title: Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors.
abstract: Anlotinib is a novel multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret. We aimed to evaluate the safety, pharmacokinetics, and antitumor activity of anlotinib in patients with advanced refractory solid tumors.
  
  
  
  Anlotinib (5-16 mg) was orally administered in patients with solid tumor once a day on two schedules: (1) four consecutive weeks (4/0) or (2) 2-week on/1-week off (2/1). Pharmacokinetic sampling was performed in all patients. Twenty-one patients were further enrolled in an expanded cohort study on the recommended dose and schedule. Preliminary tumor response was also assessed.
  
  
  
  On the 4/0 schedule, dose-limiting toxicity (DLT) was grade 3 hypertension at 10 mg. On the 2/1 schedule, DLT was grade 3 hypertension and grade 3 fatigue at 16 mg. Pharmacokinetic assessment indicated that anlotinib had long elimination half-lives and significant accumulation during multiple oral doses. The 2/1 schedule was selected, with 12 mg once daily as the maximum tolerated dose for the expanding study. Twenty of the 21 patients (with colon adenocarcinoma, non-small cell lung cancer, renal clear cell cancer, medullary thyroid carcinoma, and soft tissue sarcoma) were assessable for antitumor activity of anlotinib: 3 patients had partial response, 14 patients had stable disease including 12 tumor burden shrinkage, and 3 had disease progression. The main serious adverse effects were hypertension, triglyceride elevation, hand-foot skin reaction, and lipase elevation.
  
  
  
  At the dose of 12 mg once daily at the 2/1 schedule, anlotinib displayed manageable toxicity, long circulation, and broad-spectrum antitumor potential, justifying the conduct of further studies.
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, 100021, China.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Niu
authors.affiliation: The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, 100021, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Du
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, 100021, China.
authors.forename: Shuting
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, 100021, China.
authors.forename: Jinwan
authors.initials: J
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Fengqing
authors.initials: F
authors.lastname: Wang
authors.affiliation: School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hao
authors.affiliation: The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. chli@simm.ac.cn.
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, 100021, China. dryihebalichi@126.com.
authors.forename: Yihebali
authors.initials: Y
authors.lastname: Chi
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage*; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C000625192:anlotinib
keywords: Advanced refractory solid tumors; Anlotinib; Anti-angiogenesis; Pharmacokinetics; Phase I study; Safety