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

Academic Article

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 ≥15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the doselimiting 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 ≥4 months. PD-0325901 exposure was generally dose proportional. Doses ≥2 mg BID consistently caused ≥60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases ( ≥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. ©2010 AACR.
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    Author List

  • LoRusso PM; Krishnamurthi SS; Rinehart JJ; Nabell LM; Malburg L; Chapman PB; Deprimo SE; Bentivegna S; Wilner KD; Tan W
  • Start Page

  • 1924
  • End Page

  • 1937
  • Volume

  • 16
  • Issue

  • 6