Abstract 5388: Sequence- and regimen-dependent combination therapy with the hypoxia-activated Prodrug TH-302 and Doxorubicin in a preclinical sarcoma xenograft model
Authors: Sun Jessica D. , Liu Qian , Ahluwalia Dharmendra , Curd John G. , Hart Charles P. 
Published: February 2011

Abstract
Tumor hypoxia is associated with resistance to standard chemotherapy, cancer relapse, and poor prognosis. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP). In hypoxic conditions, bromo-isophosphoramide mustard (Br-IPM) is released and induces crosslinking of DNA. Preclinical anti-tumor activity of TH-302 was observed in a variety of in vitro and in vivo models including sarcoma. TH-302 in combination with Doxorubicin (Dox) is being explored for the treatment of soft tissue sarcoma in a Phase 1/2 clinical trial. To help guide clinical design, we conducted a series of translational studies to optimize preclinical dose sequence and regimen of TH-302 in combination with Dox, focusing on both efficacy and safety profiles.
Efficacy was investigated in the ectopic xenograft model after s.c. implantation of 1×106 HT1080, human fibrosarcoma cells into the flank of nude mice and allowing tumors to form with a size of approximately 150mm3. TH-302 was given ip at 50mg/kg (QDx5/wk x 2wks) or 100mg/kg (Q7Dx2), while Dox was administered iv at 4mg/kg (Q7Dx2). These are MTD doses. As a monotherapy, 100mg/kg weekly dose of TH-302 showed better efficacy compared with 50mg/kg daily dose (TGI 74.7% vs. 19.8%). This result can be contrasted to previous findings in the H460 NSCLC model, which showed that lower doses with more frequent dosing yielded greater efficacy. When combined with Dox, different synergistic antitumor effects were observed with different dose sequences. TH-302 given 2-4 hours before Dox was more efficacious than the other time intervals tested, e.g. 8 hours or 24hours (TGD500 of 21 days vs. 14 and 12 days, respectively).
Effect of dosing schedule on hemotoxicity was performed in CD-1 mice. TH-302 at 100mg/kg ip once, followed by Dox 6mg/kg iv once, were administered to the animals with different dosing schedules. In the monotherapy groups, a significant decrease of total white blood cells was only observed in the Dox group, while both Dox and TH-302 treatment reduced the number of neutrophils. TH-302 did not add to the hemotoxicity in the combination groups. Compared with simultaneous dosing, TH-302 given 4 hours before Dox attenuated both WBC and neutrophil drops (4.4±0.4 vs. 3.5±0.3 in WBC, and 0.8±0.1 vs. 0.6±0.04 in neutrophils).
In summary, consistent with previous studies, combination therapy of TH-302 and conventional chemotherapeutics shows a sequence- and regimen-dependent antitumor activity and toxicity profiles. In this sarcoma model, TH-302 given 2 or 4 hours before Dox yielded better efficacy while simultaneous administration of TH-302 and Dox is not supported because of the higher hemotoxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5388.