TITLE: VISTA, PHASE 3 TRIAL OF VICINIUM, AN EPCAM-TARGETED PSEUDOMONAS EXOTOXIN, IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER
INTRODUCTION AND OBJECTIVES
Vicinium is a fusion protein consisting of an Epithelial Cell Adhesion Molecule (EpCAM)-specific antibody fragment fused to PseudomonasExotoxin A, a potent inhibitor of protein synthesis. Vicinium is being developed for the treatment of Bacillus Calmette-Guérin (BCG)-unresponsive, High Grade non-muscle invasive bladder cancer (NMIBC). In Phase 1 and 2 studies, intravesical Vicinium demonstrated excellent safety profile and meaningful clinical activity as assessed by the complete response (CR) rate at 3 months of 29-40% in subjects with carcinoma in situ (CIS) NMIBC. The major objective of this pivotal phase 3 study is to confirm the clinical benefit of Vicinium in subjects with BCG-unresponsive NMIBC.
VISTA is a single arm, phase III, 3-cohort registrational trial of Vicinium in BCG-unresponsive NMIBC (high grade Ta, any T1 and CIS with or without papillary disease) (NCT02449239). Subjects must have completed ≥ 2 courses of full dose BCG and recurred with papillary NMIBC ≤ 30 weeks or with CIS ≤ 50 weeks after last BCG. Vicinium (30mg) is instilled into the bladder for 2 hours on the following schedule: two times/week for 6 weeks followed by weekly for 6 weeks and then every 2 weeks for up to 2 years. Subjects are evaluated every 13 weeks by urine cytology, cystoscopy and pathology of biopsy of any suspicious lesion. The primary endpoint is CR rate for CIS, which requires negative cytology, normal cystoscopy, or benign/low grade Ta pathology on biopsy.
At the 20 April 2018 data cut-off, the trial completed enrollment with 133 patients across 3 cohorts, including 77 subjects with CIS who were evaluable at 3 months. Prior therapy included a median of 4 courses of BCG. The 3-month CR rate across the CIS cohorts with BCG-refractory disease within 12 months of the last BCG was 42%. Vicinium was well tolerated: 46% of subjects had adverse events related to study drug, the most common being dysuria (12%), UTI or pollakiuria (10%) and hematuria (7%). Three treatment-related SAEs included renal failure (CTCAE Grade 5) with cholestatic hepatitis (Grade 4) in one subject and recovered acute kidney injury (Grade 3) in another. In an additional cohort of 34 evaluable subjects with recurrent papillary-only NMIBC, the 3-month recurrence-free rate was 68%. By immunohistochemistry > 95% of screening NMIBC samples expressed EpCAM, the target of Vicinium. The intensity of EpCAM expression did not appear to correlate with response.
Initial data from VISTA confirm the safety and efficacy of Vicinium noted in prior proof-of-concept trials. Emerging biomarker data demonstrate that EpCAM, the molecular target of Vicinium, is nearly ubiquitously expressed in high-grade NMIBC. Additional biomarker analysis is in progress. The novel mechanism of Vicinium coupled with the promising clinical benefit may provide an important alternative to existing therapies, including radical cystectomy.