Journal
CLINICAL CANCER RESEARCH
Volume 16, Issue 6, Pages 1924-1937Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-1883
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Funding
- AstraZeneca
- Ariad
- Pfizer
- Genentech
- Sanofi-Aventis
- Endocyte
- Array
- BioPharma
- Boehringer Ingelheim Pharmaceuticals
- GlaxoSmithKline
- Exelixis
- BMS
- Takeda
- Merck
- Synta Pharmaceuticals
- Geron
- Eisai
- Allos
- MethylGene
- U3 Pharma
- Hana Biosciences
- Abbott Laboratories
- Curis, Inc.
- Millenium Pharmaceuticals
- Boston Biomedical
- Novartis
- Alnylam
- MedImmune
- Amgen
- NIH
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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 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 >= 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. Clin Cancer Res; 16(6); 1924-37. (C) 2010 AACR.
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