title: A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors.
abstract: OBJECTIVE
  The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP.
  
  
  METHODS
  In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m(2), escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0.
  
  
  RESULTS
  In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m(2)/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m(2)/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t(1/2) was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease.
  
  
  CONCLUSIONS
  MK-0731 at the MTD of 17 mg/m(2)/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.
authors.affiliation: University of Wisconsin Carbone Cancer Center, 600 Highland Ave., Madison, WI 53792-5666, USA. kdh@medicine.wisc.edu
authors.forename: Kyle
authors.initials: K
authors.lastname: Holen
authors.forename: Robert
authors.initials: R
authors.lastname: DiPaola
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Tan
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Karl
authors.initials: K
authors.lastname: Hsu
authors.forename: Nancy
authors.initials: N
authors.lastname: Agrawal
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.forename: Lingling
authors.initials: L
authors.lastname: Xue
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Mark
authors.initials: M
authors.lastname: Stein
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016547:Kinesins / Q000037:antagonists & inhibitors*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C530952:4-(2,5-difluorophenyl)-N-(3-fluoro-1-methylpiperidin-4-yl)-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide; D000970:Antineoplastic Agents; C470243:KIF11 protein, human; D010880:Piperidines; D011758:Pyrroles; D016547:Kinesins