title: 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 0.5 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.
  
  
  CONCLUSIONS
  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.
authors: Division of Hematology and Oncology, Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA, USA. roger.cohen@uphs.upenn.edu
authors: Roger B
authors: RB
authors: Cohen
authors: Steinar
authors: S
authors: Aamdal
authors: Marta
authors: M
authors: Nyakas
authors: Maria
authors: M
authors: Cavallin
authors: Darron
authors: D
authors: Green
authors: Maria
authors: M
authors: Learoyd
authors: Ian
authors: I
authors: Smith
authors: Razelle
authors: R
authors: Kurzrock
mesh_terms: D000152:Acne Vulgaris / Q000139:chemically induced; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D003872:Dermatitis / Q000209:etiology; D003967:Diarrhea / Q000139:chemically induced; D004095:Dihydropyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: C581956:AZD8330; D004095:Dihydropyridines; D047428:Protein Kinase Inhibitors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human