Journal
EUROPEAN JOURNAL OF CANCER
Volume 49, Issue 7, Pages 1521-1529Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2013.01.013
Keywords
MAP kinase kinase 1; MAP kinase kinase 2; Pharmacology; Pharmacokinetics; Dose-response relationship; Drug Clinical trials; Phase I Neoplasms; Antineoplastic agents; Cohort studies; Maximum tolerated dose
Categories
Funding
- AstraZeneca
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Objective: This is the first clinical study of the MEK1/2 inhibitor AZD8330 (ARRY-424704). This phase I study defined the maximum tolerated dose (MTD) and assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8330 in patients with advanced malignancies. Methods: Patients with refractory cancer or cancer with no standard therapy received either once-daily (OD) or twice-daily (BID) oral AZD8330 on day 1 followed by a 7-day washout period and continuous dosing from day 8. The starting dose was 0.5 mg with dose escalations in subsequent cohorts until a non-tolerated dose was reached. Results: Eighty-two patients received AZD8330 across 11 cohorts. The most frequent AZD8330-related adverse events were acneiform dermatitis (13/82, 16%), fatigue (11/82, 13%), diarrhoea (11/82, 13%) and vomiting (9/82, 11%). Four patients experienced dose-limiting toxicities: mental status changes (40 mg OD; 2/9 patients and 60 mg OD; 1/3) and rash (20 mg BID; 1/9). The MTD was defined as 20 mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5-60 mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses >= 3 mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration > 3 months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors. Conclusion: AZD8330 has a manageable toxicity profile at the MTD of 20 mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response. (C) 2013 Elsevier Ltd. All rights reserved.
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