10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of
methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to
polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid
tumors, giving
10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with
10-EDAM was qualitatively similar to that of
methotrexate.
Oral mucositis was the dose-limiting toxicity;
diarrhea,
skin rash,
leukopenia,
thrombocytopenia, and mild elevations of
serum glutamic-oxaloacetic transaminase,
prothrombin, and partial
thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment.
10-EDAM produced partial remissions in three patients with
non-small cell lung cancer and one patient with
breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the
drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the
drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary
drug appeared within the first 4 h following
drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic
acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin
metastases, more extensive retention of the
drug and of its polyglutamates was observed in the
breast cancer metastases than in the
metastases from a
kidney cancer or in normal skin.