title: Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations.
abstract: OBJECTIVE
  This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors.
  
  
  METHODS
  Sequential cohorts of patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics was characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed.
  
  
  RESULTS
  Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose proportionally (5-150 mg/d), and were similar for PIC and ECT. The terminal half-life was 23 hours. At the maximum tolerated dose of 50 mg twice daily on the 7-day schedule, the mitotic index of the skin basal epithelium was increased within 24 hours after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition. One (1%) patient achieved a partial response lasting for more than 1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for ≥3 months.
  
  
  CONCLUSIONS
  This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies.
authors: UNC Lineberger Comprehensive Cancer Center, 170 Manning Drive, POB 3121, Chapel Hill, NC 27599, USA. claire_dees@med.unc.edu
authors: E Claire
authors: EC
authors: Dees
authors: Roger B
authors: RB
authors: Cohen
authors: Margaret
authors: M
authors: von Mehren
authors: Thomas E
authors: TE
authors: Stinchcombe
authors: Hua
authors: H
authors: Liu
authors: Karthik
authors: K
authors: Venkatakrishnan
authors: Mark
authors: M
authors: Manfredi
authors: Howard
authors: H
authors: Fingert
authors: Howard A
authors: HA
authors: Burris
authors: Jeffrey R
authors: JR
authors: Infante
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases