Abstract B88: Clinical trials targeting APE1/Ref-1 in pancreatic cancer with APX3330

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-12, Vol.76 (24_Supplement), p.B88-B88
• Main Authors: Kelley, Mark R., Shahda, Safi, O'Neil, Bert H., Pearce, Homer, Walling, Jackie
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PANCA16-B88

APE1/Ref-1 function is upstream of numerous transcription factors and impinges on several different pathways through its transcriptional regulatory function. These include HIF1, STAT3, NFkB, AP-1 and NRF2. These signaling pathways are known oncogenic drivers in many malignancies but particularly in pancreatic cancer (Zou et al. 2009; Fishel et al. 2011; Cardoso et al. 2012). APX3330 (formerly E3330) selectively and directly binds to APE1/Ref-1 thus inhibiting its APE1/Ref-1 redox signaling activity. Importantly, while APX3330 blocks APE1/Ref-1’s redox function, it has no effect on APE1/Ref-1 endonuclease DNA repair activity. APX3330 has been shown in multiple in vivo models of pancreatic cancer to be effective in reducing tumor volume and metastases as both a single agent and in combination with gemcitabine. Additional preclinical data will be presented. APX3330 was recently shown to augment 5-flurouracil (5-FU) in a colon cancer xenograft model as well as increased cytotoxicity in colon cancer stem cells (Lou et al. 2014). The safety and oral dosing administration schedule of APX3330 has been previously established through a prior development program that evaluated the preclinical toxicology and phase 1 and phase 2 safety and clinical profile in more than 400 non-cancer patients with active hepatitis C and abnormal liver function tests. These studies demonstrated an apparent lack of significant acute toxicity on neurologic, cardiovascular, or pulmonary function at doses up to 240 mg/day. Gastrointestinal symptoms and symptoms related to skin rash or irritation were identified as adverse events of particular interest. A Phase 1 dose-escalation study of APX3330 in patients with advanced solid tumors and a dose-expansion cohort of patients with advanced ductal adenocarcinoma of the pancreas (PDAC) is planned. In Phase 1a, we will determine the maximum-tolerated-dose and recommended Phase 2 dose for APX3330 as a single agent in patients with advanced solid tumors (~6 to 30 patients). Phase 1b, will be to characterize preliminary antitumor activity of APX3330 in a PDAC-specific dose expansion cohort and exploratory biomarker endpoints (~10 PDAC patients). The exploratory/correlative objectives for the study include analysis of peripheral blood mononuclear cells (PBMCs) for evidence of APX3330-mediated pharmacodynamic effect. Analysis will include assays for biomarkers previously identified from preclinical studies of APX3330 including TNFα; CAIX, and IL-6. In