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

Purpose: We have recently evaluated the combination of raltitrexed, levofol inic acid (LFA) and 5-fluorouracil (5-FU) in advanced head and neck and col orectal cancer, and we have shown that this combination is well tolerated a nd has clinical activity. Clinical combination studies have shown that ralt itrexed and anthracyclines can be combined at full doses without unexpected toxicities. Based on these observations, we started a phase I study of mit oxantrone plus raltitrexed administered on day 1, followed by LFA and 5-FU on day 2 in patients with advanced solid tumors. Patients and Methods: Mito xantrone was given at a starting dose of 6 mg/m(2), raltitrexed at a fixed dose of 3 mg/m(2), LFA at a fixed dose of 250 mg/m(2) and 5-FU at a startin g dose of 750 mg/m(2). Mitoxantrone and 5-FU doses were subsequently escala ted alternately up to dose-limiting toxicity. Treatment was repeated every 14 days. Results: Four dose levels were tested in 18 patients. All three pa tients treated at the fourth dose level had grade 4 neutropenia after the f irst cycle. Therefore, this level was defined as the maximum tolerated dose and the dose level immediately below (mitoxantrone 7 mg/m(2) and 5-FU 900 mg/m(2)) was selected for further evaluation. Neutropenia was the main toxi c 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 interva l, 13% to 59%). Conclusions: Mitoxantrone, raltitrexed and 5-FU can be comb ined at doses which are close to those used in monotherapy. The observed ac tivity is encouraging, especially in the subset of patients with head and n eck cancer.