Taiho Pharmaceutical Co., Ltd. has submitted an application to the Japanese Ministry of Health, Labour and Welfare for approval of the manufacture and marketing of the novel oral nucleoside anti-tumour agent TAS-102 (combination of trifluorothymidine [FTD] and tipiracil hydrochloride [TPI]). Taiho is seeking approval of TAS-102 for the indication of unresectable, advanced, recurrent colorectal cancer.

The application for approval is based on the results of a phase II clinical trial (Study 10040030) conducted at 20 facilities throughout Japan. It was a randomized, double-blind comparative study of TAS-102 and a placebo involving 172 patients with unresectable, advanced, recurrent colorectal cancer that was refractory to the standard chemotherapy of at least two or more regimens containing fluoropyrimidine, irinotecan, and oxaliplatin.

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

Taiho Pharmaceutical is currently proceeding with a global phase III clinical trial of TAS-102 in a similar colorectal cancer population (RECOURSE) with the ultimate goal of global registration and commercialization of the agent.

Taiho Pharmaceutical believes that TAS-102 will make a significant contribution to cancer patients and will continue its development efforts to broaden its use.

TAS-102 is an anti-tumour agent composed of a combination of trifluorothymidine (FTD), a nucleoside that incorporates into DNA and inhibits a variety of genetic functions required for the proliferation of cancer cells, and tipiracil hydrochloride (TPI), an inhibitor of thymidine phosphorylase (which degrades FTD) that maintains an effective blood concentration of FTD. TAS-102 is administered twice daily to achieve a total daily dose of 70mg/m2 for five days followed by two days of rest and then repeated a second time. This is followed by a 14-day rest period to make a 28-day schedule for one course.

The phase II clinical trial was conducted with the participation of 172 patients at 20 medical institutions in Japan from August 2009 to April 2010. The target for the study is an area for which there is currently no fully established therapy in Japan — specifically, patients refractory to standard chemotherapy for metastatic colorectal cancer who have received at least two or more regimens containing fluoropyrimidine, irinotecan, and oxaliplatin. Patients were randomly assigned TAS-102 (114 cases) or a placebo (58 cases). The primary endpoint was overall survival.

The Global phase III Clinical Trial (RECOURSE) is a randomized, double-blind comparative study of TAS-102 versus a placebo. It is a global phase III clinical trial that is scheduled to enroll a total of 800 patients from Japan, North America, Europe, and Australia. Patient enrollment began in June 2012. The subjects are patients with unresectable, advanced, recurrent colorectal cancer that is refractory to standard chemotherapies (fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, and EGFR monoclonal antibody in cases of KRAS wild-type tumour). The trial will compare patients randomly assigned to receive TAS-102 or placebo in order to investigate the efficacy and safety of TAS-102. The primary outcome measure is overall survival.

The principal researchers are Dr Atsushi Otsu, director of the Clinical Development Centre of the National Cancer Centre Hospital East (Japan), Dr Robert J Mayer of the Dana Farber Cancer Institute (USA), and Dr Eric Van Cutsem of the University Hospital Gasthuisberg (Belgium).

Taiho Pharmaceutical, a subsidiary of Otsuka Holdings Co., Ltd., is an R&D-driven specialty pharma focusing on the three fields of oncology, allergies and immunology, and urology.