MP13-20 SECOND-GENERATION ANTISENSE OLIGONUCLEOTIDE - HSP27 A NEW INTRAVESICAL TREATMENT FOR BLADDER CANCER: PHASE 1CLINICAL TRIAL.

Abstract

You have accessJournal of UrologyBladder Cancer: Non-Invasive I1 Apr 2016MP13-20 SECOND-GENERATION ANTISENSE OLIGONUCLEOTIDE - HSP27 A NEW INTRAVESICAL TREATMENT FOR BLADDER CANCER: PHASE 1CLINICAL TRIAL. Sebastian Frees, Eliana Beraldi, Kim Chi, Ladan Fazli, Peter Black, Martin Gleave, and Alan So Sebastian FreesSebastian Frees More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Kim ChiKim Chi More articles by this author , Ladan FazliLadan Fazli More articles by this author , Peter BlackPeter Black More articles by this author , Martin GleaveMartin Gleave More articles by this author , and Alan SoAlan So More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2501AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The treatment options to prevent recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC) are limited. Heat Shock Protein 27 (Hsp27) is a cytoprotective protein that has been linked to therapeutic resistance and disease progression in many malignancies, including bladder cancer (BCa). OGX-427 is a 2nd generation (2′-MOE) antisense oligonucleotide that potently inhibits Hsp27 expression in vitro and in vivo. A phase I clinical study was performed to assess the safety, pharmacodynamic (pd) and biologic effects of intravesical treatments of OGX-427 using a presurgical dose-escalating design for patients with BCa. METHODS Eligible patients include patients with Ta, T1 or carcinoma-in-situ and candidates for transurethral resection of the bladder tumour (TURBT), or patients with muscle invasive BCa (>cT2) and candidates for radical cystectomy (RC). Patients were treated with intravesical OGX-427 on days 1, 3, 5 and 8 and then underwent surgery on day 9-12. Dose was escalated after tolerability and safety assessment for each cohort at 20uM, 50 uM, 100uM, 250uM, 500uM, and 750uM. Dose limiting toxicities (DLTs) and adverse events (AEs) were assessed. Pharmacodynamic properties of OGX-427 was determined through assessment of knockdown of Hsp27 by immunohistochemistry of tumours after treatment. Anti-tumour activity was measured by response to treatment 9-12 days after OGX-427 intravesical administration by a secondary TURBT for patients with NMIBC and RC patients with muscle invasive disease compared to baseline histology. RESULTS Twenty-four patients were enrolled. 23 patients had NMIBC and one had cT2 disease treated by TURBT and RC, respectively. OGX-427 decreased expression of Hsp27 in tumours assessed after treatment when compared to pre-treatment. Pathological staging of surgical specimens revealed that eight patients had initial complete responses (p0). The remaining NMIBC patients had pTa tumours that ranged from G1-G2; the sole patient undergoing RC had pT2aG3 bladder cancer. No significant drug-related adverse events were reported; no dose limiting toxicity was observed CONCLUSIONS OGX-427 was well tolerated intravesically with minimal toxicity. Our results indicate early evidence for activity of OGX-427 treatment in NIMBC that requires confirmation in phase II/III studies. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e142 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Sebastian Frees More articles by this author Eliana Beraldi More articles by this author Kim Chi More articles by this author Ladan Fazli More articles by this author Peter Black More articles by this author Martin Gleave More articles by this author Alan So More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...