Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors

Cancer Chemother Pharmacol. 2011 Apr;67(4):945-54. doi: 10.1007/s00280-010-1377-y. Epub 2010 Jul 7.

Abstract

Purpose: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacokinetics
  • Aurora Kinases
  • Benzazepines / administration & dosage
  • Benzazepines / adverse effects*
  • Benzazepines / pharmacokinetics
  • Benzhydryl Compounds / therapeutic use
  • Central Nervous System Stimulants / therapeutic use
  • Disorders of Excessive Somnolence / chemically induced
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Half-Life
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Methylphenidate / therapeutic use
  • Middle Aged
  • Modafinil
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Young Adult

Substances

  • Antineoplastic Agents
  • Benzazepines
  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • MLN8054
  • Protein Kinase Inhibitors
  • Methylphenidate
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Modafinil