title: A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors.
  
  
  METHODS
  LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m²/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia.
  
  
  RESULTS
  Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m²/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m²/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m²/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed.
  
  
  CONCLUSIONS
  The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m²/day in Japanese patients with advanced solid tumors.
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakui
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mizugaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakamichi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kohei
authors.initials: K
authors.lastname: Suzuki
authors.forename: Hironori
authors.initials: H
authors.lastname: Kanda
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002173:Cancer Care Facilities; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000503:physiopathology; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D007564:Japan; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; C470243:KIF11 protein, human; D009363:Neoplasm Proteins; D013449:Sulfonamides; D013830:Thiadiazoles; C000591843:litronesib; D016547:Kinesins