title: A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias.
abstract: BACKGROUND
  ARRY-520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis.
  
  
  METHODS
  A phase 1 trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 given as a 1-hour infusion in either a single dose or on a day 1, 3, and 5 divided-dose schedule per cycle in patients with advanced or refractory myeloid leukemias. Additional objectives were to characterize pharmacokinetics, assess preliminary clinical activity, and explore biomarkers of KSP inhibition with ARRY-520. A total of 36 patients with acute myelogenous leukemia (n = 34) or myelodysplastic syndromes (n = 2) with a median age of 66 years (range, 21-88 years) were enrolled: 15 in the single-dose schedule (dose levels: 2.5, 3.75, 4.5, and 5.6 mg/m(2)) and 21 in the divided-dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m(2)/day).
  
  
  RESULTS
  The MTD was 4.5 mg/m(2) total dose per cycle for both dose schedules. Dose-limiting toxicities included mucositis, exfoliative rash, hand-foot syndrome, and hyperbilirubinemia. Grades 3 or 4 reversible drug-related myelosuppression were observed in 33 of 36 patients. Plasma pharmacokinetic analyses revealed low clearance of ARRY-520 (~3 L/hour), a volume of distribution of ~450 L, and a median terminal half-life of >90 hours. Monopolar spindles were observed in blood mononuclear cells, through use of 4',6-diamidino-2-phenylindole nucleic acid stain and antitubulin antibodies.
  
  
  CONCLUSIONS
  On the basis of the relative lack of clinical activity, further development of ARRY-520 as an antileukemic agent was halted. (Clinicaltrials.gov identifier NCT00637052).
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. hkhoury@emory.edu
authors.forename: Hanna Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.forename: Maria Cielo
authors.initials: MC
authors.lastname: Foudray
authors.forename: Martha
authors.initials: M
authors.lastname: Arellano
authors.forename: Amelia
authors.initials: A
authors.lastname: Langston
authors.forename: Beverly
authors.initials: B
authors.lastname: Bethelmie-Bryan
authors.forename: Selena
authors.initials: S
authors.lastname: Rush
authors.forename: Kevin
authors.initials: K
authors.lastname: Litwiler
authors.forename: Sharon
authors.initials: S
authors.lastname: Karan
authors.forename: Heidi
authors.initials: H
authors.lastname: Simmons
authors.forename: Adam I
authors.initials: AI
authors.lastname: Marcus
authors.forename: Mieke
authors.initials: M
authors.lastname: Ptaszynski
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D007951:Leukemia, Myeloid / Q000178:diet therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D012008:Recurrence; D019233:Retreatment; D013830:Thiadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C470243:KIF11 protein, human; D013830:Thiadiazoles; C544550:filanesib; D016547:Kinesins