Abstract LB-201: Preclinical toxicology of TRXE-002-1
Authors: Lilischkis Kimberley , Heaton Andrew , Alvero Ayesha , Mor Gil , Brown David M. 
Published: July 2016

Introduction: TRXE-002-1 is a low molecular weight super benzopyran molecule identified as having potent activity against many cancer phenotypes. It was identified from a library of analogues as being able to induce cell death in both chemoresistant CD44+/MyD88+ ovarian cancer stem cells (IC50 of ∼ 50 nM) and chemosensitive CD44-/MyD88- ovarian cancer cells, and disrupt spheroid cultures formed from cancer stem cells. In vivo studies have confirmed efficacy in a rodent intra-peritoneal model of human ovarian cancer. Here we report on pre-clinical toxicology studies conducted on TRXE-002-1.

Method: We conducted a full GLP dog CV study using a 4×4 Latin Square Crossover study design where we assessed telemetric ECG recordings from 4 male dogs post IP administration at doses up to 30 mg/kg. Thirty seconds of continuous ECG tracings were collected pre-dose (Baseline) and at 0.5, 1.5, 2.5, and, 24 hours after test article or vehicle administration. In addition, TRXE-002-1 was assessed in standard assays used to identify mutagenic potential using the bacterial reverse mutation assay. The potential for TRXE-0

2-1to induce micronuclei in the bone marrow of SPF Arc(S) Swiss mice was also investigated as a measure of clastogenicity. TRXE-002-1 toxicology was evaluated in MTD, and 28-day repeat dose GLP studies in rats and dogs.

Results: TRXE-002-1 was found to have no effect on cardiac parameters of blood pressure and electrocardiography in dogs. TRXE-002-1 had no reverse mutagenic potential using the bacterial reverse mutation pre-incubation method ± S9 metabolic activation (Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and the WP2 uvrA Escherichia coli strain). Similarly, TRX-E-002-1 was shown to be non-mutagenic using the gene mutation test at the TK locus in L5178Y mouse lymphoma cell culture with and without metabolic activation. High doses of TRXE-002-1 (200 and 400 mg/kg) caused a significant increase in incidence of micronuclei in male and female mice. Repeat intraperitoneal injection of TRXE-002-1 to male and female dogs and rats over 28 days was well tolerated. Adverse TRXE-002 1-related effects were limited to microscopic findings in the testes and epididymides for male rats and dogs at high doses. Macroscopic observations at necropsy were confined to sporadic distention of the cecum and colon and colon obstruction in rats only (high dose) with no observed gastrointestinal microscopic findings reported in either species. Other observations were mostly resolved after a 14-day recovery period, except microscopic findings in the testes from both species.

Conclusion: These data show that TRXE-002-1 has an acceptable toxicity profile in rats and dogs, and is without genotoxicity and cardiotoxicity at clinically relevant concentrations. TRXE-002-1 has been granted orphan drug status by the U.S. Food and Drug Administration (FDA) for ovarian cancer and a first-in-human clinical trial is planned for 2016.

Citation Format: Kimberley Lilischkis, Andrew Heaton, Ayesha Alvero, Gil Mor, David M. Brown. Preclinical toxicology of TRXE-002-1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-201.