|
|
Phase
I trial of temozolomide (NSC 362856) in patients with advanced cancer
Dhodapkar M, Rubin J, Reid JM, Burch PA, Pitot HC, Buckner JC, Ames MM, Suman
VJ.
Divisions of Medical Oncology and Oncology Research, and Section
of Biostatistics, Mayo Clinic, Rochester, MN 55905, USA
Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical
activity in glioma and melanoma.
The purpose of this Phase I study is to characterize the toxicity,
pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day
schedule to patients with or without prior exposure to nitrosourea (NU).
Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ
administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5
days, every 4 weeks.
Separate dose escalations were carried out in patients, with or without prior
exposure to NU.
Pharmacokinetic studies were performed during the first cycle of treatment on
days 1 and 5.
Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses
for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days
(total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2),
respectively.
Significant (grade 3 or higher) thrombocytopenia was observed in six patients
during cycle 1.
The median times to nadir and recovery were 17 and 15 days, respectively.
Nonhematological toxicity was generally manageable and consisted of fatigue,
nausea, and vomiting.
There were two complete responses (one glioma and one melanoma) in patients
without prior NU.
No objective responses were seen in patients with prior NU treatment.
Pharmacokinetic studies showed rapid absorption with a mean time to peak
concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min).
The area under the curve and the peak plasma concentrations were linear over the
dose range of 50-250 mg/m2/day.
The mean apparent oral clearances on day 1 for patients with and without prior
NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively.
Apparent oral clearances on days 1 and 5 were found to differ with respect to NU
exposure (P = 0.047).
Renal clearance of the parent drug and its metabolism to 3-methyl-2,
3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of
TMZ elimination.
We conclude that TMZ is well tolerated in this oral 5-day schedule with
dose-limiting thrombocytopenia and that it has promising activity in glioma and
melanoma.
The recommended doses for Phase II studies in patients with and without prior NU
are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.
PMID: 9815788 [PubMed - indexed for
MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9815788&dopt=Abstract
|
