STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial

Toshio Fujisawa; Takayoshi Tsuchiya; Motohiko Kato; Masafumi Mizuide; Kazuki Takakura; Makoto Nishimura; Hiromu Kutsumi; Yoko Matsuda; Tomio Arai; Shomei Ryozawa; Takao Itoi; Hiroyuki Isayama; Hideyuki Saya; Naohisa Yahagi

doi:10.1016/j.eclinm.2022.101731

STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial

EClinicalMedicine. 2022 Nov 17:55:101731. doi: 10.1016/j.eclinm.2022.101731. eCollection 2023 Jan.

Authors

Affiliations

¹ Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
² Department of Gastroenterology and Hepatology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
³ Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
⁴ Department of Gastroenterology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
⁶ Department of Gastroenterology, Hepatology and Nutrition, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁷ Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
⁸ Oncology Pathology, Department of Pathology and Host-Defense, Kagawa University, Takamastu, Kagawa, Japan.
⁹ Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
¹⁰ Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Abstract

Background: The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC).

Methods: This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000 nM in combination with S-1 (80-120 mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055).

Findings: A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3⁺ and CD8⁺ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3⁺ and CD8⁺ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3⁺ T cells correlated with longer OS. There were 8 grade 3 adverse events.

Interpretation: Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment.

Funding: The present study was supported by the Japan Agency for Medical Research and Development (AMED).

Keywords: 5-FU, fluorouracil; AMED, Japan Agency for Medical Research and Development; CHST15, carbohydrate sulfotransferase 15; CI, confidence interval; CS-E, chondroitin sulfate E; CTCAE, Common Terminology Criteria for Adverse Events; Carbohydrate sulfotransferase 15 (CHST15); DCR, disease control rate; DLT, dose-liming toxicity; ECM, extracellular matrix; EMT, epithelial mesenchymal transition; EUS-FNI, endoscopic ultrasound-guided fine needle injection; Endoscopic ultrasound-guided fine needle injection; FAS, full analysis set; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IQR, interquartile range; IRB, Institutional Review Board; LV, leucovorin; MTD, maximum tolerated dose; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; PFS, progression free survival; STNM01; TEAE, treatment emergent adverse event; TGF, transforming growth factor; Tumor-infiltrating CD3+ and CD8+ T cells; Unresectable pancreatic cancer; nal-IRI, nanoliposomal irinotecan; sCD44v6, soluble CD44 variant 6.

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States