| Abstract: |
Purpose: 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. ©2010 American Association for Cancer Research. |
| Keywords: |
adult; cancer survival; clinical article; controlled study; treatment outcome; treatment response; aged; aged, 80 and over; middle aged; survival rate; treatment failure; clinical trial; drug tolerability; neutropenia; carcinoma, squamous cell; advanced cancer; diarrhea; drug dose reduction; drug efficacy; drug withdrawal; hypophosphatemia; side effect; systemic therapy; cancer patient; adenocarcinoma; controlled clinical trial; drug eruption; phase 2 clinical trial; anemia; bone marrow suppression; leukopenia; lung non small cell cancer; nausea; thrombocytopenia; vomiting; carcinoma, non-small-cell lung; lung neoplasms; myalgia; abdominal pain; asthenia; coughing; dizziness; dyspnea; hyperglycemia; lymphocytopenia; pruritus; lung embolism; confusion; hypoalbuminemia; hypokalemia; hyponatremia; tissue distribution; multicenter study; acne; peripheral edema; xerostomia; cancer fatigue; headache; drug metabolism; drug blood level; drug dose regimen; dyspepsia; administration, oral; diplopia; dry skin; hallucination; epistaxis; visual disorder; congestive heart failure; mitogen-activated protein kinase kinases; blurred vision; hypocalcemia; agitation; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; weight gain; benzamides; carcinoma, large cell; diphenylamine; abnormal laboratory result; face edema
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