Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced solid tumors.

Abstract

PURPOSE:

Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.

EXPERIMENTAL DESIGN:

Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.

RESULTS:

Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.

CONCLUSIONS:

The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.

• Authors: Andres Cervantes, Elena Elez, Desamparados Roda, Jeffrey Ecsedy, Teresa Macarulla, Karthik Venkatakrishnan, Susana Roselló, Jordi Andreu, Jungah Jung, Juan Manuel Sanchis-Garcia, Adelaida Piera, Inma Blasco, Laura Maños, José-Alejandro Pérez-Fidalgo, Howard Fingert, Jose Baselga, Josep Tabernero
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 17 Pg. 4764-74 (Sep 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22753585 (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
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Aurora Kinases
• Azepines (administration & dosage, adverse effects, pharmacokinetics)
• Biopsy
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Neutropenia (chemically induced)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Stomatitis (chemically induced)