Phase I study of mitoxantrone, raltitrexed, levofolinic acid and 5-fluorouracil in advanced solid tumours

We have recently evaluated the combination of raltitrexed, levofolinic acid (LFA) and 5-fluorouracil (5-FU) in advanced head and neck and colorectal cancer, and we have shown that this combination is well tolerated and has clinical activity. Clinical combination studies have shown that raltitrexed and anthracyclines can be combined at full doses without unexpected toxicities. Based on these observations, we started a phase I study of mitoxantrone plus raltitrexed administered on day 1, followed by LFA and 5-FU on day 2 in patients with advanced solid tumors.

Mitoxantrone was given at a starting dose of 6 mg/m2, raltitrexed at a fixed dose of 3 mg/m2, LFA at a fixed dose of 250 mg/m2, and 5-FU at a starting dose of 750 mg/m2. Mitoxantrone and 5-FU doses were subsequently escalated alternately up to dose-limiting toxicity. Treatment was repeated every 14 days.

Four dose levels were tested in 18 patients. All three patients treated at the fourth dose level had grade 4 neutropenia after the first cycle. Therefore, this level was defined as the maximum tolerated dose and the dose level immediately below (mitoxantrone 7 mg/m2 and 5-FU 900 mg/m2) was selected for further evaluation. Neutropenia was the main toxic effect. Nonhaematologic side effects were mild. One complete response and five partial responses (all but one in patients with head and neck cancer) were observed, for an overall response rate of 33% (95% confidence interval, 13% to 59%).

Mitoxantrone, raltitrexed and 5-FU can be combined at doses which are close to those used in monotherapy. The observed activity is encouraging, especially in the subset of patients with head and neck cancer.