Results of a randomized, Phase II clinical trial for the novel oral nucleoside antitumor agent TAS-102 under development by Taiho Pharmaceutical Co., Ltd for metastatic colorectal cancer were presented at the 9th Annual Meeting of the Japanese Society of Medical Oncology held in Yokohama. (Abstract no. 10428)

TAS-102 is a novel oral nucleoside antitumor agent with a novel mechanism of action, composed of a mixture of Trifluorothymidine (FTD), which demonstrates antitumor effects through incorporation into DNA, and 5-chloro-6-(2-iminopyrrolidin-1-yl)-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI), which inhibits the degradation of FTD. Phase I trials began in Japan in 2005, and the drug continues to be developed as a treatment for colorectal cancer refractory to standard chemotherapy and for which there is presently no established therapy.

Phase II trial
The phase II trial was a randomized, double-blind, placebo-controlled study with a primary outcome measure of overall survival involving 172 patients with refractory metastatic colorectal cancer who had received standard chemotherapy at least two or more regimens containing a fluoropyrimidine, irinotecan, and oxaliplatin. Patients were randomly assigned to the TAS-102 (114 cases) or a placebo (58 cases). The study was conducted 20 medical institutions in Japan from August 2009 to April 2010.

Overall Survival
The primary endpoint was overall survival. TAS-102 and placebo were administered at dose of 70mg/m2/day twice daily for five days followed by two days rest and repeated twice. This was followed by a 14-day rest period to make a 28-day schedule for one course. In both cohorts, the 28-day cycle was repeated until the established criteria for termination were met.

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The results indicated that the TAS-102 significantly improved overall survival compared with the placebo (overall survival median: 9.0 months vs. 6.6 months) and significantly reduced the risk of mortality (HR=0.56, p=0.0011). Also, no instances of treatment-related mortality were reported. The most frequently reported adverse drug reaction with a CTCAE grade 3 or higher was neutropenia. Grade 3 or higher diarrhea, fatigue, nausea, and other adverse reactions were no more than 10%.

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Ongoing development
In light of these results, Taiho Pharmaceutical will proceed with global development of TAS-102 so that this drug can be offered as soon as possible to metastatic colorectal cancer patients who have exhausted proven treatment options and there remains a high unmet medical need.

For more information:
Emura T, Murakami Y, Nakagawa F, Fukushima M, Kitazato K. A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med. 2004 Apr;13(4):545-9.
Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007 Jun;98(6):779-89. Epub 2007 Apr 18.
Shintani M, Urano M, Takakuwa Y, Kuroda M, Kamoshida S. Immunohistochemical characterization of pyrimidine synthetic enzymes, thymidine kinase-1 and thymidylate synthase, in various types of cancer. Oncol Rep. 2010 May;23(5):1345-50.

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