Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

Temozolomide, an oral cytotoxic agent with approximately 100% bioavailabili ty after one administration, has demonstrated schedule-dependent clinical a ctivity against highly resistant cancers. Thirty patients with minimal prio r chemotherapy were enrolled in this phase I trial to characterize the drug 's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicitie s (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m(-2) was administered once daily for 5 days every 28 days. The DLT was thromboc ytopenia, and the MTD was 200 ms m(-2) day(-1). Subsequently patients recei ved the MTD to study how food affects the oral bioavailability of temozolom ide. When given orally once daily for 5 days, temozolomide was well tolerat ed and produced a non-cumulative, transient myelosuppression. The most comm on non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic metanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean T-max sim ilar to 1 h) and eliminated (mean t(1/2) = 1.8 h). Food produced a slight r eduction (9%) in absorption of temozolomide. Temozolomide 200 mg m(-2) day( -1) for 5 days, every 28 days, is recommended for phase II studies. (C) 199 9 Cancer Research Campaign.