TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

Abstract

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

“…15,23 TH-302 is a pro-drug that is activated specifically in hypoxic cells, and has demonstrated promising results both in preclinical studies and in early clinical trials. [11][12][13]25,26 However, since TH-302 is non-fluorescent, its direct visualization in tumor tissue is not possible. Therefore, we extended our techniques of assessing biomarker distribution following drug treatment to evaluate the effects of TH-302 in hypoxic and vascular regions of solid tumors.…”

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

“…We have shown that T given 2 -4 hrs before administration of conventional chemotherapeutics is an optimal schedule. 21 nP prior to G is employed in both clinica 27 and preclinical settings, 37 and it has been shown that nP is able to increase intratumoral concentration of G. 37 In this study, the animals were first dosed with TH-302 ip, followed by nP iv 2 hrs later, and then after 1 more hr, G was given ip. MTD was determined by dose escalations in a small number of CD-1 immunocompetent mice or non-tumor bearing nu/nu mice.…”

“…TH-302 exhibits hypoxia-selective in vitro cytotoxicity cross a wide variety of human cancer cell lines 19 and in vivo anti-tumor efficacy in a panel of human tumor xenograft models. 20,21 Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors in humans, with a 5-year survival rate of less than 5%. 22 Gemcitabine, a cytotoxic pyrimidine analog chemotherapeutic, has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer.…”

Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

“…Interestingly, the efficacy of TH-302 is improved when administered before rather than after treatment with one of the above chemotherapeutic agents. Accordingly, when TH-302 is used in a combination with other conventional antineoplastic agents, the efficacy of TH-302 is affected by the order in which it is administered (Liu et al, 2012).…”