A Phase 1 study of the novel GCN2 kinase activator NXP800 in patients with advanced cholangiocarcinoma

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Cholangiocarcinoma (CCA) is a malignancy associated with poor clinical outcomes, primarily due to the advanced stage of most tumors at diagnosis and the limited response to systemic, targeted, and immunotherapies. Thus, novel therapeutic approaches will be required to improve the outcomes for patients with CCA. The integrated stress response (ISR) is a signaling pathway activated in response to intrinsic and extrinsic stresses, which can activate kinases including general control nonderepressible 2 (GCN2). Prolonged activation of the ISR can promote cell death induction, making pharmacological ISR modulation a promising therapeutic strategy in cancer. NXP800, a novel GCN2 kinase activator, has shown antiproliferative activity in several cell lines and in patient-derived xenograft models of CCA. Here, we describe the study design of a Phase 1 clinical trial (NCT06420349) of the novel GCN2 kinase activator NXP800 in patients with advanced or metastatic CCA. The primary objective of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose of NXP800; secondary objectives are to determine the toxicity profile, best response, overall survival, and progression-free survival.Clinical trial registration www.clinicaltrials.gov identifier is NCT06420349.

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