A multicenter, open-label, single-arm, dose-finding and -expansion phase 1b/2 study to evaluate the safety and tolerability of nesuparib (JPI-547) in combination with irinotecan as a third-line and beyond therapy for recurrent or metastatic gastric cancer.

Abstract

TPS4247 Background: Recurrent or metastatic gastric cancer (GC) progressing after standard first- and second-line therapies has limited treatment options, leading to poor survival outcomes. Nesuparib is an orally available, next-generation dual inhibitor of tankyrase and poly(ADP-ribose) polymerase (PARP). It disrupts DNA damage repair and induces a “BRCAness” phenotype by modulating Wnt/β-catenin and Hippo signaling pathways. In a previous phase I study, nesuparib monotherapy demonstrated promising clinical activity with an overall response rate (ORR) of 28.2% and a disease control rate (DCR) of 64.1%. Preclinical models have shown synergistic anti-tumor efficacy when nesuparib is combined with irinotecan. This study aims to evaluate the safety, tolerability, and preliminary efficacy of nesuparib plus irinotecan in patients with advanced GC. Methods: This multicenter, open-label, single-arm, dose-finding and expansion phase 1b/2 study enrolls adults with histologically confirmed recurrent or metastatic GC or gastroesophageal junction adenocarcinoma who have progressed after ≥2 prior systemic therapies and have ECOG PS 0–1, measurable disease per RECIST v1.1, and UGT1A1 wild-type genotype. Phase 1b follows a standard 3+3 design with multiple predefined dose levels. Each dose level consists of a fixed combination of (1) a specific nesuparib dose (25–100 mg) administered orally once daily on either a 5-days-on/2-days-off or 3-days-on/4-days-off schedule and (2) irinotecan administered every 2 weeks at 100, 120, or 150 mg/m². The dose-limiting toxicity evaluation window is 28 days. Phase 2 enrolls patients at RP2D to further evaluate anti-tumor activity. The primary endpoint is objective response rate. Secondary endpoints include safety, disease control rate, duration of response, progression-free survival, time to response, and overall survival. Exploratory objectives include population pharmacokinetics, pharmacodynamic biomarkers, homologous recombination deficiency profiling, and circulating tumor DNA analyses. Approximately 43–49 patients are planned (18–24 in phase 1b; 25 in phase 2). Treatment continues until disease progression, unacceptable toxicity, or study withdrawal. Clinical trial information: NCT07364422 .