Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: E Claire Dees, Roger B Cohen, Margaret von Mehren, Thomas E Stinchcombe, Hua Liu, Karthik Venkatakrishnan, Mark Manfredi, Howard Fingert, Howard A Burris 3rd, Jeffrey R Infante
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 17 Pg. 4775-84 (Sep 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22767670 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Azepines
• MLN 8237
• Pyrimidines
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Aurora Kinases
• Azepines (administration & dosage, adverse effects, pharmacokinetics)
• Biological Availability
• Biopsy
• Dose-Response Relationship, Drug
• Fatigue (chemically induced)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Nausea (chemically induced)
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Neutropenia (chemically induced)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)