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A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer.

AbstractPURPOSE:
To evaluate the efficacy of mitogen-activated protein kinase/extracellular signal-related kinase kinase inhibitor PD-0325901 in advanced non-small cell lung cancer patients who had experienced treatment failure after, or were refractory to, standard systemic therapy.
EXPERIMENTAL DESIGN:
This open-label, phase II study initially evaluated 15 mg PD-0325901 twice daily administered intermittently (3 weeks on/1 week off; schedule A). As this schedule was not well tolerated, a second schedule was introduced as follows: 5 days on/2 days off for 3 weeks, followed by 1 week off (schedule B). The primary end point was objective response.
RESULTS:
All patients had received prior systemic therapy (median of two regimens, including epidermal growth factor receptor inhibitors in 26%). Of 13 patients treated on schedule A, three discontinued due to adverse events (blurred vision, fatigue, and hallucinations, respectively). Twenty-one patients received schedule B. Main toxicities included diarrhea, fatigue, rash, vomiting, nausea, and reversible visual disturbances. Hematologic toxicity consisted mainly of mild-to-moderate anemia, without neutropenia. Chemistry abnormalities were rare. Mean (coefficient of variation) PD-0325901 trough plasma concentrations were 100 ng/mL (52%) and 173 ng/mL (73%) for schedules A and B, respectively, above the minimum target concentration established in preclinical studies (16.5 ng/mL). There were no objective responses. Seven patients had stable disease. Median (95% confidence interval) progression-free survival was 1.8 months (1.5-1.9) and overall survival was 7.8 months (4.5-13.9).
CONCLUSIONS:
PD-0325901 did not meet its primary efficacy end point. Future studies should focus on PD-0325901 schedule, rational combination strategies, and enrichment of patient selection based on mode of action.
AuthorsEric B Haura, Alejandro D Ricart, Timothy G Larson, Philip J Stella, Lyudmila Bazhenova, Vincent A Miller, Roger B Cohen, Peter D Eisenberg, Paulina Selaru, Keith D Wilner, Shirish M Gadgeel
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 8 Pg. 2450-7 (Apr 15 2010) ISSN: 1557-3265 [Electronic] United States
PMID20332327 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzamides
  • mirdametinib
  • Diphenylamine
  • Mitogen-Activated Protein Kinase Kinases
Topics
  • Adenocarcinoma (drug therapy, pathology)
  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Benzamides (administration & dosage, pharmacokinetics)
  • Carcinoma, Large Cell (drug therapy, pathology)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
  • Carcinoma, Squamous Cell (drug therapy, pathology)
  • Diphenylamine (administration & dosage, analogs & derivatives, pharmacokinetics)
  • Female
  • Humans
  • Lung Neoplasms (drug therapy, pathology)
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
  • Survival Rate
  • Tissue Distribution
  • Treatment Outcome

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