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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

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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