TANDEM EUS-GUIDED FINE NEEDLE INJECTION OF INTRACYSTIC SUBMICRON PARTICLE PACLITAXEL (NANOPAC®) AS TREATMENT FOR BRANCH-DUCT IPMN: AN INTERIM SAFETY, PHARMACOKINETIC, AND EFFICACY ANALYSIS

ABSTRACT

BACKGROUND: Branch duct (BD)-IPMNs with increased risk for malignant transformation are typically treated with surgical resection, and alternate therapies are needed for patients with prohibitive risks for perioperative complications. Injection of cysts with paclitaxel may prevent or reverse transformation, but current formulations are not retained in cysts to provide durable benefit. A Submicron Particle formulation of Paclitaxel (SPP) has been designed to avoid clearance into the systemic circulation and effectively provides a depot effect releasing the drug at constant saturation levels. In this initial study of EUS-guided fine needle injection (FNI) with SPP we evaluated safety, tolerability, pharmacokinetics, and cyst response in BD-IPMNs. METHODS: A diagnosis of BD-IPMNs was confirmed by EUSguided confocal laser endomicroscopy and cyst fluid next generation sequencing. Subjects received EUS-FNI of SPP (15mg/mL concentration) at volumes equal to the aspirated cyst fluid as part of an ongoing clinical trial [NCT03188991] (Study was interrupted due to COVID-19 pandemic). This report covers 5 of the study subjects enrolled at one site. SPP was administered on two occasions 12 weeks apart in 4/5 subjects and once in 1 subject. CT Scans were performed at 0, 12, and 24 weeks to assess changes in cyst size. RESULTS: The mean6standard deviation duration of follow-up from 1st EUS-FNI was 37.3±19.8 weeks. The mean size on CT-Scan of BD-IPMNs at time 0 weeks (1st EUS-FNI) was 3.360.8 cm, 12 weeks (2nd EUS-FNI) was 3.02±1.2 cm, and 24 weeks was 3.15±1.8 cm (Table 1). The mean dosage of SPP injected by EUS-FNI was 75±39 mg for 1st dose and 40.6±15.1 mg for 2nd dose. No dose limiting toxicities, study-related serious adverse events, or clinically significant changes in blood work were observed. The paclitaxel levels (PK) in plasma and cyst fluid is shown in Figure 1. Systemic paclitaxel concentration did not exceed 1 ng/mL at any point post-administration, falling below lower limit of quantitation (25 pg/mL) within, at most, 4 weeks. Cyst fluid analysis confirmed sustained presence of SPP for at least 12 weeks. At baseline evaluation, 4 of 5 subjects had GNAS mutations in cyst fluid (Table 1). In total, DNA mutations (KRAS or GNAS) were not detectable in two of 4 (50%) subjects after EUS-FNI with SPP (Table 1);both subjects (Figure 1) had a dose-dependent high intracystic concentration (> 1000 ng/mL) of SPP immediately prior to 2nd EUS-FNI (week 12). CONCLUSION: EUS-FNI of intracystic SPP appears to be safe and tolerable in patients with BD-IPMNs. SPP is likely retained in these cysts up to 12 weeks in a dose-dependent manner and higher doses are associated with regression of mutations that are specific for BD-IPMNs. Future studies with additional injections and longer-term follow-up are needed to understand the durability of the benefits observed.(Table presented)(figure presented)