Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma.

PURPOSE: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. PATIENTS AND METHODS: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. RESULTS: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. CONCLUSIONS: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.

A Novel Simulated Training Platform and Study of Performance Among Different Levels of Learners in Flexible Cystoscopy.

INTRODUCTION: The aims of this study were to test a novel simulation platform suitable for flexible cystoscopy using a standard scope, to assess the platform's proposed use as a training tool for flexible cystoscopy, and to assess the user experience through surveyed response. METHODS: Thirty-one urologists (11 novices, 20 experts) were evaluated using a novel light-based bladder model and standard flexible cystoscope. Time to complete full inspection of the simulated bladder was measured, and the scope trajectory was recorded. Participants also completed a survey of the training platform. RESULTS: Thirty participants completed a simulated inspection of a portable bladder model with a mean ± SD time for 153.1 ± 76.1 seconds. One participant failed to complete. Novice urologists (defined as those having completed less than 50 flexible cystoscopies in clinic) had a mean ± SD time of 176.9 ± 95.8 seconds, whereas with experts, this decreased to 139.3 ± 60.7 seconds. Dynamic trajectory maps identified "blind spots" within each user's cystoscopy performance. In a poststudy follow-up, 27 participants considered the tool valuable or extremely valuable for training, whereas 19 participants considered that the tool either very well or excellently replicated the clinical setting. All participants ranked the tool as very good or excellent for overall quality of training. DISCUSSION: Advances in electronic technology make portable low-cost models a potential low-cost alternative to endourology training platforms. In providing a quantifiable measure of user performance, the tool may shorten the learning curve in flexible cystoscopy and, potentially, reduce clinical errors and provide quantifiable measures for further clinical training.