TAS-102 is an oral agent, which consists of a combination of a novel antimetabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents degradation of FTD. It has demonstrated activity in chemorefractory metastatic colorectal cancer (mCRC) patients. In the Japanese randomized phase II trial, TAS-102 improved medial overall survival when compared to placebo (9.0 vs.6.6 months, Hazard Ratio (HR) 0.56) in patients with mCRC refractory to 5-fluorouracil (5-FU), irinotecan and oxaliplatin. Subsequently, a randomized phase III study conducted in 13 countries (RECOURSE trial) confirmed this benefit on overall survival when compared to placebo (7.1 months vs. 5.3 months, HR 0.68) in patients with refractory metastatic colorectal cancer (CRC) 5.~Oxaliplatin is a third generation platinum compound, which is active when used together with 5-FU in the treatment of mCRC (FOLFOX). FOLFOX chemotherapy, which is frequently combined with anti-angiogenic agent Bevacizumab, is widely accepted as the preferred first-line regimen in the treatment of this disease in the US. Oxaliplatin is also frequently reintroduced in more advanced settings. Reintroduction is seen after progression on maintenance therapy, after resolution of previous treatment limiting neuropathy, after disease recurrence post adjuvant treatment or post metastasectomy. In the control arm of a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer (OPTIMOX1 study), oxaliplatin was reintroduced in 27% of patients. Although patients derive clinical benefit when oxaliplatin is reintroduced, the response rates are not as robust as during initial exposures. Decreased efficacy may be at least in part due to prolonged exposure and resultant resistance to 5-FU, which is a backbone in maintenance and in oxaliplatin containing regimens. Hence, the investigators propose exploring the safety and efficacy of oxaliplatin in combination with an alternative anti-metabolite TAS-102 (TAS-OX).~TAS-102 has demonstrated activity in 5-FU refractory mCRC, so the investigators hypothesize that TAS-OX may serve as an alternative drug combination for patients who have progressed or recurred after FOLFOX, and who are candidates for additional oxaliplatin therapy.~This is a 2-part clinical trial with TAS-102 in combination with oxaliplatin. The first part will be a dose-finding run-in phase and will enroll 3-18 patients. The second part, the focus of this study, will be a single arm cohort , which will further evaluate the safety, as well as efficacy, of TAS-OX in the treatment of mCRC. The subjects in part 2 will be treated with the drug doses determined in Part 1 of the trial. Up to 50 patients will be enrolled in part 2. Anticipated enrollment may be as high as 68 patients. Maximum potential enrollment is listed under anticipated enrollment, below.
This study will examine the safety and effectiveness of oxaliplatin in combination with TAS-102 (TAS-OX) for treatment of patients with metastatic colorectal cancer whose cancer has progressed or recurred after FOLFOX chemotherapy.