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

E Claire Dees1, Jeffrey R Infante, Roger B Cohen

  • 1UNC 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

Cancer Chemotherapy and Pharmacology
|July 8, 2010
PubMed
Abstract

Insights

This study assessed MLN8054, an Aurora A kinase inhibitor, in patients with advanced solid tumors. The maximum tolerated dose was limited by reversible somnolence, preventing further trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aurora A kinase is crucial for mitotic spindle function and is overexpressed in many cancers, suggesting its role in oncogenesis.
  • MLN8054 is a selective small-molecule inhibitor targeting Aurora A kinase, representing a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

  • To evaluate the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054 in patients with advanced solid tumors.
  • To assess the safety and tolerability of MLN8054 as a first-in-human trial.

Main Methods:

  • A dose-escalation, first-in-human study involving escalating cohorts of patients with advanced solid tumors.
  • MLN8054 was administered orally for 7, 14, or 21 days, followed by a 14-day treatment-free period.
  • Pharmacokinetic and pharmacodynamic assessments were conducted through serial blood sampling and skin biopsies.

Main Results:

  • Sixty-one patients received MLN8054 at various doses and schedules, including combinations with methylphenidate or modafinil.
  • The maximum tolerated dose (MTD) was determined to be 60 mg four times daily with daytime doses (QID/M) for 14 days, primarily limited by reversible grade 3 benzodiazepine-like effects (somnolence).
  • MLN8054 demonstrated rapid absorption, dose-proportional exposure, and a terminal half-life of 30-40 hours. Three patients achieved stable disease for over 6 cycles.

Conclusions:

  • Dosing of MLN8054 for up to 14 days within a 28-day cycle was found to be feasible.
  • Reversible somnolence emerged as the dose-limiting toxicity, hindering the achievement of predicted plasma concentrations for target modulation.
  • A recommended dose for Phase 2 investigation was not established, and a second-generation Aurora A kinase inhibitor is currently under development.

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