Phase 3 Multicenter Evaluation of UGN-102 (Mitomycin) Efficacy and Safety in Low Grade Non-Muscle-Invasive Bladder Cancer at Intermediate Recurrence Risk

Trial ID: 2023-506680-34-00
Protocol: BL011
Sponsor: Urogen Pharma Ltd.

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Diseases & Conditions

Bladder cancer

Objectives

The primary objective of this study is to evaluate the **tumor ablative effect** of UGN-102 in patients with low-grade non-muscle-invasive bladder cancer (LG NMIBC). This is clinically relevant as it aims to assess the efficacy of UGN-102 as a primary chemoablative therapy, potentially offering a non-surgical treatment option for patients at intermediate risk of recurrence.

Secondary objectives include:

To evaluate the durability of response with respect to duration of response (DOR).
To evaluate the durability of response with respect to disease control rate (DCR) at scheduled disease assessment time points and disease-free survival (DFS).
To evaluate the safety and tolerability of intravesical instillations of UGN-102 in patients with LG NMIBC.
To evaluate time to recurrence (TTR) following standard of care (SOC) treatment in patients who have no complete response (NCR) at the 3-month visit.
To evaluate the preliminary responses following SOC treatment in 3-month complete response (CR) patients who have disease recurrence or progression during the follow-up period.
To evaluate the impact of UGN-102 on subsequent SOC treatment in patients who have NCR at the 3-month visit or disease recurrence or progression during the follow-up period.
To assess the effect of UGN-102 on patient-reported outcome (PRO) measures, including disease-related symptoms and physical, mental, and social health.

Participants

The clinical trial involves a total of **79 participants** diagnosed with **Non-Muscle Invasive Bladder Cancer** (NMIBC). The study population includes both male and female subjects, aged 18 years and older, who have been histologically confirmed to have low-grade NMIBC through a cold cup biopsy. Participants were selected based on their history of NMIBC requiring treatment with transurethral resection of bladder tumor (TURBT) and must have intermediate risk disease, characterized by factors such as multiple tumors, solitary tumors larger than 3 cm, or early/frequent recurrence. All participants are required to have adequate organ and bone marrow function, as determined by routine laboratory tests, and a negative voiding cytology for high-grade disease within 8 weeks before screening. The trial does not include a vulnerable population, and both genders are represented, with contraceptive measures in place for those of childbearing potential. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **UGN-102 (Mitomycin)** as a primary chemoablative therapy in patients with low-grade non-muscle-invasive bladder cancer (NMIBC) at intermediate risk of recurrence. This is a Phase 3, single-arm, multicenter study. The trial will involve a series of study visits, beginning with an inclusion (screening) visit, followed by treatment and follow-up visits, and concluding with an end-of-study visit. The expected duration of the trial is from April 2022 to July 2028, with participant involvement anticipated to last for the duration of the treatment period and follow-up assessments.

Participants will be screened to ensure they meet the inclusion criteria, which include being 18 years or older, having histologically confirmed low-grade NMIBC, and demonstrating adequate organ and bone marrow function. The primary endpoint is the complete response rate (CRR) at the 3-month visit, assessed through cystoscopy, biopsy, and urine cytology. Secondary endpoints include duration of response (DOR), disease control rate (DCR), and disease-free survival (DFS), along with safety evaluations through adverse event reporting and laboratory tests.

The trial will involve regular follow-up visits to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will assess the overall outcomes and safety of the treatment. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The study aims to provide comprehensive data on the efficacy and safety of UGN-102 in treating NMIBC, contributing valuable insights into its potential as a therapeutic option.

Treatment

The clinical trial involves the use of **UGN-102 (Mitomycin)**, an investigational medication formulated as an **intravesical solution**. This pharmaceutical form is specifically designed for **intravesical use**, meaning it is administered directly into the bladder. The active substance in UGN-102 is **mitomycin**, a chemical compound known for its antineoplastic properties. The maximum daily dose of UGN-102 is 75 mg, with a total maximum dose of 450 mg over the course of the treatment. The treatment period is limited to a maximum of 6 weeks. The administration schedule and dosage are carefully monitored to ensure participant compliance and safety throughout the trial.

In this study, UGN-102 is evaluated as a primary chemoablative therapy for patients with low-grade non-muscle-invasive bladder cancer (NMIBC) at intermediate risk of recurrence. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this single-arm study. The focus is solely on assessing the efficacy and safety of UGN-102 in the specified patient population. Compliance with the dosing schedule is monitored through regular assessments and documentation to ensure adherence to the protocol.

Efficacy

The efficacy of UGN-102 (Mitomycin) in the treatment of low-grade non-muscle-invasive bladder cancer (NMIBC) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the Complete Response Rate (CRR), which is defined as the proportion of patients who achieve a complete response (CR) at the 3-month visit following the first instillation of UGN-102. This will be determined using cystoscopy, for-cause biopsy, and urine cytology.

Secondary endpoints include the Duration of Response (DOR) in patients who achieved CR at the 3-month visit, which is the time from evidence of CR to the earliest date of recurrence or progression, or death due to any cause. The Disease Control Rate (DCR) at scheduled disease assessment time points is also evaluated, defined as the proportion of patients maintaining CR up to each follow-up assessment. Disease-Free Survival (DFS) is measured from the first dose to the earliest date of recurrence or progression, or death due to any cause.

Exploratory endpoints include Time to Recurrence (TTR) in patients with residual disease at the 3-month visit, the number of response outcomes at the first disease assessment visit after standard of care, and the proportion of patients whose planned NMIBC treatment was downgraded following treatment with UGN-102. Additionally, changes from baseline in patient scores on the QLQ C30 and QLQ-NMIBC24 questionnaires will be explored.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Patient must be ≥ 18 years of age at the time of signing the ICF.
Patient who has LG NMIBC (Ta) histologically confirmed by cold cup biopsy at Screening or within 8 weeks before Screening.
History of LG NMIBC requiring treatment with TURBT. Note: This refers to a previous episode(s) and not to the current episode for which the patient is being screened.
Has intermediate risk disease, defined as having 1 or 2 of the following: a. Presence of multiple tumors. b. Solitary tumor > 3 cm. c. Early or frequent recurrence (≥ 1 occurrence of LG NMIBC within 1 year of the current diagnosis at the initial Screening Visit).
Negative voiding cytology for HG disease within 8 weeks before Screening.
Has adequate organ and bone marrow function as determined by routine laboratory tests as below: • Leukocytes ≥ 3,000/μL (≥ 3 × 109/L). • Absolute neutrophil count ≥ 1,500/μL (≥ 1.5 × 109/L). • Platelets ≥ 100,000/μL (≥ 100 × 109/L). • Hemoglobin ≥ 9.0 g/dL. • Total bilirubin ≤ 1.5 × upper limit of normal (ULN). • Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 2.5 × ULN. • Alkaline phosphatase (ALP) ≤ 2.5 × ULN. • Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min
Has an anticipated life expectancy of at least the duration of the trial.
Both male and female patients: Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a.Female partner of male patient: Willing to use 2 acceptable forms of effective contraception from enrollment through 6 months post treatment if the female partner is of childbearing potential (defined as premenopausal women who have not been sterilized). Acceptable methods of birth control which are considered to have a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as implants, injectable, combined (estrogen/progesterone) oral contraceptives, intrauterine devices (only hormonal), condoms with spermicide, sexual abstinence* or vasectomized partner. *Sexual abstinence is defined as refraining from intercourse from enrollment through 6 months post treatment. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is NOT an acceptable method of contraception. b.Female patient: Willing to use 2 acceptable forms of effective contraception from enrollment through 6 months post treatment if the patient is of childbearing potential (defined as premenopausal women who have not been sterilized).

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Exclusion Criteria

Received Bacillus Calmette-Guérin (BCG) treatment for urothelial carcinoma (UC) within previous 1 year.
History of HG bladder cancer (papillary or carcinoma in situ [CIS]) in the past 2 years.
Known allergy or sensitivity to mitomycin that in the Investigator’s opinion cannot be readily managed.
Clinically significant urethral stricture that would preclude passage of a urethral catheter.
History of: a. Neurogenic bladder. b. Active urinary retention. c. Any other condition that would prohibit normal voiding.
Past or current muscle invasive bladder cancer (ie, T2, T3, T4) or metastatic UC.
Current tumor grading of T1.
Concurrent upper tract urothelial carcinoma (UTUC).
Evidence of active urinary tract infection (UTI) that in the Investigator’s opinion cannot be treated and resolved prior to biopsy and/or administration of study treatment.
Is pregnant or breastfeeding.
Has an underlying substance abuse or psychiatric disorder such that, in the opinion of the Investigator, the patient would be unable to comply with the protocol.
History of prior treatment with an intravesical chemotherapeutic agent in the past 2 years except for a single dose of chemotherapy immediately after any previous TURBT.
Has participated in a study with an investigational agent or device within 30 days of enrollment.
Has previously participated in a study in which they received UGN-102.
Has any other active malignancy requiring treatment with systemic anticancer therapy (eg, chemotherapy, immunotherapy, radiation therapy). Superficial cancers such as cutaneous basal cell or squamous cell carcinomas that can be treated locally are allowed.
Has any other clinically significant medical or surgical condition that in the Investigator’s opinion could compromise patient safety or the interpretation of study results.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	07 Apr 2022	2
Bulgaria	Not Recruiting	07 Apr 2022	85
Estonia	Not Recruiting	07 Apr 2022	14
Latvia	Not Recruiting	07 Apr 2022	38
Lithuania	Not Recruiting	07 Apr 2022	7
Poland	Not Recruiting	07 Apr 2022	7
Spain	Not Recruiting	07 Apr 2022	8