Abstract P3-04-03: Safety, tolerability, and efficacy of the novel intravenous manganese-based contrast agent SN132D in patients with breast cancer: initial results of a Phase I, First-In-Human clinical trial SPAGOPIX-01
Authors: Wärnberg Fredrik , Karakatsanis Andreas , Shcherbina Liliya , Sjöberg Folke , Hargreaves Paul , Curiac Ioan-Dan , Johansson Edvin , Axelsson Oskar , Hansen Mats 
Published: March 2023

Abstract
Introduction: SN132D is a manganese (Mn) -containing, polymeric nanomaterial developed as an intravenous contrast agent for tumor selective MRI. It was designed for optimal physiological targeting and preferential accumulation in malignant lesions by means of the Enhanced Permeability and Retention (EPR) effect. Combined non-clinical data have demonstrated proof of concept (PoC) in various in vivo cancer models and a safety profile in line with FIH administration of SN132D in the SPAGOPIX-01 clinical study. Methods: SPAGOPIX-01 is a Phase I, FIH, open-label, non-randomized and non-placebo-controlled study in participants with diagnosed breast cancer. MRI was performed prior to and at 2 h and 4 h after the end of the SN132D infusion. SN132D safety and tolerability were the primary objectives. MRI enhancing properties of SN132D in primary tumor, liver, and pancreas as well as pharmacokinetics of SN132D were secondary objectives. Results: So far, 12 female breast cancer patients of planned up to 20 have been enrolled between September 2019 and December 2021. Of these, six patients received SN132D at 10 μmol Mn/kg (cohort 1) and six patients at 20 μmol Mn/kg (cohort 2). In cohort 1 (10 μmol Mn/kg), SN132D was well-tolerated. No clinically significant findings were observed for clinical laboratory tests, vital signs, 12-lead electrocardiogram (ECG), or physical examination. No serious adverse events (SAEs) were registered; nine mild AEs were reported for four subjects. The most reported AEs in patients administered 10 μmol Mn/kg SN132D were injection site reactions (2 AEs) and flushing (2 AEs). In cohort 2, SN132D was also well-tolerated. No clinically significant findings were observed for vital signs, ECG, or physical examination. No SAEs were registered; 12 AEs were reported for six patients. The most common AE was transiently elevated transaminase levels, with single reports from four patients. The second and third most common AEs were moderate vomiting (reported twice from a single patient) and mild flushing. Remaining AEs were single events reported by single patients. None of the AEs required treatment and all resolved without any intervention. Pharmacokinetics of SN132D was assessed at up to 24 h post dose. In cohort 1, SN132D, based on Mn plasma concentrations, had a mean Cmax of 0.915±0.187 μg/mL, a mean initial half-life of 7.17± 1.02 min, a mean AUCinf of 0.890±0.20 h*μg/mL and a mean plasma clearance of 0.646±0.157 L/h/kg. In cohort 2, SN132D had a mean Cmax of 2.0±0.341μg/mL, a mean initial half-life of 7.0±1.60 min, a mean AUCinf of 2.04±0.28 h*μg/mL and a mean plasma clearance of 0.548±0.068 L/h/kg. MR image analysis in cohort 1 revealed that although contrast was insufficient for the generation of clinically relevant tumor images at the 10 μmol Mn/kg dose level, there was still a measurable enhancement. In cohort 2, MR images were analyzed for five subjects and clinically relevant contrast increase in the primary tumor without signal increase in the background was observed in all patients. In addition, all MRI images, including both dose cohorts, showed contrast increase in both liver and pancreas at post-dose imaging timepoints. Conclusions: Initial clinical data generated to date demonstrate an acceptable safety profile and PoC for SN132D in the breast cancer patients. Physiological targeting with functional nanoparticles appears suitable for tumor MRI imaging. Our data are in agreement with preclinical data in rodent tumor models. The data are supporting the continuation of the SPAGOPIX-01 clinical trial and we will further explore SN132D in a cohort of pancreatic cancer patients with liver involvement.
Citation Format: Fredrik Wärnberg, Andreas Karakatsanis, Liliya Shcherbina, Folke Sjöberg, Paul Hargreaves, Ioan-Dan Curiac, Edvin Johansson, Oskar Axelsson, Mats Hansen. Safety, tolerability, and efficacy of the novel intravenous manganese-based contrast agent SN132D in patients with breast cancer: initial results of a Phase I, First-In-Human clinical trial SPAGOPIX-01 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-04-03.