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.
OBJECTIVE
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.
Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
Junning
J
Cao
Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
Jian
J
Zhang
Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
Wei
W
Peng
Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
Zhiyu
Z
Chen
Hutchison MediPharma Ltd, Zhangjiang Hi-Tech Park, Pudong, Shanghai, 201203, People's Republic of China.
Songhua
S
Fan
Hutchison MediPharma Ltd, Zhangjiang Hi-Tech Park, Pudong, Shanghai, 201203, People's Republic of China.
Weiguo
W
Su
Hutchison MediPharma Ltd, Zhangjiang Hi-Tech Park, Pudong, Shanghai, 201203, People's Republic of China.
Ke
K
Li
Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China. fudanlijin@163.com.
Jin
J
Li
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors; D055815:Young Adult
D000970:Antineoplastic Agents; D001572:Benzofurans; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C000591844:HMPL-013; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
Advanced solid tumors; Fruquintinib; Phase I study; Safety and pharmacokinetics; VEGFR