A DOSE-SEEKING TRIAL OF EDATREXATE IN COMBINATION WITH VINBLASTINE, ADRIAMYCIN, CISPLATIN, AND FILGRASTIM (EVAC G-CSF) IN PATIENTS WITH ADVANCED MALIGNANCIES - PROMISING ANTINEOPLASTIC ACTIVITY AGAINST NONSMALL CELL LUNG CARCINOMAS/

PURPOSE To determine the maximum tolerated dose, toxicities, and poten tial antitumor activity of edatrexate (E), an antifolate agent with en hanced in vitro antitumor activity as compared with methotrexate (M), when given in combination with vinblastine, doxorubicin, cisplatin, an d filgrastim (G-CSF) to patients with advanced malignancies. PATIENTS AND METHODS Thirty-seven patients with advanced malignancies were trea ted with escalating doses of edatrexate in combination with vinblastin e (V), doxorubicin (A), cisplatin (C), and filgrastim (EVAC/G-CSF) fol lowing three different subsequently developed schedules. Schedule 1 wa s patterned after the MVAC regimen, a combination chemotherapy program with activity against different epithelial malignancies, and consiste d of E, 40 mg/m(2)/day, days 1/15/22; V,3 mg/m(2)/day, days 2/15/22; A , 30 mg/m(2)/day, day 2; C, 70 mg/m(2)/day, day 2; repeated every 28 d ays. Schedules 2 and 3 were designed to avoid observed dose-limiting t oxicity on schedule 1 consisting of transient elevation of serum creat inine levels and delayed myelosuppression. Schedule 2 consisted of E, 40 or 60 mg/m(2)/day, days 1 and 15; V, 3 mg/m(2)/day, days 2 and 15; A, 30 mg/m(2)/day, day 2; C, 30 mg/m(2)/day, days 1 and 2; cycled ever y 28 days. Schedule 3 consisted of E, 60) to 120 mg/m(2)/day, day 1; V , 3 mg/m(2)/day, day 2; A, 30 mg/m(2)/day, day 2; C, 30 mg/m(2)/day, d ays 1 and 2; cycled every 21 days. Filgrastim 5 mu g/kg/day was given to all patients subcutaneously until the absolute neutrophil count was greater than 10,000/mu L postnadir. Three patients were treated on sc hedule 1, 10 on schedule 2 (four at an E dose of 40 mg/m(2)/day and si x at an E dose of 60 mg/m(2)/day), and 24 on schedule 3 (six at each o f the following E dosages: 60, 80, 100, and 120 mg/m(2)/day). RESULTS Dose-limiting toxicities of grade 3 to 4 leukopenia and transient elev ation of serum creatinine values were observed in two of three patient s treated on schedule 1. A dose-limiting toxicity of grade 3 to 4 leuk openia was noted. in two of six patients treated on schedule 2 at an e datrexate dose of 60 mg/m(2)/day. Two of six patients treated on sched ule 3 at an edatrexate dose of 120 mg/m(2)/day had a dose-limiting tox icity of grade 3 stomatitis (one patient) and grade 3 cytopenia (one p atient). Nineteen of 37 patients with evaluable or measurable disease had a response to treatment (response rate 51%, 95% confidence interva ls = 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 (conf idence interval = 163-808 days) and a 1-year survival rate of 60% (con fidence interval = 35%-85%) was seen in patients with advanced non-sma ll cell lung cancer. CONCLUSIONS The maximum tolerated dose and the re commended phase II dose of edatrexate is 100 mg/m(2)/day when administ ered as part of the EVAC/G-CSF program following schedule 3. Promising antineoplastic activity against non-small cell lung carcinomas was ob served, and a phase II study is planned.