Abstract
Purpose
Fruquintinib (HMPL-013) is a novel oral small molecule compound that selectively inhibits vascular endothelial growth factor receptors-1, -2, and -3 with potent inhibitory effects on multiple human tumor xenografts. This first-in-human study was conducted to assess the maximum tolerated dose and dose-limiting toxicities, safety and tolerability, pharmacokinetics, and preliminary anti-tumor activity of fruquintinib.
Methods
Patients 18–70 years old with advanced solid tumors refractory to standard therapies were recruited. Fruquintinib was administered orally in 4-week repeating cycles in two regimens, either once daily continuously or once daily for 3-week on/1-week off, until discontinuation due to toxicity or tumor progression. Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.3. Pharmacokinetic parameters were measured after a single dose and in multiple dosing. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.0.
Results
Forty patients were enrolled into 5 cohorts in continuous regimen and 2 cohorts in 3-week-on/1-week-off regimen. The most common grade 3/4 adverse events were hand–foot skin reaction, hypertension, and thrombocytopenia. PK analysis showed good and rapid absorption followed by slow terminal elimination with a mean half-life of approximately 42 h which was consistent across all dose groups. Thirty-four patients were evaluable for tumor response, including 14 with partial response and 14 with stable disease.
Conclusions
Fruquintinib showed an acceptable safety profile and preliminary evidence of anti-tumor activity in patients with advanced solid tumors. The recommended dose was determined to be either 4 mg QD on a continuous regimen or 5 mg QD on a 3-week-on/1-week-off regimen.
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Acknowledgments
This study was supported financially by Hutchison MediPharma Ltd. We would like to thank Dr. Yang Sai and Dr. Yi Gu of Hutchison MediPharma Ltd. for providing assistance in pharmacokinetic data analysis.
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Songhua Fan, Weiguo Su, and Ke Li are employees of Hutchison MediPharma Ltd. Other authors declared no conflict of interest.
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Cao, J., Zhang, J., Peng, W. et al. A Phase I study of safety and pharmacokinetics of fruquintinib, a novel selective inhibitor of vascular endothelial growth factor receptor-1, -2, and -3 tyrosine kinases in Chinese patients with advanced solid tumors. Cancer Chemother Pharmacol 78, 259–269 (2016). https://doi.org/10.1007/s00280-016-3069-8
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DOI: https://doi.org/10.1007/s00280-016-3069-8