Abstract B278: PR610: A novel hypoxia-selective tyrosine kinase inhibitor in phase I clinical trial.
Authors: Patterson Adam V. , Jaiswal Jagdish , Carlin Kendall , Abbattista Maria R. , Guise Christopher P. , Silva Shevan , Lee Ho , Lu Guo-Liang , Anderson Robert F. , Melink Teresa J. , Gutheil John C. , Smaill Jeff B. 
Published: August 2014

Abstract
PR610 is a hypoxia-selective irreversible Human Epidermal Growth Factor Receptor (HER) family inhibitor currently in phase I clinical trials in New Zealand and the USA (clinical trial ID NCT01631279). The prodrug PR610 releases the TKI (Tyrosine Kinase Inhibitor) PR610E, a picomolar irreversible inhibitor of EGFR (HER1), under oxygen-limiting conditions typically found in solid tumors. Human neoplastic cell lines exposed to PR610 show an anoxia-selective anti-proliferative response that is associated with G1 arrest and induction of apoptosis arising from inhibition of EGFR auto-phosphorylation and downstream silencing of associated signal transduction pathways. PR610 is optimized for long tumor residency (T½ &gt;2 days); in a preclinical model of erlotinib-resistant NSCLC, a single injection of PR610 produces profound, global shutdown of signal transduction via EGFRT790M/L858R. Tumor PR610E concentrations were above cellular anti-proliferative IC50 concentrations for over 5 days, being more than sufficient to induce apoptosis via “oncogenic shock”.
Pharmacokinetic (PK) studies of PR610 show significant differences in species toxicokinetics. Both the rat and dog preclinical toxicology models display considerable systemic conversion of PR610 to PR610E (6% - 30% and 24% - 29% of prodrug AUC, respectively) with attendant symptoms of EGFR inhibition including acneiform skin rash and diarrhea. In contrast NIH-III nude mice display minimal circulating TKI (PR610E) relative to PR610 (1.5% - 1.7% of AUC) consistent with a substantially improved tolerance as judged by PR610 plasma AUCinf at the maximum tolerated dose (MTD). Human subjects from the phase I clinical trial consistently experience the lowest systemic levels of PR610E (Mean 1.06% ± 0.69%; range 0.34% - 2.7%; n=20) across dose levels ranging from 10 - 150 mg/m2. Notably, a dose of 150 mg/m2 in human subjects produces a PR610 plasma AUCinf equivalent to that measured for 30 mg/kg PR610 in NIH-III mice, a dose that is active in several HER-dependent subcutaneous tumor xenograft models. Collectively, these data indicate that PR610 has the desirable characteristics of a deactivated prodrug in human subjects and preclinical models predict that an active dose range has been reached in the phase I trial. PR610 is a first-in-class hypoxia-selective EGFR/HER2 inhibitor with exciting clinical potential.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B278.
Citation Format: Adam V. Patterson, Jagdish Jaiswal, Kendall Carlin, Maria R. Abbattista, Christopher P. Guise, Shevan Silva, Ho Lee, Guo-Liang Lu, Robert F. Anderson, Teresa J. Melink, John C. Gutheil, Jeff B. Smaill. PR610: A novel hypoxia-selective tyrosine kinase inhibitor in phase I clinical trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B278.