Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib
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To evaluate the safety, tolerability, pharmacokinetics and antitumor activities of famitinib (famitinib l-malate), a novel oral multitargeting tyrosine kinase inhibitor that acts against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, stem cell factor receptor (c-kit), FMS-like tyrosine kinase-3 receptor and protooncogene tyrosine kinase receptor in patients with advanced solid cancer.
Patients received once daily oral famitinib. Doses were increased from 4 to 8, 13, 20, 27, 24, 25 and eventually 30 mg. Each cycle was defined as 28 days. The pharmacokinetic profile and various biomarkers were evaluated during the first cycle. Antitumor efficacy was evaluated every 8 weeks.
Fifty-four patients were evaluable for safety and efficacy. Dose-limiting toxicities were observed in 2 of 3 patients at 30 mg. The dose-limiting toxicities observed in the first cycle of famitinib treatment included hypertension, hand-foot skin reaction and diarrhea. Grade 3 hypertriglyceridemia/hypercholesterolemia and proteinuria were notable side effects in the subsequent treatment cycles. Other common side effects included bone marrow suppression, oral mucositis, fatigue, pain, elevated transaminase or bilirubin, peripheral sensory disturbance and hypothyroidism, most of which were mild to moderate in severity. Pharmacokinetic studies revealed no significant accumulation of famitinib or its major metabolite, M3. The half-lives of famitinib and M3 were approximately 28.7–33.8 and 41.3–47.7 h, respectively. Food demonstrated a minimal effect on the pharmacokinetics of famitinib. Eight partial responses were determined, including 6 cases of renal cell carcinoma, 1 case of gastrointestinal stromal tumor (GIST) and 1 case of alveolar soft part sarcoma. Fourteen patients demonstrated stable disease with various degrees of tumor shrinkage.
Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25 mg.
KeywordsFamitinib Phase I trial Safety Pharmacokinetics Antitumor activity
Conflict of interest
This research was sponsored by Jiangsu Hengrui Medicine Co. Ltd. The following author has a financial relationship to the sponsor: Jiang HY was an employee of Jiangsu Hengrui Medicine Co. Ltd.
- 6.Lou LG, Mi Y, Xu YP, Chengying Xie, Zhao HB (2011) Preclinical antitumor study of famitinib, an orally available multi-targeted kinase inhibitor of VEGFR/PDGFR/c-Kit in phase I clinical trials. In Proceedings of the 102 th annual meeting of the American Association for Cancer Research, 2011 Apr 2–6. AACR, Orlando, Florida, Abstr3604Google Scholar
- 10.Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J et al (2006) Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs 17(3):353–358PubMedCrossRefGoogle Scholar
- 14.Qin S, Jin J, Guo J, Wang J, Zhou F, Huang Y et al (2012) A phase IV multicenter study of the efficacy and safety of sunitinib as first-line therapy in Chinese patients with metastatic renal cell carcinoma. Ann Oncol 23(Suppl 9):abstr851pGoogle Scholar
- 16.Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR et al (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22(5):909–918PubMedCrossRefGoogle Scholar
- 21.Tariq Mahmood S, Agresta S, Vigil CE, Rau J, Wimberger P, Sehouli J et al (2011) Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. Int J Cancer 129(8):1963–1969PubMedCrossRefGoogle Scholar
- 22.Bertuzzi A, Stroppa EM, Secondino S, Pedrazzoli P, Zucali P, Quagliuolo P et al (2010) Efficacy and toxicity of sorafenib monotherapy in patients with advanced soft tissue sarcoma failing anthracycline-based chemotherapy. J Clin Oncol 28(15s):abstr10025Google Scholar
- 23.Palassini E, Stacchiotti S, Negri T, Brich S, Marrari A, Morosi C et al (2010) Sunitinib malate (SM) in alveolar soft sarcoma (ASPS). J Clin Oncol 28(15s):abstr10014Google Scholar