Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies

Purpose: To determine the principal toxicities, characterize the pharmacoki netics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-fo r-5-days schedule, and recommend a dose for subsequent disease-directed stu dies in both minimally pretreated (MP) and heavily pretreated (HP) patients . Patients and Methods: patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150 , and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK pl asma was sampled on days 1 and 5. TMZ concentrations were analyzed and pert inent PK parameters were related to the principal toxicities of TMZ in PD a nalyses. Results: Twenty-four patients were treated with 85 courses of TMZ. Thromboc ytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive ef fects was unacceptably high at TMZ doses exceeding 150 mg/m2/d in both MP a nd HP patients. TMZ was absorbed rapidly with maximum concentrations achiev ed in 0.90 hours, on average, and elimination was rapid, with a half-life a nd systemic clearance rate (Cl-S/F) averaging 1.8 hours and 115 mL/min/m(2) , respectively. When clearance was normalized to body-surface area (BSA), i nterpatient variability in CIS/F was reduced from 20% to 13% on day 1 and f rom 16% to 10% on day 5. patients who experienced DLT had significantly hig her maximum drug concentration (median 16 v 9.5 mu g/mL, P = .0084) and are a under the concentration-time curve (median 36 v 23 mu g-h/ml, P = .0019) values on day 5. Conclusion: Prior myelosuppressive therapy war not a determinant of toxicit y. TMZ 150 mg/m2/d administered as a single oral dose daily for 5 days ever y 4 weeks is well tolerated by MP and HP patients, with higher doses result ing in unacceptably high rates of severe hematologic toxicity. TMZ doses sh ould be individualized according to BSA rather than use of a prespecified o ral dose for all individuals. TMZ is an optimal agent to develop in combina tion with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies. (C) 1999 by American Society of Clinical Oncol ogy.