TY - JOUR
T1 - Phase I study of intraperitoneal irinotecan with systemic capecitabine and oxaliplatin for patients with gastric peritoneal metastases
AU - Guchelaar, Niels A.D.
AU - Tops-Welten, Marion W.
AU - van der Sluis, Pieter C.
AU - Noordman, Bo J.
AU - Koolen, Stijn L.W.
AU - Lagarde, Sjoerd M.
AU - Nieuwenhuijzen, Grard A.P.
AU - de Neijs, Micha J.
AU - van Hellemond, Irene E.G.
AU - Luyer, Misha D.P.
AU - Creemers, Geert Jan
AU - De Hingh, Ignace H.J.T.
AU - Mostert, Bianca
AU - Wijnhoven, Bas P.L.
AU - Mathijssen, Ron H.J.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/10/1
Y1 - 2025/10/1
N2 - Background: Peritoneal metastases of gastric cancer are associated with a poor prognosis (median overall survival (OS) ~9 months). Catheter-based intraperitoneal (CBIP) chemotherapy is a locoregional approach to deliver chemotherapy leading to higher intraperitoneal (IP) concentrations of cytotoxic drugs compared to intravenous administration. Method: This multicenter, open-label 3 + 3 + 3 dose-escalation phase I trial evaluated 3-weekly IP irinotecan with oral capecitabine and intravenous oxaliplatin (CAPOX). Patients with HER2-negative gastric cancer and macroscopic peritoneal metastases were included. IP irinotecan was administered on day 1 of a 3-weekly cycle. The primary objective was to establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary endpoints included safety, the pharmacokinetic profile of IP irinotecan, and clinical efficacy. Results: A single DLT occurred in six patients in both the 50 mg and the 75 mg dose cohort. Two DLTs were observed in the three patients in the 100 mg dose cohort, estimating 75 mg IP irinotecan as the MTD. Treatment was well tolerated, with primarily low-grade adverse events, including gastrointestinal toxicity, bone marrow suppression, and peripheral neuropathy. The exposure to the active metabolite SN-38 was higher intraperitoneally than systemically (ratio of 2.1, range: range: 0.9–7.4). The median OS was 11.8 months (95 % CI: 5.5–18.0 months). Conclusion: Administration of 3-weekly CBIP irinotecan concomitant to systemic CAPOX was well tolerated at 75 mg in patients with gastric cancer and peritoneal metastases. Giving its promising clinical outcomes and the safety profile, CBIP of irinotecan provides a potential new treatment modality. A phase II study will commence to assess its feasibility and efficacy.
AB - Background: Peritoneal metastases of gastric cancer are associated with a poor prognosis (median overall survival (OS) ~9 months). Catheter-based intraperitoneal (CBIP) chemotherapy is a locoregional approach to deliver chemotherapy leading to higher intraperitoneal (IP) concentrations of cytotoxic drugs compared to intravenous administration. Method: This multicenter, open-label 3 + 3 + 3 dose-escalation phase I trial evaluated 3-weekly IP irinotecan with oral capecitabine and intravenous oxaliplatin (CAPOX). Patients with HER2-negative gastric cancer and macroscopic peritoneal metastases were included. IP irinotecan was administered on day 1 of a 3-weekly cycle. The primary objective was to establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary endpoints included safety, the pharmacokinetic profile of IP irinotecan, and clinical efficacy. Results: A single DLT occurred in six patients in both the 50 mg and the 75 mg dose cohort. Two DLTs were observed in the three patients in the 100 mg dose cohort, estimating 75 mg IP irinotecan as the MTD. Treatment was well tolerated, with primarily low-grade adverse events, including gastrointestinal toxicity, bone marrow suppression, and peripheral neuropathy. The exposure to the active metabolite SN-38 was higher intraperitoneally than systemically (ratio of 2.1, range: range: 0.9–7.4). The median OS was 11.8 months (95 % CI: 5.5–18.0 months). Conclusion: Administration of 3-weekly CBIP irinotecan concomitant to systemic CAPOX was well tolerated at 75 mg in patients with gastric cancer and peritoneal metastases. Giving its promising clinical outcomes and the safety profile, CBIP of irinotecan provides a potential new treatment modality. A phase II study will commence to assess its feasibility and efficacy.
KW - Chemotherapy
KW - Irinotecan
KW - Maximum tolerated dose
KW - Peritoneal neoplasms
KW - Stomach neoplasms
U2 - 10.1016/j.biopha.2025.118491
DO - 10.1016/j.biopha.2025.118491
M3 - Article
SN - 0753-3322
VL - 191
JO - Biomedicine & Pharmacotherapy
JF - Biomedicine & Pharmacotherapy
M1 - 118491
ER -