Open AccessEffect of axitinib (AG‐013736) on fatigue, thyroid‐stimulating hormone, and biomarkers: A phase I study in Japanese patients
Author(s) -
Mukohara Toru,
Nakajima Hikaru,
Mukai Hirofumi,
Nagai Shunji,
Itoh Kuniaki,
Umeyama Yoshiko,
Hashimoto Junichi,
Minami Hironobu
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01465.x
Subject(s) - axitinib , medicine , adverse effect , pharmacodynamics , pharmacokinetics , endocrinology , dosing , thyroid , area under the curve , gastroenterology , cancer , sunitinib
Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, antitumor activity, and recommended starting dose of axitinib in patients with advanced solid tumors. Twelve patients received single‐dose axitinib 5 mg and were monitored for ≥48 h. Continuous 5 mg twice‐daily dosing was then initiated. One patient had dose‐limiting toxicity (grade 3 proteinuria and fatigue). Common treatment‐related adverse events were anorexia, fatigue, and diarrhea. Grade 3 treatment‐related adverse events were fatigue and hypertension. Maximum axitinib plasma concentration occurred 1–4 h after steady‐state dosing. Eleven patients experienced thyroid‐stimulating hormone elevation; time‐course change and fatigue onset appeared to be related in some patients. Significant correlation was observed between thyroid‐stimulating hormone change and area under the plasma concentration–time curve (AUC; r = 0.80, P = 0.005). Axitinib decreased plasma soluble vascular endothelial growth factor receptor 2 (s‐VEGFR2), with significant correlation between change in s‐VEGFR2 and AUC ( r = −0.92, P < 0.0001). Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib. Tumor size decreased in nine patients. The time‐course of thyroid‐stimulating hormone change appeared correlated with fatigue. There were significant correlations between thyroid‐stimulating hormone or s‐VEGFR2 and axitinib exposure. Axitinib 5 mg twice‐daily is the recommended starting dose for Japanese patients. This trial is registered with ClinicalTrials.gov, identifier NCT00447005. ( Cancer Sci 2010) ( Cancer Sci 2010; 101: 963–968)