Abstract PR01: A phase I study targeting the APE1/Ref-1 DNA repair-redox signaling protein with the APX3330 inhibitor

APX3330 is an orally administered anti-cancer small molecule that targets the APE1/Ref-1 protein (apurinic endonuclease 1 / redox effector factor 1). APE1/Ref-1 is both a DNA repair and reduction-oxidation (redox) signaling protein that participates in the DNA base excision repair (BER) pathway. Additionally, APE1/Ref-1 regulates the redox status of a number of important transcription factors (TFs) in tumor cells. These include NFkB, STAT3, and HIF-1a. APE1/ref-1 converts these TFs from an off (oxidized) to an on (reduced) state allowing them to bind to the promoter sequence of genes regulating tumor growth, metastasis, metabolism and survival of tumor cells. APX3330 selectively binds to APE1/Ref-1, specifically inhibiting its redox signaling activity. APE1/Ref-1 also plays a key role in a variety of inflammatory disorders beyond cancers including diabetic macular edema, inflammatory bowel disorders and others. Data will be presented for study NCT03375086 evaluating APX3330 in patients with incurable malignancies. Eligibility required adequate organ function, PS 0-2 and tumors not amenable to curative therapy. Primary and secondary objectives included determining the recommended phase 2 dose (RP2D), the safety and PK/PD profiles of APX3330 and reporting any RECIST anti-tumor activity. Patients received APX3330 b.i.d., in 21-day cycles. APX3330 was well tolerated at dose levels from 240-600 mg/d. The most frequent treatment-related adverse events (all grades) included G1 nausea (16%) and fatigue (16%). Six subjects had disease stabilization for > 4 cycles, and of these, four subjects with the following diagnosis, RECIST response and days on study included: colorectal cancer, PR (partial response), 357 days; endometrial, SD (stable disease), 421days; melanoma, SD, 337 days; prostate, SD, 252 days. All study objectives were completed and determined that APX3330 is safe for chronic dosing from 240 up to and including 600 mg/day. It provides clinical benefit to patients with a variety of tumor types (e.g., endometrial, colorectal, prostate and melanoma cancer). Pharmacodynamic (PD) studies from patient biopsy evaluation indicates APX3330-mediated effect upon cancer cells, including decrease in transcription factors activity for those regulated by the APE1/Ref-1 protein. Differentially expressed proteins (DEPs) were analyzed comparing pre-treatment and on-treatment tumor biopsies. Specifically studied were NFkB, HIFa and STAT3 genes downstream of these three TFs. Circulating tumor cell (CTC) analysis was performed on sixteen patients who had baseline and on-treatment samples that were evaluated longitudinally. Of these, 7/16 (44%) of patients showed a reduction in CTCs after initiation of treatment with APX3330. APE1/Ref-1 serum levels were determined to be elevated in aggressive tumors and were reduced following treatment with APX3330 in SD patients (past four treatment cycles). Pharmacokinetic (PK) data indicate confirmation of pre-clinical data. Conclusions: APX3330 is an orally administered inhibitor of APE1/Ref-1 specifically targeting the redox signaling function of this protein. This phase I study identified 600 mg PO daily as the RP2D for further development. RECIST evaluation identified signs of clinical activity in this un-selected population of patients with advanced cancer. PD analyses (proteomics, CTC, serum) indicate APX3330 mediated targeting of the APE1/Ref-1 protein. Citation Format: Mark R. Kelley, Safi Shahda, Nehal J. Lakhani, Bert O9Neil, Lincy Chu, Amanda K. Anderson, Jun Wan, Amber L. Mosley, Hao Liu, Richard A. Messmann. A phase I study targeting the APE1/Ref-1 DNA repair-redox signaling protein with the APX3330 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR01. doi:10.1158/1535-7163.TARG-19-PR01