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 - 08/06/20

Doi : 10.1016/S1470-2045(20)30147-9

Nir Kleinmann, MD ^a, Surena F Matin, ProfMD ^b, Phillip M Pierorazio, MD ^c, John L Gore, ProfMD ^d, Ahmad Shabsigh, MD ^e, Brian Hu, MD ^f, Karim Chamie, MD ^g, Guilherme Godoy, MD ^h, Scott Hubosky, MD ⁱ, Marcelino Rivera, MD ^j, Michael O’Donnell, ProfMD ^k, Marcus Quek, ProfMD ^l, Jay D Raman, ProfMD ^m, John J Knoedler, MD ^m, Douglas Scherr, ProfMD ⁿ, Joshua Stern, MD ^o, Christopher Weight, MD ^p, Alon Weizer, ProfMD ^q, Michael Woods, ProfMD ^l, Hristos Kaimakliotis, MD ^r, Angela B Smith, MD ^s, Jennifer Linehan, MD ^t, Jonathan Coleman, MD ^u, Mitchell R Humphreys, MD ^v, Raymond Pak, MD ^w, David Lifshitz, MD ^x, Michael Verni, MD ^y, Mehrad Adibi, MD ^b, Mahul B Amin, ProfMD ^z, Elyse Seltzer, MD ^aa, Ifat Klein, PhD ^ab, Marina Konorty, PhD ^ab, Dalit Strauss-Ayali, PhD ^ab, Gil Hakim, BSc ^ab, Mark Schoenberg, ProfMD ^o,^aa, Seth P Lerner, ProfMD ^h,⁎

^a Department of Urology, Sheba Medical Center, Ramat Gan, Israel

^b Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

^c Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA

^d Department of Urology, University of Washington Medical Center, Seattle, WA, USA

^e Department of Urology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

^f Department of Urology, Loma Linda University, Loma Linda, CA, USA

^g Department of Urology, University of California Los Angeles, Los Angeles, CA, USA

^h Department of Urology, Baylor College of Medicine, Houston, TX, USA

ⁱ Department of Urology, Sidney Kimmel Medical College at Thomas Jefferson University Hospitals, Philadelphia, PA, USA

^j Department of Urology, Mayo Clinic Health System, Rochester, MN, USA

^k Department of Urology, University of Iowa, Iowa City, IA, USA

^l Department of Urology, Loyola University Medical Center, Maywood, IL, USA

^m Division of Urology, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA

ⁿ Department of Urology, Weill Medical College of Cornell University, New York, NY, USA

^o Department of Urology, Albert Einstein College of Medicine, Bronx, NY, USA

^p Department of Urology, University of Minnesota Health, Minneapolis, MN, USA

^q Department of Urology, University of Michigan, Ann Arbor, MI, USA

^r Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

^s Department of Urology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

^t Department of Urology, John Wayne Cancer Institute, Santa Monica, CA, USA

^u Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

^v Department of Urology, Mayo Clinic Phoenix, Scottsdale, AZ, USA

^w Department of Urology, Mayo Clinic Jacksonville, Jacksonville, FL, USA

^x Department of Urology, Rabin Medical Center, Tel Aviv, Israel

^y Urology Center of Las Vegas, Las Vegas, NV, USA

^z Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA

^aa UroGen Pharma, New York, NY, USA

^ab UroGen Pharma, Ra’anana, Israel

^* Correspondence to: Prof Seth P Lerner, Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA Department of Urology Baylor College of Medicine Houston TX 77030 USA

Summary

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 mitomycin-containing 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.

Funding

UroGen Pharma.

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Vol 21 - N° 6

P. 776-785 - juin 2020 Retour au numéro

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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 - 08/06/20

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