Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, A Mitomycin-Containing Reverse Thermal Gel (OLYMPUS): An Open-Label, Single-Arm, Phase 3 Trial

Background: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycincontaining reverse thermal gel.

Methods: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5–15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient’s renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4–6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128.

Findings: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47–71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1–12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment.

Interpretation: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients.

Nir Kleinmann, Surena F Matin, Phillip M Pierorazio, John L Gore, Ahmad Shabsigh, Brian Hu, Karim Chamie, Guilherme Godoy, Scott Hubosky, Marcelino Rivera, Michael O’Donnell, Marcus Quek, Jay D Raman, John J Knoedler, Douglas Scherr, Joshua Stern, Christopher Weight, Alon Weizer, Michael Woods, Hristos Kaimakliotis, Angela B Smith, Jennifer Linehan, Jonathan Coleman, Mitchell R Humphreys, Raymond Pak, David Lifshitz, Michael Verni, Mehrad Adibi, Mahul B Amin, Elyse Seltzer, Ifat Klein, Marina Konorty, Dalit Strauss-Ayali, Gil Hakim, Mark Schoenberg, Seth P Lerner

Department of Urology, Sheba Medical Center, Ramat Gan, Israel (N Kleinmann MD); Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA (Prof S F Matin MD, M Adibi MD); Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA (P M Pierorazio MD); Department of Urology, University of Washington Medical Center, Seattle, WA, USA (Prof J L Gore MD); Department of Urology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA (A Shabsigh MD); Department of Urology, Loma Linda University, Loma Linda, CA, USA (B Hu MD); Department of Urology, University of California Los Angeles, Los Angeles, CA, USA (K Chamie MD); Department of Urology, Baylor College of Medicine, Houston, TX, USA (G Godoy MD, Prof S P Lerner MD); Department of Urology, Sidney Kimmel Medical College at Thomas Jefferson University Hospitals, Philadelphia, PA, USA (S Hubosky MD); Department of Urology, Mayo Clinic Health System, Rochester, MN, USA (M Rivera MD);Department of Urology, University of Iowa, Iowa City, IA, USA (Prof M O’Donnell MD); Department of Urology, Loyola University Medical Center, Maywood, IL, USA (Prof M Quek MD, Prof M Woods MD); Division of Urology, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA (Prof J D Raman MD, J J Knoedler MD); Department of Urology, Weill Medical College of Cornell University, New York, NY, USA (Prof D Scherr MD); Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA (J Stern MD, Prof M Schoenberg MD); Department of Urology, University of Minnesota Health, Minneapolis, MN, USA (C Weight MD); Department of Urology, University of Michigan, Ann Arbor, MI, USA (Prof A Weizer MD); Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA (H Kaimakliotis MD); Department of Urology, University of North Carolina School of Medicine, Chapel Hill, NC, USA (A B Smith MD); Department of Urology, John Wayne Cancer Institute, Santa Monica, CA, USA (J Linehan MD); Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA (J Coleman MD); Department of Urology, Mayo Clinic Phoenix, Scottsdale, AZ, USA (M R Humphreys MD); Department of Urology, Mayo Clinic Jacksonville, Jacksonville, FL, USA (R Pak MD); Department of Urology, Rabin Medical Center, Tel Aviv, Israel (D Lifshitz MD); Urology Center of Las Vegas, Las Vegas, NV, USA (M Verni MD); Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA (Prof M B Amin MD); UroGen Pharma, New York, NY, USA (E Seltzer MD, Prof M Schoenberg); and UroGen Pharma, Ra’anana, Israel (I Klein PhD, M Konorty PhD, D Strauss-Ayali PhD, G Hakim BSc) Correspondence to: Prof Seth P Lerner, Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA

Source: Nir Kleinmann et al. "Primary Chemoablation of Low-Grade Upper Tract Urothelial Carcinoma Using UGN-101, A Mitomycin-Containing Reverse Thermal Gel (OLYMPUS): An Open-Label, Single-Arm, Phase 3 Trial." The Lancet Oncology. 2020. DOI: https://doi.org/10.1016/S1470-2045(20)30147-9
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