Phase I trial of sequential administration of raltitrexed (Tomudex) and 5-iodo-2 '-deoxyuridine (IdUrd)

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase with clinical activity in colorectal cancer. The combination of raltitrexed and 5-iodo-2'-deoxyuridine (IdUrd, a cytotoxic pyrimidine analog) resulted in i ncreased IdUrd incorporation into DNA and exhibited in vitro synergism agai nst colon and bladder human carcinoma cell lines. We designed a phase I tri al to determine the MTD, pharmacokinetics, and biologic effects of escalati ng doses of the combination of IdUrd given as a 24-hour infusion after a ra ltitrexed 15-minute infusion every three weeks. Thirty-four patients receiv ed 95 courses of raltitrexed and IdUrd at doses ranging from raltitrexed 1 mg/m(2) and IdUrd 750 mg/m(2) to raltitrexed 2.5 mg/m(2) and IdUrd 10,400 m g/m(2). The median number of cycles administered was 2 (range 1-10). Dose limiting hematologic toxicity occurred at doses of raltitrexed 2.5 mg/m(2) and IdUrd 10,400 mg/m(2). In addition, we determined the mean plasma concentrations C(s)s of IdUrd, the iodouracil level at 22 hours and the IdUrd clearance. R altitrexed did not appear to affect the pharmacokinetics of IdUrd in the do se range tested. The recommended phase II dose is raltitrexed 2 mg/m(2) and IdUrd 10,400 mg/m(2) repeated every three weeks. Evidence of potential ant itumor activity was observed: 1 patient (with colon cancer) had a partial r esponse while 15 others had stable disease.