Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers Journal Article
| Authors: | LoRusso, P. M.; Krishnamurthi, S. S.; Rinehart, J. J.; Nabell, L. M.; Malburg, L.; Chapman, P. B.; Deprimo, S. E.; Bentivegna, S.; Wilner, K. D.; Tan, W.; Ricart, A. D. |
| Article Title: | 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 ≥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. |
| Keywords: | mitogen activated protein kinase; adult; controlled study; human tissue; treatment outcome; treatment response; aged; aged, 80 and over; middle aged; survival rate; unclassified drug; major clinical study; clinical trial; drug activity; drug tolerability; fatigue; diarrhea; recommended drug dose; cancer patient; neurotoxicity; neoplasms; colorectal cancer; ki 67 antigen; drug inhibition; melanoma; controlled clinical trial; multiple cycle treatment; breast cancer; mitogen activated protein kinase inhibitor; lung non small cell cancer; nausea; vomiting; tumor biopsy; antineoplastic activity; continuous infusion; dizziness; drug dose escalation; pruritus; rash; enzyme phosphorylation; tissue distribution; peripheral edema; maximum tolerated dose; phase 1 clinical trial; periorbital edema; administration, oral; ataxia; mitogen-activated protein kinase kinases; blurred vision; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; benzamides; gait disorder; diphenylamine; drug intermittent therapy; pd 0315209; pd 0326116; maximum permissible dose; retina vein occlusion |
| Journal Title: | Clinical Cancer Research |
| Volume: | 16 |
| Issue: | 6 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-03-15 |
| Start Page: | 1924 |
| End Page: | 1937 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-09-1883 |
| PUBMED: | 20215549 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 8" - "Export Date: 20 April 2011" - "CODEN: CCREF" - "Source: Scopus" |
