Clinical trial NCT04688931: A Phase 3 Study of UGN-102 for Low-Grade Intermediate-Risk Non-Muscle Invasive Bladder Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Bladder Cancer
Urothelial Carcinoma
Urothelial Carcinoma Bladder
Keywords: 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
Lead sponsor: UroGen Pharma Ltd.
Sponsor class: INDUSTRY
First posted: 2020-12-30
Enrollment: 282
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This global, randomized, controlled, open-label Phase 3 study was 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: Eligible patients were randomized in a 1:1 ratio to UGN-102 ± TURBT or TURBT alone. Randomization was stratified by the presence of a previous LG-NMIBC episode within 1 year of the current diagnosis (yes or no). Starting on 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 underwent TURBT.

All patients returned to the clinic approximately 3 months after the start of treatment for a disease assessment visit. Response to treatment was determined based on visual observation (white light cystoscopy), histopathology of any remaining or new lesions, and voiding urine cytology. Patients confirmed to have a complete response (CR), defined as having no detectable disease (NDD) in the bladder, received no further treatment and entered the Follow-up Period of the study. Patients confirmed to have a non-complete response (NCR) due to residual LG disease in either treatment arm underwent TURBT of any remaining lesions and then entered the Follow-up Period of the study.

During the Follow-up Period, patients returned to the clinic every 3 months to determine if they remained disease free. Patients remained on study until completion of all follow-up visits or until disease recurrence, disease progression, or death was documented, whichever occurred first. Patients determined to have a protocol-defined recurrence or progression at any follow-up or unscheduled visit were 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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Patient who has newly diagnosed or historic LG-NMIBC (Ta) histologically confirmed by cold cup biopsy at Screening or within 8 weeks of Screening.
3. 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).
4. Negative voiding cytology for HG disease within 6 weeks of Screening.
5. 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.
6. Has no evidence of active urinary tract infection (UTI).
7. 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:

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 1 year.
3. History of HG papillary UC in the past 2 years.
4. Known allergy or sensitivity to mitomycin that in the investigator's opinion cannot be readily managed.
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 UC.
9. Current tumor stage of T1.
10. 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.
11. History of prior treatment with an intravesical chemotherapeutic agent except for a single dose of chemotherapy immediately after any previous TURBT.
12. Has previously participated in a study in which they received UGN-102.
13. Has participated in a study with an investigational agent or device within 30 days of randomization.

Primary outcomes:
measure: Disease-free Survival (DFS)
timeFrame: 15 months
Secondary outcomes:
measure: Time to Recurrence (TTR)
timeFrame: 15 months
measure: Complete Response Rate (CRR)
timeFrame: 3 months
measure: Duration of Response (DOR)
timeFrame: 12 months
measure: Observed CRR at Scheduled Disease Assessment Time Points
timeFrame: 12 months
measure: Number of TURBTs
timeFrame: 3 months
measure: Changes From Baseline in Health-related Quality of Life
timeFrame: Pre-treatment to 3 months after the start of treatment
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs of Special Interest
timeFrame: Up to 21 months
measure: Number of Participants With Post-baseline Potentially Clinically Significant (PCS) Hematology Values
timeFrame: Up to 6 months
measure: Number of Participants With Post-baseline PCS Serum Chemistry Values
timeFrame: Up to 6 months
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Institute of Urology, PLLC
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: Urology Group of Southern California
state: California
city: San Diego
country: United States
facility: San Diego Clinical Trials
state: California
city: Santa Monica
country: United States
facility: Providence Saint John's Health Center
state: California
city: Sherman Oaks
country: United States
facility: Skyline Urology
state: California
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
city: Lake Barrington
country: United States
facility: Comprehensive Urologic Care
state: Illinois
city: Jeffersonville
country: United States
facility: First Urology, PSC
state: Indiana
city: Wichita
country: United States
facility: Wichita Urology Group
state: Kansas
city: Shreveport
country: United States
facility: Regional Urology, LLC
state: Louisiana
city: Baltimore
country: United States
facility: Chesapeake Urology Research Associates
state: Maryland
city: Hanover
country: United States
facility: Chesapeake Urology Research Associates
state: Maryland
city: Omaha
country: United States
facility: Adult & Pediatric Urology, PC
state: Nebraska
city: Las Vegas
country: United States
facility: Urology Center
state: Nevada
city: Bloomfield
country: United States
facility: New Jersey Urology
state: New Jersey
city: Englewood
country: United States
facility: New Jersey Urology
state: New Jersey
city: Morristown
country: United States
facility: Garden State Urology
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Cheektowaga
country: United States
facility: Great Lakes Physician dba WNY Urology Associates
state: New York
city: Garden City
country: United States
facility: AccuMed Research Associates
state: New York
city: New York
country: United States
facility: Manhattan Medical Research
state: New York
city: Stony Brook
country: United States
facility: Stony Brook Cancer Center
state: New York
city: Syracuse
country: United States
facility: Associated Medical Professionals of NY, PLLC
state: New York
city: Chapel Hill
country: United States
facility: UNC Chapel Hill Memorial Hospital
state: North Carolina
city: Middleburg Heights
country: United States
facility: Clinical Research Solutions
state: Ohio
city: Bala-Cynwyd
country: United States
facility: Centers for Advanced Urology, LLP d.b.a Mid-Atlantic Urology
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center and College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: San Antonio
country: United States
facility: Urology San Antonio
state: Texas
city: Blagoevgrad
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Puls", Department of Urology
city: Blagoevgrad
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment - Blagoevgrad
city: Burgas
country: Bulgaria
facility: Complex Oncology Center - Burgas
city: Gabrovo
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Dr. Tota Venkova", Gabrovo, Department of Urology
city: Lom
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Sveti Nikolai Chudotvorets", Lom
city: Montana
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "City Clinic - Sveti Georgi"
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski", Pleven, Urology Clinic
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Sveta Marina" - Pleven, Department of Urology
city: Plovdiv
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Park Hospital
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Sveti Georgi", Plovdiv, Clinic of Urology
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment, Plovdiv, Department of Urology
city: Ruse
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment 'Kanev', Ruse, Department of Urology
city: Shumen
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment - Shumen, Shumen, Department of Urology
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Aleksandrovska", Sofia, Urology Clinic
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov", Sofia, Urology Clinic
city: Targovishte
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment - Targovishte
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment, Varna part of Military Medical Academy, Clinic of Urology
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Sveta Anna", Varna, Urology Clinic
city: Varna
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Sveta Marina"
city: Veliko Tarnovo
country: Bulgaria
facility: Multiprofile Regional Hospital for Active Treatment "Dr. Stefan Cherkezov", Veliko Tarnovo, Department of Urology
city: Vratsa
country: Bulgaria
facility: First Private Hospital Vratsa, Department of Urology
city: Yambol
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Sveti Pantaleymon", Yambol, Department of Urology
city: Kohtla-Järve
country: Estonia
facility: East Viru Central Hospital, Surgery Clinic
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital Ltd., Surgery Clinic, Centre of Urology
city: Tallinn
country: Estonia
facility: West Tallinn Central Hospital Ltd., Department of Urology
city: Tallinn
country: Estonia
facility: North Estonia Medical Centre Foundation Ltd., Surgery Clinic, General and Oncology Urology Centre
city: Tartu
country: Estonia
facility: Tartu University Hospital, Surgery Clinic, Department of Urology and Kidney Transplantation
city: Tbilisi
country: Georgia
facility: LTD Central University Clinic After Academic N. Kipshidze
city: Tbilisi
country: Georgia
facility: JSC Jerarsi, Department of Urology
city: Tbilisi
country: Georgia
facility: LTD Acad. F. Todua Medical Center - LTD Research Institute of Clinical Medicine, Clinical Research Department
city: Tbilisi
country: Georgia
facility: LTD Gidmedi, Urology Department
city: Tbilisi
country: Georgia
facility: LTD L. Managadze National Center of Urology, Department of Urology
city: Tbilisi
country: Georgia
facility: LTD MMT Hospital, Urology Department
city: Tbilisi
country: Georgia
facility: Malkhaz Katsiashvili Multiprofile Emergency Medicine Center LTD, Department of Urology
city: Tbilisi
country: Georgia
facility: Pineo Medical Ecosystem Ltd., Department of Urology
city: Tbilisi
country: Georgia
facility: Tbilisi State Medical University and Ingorokva High Technology Medical Center University Clinic LTD, Urology Department
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical Center
city: H̱olon
country: Israel
facility: Edith Wolfson Medical Center
city: Petah tikva
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Liepāja
country: Latvia
facility: Liepajas Regional Hospital, Urology Department
city: Riga
country: Latvia
facility: P. Stradins Clinical University Hospital, Center for Urology
city: Riga
country: Latvia
facility: LLC Riga East University Hospital, Clinic of Urology and Oncologic Urology
city: Riga
country: Latvia
facility: Daugavpils Regional Hospital, Urology Department
city: Bydgoszcz
country: Poland
facility: Jan Biziel University Hospital #2 in Bydgoszcz, Teaching Department of Urology
city: Gliwice
country: Poland
facility: AKMED
city: Katowice
country: Poland
facility: Prof.E Michalowski Specialist Hospital
city: Kraków
country: Poland
facility: SCM sp. z o.o. (LLC)
city: Warsaw
country: Poland
facility: "City Clinic" Limited Liability Company
city: Warsaw
country: Poland
facility: Miedzyleski Specialist Hospital in Warsaw, Department of Urology
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital #1
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk A.I. Kryzhanovsky Regional Oncology Center
city: Moscow
country: Russian Federation
facility: D.D. Pletnyov City Clinical Hospital, Department of Oncourology
city: Moscow
country: Russian Federation
facility: Moscow City Oncology Hospital #62
city: Murmansk
country: Russian Federation
facility: Murmansk Bayandin Regional Clinical Hospital
city: Nizhny Novgorod
country: Russian Federation
facility: Privolzhsky Regional Medical Center, Urology Department
city: Obninsk
country: Russian Federation
facility: Tsyb Medical Radiology Research Center, Oncourology Department
city: Omsk
country: Russian Federation
facility: Clinical Oncology Center, Department of Urology and Oncology
city: Penza
country: Russian Federation
facility: N.N. Burdenko Penza Regional Clinical Hospital, Department of Urology
city: Pyatigorsk
country: Russian Federation
facility: Pyatigorsk City Clinical Hospital, Department of Urology
city: Saint Petersburg
country: Russian Federation
facility: Leningrad Regional Clinical Oncology Center, Department of Chemotherapy
city: Saint Petersburg
country: Russian Federation
facility: Aleksandrovskaya City Hospital, Department of Urology
city: Saint Petersburg
country: Russian Federation
facility: St. Petersburg Clinical Hospital under the Russian Academy of Sciences, Department of Urology
city: Saint Petersburg
country: Russian Federation
facility: A.M. Nikiforov Russian Center for Emergency and Radiology Medicine, Department of Urology
city: Saint Petersburg
country: Russian Federation
facility: St. Luka Clinical Hospital, Department of Urology
city: Saint Petersburg
country: Russian Federation
facility: St.-Petersburg Scientific Research Institute of Phthisiopulmonology
city: Saint Petersburg
country: Russian Federation
facility: Medical and Sanitary Unit #70 of "Passazhiravtotrans"
city: Saint Petersburg
country: Russian Federation
facility: I.I. Mechnikov North-Western State Medical University, Department of Urology
city: Saint Petersburg
country: Russian Federation
facility: Railway Clinical Hospital under OAO Russian Railways
city: Saint Petersburg
country: Russian Federation
facility: First I.P. Pavlov State Medical University of St. Petersburg
city: Saint Petersburg
country: Russian Federation
facility: N.N. Petrov National Medical Research Center of Oncology, Oncourology Department
city: Saint Petersburg
country: Russian Federation
facility: City Hospital #15, Urology Department #12
city: Tomsk
country: Russian Federation
facility: Siberian State Medical University
city: Tyumen
country: Russian Federation
facility: Regional Oncology Center, Tyumen, Oncology Department
city: Ufa
country: Russian Federation
facility: Republican Clinical Oncology Center
city: Volzhskiy
country: Russian Federation
facility: Volgograd Regional Center for Urology and Nephrology, Urology Department
city: Yaroslavl
country: Russian Federation
facility: Medical Center for Diagnostics and Prevention Plus
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia, Clinic of Urology
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Bezanijska Kosa, Clinic of Surgery, Department of Urology
city: Belgrade
country: Serbia
facility: Clinical Hospital Center Zemun, Urology unit
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac, Clinic of Urology, Nephrology and Dialysis
city: Chernihiv
country: Ukraine
facility: Chernihiv Medical Center of Modern Oncology
city: Chernivtsi
country: Ukraine
facility: Regional Communal Noncommercial Enterprise: Chernivtsi Regional Clinical Hospital
city: Chernivtsi
country: Ukraine
facility: Regional Municipal Non-commercial Enterprise "Chernivtsi Emergency Medical Hospital", Urology Department
city: Dnipro
country: Ukraine
facility: Public Enterprise "Dnipropetrovsk I.I. Mechnikov Regional Clinical Hospital" under Dnipropetrovsk Regional Council, Urology Department #2
city: Dnipro
country: Ukraine
facility: Public Non-Profit Enterprise "City Clinical Hospital #6" under Dnipro City Council, Department of Urology
city: Dnipro
country: Ukraine
facility: Public Non-Profit Enterprise "City Clinical Hospital #4" under Dnipro City Council, Department of Geriatric Urology Care
city: Ivano-Frankivs'k
country: Ukraine
facility: Public Non-Profit Enterprise "Regional Clinical Hospital under Ivano-Frankivsk Regional Council", Department of Urology
city: Ivano-Frankivs'k
country: Ukraine
facility: Prykarpattia Clinical Oncology Center under Ivano-Frankivsk Regional Council
city: Kharkiv
country: Ukraine
facility: Public Non-Profit Enterprise under Kharkiv Regional Council "V.I. Shapoval Regional Medical Clinical Center for Urology and Nephrology", Urology Department #5
city: Kharkiv
country: Ukraine
facility: Communal Non-Profit Enterprise "Regional Center of Oncology", Department of Oncourology
city: Kharkiv
country: Ukraine
facility: Public Non-Profit Enterprise under Kharkiv Regional Council "Regional Clinical Specialized Center for Radiation Protection of Population", Department of Surgery
city: Kherson
country: Ukraine
facility: Communal non-commercial enterprise of Kherson regional council "Kherson regional oncological dispensary"
city: Kyiv
country: Ukraine
facility: State Institution: Institute of Urology under the National Academy of Medical Sciences of Ukraine
city: Luts'k
country: Ukraine
facility: Volyn Regional Medical Oncology Centre
city: Lviv
country: Ukraine
facility: Communal Noncommercial Enterprise of Lviv Regional Council "Lviv Regional Clinical Hospital", Department of Urology
city: Lviv
country: Ukraine
facility: Public Non-profit Enterprise under Lviv Regional Council: Lviv Regional Treatment and Diagnostics Oncology Center
city: Lviv
country: Ukraine
facility: Municipal Non-Profit Enterprise "Lviv Clinical Emergency Care Hospital", Department of Urology
city: Odesa
country: Ukraine
facility: Public Non-Profit Enterprise "Odesa Regional Clinical Hospital" under Odesa Regional Council
city: Odesa
country: Ukraine
facility: Public Non-Profit Enterprise "City Clinical Hospital #10" under Odesa City Council, Department of Urology and Nephrology
city: Sumy
country: Ukraine
facility: Sumy Regional Clinical Oncology Center
city: Ternopil'
country: Ukraine
facility: Public Non-Profit Enterprise Ternopil Regional Clinical Oncology Center, Department of Chemotherapy
city: Uzhhorod
country: Ukraine
facility: Municipal non-profit enterprise "Transcarpathian antitumor center" of the Transcarpathian Regional Council
city: Vinnytsia
country: Ukraine
facility: Communal Nonprofit Enterprise "Podilsky Regional Center of Oncology of Vinnytsia Regional Council"
city: Zaporizhia
country: Ukraine
facility: Municipal Nonprofit Enterprise: Zaporizhia Regional Clinical Hospital under Zaporizhia Regional Council, Department of Urology
Study officials:
affiliation: Atlantic Health System
name: Sandip Prasad, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Prasad SM, Huang WC, Shore ND, Hu B, Bjurlin M, Brown G, Genov P, Shishkov D, Khuskivadze A, Ganev T, Marchev D, Orlov I, Kopyltsov E, Zubarev V, Nosov A, Komlev D, Burger B, Raju S, Meads A, Schoenberg M. Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 +/- Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS). J Urol. 2023 Oct;210(4):619-629. doi: 10.1097/JU.0000000000003645. Epub 2023 Aug 7.