Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers.

Abstract

PURPOSE:

To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients.

EXPERIMENTAL DESIGN:

Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics.

RESULTS:

Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving >or=15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the dose-limiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease >or=4 months. PD-0325901 exposure was generally dose proportional. Doses >or=2 mg BID consistently caused >or=60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (>or=50%) in Ki-67.

CONCLUSIONS:

PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use.

• Authors: Patricia M LoRusso, Smitha S Krishnamurthi, John J Rinehart, Lisle M Nabell, Lisa Malburg, Paul B Chapman, Samuel E DePrimo, Steven Bentivegna, Keith D Wilner, Weiwei Tan, Alejandro D Ricart
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 6 Pg. 1924-37 (Mar 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20215549 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• mirdametinib
• Diphenylamine
• Mitogen-Activated Protein Kinase Kinases

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Benzamides (pharmacokinetics, pharmacology)
• Diphenylamine (analogs & derivatives, pharmacokinetics, pharmacology)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, metabolism, pathology)
• Survival Rate
• Tissue Distribution
• Treatment Outcome