A phase I/IIa trial of the RNA oligonucleotide STNM01 by EUS-FNI to investigate the safety and efficacy in patients with first-line refractory, unresectable pancreatic cancer.

Abstract

4120 Background: Carbohydrate sulfotransferase 15 (CHST15) is an enzyme that synthesizes heavily sulfated matrix glycosaminoglycan and shown to promote tumor invasion and correlate with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). To explore the role of CHST15 blockage, we conducted a Phase I/IIa (P I/IIa) study to investigate the safety and efficacy of EUS guided locoregional injection of STNM01, a synthetic RNA oligonucleotide, in patients with unresectable PDAC, refractory to first-line chemotherapy. Methods: This was an open-label and dose-escalation study of STNM01 as second-line (2L) therapy in unresectable PDAC patients at 4 centers in Japan. One cycle consists of locoregional injection with STNM01 three times at 2 week-interval in 4 weeks (Days 0, 14 and 28 of dosing) in combination with systemic 2L chemotherapy. A 3+3 dose cohort escalation design initiated with 250 nM (n = 3) followed by 1,000 nM (n = 3), 2,500 nM (n = 3) and 10,000 nM (n = 4) was used for P I part. P IIa part (n = 9) was subsequently conducted with MTD or the highest dose level determined by P I. The primary outcome was incidence of DLT at the end of cycle 1. The secondary outcomes included overall survival (OS), local tumor response, histology and safety. This study was registered with jRCT (jRCT2031190055). Results: A total of 22 patients across 4 doses were enrolled in the study of which 21 were evaluable as per protocol population. All patients received S-1 as a systemic 2L chemotherapy and total 3 cycles were repeated at maximum. The most common AEs were abdominal pain and pyrexia. There were 9 grade 3 AEs. No drug-related SAE as well as DLT was observed. Since MTD was not reached in P I, P IIa was conducted with the highest dose, 10,000 nM. The 6-month survival rate in the entire population (n = 21) and in the highest dose population (n = 12; 3 for P I and 9 for P IIa) was 66.7 and 83.3%, respectively. In histological analyses, the % positive area of CHST15 tended to show dose-dependent suppression at the end of cycle 1, especially with 70.0% reduction from baseline in the highest dose population. Increased tumoral infiltrations of CD3+, CD8+ and CD20+ cells were observed during study period in the highest dose population. Local tumor response for the entire population showed 14 patients (66.7%) with stable disease. Notably, one patient showed complete disappearance on the CT image of both primary and metastatic tumors in the regional lymph node. Conclusions: Repeated locoregional injection of STNM01 is safe and well tolerated in patients with unresectable PDAC as combined 2L therapy. The 6-month survival rate of 10,000 nM of STNM01 was 83.3%, which is remarkable compared with previously reported data. Unexpected mode of action for tumoral lymphocyte infiltration also suggests the promising potential of locoregional injection of STNM01 as a new therapeutic option for PDAC. Clinical trial information: jRCT2031190055.