Abstract
Purpose
Halofuginone (tempostatin™) is a synthetic derivative of a quinazolinone alkaloid
showing anti-angiogenic, anti-metastatic and anti-proliferative effects in preclinical
studies. The objectives of this phase I study were to assess the dose-limiting toxicities
(DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics
(PKs) of halofuginone when administered once or twice daily orally to patients with
advanced solid tumours.
Methods
Patients were treated with escalating doses of halofuginone at doses ranging from
0.5 to 3.5 mg/day. For pharmacokinetic analysis plasma sampling was performed during the first
and second course and assayed using a validated high-performance liquid chromatographic
assay with mass spectrometric detection.
Results
Twenty-four patients received a total of 106 courses. The ‘acute’ MTD was reached
at 3.5 mg/day, with nausea, vomiting, and fatigue as DLT. The recommended dose for chronic
administration was defined as 0.5 mg/day with the requirement of 5HT3 antagonists to control nausea and vomiting considered
as DLT. Several patients experienced bleeding complications on treatment with halofuginone
in which a causal relationship could not be excluded. The PKs of halofuginone were
linear over the dose range studied with a large interpatient variability.
Conclusions
In this study the DLT of halofuginone was nausea, vomiting, and fatigue. The recommended
dose for phase II studies of halofuginone is 0.5 mg administered orally, once daily.
Keywords
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Article info
Publication history
Accepted:
December 16,
2005
Received in revised form:
December 16,
2005
Received:
July 8,
2005
Identification
Copyright
© 2006 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
