First-in-human Evaluation of a Prostate-specific Membrane Antigen-targeted Near-infrared Fluorescent Small Molecule for Fluorescence-based Identification of Prostate Cancer in Patients with High-risk Prostate Cancer Undergoing Robotic-assisted Prostatectomy

Background: Men with high -risk prostate cancer undergoing surgery likely recur due to failure to completely excise regional and/or local disease. Objective: The first -in -human evaluation of safety, pharmacokinetics, and exploratory efficacy of IS -002, a novel near -infrared prostate -specific membrane antigen (PSMA)targeted fluorescence imaging agent, designed for intraoperative prostate cancer visualization. Design, setting, and participants: A phase 1, single -center, dose -escalation study was conducted in 24 men with high -risk prostate cancer scheduled for robotic -assisted radical prostatectomy with (extended) pelvic lymph node dissection using the da Vinci surgical system. Outcome measurements and statistical analysis: Adverse events (AEs), vital signs, complete blood count, complete metabolic panel, urinalysis, and electrocardiogram were assessed over a 14-d period and compared with baseline. The pharmacokinetic profile of IS -002 was determined. Diagnostic accuracy was assessed for exploratory efficacy. Results and limitations: AEs predominantly included discoloration of urine (n = 22/24; expected, related, grade 1). There were no grade >= 2 AEs. IS -002 Cmax and area under the curve increased with increasing dose. Plasma concentrations declined rapidly in a biphasic manner, with the median terminal half-lives ranging from 5.0 to 7.6 h, independent of dose and renal function. At 25 lg/kg, the exploratory efficacy readouts for the negative and positive predictive values were, 97% and 45% for lymph nodes, and 100% and 80% for residual/locoregional disease detection, respectively. Conclusions: IS -002 is safe and well tolerated, and has the potential to enable intraoperative tumor detection that could not be identified using standard imaging.