Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer.

摘要: Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study to characterize the toxicity, pharmacokinetics, antitumor TMZ administered on an oral 5-day schedule patients or without prior exposure nitrosourea (NU). Thirty-six eligible received total 77 cycles therapy p.o. at doses ranging from 50 mg/m2/day 250 for 5 days, every 4 weeks. Separate dose escalations were carried out patients, NU. Pharmacokinetic studies performed during first cycle treatment days 1 5. Dose-limiting toxicity was thrombocytopenia, maximally tolerated NU 150 (total dose, 750 mg/m2) 1250 mg/m2), respectively. Significant (grade 3 higher) thrombocytopenia observed six 1. median times nadir recovery 17 15 Nonhematological generally manageable consisted fatigue, nausea, vomiting. There two complete responses (one one melanoma) No objective seen treatment. showed rapid absorption mean time peak concentration 60 min t1/2 109 (range, 80-121 min). area under curve plasma concentrations linear over range 50-250 mg/m2/day. apparent clearances day 102+/- 27 115+/- 22 ml/min/m2, Apparent found differ respect (P = 0.047). Renal clearance parent drug its metabolism 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid minor pathways elimination. We conclude that well dose-limiting it has promising recommended II are 125 225