Journal article
Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial
The lancet oncology, Vol.22(1), pp.107-117
01/01/2021
DOI: 10.1016/S1470-2045(20)30540-4
PMCID: PMC7988888
PMID: 33253641
Abstract
Background BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive nonmuscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscleinvasive bladder cancer.
Methods In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prosta tic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 x 10(11) viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.
Findings Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53.4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45.5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.
Interpretation Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
Details
- Title: Subtitle
- Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial
- Creators
- Stephen A. Boorjian - Mayo Clinic Rochester, MNMehrdad Alemozaffar - Kaiser PermanenteBadrinath R. Konety - University of MinnesotaNeal D. Shore - Carolina Urologic Research CenterLeonard G. Gomella - Thomas Jefferson UniversityAshish M. Kamat - The University of Texas MD Anderson Cancer CenterTrinity J. Bivalacqua - Johns Hopkins UniversityJeffrey S. Montgomery - University of MichiganSeth P. Lerner - Baylor College of MedicineJoseph E. Busby - University of South CarolinaMichael Poch - University of South FloridaPaul L. Crispen - University of Florida HealthGary D. Steinberg - New York UniversityAnne K. Schuckman - University of Southern CaliforniaTracy M. Downs - University of Wisconsin–MadisonRobert S. Svatek - The University of Texas at San Antonio Health Science CenterJoseph Mashni - MD Anderson Cancer Center MadridBrian R. Lane - Michigan State UniversityThomas J. Guzzo - University of PennsylvaniaGennady Bratslavsky - SUNY Upstate Medical UniversityLawrence I. Karsh - The Urology Center of ColoradoMichael E. Woods - University of North Carolina at Chapel HillGordon Brown - New Jersey UrologyDaniel Canter - Ochsner Health SystemAdam Luchey - West Virginia UniversityYair Lotan - The University of Texas Southwestern Medical CenterTracey Krupski - University of VirginiaBrant A. Inman - Duke UniversityMichael B. Williams - Urology of VirginiaMichael S. Cookson - University of OklahomaKirk A. Keegan - Vanderbilt UniversityGerald L. Andriole - Washington University in St. LouisAlexander I. Sankin - Yeshiva UniversityAlan Boyd - Boyds (United Kingdom)Michael A. O'Donnell - Univ Iowa, Dept Urol, Iowa City, IA 52242 USADavid Sawutz - FKD Therapies OyRichard Philipson - TrizellRuth Coll - TrizellVikram M. Narayan - The University of Texas MD Anderson Cancer CenterF. Peter Treasure - Statistical ServiceSeppo Yla-Herttuala - Finland UniversityNigel R. Parker - Finland UniversityColin P. N. Dinney - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- The lancet oncology, Vol.22(1), pp.107-117
- DOI
- 10.1016/S1470-2045(20)30540-4
- PMID
- 33253641
- PMCID
- PMC7988888
- NLM abbreviation
- Lancet Oncol
- ISSN
- 1470-2045
- eISSN
- 1474-5488
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- FKD Therapies Oy
- Language
- English
- Date published
- 01/01/2021
- Academic Unit
- Urology
- Record Identifier
- 9984320073102771
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