A Phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: First clinical agent targeting APE1/Ref-1 in Cancer.

Purpose: 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 tumor was aimed at determining the recommended Phase 2 dose (RP2D) while assessing safety, pharmacokinetics, and biomarker evidence of target engagement. Clinical trial: NCT03375086 . Patients and Methods: Nineteen cancer patients were treated, with eight completing follow-up. Subjects received APX3330 orally twice daily in 21-day cycles, starting at 240 mg/day and escalating in 120 mg/day increments. Adverse event (AE) monitoring followed a 1 pt/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 subjects had stable disease for >4 cycles, with four remaining on study for 252- 421 days. No treatment-related serious adverse events occurred. One subject (720 mg cohort) withdrew due to Grade 3 maculopapular rash (dose-limiting toxicity). Laboratory assessments and ECGs showed no clinically significant abnormalities. Conclusions: APX3330 demonstrated clinical benefit by stabilizing disease in ∼33% of subjects. Ref-1 target engagement was confirmed via biomarker analyses, with reduced serum Ref-1 and circulating tumor cells. The RP2D is 600 mg daily, with APX3330 showing a favorable safety profile and target-mediated effects.