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.
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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)
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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
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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
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