A dose-seeking trial of edatrexate in combination with vinblastine, andriamycin, cisplatin, and filgrastim (EVAC/G-CSF) in patients with advanced malignancies: Promising antineoplastic activity against non-small cell lung carcinomas

PURPOSE: To determine the maximum tolerated dose, toxicities, and potential antitumor activity of edatrexate (E), an anti-folate agent with enhanced in vitro antitumor activity as compared with methotrexate (M), when given in combination with vinblastine, doxorubicin, cisplatin, and filgrastim (G-CSF) to patients with advanced malignancies. PATIENTS AND METHODS: Thirty- seven patients with advanced malignancies were treated with escalating doses of edatrexate in combination with vinblastine (V), doxorubicin (A), cisplatin (C), and filgrastim (EVAC/G-CSF) following three different subsequently developed schedules. Schedule 1 was patterned after the MVAC regimen, a combination chemotherapy program with activity against different epithelial malignancies, and consisted of E, 40 mg/m²/day, days 1/15/22; V, 3 mg/m²/day, days 2/15/22; A, 30 mg/m²/day, day 2; C, 70 mg/m²/day, day 2; repeated every 28 days. Schedules 2 and 3 were designed to avoid observed dose-limiting toxicity on schedule 1 consisting of transient elevation of serum creatinine levels and delayed myelosuppression. Schedule 2 consisted of E, 40 or 60 mg/m²/day, days 1 and 15; V, 3 mg/m²/day, days 2 and 15; A, 30 mg/m²/day, day 2; C, 30 mg/m²/day, days 1 and 2; cycled every 28 days. Schedule 3 consisted of E, 60 to 120 mg/m²/day, day 1; V, 3 mg/m²/day, day 2; A, 30 mg/m²/day, day 2; C, 30 mg/m²/day, days 1 and 2; cycled every 21 days. Filgrastim 5 μg/kg/day was given to all patients subcutaneously until the absolute neutrophil count was greater than 10,000/μL postnadir. Three patients were treated on schedule 1, 10 on schedule 2 (four at an E dose of 40 mg/m²/day and six at an E dose of 60 mg/m²/day), and 24 on schedule 3 (six at each of the following E dosages: 60, 80, 100, and 120 mg/m²/day). RESULTS: Dose-limiting toxicities of grade 3 to 4 leukopenia and transient elevation of serum creatinine values were observed in two of three patients treated on schedule 1. A dose-limiting toxicity of grade 3 to 4 leukopenia was noted in two of six patients treated on schedule 2 at an edatrexate dose of 60 mg/m²/day. Two of six patients treated on schedule 3 at an edatrexate dose of 120 mg/m²/day had a dose-limiting toxicity of grade 3 stomatitis (one patient) and grade 3 cytopenia (one patient). Nineteen of 37 patients with evaluable or measurable disease had a response to treatment (response rate 51%, 95% confidence intervals = 35%-67%). Nine of 15 patients with metastatic non-small cell lung cancer responded, including one complete remission (response rate 60%, confidence intervals = 35%-85%). A median survival of 517 days (confidence interval = 163-808 days) and a 1-year survival rate of 60% (confidence interval = 35%-85%) was seen in patients with advanced non-small cell lung cancer. CONCLUSIONS: The maximum tolerated dose and the recommended phase II dose of edatrexate is 100 mg/m²/day when administered as part of the EVAC/G-CSF program following schedule 3. Promising antineoplastic activity against non-small cell lung carcinomas was observed, and a phase II study is planned.