A phase I study of the APE1 protein inhibitor APX3330 in patients with advanced solid tumors.

Safi Shahda Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN info_outline Safi Shahda, Nehal J. Lakhani, Bert O'Neil, Drew W. Rasco, Jun Wan, Amber L Mosley, Hao Liu, Mark R. Kelley, Richard Adam Messmann

Authors Safi Shahda Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN info_outline Safi Shahda, Nehal J. Lakhani, Bert O'Neil, Drew W. Rasco, Jun Wan, Amber L Mosley, Hao Liu, Mark R. Kelley, Richard Adam Messmann Organizations Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, START-Midwest, Grand Rapids, MI, Indiana University School of Medicine, Indianapolis, IN, South Texas Accelerated Research Therapeutics (START), San Antonio, TX, Indiana University School of Medicine, Dept of Radiation Oncology, Indianapolis, IN, Indiana University, Indianapolis, IN, Indiana Univ School of Medicine, Indianapolis, IN, Apexian Pharmaceuticals, Indianapolis, IN Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: APX3330 is an orally administered anti-cancer, anti-CIPN agent targeting the APE1 protein. APE1 maintains NFkB, STAT3, AP-1 and HIF-1a in a reduced form, acting as a regulator of transcription factors. A dual function protein, APE1 also plays a role in protecting against oxidative DNA damage in neurons. APX3330 is a highly selective inhibitor of APE1 redox function in tumors that enhances the neuronal protection function of APE1. Methods: We report on study NCT03375086 evaluating APX3330 in patients with incurable malignancies. Eligibility required adequate organ function, PS 0-2 and tumors not amenable to curative therapy. 1° and 2° 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. AE evaluation included 1 pt/cohort until the occurrence of ≥ G2 toxicity at which time the study proceeded in a 3+3 design. Additional patient were also recruited in cohorts in order to attain PK/PD and biopsy samples. Results: Between 2/18 and 8/18, 19 subjects (13M, 6F) with median age of 69 y started therapy. Dose (mg/d) escalation and number of patients treated (n) per each cohort proceeded as follows: 240 mg (1), 360 (4), 480 (2), 600 (6) and 720 (6). APX3330 was well tolerated at dose levels from 240-600 mg/d. The most frequent treatment-related adverse event (all grades) was G1 fatigue. A G3 rash occurred in two subjects at the 720 mg level defining 600 mg/d as the RP2D for further development. Six subjects had disease stabilization for ≥ 4 cycles, and of these, four subjects with the following diagnosis, RECIST response and days on study included: (CRC, PR, 356), (Endometrial, SD, 316), (Melanoma, SD, 245), (Prostate, SD, 246). Final PK and PD data, including proteomic, transcriptome, APE1 serum levels and CTC analyses are pending and will be reported at the conference. Conclusions: APX3330 is an orally administered inhibitor of APE1. 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 indicate APX3330 mediated targeting of the APE1 protein. Clinical trial information: NCT03375086