A phase I trial of intravesical antisense oligonucleotide targeting heat shock protein 27 (OGX-427) for the treatment of non-muscle-invasive bladder cancer.

286 Background: 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 shown to be important in a variety of malignancies, including bladder cancer (BCa), where it has been linked to therapeutic resistance and disease progression. OGX-427 is a 2nd generation (2’-MOE) antisense oligonucleotide that potently inhibits Hsp27 expression in vitro and in vivo. Methods: We initiated a phase I clinical study to assess the safety, pharmacokinetic (pk), pharmacodynamic (pd) and biologic effects of intravesical treatments of OGX-427 using a presurgical dose-escalating design for patients with BCa. Eligible patients include patients with Ta, T1 or carcinoma-in-situ and candidates for transurethral resection of the bladder tumor (TURBT), or patients with muscle invasive BCa (>cT2) and candidates for radical cystectomy (RC). Patients are treated with intravesical OGX-427 on days 1,3,5, and 8 and then undergo surgery on day 9-12. Dose is escalated after tolerability and safety assessment for each cohort at 20uM, 50 uM, 100uM, 250uM, 500uM, and 750uM. Results: To date, we have enrolled 13 patients in the trial and have completed the 250uM cohort. 12 patients had NMIBC and one had cT2 disease and underwent a cystectomy. No significant drug-related adverse events have been reported; no dose limiting toxicity was observed and only one patient developed gross hematuria (grade 1) within 24 hours of administration of drug that spontaneously resolved. Pathological staging of surgical specimens revealed that five patients (38%) had complete responses (p0). The remaining NMIBC patients had pTa tumors that ranged from G1-G2; the sole patient undergoing cystectomy had pT2aG3 bladder cancer. Accrual of the two remaining cohorts will be complete shortly and the pd and pk analysis will be performed once all specimens are available. Conclusions: OGX-427 is well tolerated intravesically with minimal toxicity. Our results indicate early evidence of activity of OGX-427 against bladder cancer that requires confirmation in phase II/III studies.