Abstract 284: IT-139 holds potential for combination therapy
Authors: Costich Tara Lee , Sethuraman Jyothi , Crouse Rick , Bakewell Suzanne 
Published: July 2016

IT-139, sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] is a ruthenium based small molecule that has successfully completed a phase I clinical trial in 41 patients with mild to moderate systemic toxicities. There were no dose limiting hematologic toxicities observed. IT-139 holds potential for continued clinical development because of its aqueous solubility, long half-life and manageable toxicity. Stable disease was observed in 11 of the 41 patients of the Phase I clinical trial, but we believe IT-139's future clinical development will be in combination therapy. In vitro studies revealed potential for additive and synergistic combinations. Few in vivo combination studies were completed previously due to challenges associated with administration. Here we show that by overcoming the administration challenges in our animal models we were able to identify a dependable maximum tolerated dose (MTD), optimize dosing regimens for combination xenograft efficacy studies and extend the length of treatment in efficacy studies. In an HCT116 subcutaneous model, increased efficacy was demonstrated when IT-139 was dosed in combination with oxaliplatin over oxaliplatin alone. In an A549 lung carcinoma subcutaneous model, increased efficacy was observed when IT-139 was dosed in combination with cisplatin over cisplatin alone. Increased toxicity from the combined treatment was observed after the initial treatment and the chemotherapeutic dose was reduced for the duration of the study. However, clinical pharmacokinetic results confirmed IT-139's long plasma half-life and metabolic studies have confirmed its high affinity for plasma proteins. Based on these data we staggered the dosing of IT-139 by 24 hrs allowing us to dose both IT-139 and a chemotherapeutic agent at their MTDs. This dosing regimen saw an increase in efficacy in an HT-29 colorectal xenograft model treated with IT-139 and the anti-metabolite 5-FU over treatment with 5-FU alone. We also observed improved efficacy with IT-139 dosed weekly instead of the q4d schedule, suggesting that the pharmacokinetics of IT-139 allows less frequent dosing without compromising efficacy. The toxicology report from IT-139 dosed at 50 mg/kg shows microscopic alterations in the liver and kidney. Minimal to moderate hepatocellular alterations were noted in periportal regions at 48 hrs. Renal tubular necrosis was noted at 24, 48 and 72 hrs, but tubular regeneration was noted at 48 and 72 hrs time points. In the combination therapy (IT-139 at 50 mg/kg plus oxaliplatin) mice there were no results in the liver and kidneys to suggest exacerbation of the noted alterations. There were no observations of either liver or kidney toxicity in the Phase I human study. These findings further attest to the potential of IT-139 in combination therapy, but suggest further investigation to identify the optimal dosing regimen. Current mechanism of action studies will collaborate and support our in vivo studies for the future success of IT-139's return to the clinic.

Citation Format: Tara Lee Costich, Jyothi Sethuraman, Rick Crouse, Suzanne Bakewell. IT-139 holds potential for combination therapy. [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 284.