Temozolomide in patients with advanced cancer: phase I and pharmacokinetic study.
OBJECTIVE
To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and potential antitumor activity of temozolomide administered as a single dose every 28 days.


METHODS
Open label, phase I, dose-escalation trial.


METHODS
University-affiliated cancer center.


METHODS
Eleven patients aged 33-73 years with a documented solid tumor or lymphoma who failed therapy of proven efficacy for their disease or had a disease for which no conventional therapy was available.


METHODS
Temozolomide 500 mg/m2 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m2. No intrapatient dose escalation was allowed. At least two patients were enrolled at each dose level. Patients who did not have progressive disease and did not experience a dose-limiting toxicity, or experienced a dose-limiting toxicity but were eligible for dose reduction, were eligible to continue on the study.


RESULTS
Pharmacokinetic analysis was performed for temozolomide and its active metabolite, 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC). Neutropenia and thrombocytopenia were dose limiting at 1000 mg/m2. Temozolomide was absorbed rapidly (mean time to maximum concentration 1.4 hrs) and eliminated, with average half-life and apparent oral systemic clearance values of 1.8 hours and 97 ml/minute/m2, respectively. Mean systemic exposure to MTIC was 3.7% of temozolomide. No objective responses were observed. The maximum tolerated dose of temozolomide was 750 mg/m2.


CONCLUSIONS
Temozolomide 750 mg/m2 administered orally every 28 days was well tolerated. Alternate temozolomide dosing schedules such as continuous daily administration may enhance antitumor activity through sustained depletion of the DNA repair protein O6-alkylguanine DNA alkyltransferase.
Rudek
Michelle A
MA
Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, Maryland 21231, USA.
Donehower
Ross C
RC
Statkevich
Paul
P
Batra
Vijay K
VK
Cutler
David L
DL
Baker
Sharyn D
SD
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000477:Alkylating Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D002214:Capsules; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006207:Half-Life; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D000077204:Temozolomide; D013921:Thrombocytopenia / Q000139:chemically induced / Q000150:complications; D014018:Tissue Distribution; D017211:Treatment Failure
D000477:Alkylating Agents; D002214:Capsules; D003606:Dacarbazine; D000469:Alkaline Phosphatase; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide; D001663:Bilirubin; D000077204:Temozolomide