Purpose: APX3330 is an oral agent targeting the redox signaling activity of Ape1/Ref1 (Ref1), a key regulator of transcription factors involved in inflammation and tumorigenesis. APX3330 selectively inhibits Ref1s 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 Ref1 levels and circulating tumor cells. Results: Six subjects had stable disease for >4 cycles, with four remaining on study for 252 to 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 approximately 33% of subjects. Ref1 target engagement was confirmed via biomarker analyses, with reduced serum Ref1 and circulating tumor cells. The RP2D is 600 mg daily, with APX3330 showing a favorable safety profile and target-mediated effects.

Mark R. Kelley licensed APX3330 to Apexian Pharmaceuticals LLC through the Indiana University Research and Technology Corporation. Second-generation compounds are also licensed to Apexian Pharmaceuticals. Apexian has licensed APX3330 to Ocuphire Parma now named Opus Genetics, Inc. Neither Apexian Pharmaceuticals nor Ocuphire Pharma/Opus Genetics had control or oversight of the studies, interpretation, or presentation of the data in this manuscript. Authors do not have any conflict of interests.

NCT03375086

This work was supported by grants from the National Cancer Institute to M.R.K (R01CA282478, R01CA167291, R01CA254110, and R01 CA282478-S1 to E.K.K). Additional supported came from the Riley Childrens Foundation and the IU Simon Comprehensive Cancer Center, P30CA082709 to M.R.K. This Phase I trial was also supported by Apexian Pharmaceuticals who had no control over the presentation of the material in this manuscript.

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The Institutional Review Board of Indiana University School of Medicine approved the clinical trial. It was also approved by the Clinical Review Center of the CTSI at IUSM. All participants were provided written informed consent before enrollment in the study. The trial was registered at ClinicalTrials.gov under the identifier NCT03375086.

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