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A Phase I study targeting the APE1/Ref-1 redox signaling protein with APX3330: First clinical agent targeting
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.
Insights
APX3330, an oral agent targeting Ape1/Ref-1, showed clinical benefit in advanced solid tumors. The recommended Phase 2 dose is 600 mg daily, with a favorable safety profile and confirmed target engagement.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Ape1/Ref-1 (Ref-1) is a key regulator in inflammation and tumorigenesis.
- APX3330 is an oral agent that selectively inhibits Ref-1's redox function.
- APX3330 does not affect Ref-1's DNA repair function.
Purpose of the Study:
- Determine the recommended Phase 2 dose (RP2D) of APX3330.
- Assess the safety and pharmacokinetics of APX3330 in patients with advanced solid tumors.
- Evaluate biomarker evidence of target engagement for APX3330.
Main Methods:
- Phase 1, multicenter, open-label, dose-escalation study.
- Nineteen patients with advanced solid tumors were treated with escalating oral doses of APX3330.
- Safety, antitumor activity (RECIST 1.1), and pharmacodynamic markers (serum Ref-1, circulating tumor cells) were assessed.
Main Results:
- Six patients (approx. 33%) achieved stable disease for over 4 cycles.
- No treatment-related serious adverse events were reported.
- Dose-limiting toxicity (Grade 3 rash) observed at 720 mg/day; RP2D established at 600 mg daily.
Conclusions:
- APX3330 demonstrated clinical benefit in stabilizing disease in advanced solid tumors.
- Biomarker analyses confirmed Ref-1 target engagement.
- APX3330 exhibits a favorable safety profile and target-mediated effects at the RP2D of 600 mg daily.
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