The OLYMPUS Study - Optimized DeLivery of Mitomycin for Primary UTUC Study

Study Overview
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Brief Summary
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The study is investigating the ability of UroGen's UGN-101 to treat urothelial carcinoma tumors from the upper urinary tract.

Detailed Description
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Trial TC-UT-03 is a prospective, open label, single-arm trial, designed to assess the efficacy, safety, and tolerability of treatment with UGN-101 instilled in the upper urinary system of patients with non-invasive low-grade (LG), Upper Tract Urothelial Carcinoma (UTUC). Upon signing of informed consent, the patients will undergo a screening visit for eligibility evaluation. Eligible patients will be treated with UGN-101 once weekly for a total of 6 times; in a retrograde fashion. Patients who will demonstrate complete response (CR) will be treated with UGN-101 once monthly as a maintenance therapy for a total of 11 instillations or up to the first recurrence whichever comes first. Five (5) weeks (± 1 w) following the last instillation, the Primary Disease Evaluation (PDE) Visit, during which safety and efficacy will be assessed, will take place. During this visit, the ablative effect of the UGN-101 will be assessed visually, by upper tract washed urine cytology, and if there are remaining tumors, by biopsy or brush biopsy if technically feasible. Patient demonstrating CR at PDE will undergo monthly maintenance instillations of UGN-101 up to 11 months post PDE. Safety follow-up for these patients will be done until one month post last instillation or at the end of the follow-up period in FU visit 12, which is the earlier. For patients who did not demonstrate Complete Response, to the extent that it is possible, all remaining tumors lesions will be biopsied. The patients shall undergo any additional surgical or other treatment the Principal Investigator (PI) decides deem necessary to remove remaining tumor. An independent Data Monitoring Committee (DMC) was assigned to this trial. Accumulating safety, tolerability and efficacy data will be monitored periodically by the DMC according to a pre-specified process and frequency detailed in the DMC charter.

Official Title
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A Phase 3 Multicenter Trial Evaluating the Efficacy and Safety of UGN-101 on Ablation of Upper Urinary Tract Urothelial Carcinoma

Conditions
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Carcinoma, Transitional Cell, Transitional Cell Carcinoma of Renal Pelvis

Intervention / Treatment
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* Drug: UGN-101 instillations


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Patient is at least 18 years of age. Naive or recurrent patients with low grade (LG), non-invasive Upper Tract Urothelial Carcinoma (UTUC) in the pyelocalyceal system. Patient has at least one (1) measurable papillary LG tumor, evaluated visually, ≤ 15 mm. The largest lesion should not exceed 15mm. Biopsy taken from one or more tumors located above the ureteropelvic junction (UPJ) showing LG urothelial carcinoma. Diagnosed not more than 2 months prior to the screening. Patient should have at least one remaining papillary LG tumor evaluated visually with a diameter of at least 5 mm. Wash urine cytology sampled from the pyelocalyceal system documenting the absence of High Grade (HG) urothelial cancer, diagnosed not more than 2 months prior to the screening. Patient with bilateral LG UTUC may be enrolled if at least one side meets the inclusion criteria for the trial and if the other kidney does not require further treatments (The other kidney can be treated prior to the beginning of the study). Main Exclusion Criteria: Patient received Bacille de Calmette et Guérin (BCG) treatment for Urothelial carcinoma (UC) during the 6 months prior to Visit 1. The patient has untreated concurrent urothelial cancer in other locations other than the target area (unless treated during screening) Carcinoma in situ (CIS) in the past in the urinary tract. Patient has a history of invasive urothelial carcinoma in the urinary tract during the past 5 (Five) years. Patient has a history of high grade papillary urothelial carcinoma in the urinary tract during the past 2 (Two) years. Patient is actively being treated or intends to be treated with systemic chemotherapy during the duration of the trial.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UGN-101 instillations<br>The Mitomycin C (MMC) concentration of UGN-101 to be used in this trial will be 4 mg MMC per 1 mL of TC-3 gel, maximum dose is 15ml. 6 once weekly intravesical instillations for the ablation treatment. | Drug: UGN-101 instillations<br>* Treatment with UGN-101 once weekly for a total of 6 times; in a retrograde fashion. Patients who will demonstrate complete response (CR) will be treated with UGN-101 once monthly as a maintenance therapy for a total of 11 instillations or up to the first recurrence whichever comes first.<br>* Other names: UGN-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Efficacy Endpoint Was the Number of Patients Attaining Complete Response (CR) at the End of the Treatment Period (PDE Visit). | The primary efficacy endpoint was the number of patients attaining complete response (CR) at the end of the treatment period (Primary Disease Evaluation (PDE) visit). The CR was defined dichotomously as Success if CR was confirmed at PDE visit (or relevant follow-up), and Failure otherwise. | An average of 11 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Key Secondary Efficacy Endpoint Was Long-term Durability of Complete Response (CR): Number of Patients Who Maintained CR at 12 Month Post PDE Visit. This Endpoint Was Defined Only for Those Patients Who Achieved CR at the PDE Visit. | Continuously: Duration of CR or time-to-recurrence since the Primary Disease Evaluation (PDE) Visit (i.e., time in days from the visit at which CR was determined until recurrence or censoring). This endpoint served as the main long-term durability endpoint. Dichotomously: Success if CR was still present at the 12 month post-PDE Visit (at Follow-Up Visit 4), and Failure otherwise. This endpoint served as a supportive long-term durability endpoint. | 12 months | 
| Durability of Complete Response (CR) for Each Follow-up Time Point. | Durability of CR defined dichotomously as Success if CR was achieved at Primary Disease Evaluation (PDE) visit and remained at follow-up Visit 1, Visit 2 and Visit 3 (3, 6, 9 and 12 months post PDE visit), and Failure otherwise. | 3, 6, 9 and 12 months | 
| Clinical Benefit for Patients With Partial Response (PR) at the Primary Disease Evaluation (PDE) Visit. Clinical Benefit Endpoint Was Analyzed Using the Intent-to-Treat (ITT) Analysis Set, Including Patients Who Achieved Partial Response at PDE Visit. | Clinical benefit for patients with partial response (PR) at the PDE visit. Clinical benefit endpoint was analyzed using the Intent-to-Treat (ITT) Analysis Set, including patients who achieved partial response at PDE Visit.Partial response at PDE visit will be defined dichotomously, similarly to the primary efficacy endpoint. For subjects with partial response at PDE visit, originally planned and actual treatments will be compared. | An average of 11 weeks | 
| Pharmacokinetic: The PK Profiles of the First UGN-101 Instillation in the Blood Were to be Examined for the First 6 Patients. | Cmax: maximum plasma concentration Analysis of individual plasma concentration versus time profiles showed that at 6 hours post instillation, the plasma concentrations of all 6 patients were below 2 ng/mL, with the plasma concentration of one patient dropping below the LOQ (i.e., < 0.100 ng/mL). The mean Cmax was 6.24 ng/mL (range: 2.43 to 12.80 ng/mL). The highest individual observed Cmax value of 12.80 ng/mL was 187-fold and 40 fold lower than the observed Cmax level following an intravenous bolus dose of 30 mg or 10 mg mitomycin (2.4 μg/mL and 0.52 μg/mL, respectively) and is 31 fold lower than the threshold value of 400 ng/mL for myelosuppression observed with mitomycin. | Blood samples were collected at 0 minutes (pre-dose) and 30 minutes, 1, 2, 3, 4, 5, and 6 hours following the first instillation of UGN-101 | 
| Pharmacokinetic: The PK Profiles of the First UGN-101 Instillation in the Blood Were to be Examined for the First 6 Patients. | Tmax: time to maximum plasma concentration Analysis of individual plasma concentration versus time profiles showed that at 6 hours post instillation, the plasma concentrations of all 6 patients were below 2 ng/mL, with the plasma concentration of one patient dropping below the LOQ (i.e., < 0.100 ng/mL). The mean Cmax was 6.24 ng/mL (range: 2.43 to 12.80 ng/mL), and the Tmax was 1.79 hours (range: 0.50 to 5.17 hours) after instillation. The highest individual observed Cmax value of 12.80 ng/mL was 187-fold and 40 fold lower than the observed Cmax level following an intravenous bolus dose of 30 mg or 10 mg mitomycin (2.4 μg/mL and 0.52 μg/mL, respectively) and is 31 fold lower than the threshold value of 400 ng/mL for myelosuppression observed with mitomycin. | Blood samples were collected at 0 minutes (pre-dose) and 30 minutes, 1, 2, 3, 4, 5, and 6 hours following the first instillation with UGN-101 | 
| Pharmacokinetic: The PK Profiles of the First UGN-101 Instillation in the Blood Were to be Examined for the First 6 Patients. | Half-life (t½): terminal half-life The mean apparent t½ following instillation of mitomycin into the upper urinary tract (UUT) was 1.27 hours (76 minutes), which was longer than the true t½ of mitomycin following a 30 mg bolus injection (mean t½ value of approximately 17 minutes). The apparent t½ demonstrates that UGN-101 dissolved gradually, resulting in prolonged exposure of mitomycin following local instillation into the UUT. | Blood samples were collected at 0 minutes (pre-dose) and 30 minutes, 1, 2, 3, 4, 5, and 6 hours following the first instillation with UGN-101 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TC-3, T1, Gel, Local, Mitomycin C, Prolonged Release, Slow Release, Kidney Sparing, T0, Low Grade, Transitional Cell Carcinoma of Renal Pelvis, TCC, UGN-101, UTUC, Ureteral, Upper Tract, Carcinoma, Kidney, Renal