Efficacy and Safety Evaluation of UGN-104 in Low-grade Upper Tract Urothelial Carcinoma: A Phase 3, Single-arm, Multicenter Study

The primary objective of this Phase 3, single-arm, multicenter study is to evaluate the **tumor ablative effect** of UGN-104, a novel formulation of UGN-101, in patients with **low-grade upper tract urothelial cancer (LG-UTUC)**. This objective is clinically relevant as it aims to determine the efficacy of UGN-104 in reducing or eliminating tumor presence, which is crucial for improving patient outcomes in this specific cancer type.

Secondary objectives include:

• To evaluate the durability of response with respect to duration of response (DOR) and disease control rate (DCR) at scheduled disease assessment time points.
• To evaluate the safety and tolerability of UGN-104 in patients with LG-UTUC.
• To assess the pharmacokinetic (PK) profile of mitomycin in plasma in a subgroup of patients treated with UGN-104.
• Exploratory: To assess the effect of UGN-104 on patient-reported outcome (PRO) measures including quality of life, treatment satisfaction, and patient global impression of change (PGI-C).

The clinical trial involves a total of **31 participants** diagnosed with **low-grade upper tract urothelial cancer** (LG-UTUC). The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who are not part of a vulnerable population. Participants were selected based on specific inclusion criteria, such as having at least one measurable papillary low-grade tumor in the pyelocalyceal system, and an Eastern Cooperative Oncology Group (ECOG) performance status of less than 3. All participants are required to have adequate organ and bone marrow function, as well as a life expectancy of more than 24 months. Lifestyle considerations include the requirement for effective contraception for both male and female participants of childbearing potential, consistent with local regulations. The trial does not specify any particular dietary or physical activity requirements. Participants must not have an active urinary tract infection at the time of enrollment, and any asymptomatic bacteriuria is managed at the discretion of the principal investigator. The selection process ensures that the trial population is well-defined and suitable for evaluating the tumor ablative effect of UGN-104 in patients with LG-UTUC.

The clinical trial is designed to evaluate the efficacy and safety of **UGN-104**, a novel formulation of UGN-101, for the treatment of patients with **low-grade upper tract urothelial cancer** (LG-UTUC). This is a Phase 3, single-arm, multicenter study. The primary objective is to assess the tumor ablative effect of UGN-104 in patients with LG-UTUC. The trial is expected to commence recruitment on June 26, 2025, and conclude by September 30, 2027. Participants will be involved in the study for a maximum treatment period of 12 weeks, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with the study protocol.

The study will include several key visits: an initial screening visit to confirm eligibility, followed by treatment visits where UGN-104 will be administered intravesically. The primary endpoint will be evaluated at the post-dose evaluation (PDE) visit, which occurs 5 ± 1 weeks after the sixth instillation of UGN-104. Follow-up visits will be scheduled to monitor the duration of response (DOR) and disease control rate (DCR), as well as to assess safety and tolerability through adverse event reporting and standard clinical tests. The end-of-study visit will conclude the participant's involvement, assessing any long-term effects and overall outcomes.

Inclusion criteria require participants to be at least 18 years old, with a confirmed diagnosis of LG-UTUC, and to have adequate organ and bone marrow function. Exclusion criteria are not explicitly detailed in the provided data. Participants must adhere to contraceptive guidelines and have no active urinary tract infection at the time of treatment. The study will monitor primary and secondary endpoints, including complete response rate (CRR) and safety assessments, to determine the therapeutic potential of UGN-104 in this patient population.

The clinical trial involves the administration of **UGN-104**, a novel formulation of UGN-101, for the treatment of patients with low-grade upper tract urothelial cancer (LG-UTUC). **UGN-104** is presented as a **lyophilized powder** and is intended for **intravesical use**. The active substance in UGN-104 is **mitomycin**, a chemical cytostatic agent. The maximum daily dose of UGN-104 is 15 ml, with a total maximum dose of 255 ml over a treatment period of up to 12 weeks. The administration schedule is designed to ensure optimal exposure to the active compound, and participant compliance will be monitored throughout the study.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy and safety of UGN-104. The trial is structured as a single-arm study, emphasizing the tumor ablative effect of the investigational drug in the specified patient population. The pharmaceutical form and administration route are chosen to maximize the therapeutic potential of the active substance, mitomycin, in targeting urothelial cancer cells.

Efficacy in this clinical trial will be assessed primarily through the **Complete Response Rate (CRR)**, which is defined as the proportion of patients who achieve a complete response (CR) at the Post-Dose Evaluation (PDE) Visit. This visit is scheduled 5 ± 1 weeks after the sixth instillation of UGN-104. The determination of CR will be based on wash urine cytology, ureteroscopy, and for-cause biopsy.

Secondary endpoints include the Duration of Response (DOR) in patients who achieved CR at the PDE Visit. DOR is defined as the time from the date of evidence of CR at the PDE Visit to the earliest date of recurrence, progression, or death, as determined by cytology, ureteroscopy, or for-cause biopsy, or death due to any cause, whichever occurs first. Additionally, the Disease Control Rate (DCR) will be evaluated at scheduled disease assessment time points, defined as the proportion of patients who achieve and maintain CR up to that particular follow-up disease assessment.

Exploratory endpoints will assess changes from baseline in patient scores on the QLQ-C30 and TSQM questionnaires, as well as the proportion of study participants reporting improvement at the end of the study on the Patient Global Impression of Change (PGI-C). The timing of reported improvements will also be analyzed to understand when changes occur.