title: A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies.
abstract: BACKGROUND
  This Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma.
  
  
  METHODS
  In this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD.
  
  
  RESULTS
  29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs).
  
  
  CONCLUSIONS
  AZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. gerecitj@mskcc.org
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.forename: Joe J
authors.initials: JJ
authors.lastname: Stephenson
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Lewis
authors.forename: Anna
authors.initials: A
authors.lastname: Osmukhina
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.forename: Kaida
authors.initials: K
authors.lastname: Wu
authors.forename: Zhiping
authors.initials: Z
authors.lastname: You
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Skolnik
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D016547:Kinesins / Q000037:antagonists & inhibitors*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D011744:Pyrimidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; C470243:KIF11 protein, human; C568512:N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide; D011744:Pyrimidinones; D016547:Kinesins