A Phase 2b Study of UGN-102 for Low Grade Intermediate Risk Non-Muscle-Invasive Bladder Cancer (OPTIMA II)

A Phase 2b, Single-Arm, Multicenter Trial to Evaluate the Efficacy and Safety of UGN-102 as Primary Chemoablative Therapy in Patients With Low Grade (LG) Non-Muscle-Invasive Bladder Cancer (NMIBC) at Intermediate Risk of Recurrence

This Phase 2b, single-arm, multicenter study evaluated the efficacy and safety of UGN-102 as primary chemoablative therapy in patients with low grade intermediate risk non-muscle-invasive bladder cancer (LG IR NMIBC).

Study Overview

• Status: Completed
• Conditions: Bladder Cancer; Urothelial Carcinoma Bladder; Urothelial Carcinoma
• Intervention / Treatment: Drug: UGN-102

Detailed Description

Eligible patients were treated with 6 once-weekly intravesical instillations of UGN-102.

The ablative effect of UGN-102 was evaluated at the 3-month Visit, which occurred 5 weeks ± 1 week after the last weekly instillation (3 months after initiation of study drug). Response was determined based on visual evaluation by cystoscopy (appearance, number, and size of the lesions) and, if there were remaining lesions, by histopathology of the remaining lesions. Complete response (CR) was defined as having no detectable disease (NDD) and was assessed visually during cystoscopy and also by urine cytology. In the event that the investigator was not sure, and there was suspect tissue, a small biopsy was taken from the suspect tissue to confirm CR in addition to cystoscopy and urine cytology.

Patients who achieved a CR continued to have monthly telephone contacts to document any adverse events (AEs) and changes in concomitant medications and were assessed at 6, 9, and 12 months after the first instillation of UGN-102 for evidence of disease recurrence. Patients who had a non-complete response (non-CR) discontinued the study and continued with standard of care according to their treating physician.

Safety was determined based on a review of AEs, laboratory assessments, and physical examination findings.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 3436212
    • Carmel Medical Center
  • Petah tikva, Israel, 49372
    • Rabin Medical Center
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Arkansas Urology
  • California
    • Loma Linda, California, United States, 92350
      • Loma Linda University
    • Santa Monica, California, United States, 90404
      • Providence Medical Institute
  • Florida
    • Pompano Beach, Florida, United States, 33060
      • Clinical Research Center of Florida
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • John Hopkins University
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Adult & Pediatric Urology, PC
  • Nevada
    • Las Vegas, Nevada, United States, 89144
      • Urology Las Vegas
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10016
      • Manhattan Medical Research
    • New York, New York, United States, 10461
      • Montefiore Medical Center (Albert Einstein)
    • New York, New York, United States, 14225
      • Western New York Urology Associates
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27572
      • The University of North Carolina
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey State College
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Nashville, Tennessee, United States, 37209
      • Urology Associates, PC
  • Texas
    • Fredericksburg, Texas, United States, 78233
      • Urology San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Willing and able to sign an informed consent and comply with the protocol.
2. Has newly diagnosed or historic LG NMIBC (Ta) histologically confirmed by cold cup biopsy at screening or within 6 weeks of screening.

3. Is at intermediate risk of recurrence, 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).
4. Has negative voiding cytology for high grade (HG) disease at or within 6 weeks of enrollment.
5. Willing to use 2 acceptable forms of effective contraception from enrollment through 6 months post treatment if the participant is female or the female partner of a male participant and is of childbearing potential (defined as premenopausal women who have not been sterilized).

6. Has adequate organ and bone marrow function as determined by routine laboratory tests as below:

   • Leukocytes ≥ 3,000 per μL;
   • Absolute neutrophil count ≥ 1,500 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 ≤ 2.5 × ULN;
   • Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min.

7. Has no evidence of active urinary tract infection (UTI) at Screening and Baseline visits.

   • In the case of symptomatic UTI, the patient will be treated with a full course of antibiotics, and study drug will be postponed until resolution. In the case of asymptomatic bacteriuria, the use of prophylactic antibiotics and postponement of study drug is left to the discretion of the Principal Investigator (PI).

Exclusion Criteria:

1. History of carcinoma in situ (CIS) on preliminary cystoscopy within 5 years of enrollment.
2. Received Bacillus Calmette-Guérin (BCG) treatment for urothelial carcinoma (UC) within previous 2 years.
3. History of HG papillary UC in the past 2 years.
4. Known allergy or sensitivity to mitomycin.
5. Clinically significant urethral stricture that would preclude passage of a urethral catheter.
6. History of pelvic radiotherapy.

7. History of:

   • Neurogenic bladder;
   • Active urinary retention;
   • Any other condition that would prohibit normal voiding.
8. Past or current muscle invasive (ie, T2, T3, T4) or metastatic UC or concurrent upper tract urothelial carcinoma (UTUC).
9. Has participated in a study with an investigational agent or device within 30 days of enrollment.
10. History of prior treatment with an intravesical chemotherapeutic agent with the exception of a single dose of chemotherapy immediately after any previous transurethral resection of bladder tumors (TURBT).
11. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: UGN-102; Patients were treated with 6 once-weekly intravesical instillations of UGN-102.

Drug: UGN-102; 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. The UGN-102 admixture for intravesical instillations contains 75 mg mitomycin in 56 mL admixture (1.33 mg mitomycin per 1 mL).; Other Names: UGN-102 (mitomycin) for intravesical solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate for UGN-102 Treatment	To evaluate the tumor ablative effect of UGN-102 in patients with LG NMIBC. CR rate was defined as the percentage of patients with no detectable disease (NDD) as determined by cystoscopy, for cause biopsy, and urine cytology.	3 months after the first instillation of UGN-102

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durable Complete Response (DCR) Rate	To evaluate the durability of response in patients with LG NMIBC who achieve CR. DCR rate was defined as the percentage of patients who maintained CR at the respective time point.	6, 9, and 12 months after the first instillation of UGN-102
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Study Drug or Procedure Related TEAEs, TEAEs by Maximum Severity, TEAEs Leading to Treatment Discontinuation, and Serious TEAEs.	The number of patients with each type of event will be summarized. Adverse event severity was graded according to Common Terminology Criteria for Adverse Events version 5.0 as follows: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe or medically significant), Grade 4 (life-threatening), Grade 5 (fatal).	Up to 12 months
Number of Participants With Post-baseline Potentially Clinically Significant (PCS) Laboratory Values	The number of patients who met PCS criteria for chemistry or hematology parameters post-baseline will be summarized	Up to 12 months
Number of Participants With Post-baseline PCS Vital Signs Values	The number of patients who met PCS criteria for vital signs parameters post-baseline will be summarized	Up to 12 months
Number of Participants With Post-baseline Clinically Significant (CS) Physical Examination Findings	The number of patients with abnormal, CS physical examination findings post-baseline will be summarized	Up to 12 months
Number of Participants With Post-baseline CS Urology-oriented Physical Examination Findings	The number of patients with abnormal, CS urology-oriented physical examination findings post-baseline will be summarized	Up to 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitomycin Plasma Concentrations	Mitomycin plasma concentrations were assessed in a subset of 6 patients treated with UGN-102	0 (pre-instillation), 0.5, 1, 2, 3, 4, 5, and 6 hours after the first instillation of UGN-102
Mitomycin Area Under the Plasma Concentration-time Curve (AUC)	Mitomycin AUC was assessed in a subset of 6 patients treated with UGN-102	0 (pre-instillation) to 6 hours after the first instillation of UGN-102
Mitomycin Maximum Plasma Concentration (Cmax)	Mitomycin Cmax was assessed in a subset of 6 patients treated with UGN-102	0 (pre-instillation), 0.5, 1, 2, 3, 4, 5, and 6 hours after the first instillation of UGN-102

Collaborators and Investigators

• Sponsor: UroGen Pharma Ltd.
• Investigators: Study Director: Elyse Seltzer, MD, UroGen Pharma

Publications and helpful links

General Publications

• Chevli KK, Shore ND, Trainer A, Smith AB, Saltzstein D, Ehrlich Y, Raman JD, Friedman B, D'Anna R, Morris D, Hu B, Tyson M, Sankin A, Kates M, Linehan J, Scherr D, Kester S, Verni M, Chamie K, Karsh L, Cinman A, Meads A, Lahiri S, Malinowski M, Gabai N, Raju S, Schoenberg M, Seltzer E, Huang WC. Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial. J Urol. 2022 Jan;207(1):61-69. doi: 10.1097/JU.0000000000002186. Epub 2021 Aug 26.
• Stover AM, Basak R, Mueller D, Lipman R, Teal R, Hilton A, Giannone K, Waheed M, Smith AB. Minimal Patient-Reported Side Effects for a Chemoablative Gel (UGN-102) Used as Frontline Treatment in Adults with Nonmuscle-Invasive Bladder Cancer. J Urol. 2022 Sep;208(3):580-588. doi: 10.1097/JU.0000000000002747. Epub 2022 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2018
• Primary Completion (Actual): January 3, 2020
• Study Completion (Actual): October 21, 2020

Study Registration Dates

• First Submitted: May 8, 2018
• First Submitted That Met QC Criteria: June 3, 2018
• First Posted (Actual): June 15, 2018

Study Record Updates

• Last Update Posted (Actual): September 16, 2022
• Last Update Submitted That Met QC Criteria: September 1, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: NMIBC; Non-muscle invasive bladder cancer; Mitomycin; Low grade non-muscle invasive bladder cancer; Intermediate risk non-muscle invasive bladder cancer; UGN-102
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Mitomycins; Mitomycin
• Other Study ID Numbers: TC-BC-12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No