The dosing regimen for this trial specifies a maximum daily dose of **1000 mg/m²** and a maximum total dose of **3000 mg/m²** over the course of the treatment. The treatment period is set to a maximum of **9 weeks**. The administration of **GEMCITABINE** is conducted under controlled conditions to ensure participant safety and adherence to the protocol.

In addition to the experimental treatment, participants may receive standard-of-care chemotherapy as part of the study design. This non-experimental treatment serves as a comparator to evaluate the efficacy and safety of the experimental regimen. The trial aims to assess the feasibility of administering either neo-adjuvant or adjuvant chemotherapy in patients with adequate renal function. Monitoring of participant compliance with the dosing schedule is conducted throughout the trial to ensure accurate assessment of the treatment's effects.

Efficacy in the clinical trial titled "Neo-adjuvant versus Adjuvant chemotherapy in Upper Tract Urothelial Carcinoma: A feasibility phase II randomized clinical trial ('URANUS')" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients with Upper Tract Urothelial Carcinoma (UTUC) who are randomized to either neo-adjuvant or adjuvant chemotherapy and are able to start and complete three courses of the planned chemotherapy regimen. This will provide a direct measure of treatment feasibility and patient adherence to the chemotherapy protocol.

Secondary endpoints include 1-, 2-, and 3-year **Disease-Free Survival (DFS)**, Overall Survival (OS), and Cancer-Specific Survival (CSS). These endpoints will be used to evaluate the long-term efficacy of the chemotherapy regimens in terms of survival outcomes. The collection and analysis of these endpoints will be conducted at specified intervals throughout the trial duration, with the final analysis occurring at the end of the study period, estimated to conclude by December 31, 2025. The trial will utilize standard clinical and laboratory assessments to gather data on these endpoints, ensuring a comprehensive evaluation of the treatment's efficacy.