title: Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors.
abstract: OBJECTIVE
  Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.
  
  
  METHODS
  In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3-6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics.
  
  
  RESULTS
  Sixty-one patients received 5, 10, 20, 30, or 40 mg once daily for 7 days; 25, 35, 45, or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70, or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7-21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose proportional, and terminal half-life was 30-40 h. Three patients had stable disease for >6 cycles.
  
  
  CONCLUSIONS
  MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina, 170 Manning Drive, 3rd floor POB, CB 7305, Chapel Hill, NC 27599, USA. claire_dees@med.unc.edu
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Hadi
authors.initials: H
authors.lastname: Danaee
authors.forename: Yih
authors.initials: Y
authors.lastname: Lee
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.forename: Katherine
authors.initials: K
authors.lastname: Galvin
authors.forename: Bradley
authors.initials: B
authors.lastname: Stringer
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Omar
authors.initials: O
authors.lastname: Eton
authors.forename: Howard
authors.initials: H
authors.lastname: Fingert
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D064127:Aurora Kinases; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008774:Methylphenidate / Q000627:therapeutic use; D008875:Middle Aged; D000077408:Modafinil; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; C518940:MLN8054; D047428:Protein Kinase Inhibitors; D008774:Methylphenidate; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000077408:Modafinil