A Phase 3 Study of UGN-102 for Low Grade Intermediate Risk Non-Muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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This is a global, randomized, controlled, open-label Phase 3 study designed to assess the long-term efficacy and safety of UGN-102 (mitomycin) for intravesical solution with or without (±) transurethral resection of bladder tumors (TURBT) versus TURBT alone for the treatment of patients with low grade intermediate risk non-muscle invasive bladder cancer (LG IR NMIBC).

Detailed Description
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Eligible patients will be randomized in a 1:1 ratio to UGN-102 ± TURBT or TURBT alone. Randomization will be stratified by the presence of a previous LG NMIBC episode within 1 year of the current diagnosis (yes or no). Starting at Day 1, patients randomized to the UGN-102 ± TURBT arm will receive 6 weekly intravesical instillations of UGN-102 and patients randomized to the TURBT alone arm will undergo TURBT. Patients in both treatment arms will return to the clinic at approximately 3 months after the start of treatment to determine response to treatment. Patients confirmed to have a complete response (CR) will receive no further treatment and will enter the Follow-up Period of the study. Patients confirmed to have a non-complete response (NCR) will undergo TURBT of any remaining lesions and then enter the Follow-up Period of the study. During the Follow-up Period, patients will return to the clinic every 3 months to determine durability of response. Patients will remain on study until completion of all follow-up visits or until disease recurrence, disease progression, or death is documented, whichever occurs first. Patients determined to have a protocol-defined recurrence or progression at any follow-up or unscheduled visit will be considered to have completed the study and released to the care of their treating physician. Study enrollment was stopped early by the sponsor to pursue an alternative development strategy for UGN-102 in the treatment of bladder cancer. Patients who had consented at the time the trial terminated were permitted to continue, but follow-up was terminated once the last patient had been followed for 15 months after the start of treatment.

Official Title
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A Randomized, Controlled, Open-Label Study of the Efficacy, Durability, and Safety of UGN-102 With or Without TURBT in Patients With Low Grade Intermediate Risk Non-Muscle Invasive Bladder Cancer (LG IR NMIBC)

Conditions
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Bladder Cancer, Urothelial Carcinoma, Urothelial Carcinoma Bladder

Intervention / Treatment
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* Drug: UGN-102
* Procedure: TURBT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. Patient who has newly diagnosed or historic LG NMIBC (Ta) histologically confirmed by cold cup biopsy at Screening or within 8 weeks of Screening. Has intermediate risk disease, defined as having 1 or 2 of the following: Presence of multiple tumors; Solitary tumor > 3 cm; Recurrence (≥ 1 occurrence of LG NMIBC within 1 year of the current diagnosis). Negative voiding cytology for high grade (HG) disease within 6 weeks of Screening. Has adequate organ and bone marrow function as determined by the following routine laboratory tests: Leukocytes ≥ 3,000 cells per μL; Absolute neutrophil count ≥ 1,500 cells per μL; Platelets ≥ 100,000 per μL; Hemoglobin ≥ 9.0 g/dL; Total bilirubin ≤ 1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; Alkaline phosphatase (ALP) ≤ 2.5 × ULN; Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min. Has no evidence of active urinary tract infection (UTI). Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for clinical study participants. Women of childbearing potential (defined as premenopausal women who have not been sterilized), including female patients and female partners of male patients, must be willing to use 2 acceptable forms of effective contraception from enrollment through 6 months post-treatment. Exclusion Criteria: History of carcinoma in situ (CIS) on preliminary cystoscopy within 5 years of enrollment. Received Bacillus Calmette-Guérin (BCG) treatment for urothelial carcinoma (UC) within previous 1 year. History of HG papillary UC 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 pelvic radiotherapy. History of: Neurogenic bladder; Active urinary retention; Any other condition that would prohibit normal voiding. Past or current muscle invasive (ie, T2, T3, T4) or metastatic UC or concurrent upper tract UC. Current tumor grading of T1. 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 except for a single dose of chemotherapy immediately after any previous TURBT. Has previously participated in a study in which they received UGN-102. Has participated in a study with an investigational agent or device within 30 days of randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UGN-102 ± TURBT<br>6 weekly intravesical instillations of UGN-102 (75 mg mitomycin) starting on Day 1 + TURBT for patients who have a NCR at the 3-month Visit (3 months after the start of treatment with UGN-102). | Drug: UGN-102<br>* UGN-102 consists of mitomycin and sterile hydrogel (a proprietary thermally responsive gel) that is used to reconstitute mitomycin before instillation. The reverse thermal properties of UGN-102 allow for local administration of mitomycin as a liquid, with subsequent conversion to a semi-solid gel depot following instillation into the bladder.<br>* Other names: UGN-102 (mitomycin) for intravesical solution;Procedure: TURBT<br>* The current standard of care for treatment of LG IR NMIBC is TURBT under general anesthesia.<br>* Other names: Transurethral resection of bladder tumors;|
| Active Comparator: TURBT Alone<br>TURBT on Day 1 + repeat TURBT for patients who have a NCR at the 3-month Visit (3 months after the initial TURBT). | Procedure: TURBT<br>* The current standard of care for treatment of LG IR NMIBC is TURBT under general anesthesia.<br>* Other names: Transurethral resection of bladder tumors;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) | DFS is defined as the time from randomization until the earliest date of any of the following events: failure to be rendered free of local disease at the 3-month Visit (TURBT arm only), recurrence of LG disease after the 3-month Visit (ie, during the Follow-up Period), progression to HG disease, or death due to any cause. | Up to 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to recurrence (TTR) | TTR is defined as the time from randomization until the earliest date of any of the following events: failure to be rendered free of local disease at the 3-month Visit (TURBT arm only), recurrence of LG disease after the 3-month Visit (ie, during the Follow-up Period), or progression to HG disease. | Up to 21 months | 
| Complete response rate (CRR) | CRR is defined as the percentage of patients who achieve CR at the 3-month Visit. | 3 months | 
| Duration of response (DOR) | DOR is defined as the time from first documented CR until the earliest date of recurrence of LG disease, progression to HG disease, or death due to any cause. DOR applies only to patients who achieve CR at the 3-month Visit. | Up to 18 months | 
| Observed CRR at scheduled disease assessment time points | Observed CRR at scheduled disease assessment time points is defined as the percentage of patients who achieve CR at the 3-month Visit and maintain CR up to a particular follow-up visit. | Up to 21 months | 
| Incidence of TURBT | Incidence of TURBT is defined as the percentage of patients requiring TURBT and the average number of TURBTs per patient in each treatment arm. | 3 months | 
| Changes from baseline in health-related quality of life | The European Organisation for Research and Treatment of Cancer (EORTC) 24-item quality of life questionnaire for patients with NMIBC (QLQ-NMIBC24) is a patient-reported instrument that assesses 11 domains (urinary symptoms, malaise, future worries, bloating and flatulence, intravesical treatment issues, sexual intimacy, risk of contaminating partner, male sexual problems, female sexual problems, sexual function, and sexual enjoyment). Descriptive statistics will be used to summarize the scored scales for each of the domains and the change from baseline in the domain scores at each scheduled assessment time point. | Up to 21 months | 
| Incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of special interest, and abnormal clinical laboratory test results (hematology, serum chemistry, and urinalysis). | The percentage of patients with each type of event will be summarized. | Up to 21 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-muscle invasive bladder cancer, Low grade non-muscle invasive bladder cancer, Intermediate risk non-muscle invasive bladder cancer, NMIBC, UGN-102, Mitomycin, Transurethral resection of bladder tumors, TURBT