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A phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: first clinical agent targeting
Mark R Kelley1,2,3, Jun Wan2,4, Sheng Liu2,4
1Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, United States.
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 240 mg/d and escalating in 120 mg/d 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 of nineteen subjects had stable disease, and no treatment-related SAEs were observed. 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 showed preliminary signals of disease control and on-target pharmacology in this first-in-human study. Based on safety and PD, the RP2D is 600 mg/d. Given the small sample size, efficacy conclusions are exploratory (ClinicalTrials.gov Identifier: NCT03375086).
Insights
APX3330, an oral agent targeting APE1/Ref-1 redox activity, showed preliminary disease control in advanced solid tumors. The recommended Phase 2 dose was determined to be 600 mg/day based on safety and pharmacodynamics.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- APX3330 targets the redox signaling of APE1/Ref-1 (Ref-1), a key regulator in inflammation and tumorigenesis.
- APX3330 selectively inhibits Ref-1's redox function, preserving its DNA repair role.
Purpose of the Study:
- Determine the recommended Phase 2 dose (RP2D) for APX3330 in advanced solid tumors.
- Assess the safety, pharmacokinetics, and biomarker evidence of target engagement for APX3330.
Main Methods:
- Phase 1, multicenter, open-label, dose-escalation study.
- Nineteen patients with advanced solid tumors received oral APX3330 in 21-day cycles.
- Dose escalation from 240 mg/day with safety monitoring and pharmacodynamic assessments.
Main Results:
- Six of nineteen subjects achieved stable disease; no treatment-related SAEs were observed.
- One dose-limiting toxicity (Grade 3 rash) occurred at 720 mg/day.
- Laboratory assessments and ECGs revealed no significant abnormalities.
Conclusions:
- APX3330 demonstrated preliminary disease control and on-target pharmacology in a first-in-human study.
- The RP2D was established at 600 mg/day based on safety and pharmacodynamic data.
- Efficacy conclusions are exploratory due to the small sample size (ClinicalTrials.gov Identifier: NCT03375086).
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