Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients.
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 > or =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.
Mukohara
Toru
T
National Cancer Center Hospital East, Oncology/Hematology, Kashiwa, Japan.
Nakajima
Hikaru
H
Mukai
Hirofumi
H
Nagai
Shunji
S
Itoh
Kuniaki
K
Umeyama
Yoshiko
Y
Hashimoto
Junichi
J
Minami
Hironobu
H
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077784:Axitinib; D015415:Biomarkers; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007191:Indazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D013972:Thyrotropin / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D007093:Imidazoles; D007191:Indazoles; D013972:Thyrotropin; D000077784:Axitinib; D040301:Vascular Endothelial Growth Factor Receptor-2