dihydropyridines and Vomiting

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.. 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.. 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 20mg 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.. 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.

Topics: Acne Vulgaris; Adolescent; Adult; Area Under Curve; Dermatitis; Diarrhea; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Metabolic Clearance Rate; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Treatment Outcome; Vomiting; Young Adult