title: A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors.
abstract: OBJECTIVE
  Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5.
  
  
  METHODS
  This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated.
  
  
  RESULTS
  In part A, 29 patients received at least one dose of AZD4877 (5 mg, n = 4; 7.5 mg, n = 4; 10 mg, n = 3; 15 mg, n = 3; 20 mg, n = 3; 30 mg, n = 6; 36 mg, n = 3; 45 mg, n = 3). The MTD was defined as 30 mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30 mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25 mg, was evaluated in part B (n = 14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure.
  
  
  CONCLUSIONS
  The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30 mg. At the selected 25 mg dose, AZD4877 had an acceptable safety profile.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Infante
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: J
authors.initials: J
authors.lastname: Spratlin
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Wu
authors.forename: J M
authors.initials: JM
authors.lastname: Skolnik
authors.forename: L
authors.initials: L
authors.lastname: Hylander-Gans
authors.forename: A
authors.initials: A
authors.lastname: Osmukhina
authors.forename: D
authors.initials: D
authors.lastname: Huszar
authors.forename: R S
authors.initials: RS
authors.lastname: Herbst
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012720:Severity of Illness Index
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