title: Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors.
abstract: OBJECTIVE
  The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy.
  
  
  METHODS
  Different doses of oral icotinib were administered once every 8 h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects' blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay.
  
  
  RESULTS
  Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6 h, and the T(max) was around 2 h. The steady-state concentration of icotinib administered at a dose of 125 mg once every 8 h (Q8H) was significantly higher than that achieved by a dose of 100mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks.
  
  
  CONCLUSIONS
  Oral icotinib was generally well tolerated, with manageable and reversible adverse events (AEs) and showed positive clinical anti-tumor activities in patients with advanced NSCLC. The recommended dose for phase II/III studies with icotinib is 125 mg or 150 mg Q8H.
authors.affiliation: Department of Respiratory Disease, The First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79, Qingchun Road, Hangzhou, Zhejiang, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhao
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shentu
authors.forename: Nong
authors.initials: N
authors.lastname: Xu
authors.forename: Jianya
authors.initials: J
authors.lastname: Zhou
authors.forename: Guangdie
authors.initials: G
authors.lastname: Yang
authors.forename: Yinan
authors.initials: Y
authors.lastname: Yao
authors.forename: Fenlai
authors.initials: F
authors.lastname: Tan
authors.forename: Dongyang
authors.initials: D
authors.lastname: Liu
authors.forename: Yingxiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D043844:Crown Ethers / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D005499:Folliculitis / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011799:Quinazolines / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)