A phase I study of raltitrexed (Tomudex) combined with carmofur in metastatic colorectal cancer.

Objectives: The aim of the study was to define the maximum tolerated dose (MTD) of the combination of raltitrexed plus carmofur, and to evaluate the tolerability and efficacy of this combination in metastatic colorectal cancer.

Methods: Twenty-eight patients (23 receiving first-line therapy, 5 receiving second-line therapy) entered the study; 16 were chemonaive. Raltitrexed (Tomudex) 1.5-3.0 mg/m(2) was given as a 15- to 30-min intravenous infusion on day 1 of a 21-day cycle followed by carmofur 300-400 mg/m(2) orally 3 times daily on days 2-14. Therapy was given until disease progression or dose-limiting toxicity (DLT) occurred.

Results: A total of 170 cycles of therapy were administered. The MTD was reached at the raltitrexed dose of 3.0 mg/m(2) and the carmofur dose of 400 mg/m(2). DLTs included grade 3-4 diarrhea, fatigue, anorexia, mucositis, anemia, thrombocytopenia, neutropenia, neurological symptoms and febrile neutropenia. Eleven of the 22 evaluable first-line patients achieved a partial response (response rate 50%, 95% confidence interval 29-71%), 8 had stable disease and 3 had disease progression. One of the 5 patients who received second-line therapy responded.

Conclusions: The recommended dose of this combination therapy for further evaluation is raltitrexed 3.0 mg/m(2) plus carmofur 300 mg/m(2). This combination has unique but manageable toxicity and promising efficacy in metastatic colorectal cancer.