A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies

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.