Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.

Abstract

PURPOSE:

To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.

EXPERIMENTAL DESIGN:

BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes.

RESULTS:

Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy.

CONCLUSION:

This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.

• Authors: Colin D Weekes, Daniel D Von Hoff, Alex A Adjei, Diane P Leffingwell, S Gail Eckhardt, Lia Gore, Karl D Lewis, Glen J Weiss, Ramesh K Ramanathan, Grace K Dy, Wen W Ma, Beth Sheedy, Cory Iverson, Jeffrey N Miner, Zancong Shen, Li-Tain Yeh, Ronald L Dubowy, Michael Jeffers, Prabhu Rajagopalan, Neil J Clendeninn
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 5 Pg. 1232-43 (Mar 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23434733 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
• Protein Kinase Inhibitors
• Sulfonamides
• Diphenylamine
• Mitogen-Activated Protein Kinase 1

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Cohort Studies
• Diphenylamine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Female
• Follow-Up Studies
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Prognosis
• Protein Kinase Inhibitors (pharmacokinetics, therapeutic use)
• Sulfonamides (pharmacokinetics, therapeutic use)
• Tissue Distribution
• Young Adult