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A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies
- Source :
-
European Journal of Cancer . May2013, Vol. 49 Issue 7, p1521-1529. 9p. - Publication Year :
- 2013
-
Abstract
- Abstract: 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 0.5mg 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 (40mg OD; 2/9 patients and 60mg OD; 1/3) and rash (20mg BID; 1/9). The MTD was defined as 20mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5–60mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses ⩾3mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration >3months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors. Conclusion: AZD8330 has a manageable toxicity profile at the MTD of 20mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response. [Copyright &y& Elsevier]
- Subjects :
- *ANTINEOPLASTIC agents
*TUMORS
*DESCRIPTIVE statistics
Subjects
Details
- Language :
- English
- ISSN :
- 09598049
- Volume :
- 49
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- European Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 86885625
- Full Text :
- https://doi.org/10.1016/j.ejca.2013.01.013