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

Eur J Cancer. 2013 May;49(7):1521-9. doi: 10.1016/j.ejca.2013.01.013. Epub 2013 Feb 21.

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 0.5 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 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.

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.

Trial registration: ClinicalTrials.gov NCT00454090.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acne Vulgaris / chemically induced
  • Adolescent
  • Adult
  • Area Under Curve
  • Dermatitis / etiology
  • Diarrhea / chemically induced
  • Dihydropyridines / adverse effects
  • Dihydropyridines / pharmacokinetics
  • Dihydropyridines / therapeutic use*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fatigue / chemically induced
  • Female
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / antagonists & inhibitors
  • MAP Kinase Kinase 2 / metabolism
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • Treatment Outcome
  • Vomiting / chemically induced
  • Young Adult

Substances

  • AZD8330
  • Dihydropyridines
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human

Associated data

  • ClinicalTrials.gov/NCT00454090