Final results of a phase I and pharmacokinetic study of γ-methylene-10-deazaaminopterin (MDAM) administered intravenously daily for five consecutive days in patients with solid tumors

Purpose: To determine the maximum tolerated dose (MTD) of γ-methylene-10-deazaaminopterin (MDAM), a unique antifolate structurally similar to methotrexate (MTX), in the treatment of patients with solid tumors and to characterize toxicity and pharmacokinetic profiles of MDAM administered intravenously for five consecutive days repeated every 21 days. Methods: A group of 18 patients with treatment-refractory colorectal cancer (CRC) were given MDAM at increasing dose levels from 80 to 300 mg/m² per day intravenously for 5 days every 3 weeks. Results: A total of 18 patients were entered into the study. Grade 2 or less nausea, vomiting, diarrhea, anorexia and fatigue were observed at doses ≥160 mg/m² per day. Both patients enrolled at 300 mg/m² per day experienced grade 3 stomatitis and one patient had grade 4 granulocytopenia. At 270 mg/m² per day, grade 3 stomatitis (n = 2), thrombocytopenia (n = 1) and hyperbilirubinemia (n = 1) were observed. All toxicities were relatively brief in duration and reversible. Leucovorin rescue was not required. Of 17 evaluable patients, no complete or partial responses were observed, and 3 patients demonstrated stable disease. Pharmacokinetic analyses were performed in 16 of the 18 patients receiving MDAM at doses of 80, 160, 240, 270 and 300 mg/m². Normalized clearance of MDAM was approximately 1.5 times that reported for MTX (125 vs 80 ml/min per m²) in adults. Conclusion: MDAM is a novel antifolate with potential pharmacokinetic and safety advantages over MTX. Based on the results of this phase I study, stomatitis emerged as the dose-limiting toxicity and the recommended starting dose for phase II trials using this schedule and route of administration is 240 mg/m² per day.