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

Carcinoma, Transitional Cell Clinical Trial

— Olympus  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02793128
• Other study ID #: TC-UT-03-P
• Status: Completed
• Phase: Phase 3
• Start date: April 4, 2017
• Est. completion date: March 5, 2020

Study information

• Verified date: December 2020
• Source: UroGen Pharma Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 71
• Est. completion date: March 5, 2020
• Est. primary completion date: April 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Main Inclusion Criteria:

1. Patient is at least 18 years of age.

2. Naive or recurrent patients with low grade (LG), non-invasive Upper Tract Urothelial Carcinoma (UTUC) in the pyelocalyceal system.

3. Patient has at least one (1) measurable papillary LG tumor, evaluated visually, = 15 mm. The largest lesion should not exceed 15mm.

4. 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.

5. Patient should have at least one remaining papillary LG tumor evaluated visually with a diameter of at least 5 mm.

6. 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.

7. 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:

1. Patient received Bacille de Calmette et Guérin (BCG) treatment for Urothelial carcinoma (UC) during the 6 months prior to Visit 1.

2. The patient has untreated concurrent urothelial cancer in other locations other than the target area (unless treated during screening)

3. Carcinoma in situ (CIS) in the past in the urinary tract.

4. Patient has a history of invasive urothelial carcinoma in the urinary tract during the past 5 (Five) years.

5. Patient has a history of high grade papillary urothelial carcinoma in the urinary tract during the past 2 (Two) years.

6. Patient is actively being treated or intends to be treated with systemic chemotherapy during the duration of the trial.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Transitional Cell Carcinoma of Renal Pelvis

Intervention

Drug:
• UGN-101 instillations
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.

Locations

Country	Name	City	State
Israel	Hasharon Hospital (Rabin Medical Center)	Petah Tikva
Israel	Sheba Medical Center	Ramat Gan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	John Hopkins University	Baltimore	Maryland
United States	Montefiore Medical Center (Albert Einstein)	Bronx	New York
United States	University of north carolina - chapel hill	Chapel Hill	North Carolina
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Penn State College of Medicine	Hershey	Pennsylvania
United States	Baylor College of Medicine	Houston	Texas
United States	MD Anderson	Houston	Texas
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	Urology Center Las Vegas	Las Vegas	Nevada
United States	Loma Linda Cancer Center	Loma Linda	California
United States	University of California	Los Angeles	California
United States	Loyola University Medical Center, Department of Urology	Maywood	Illinois
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical Center	New York	New York
United States	Thomas Jefferson University Hospitals	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Mayo Clinic health system	Rochester	Minnesota
United States	Providence Medical Institute	Santa Monica	California
United States	Seattle Cancer Care Alliance (University of Washington)	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
UroGen Pharma Ltd.

Countries where clinical trial is conducted

United States,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety Adverse Event Outcomes: Safety Was Monitored Throughout the Study by Reviewing Adverse Events (AEs).	Treatment-emergent AEs were most frequently reported from the Renal and urinary disorders system organ class (SOC), 59 (83.1%) patients, as expected, given the underlying indication of low grade (LG) Upper tract urothelial carcinoma (UTUC) in the study population, chemotherapeutic drug in a gel matrix instilled in the upper urinary tract (UUT), and the study procedure of treatment instillation via a ureteral catheter. The toxicity within the upper urinary tract was considered consistent with the disease under study and the mode of administration of UGN-101. Most events in the Renal and urinary disorders SOC were mild to moderate in severity and resolved. No new risks were identified and the overall safety profile was consistent with the known safety profile of endoscopic administration of intravesical mitomycin and of mitomycin. Overall, based on the safety and efficacy results to date, the benefit-risk profile of UGN-101 is favorable for the treatment of LG-UTUC.	Through study completion, an average of 15 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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