A phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: first clinical agent targeting APE1/Ref-1 in cancer

Abstract

Background: APX3330 is an oral agent targeting the redox signaling activity of APE1/Ref-1 (Ref-1), a key regulator of transcription factors involved in inflammation and tumorigenesis. APX3330 selectively inhibits Ref-1’s redox function without affecting its DNA repair role. This Phase 1, multicenter, open-label, dose-escalation study in advanced solid tumors was aimed at determining the recommended Phase 2 dose (RP2D) while assessing safety, pharmacokinetics, and biomarker evidence of target engagement. Methods: Nineteen cancer patients were treated, with eight completing follow-ups. Subjects received APX3330 orally twice daily in 21-day cycles, starting at 240mg/d and escalating in 120mg/d increments. Adverse event (AE) monitoring followed a 1pt/cohort approach until a >G2 toxicity event, after which a 3+3 design was implemented. Treatment continued until disease progression, consent withdrawal, or intolerable toxicity. Antitumor activity was assessed using RECIST 1.1, and pharmacodynamic markers included serum Ref-1 levels and circulating tumor cells. Results: Six of nineteen subjects had stable disease, and no treatment-related SAEs were observed. One subject (720mg cohort) withdrew due to Grade 3 maculopapular rash (dose-limiting toxicity). Laboratory assessments and ECGs showed no clinically significant abnormalities. Conclusions: APX3330 showed preliminary signals of disease control and on-target pharmacology in this first-in-human study. Based on safety and PD, the RP2D is 600mg/d. Given the small sample size, efficacy conclusions are exploratory (ClinicalTrials.gov Identifier: NCT03375086).