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

Abstract

Summary Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior 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 toxicities (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 thrombocytopenia, and the MTD was 200 mg m -2 day -1 . Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean T max~1 h) and eliminated (mean t 1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m -2 day -1 for 5 days, every 28 days, is recommended for phase II studies.

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

“…Peak plasma concentration was 13.7 mg ml À1 (Brada et al, 1999) Etoposide 10.5 mg ml À1 1.05 mg ml À1…”

Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy

“…The clinically relevant regimen for TMZ consists of 150-200 mg/m 2 /day, via oral administration, on days 1-5 of a 28-day cycle. 1 However, its peak concentration measured is only 50 mmol/l in patient's blood samples [9][10][11][12] and 5 mmol/l in the CSF. 12 Thus, it has been proposed that the intratumoral concentration may not exceed 50 mmol/l.…”

Temozolomide induces senescence but not apoptosis in human melanoma cells

“…Figure 1A and B show that TMZ inhibited colony formation in MM200 and IgR3 cell lines even when used at concentrations as low as 25 mM. At 100 mM, a clinically relevant concentration (Brada et al, 1999), colony formation was reduced to 22% of the control in IgR3 and 23% in MM200 cells. In contrast, inhibition of colony formation in SK-mel-28 and Mel-FH cells was observed only when TMZ was used at 75 mM or higher.…”