title: The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer.
abstract: OBJECTIVE
  In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 (ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation.
  
  
  METHODS
  In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter.
  
  
  RESULTS
  The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve(0-24), exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC(50) of 352 ng/mL and maximum inhibition (E(max)) of approximately 91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy.
  
  
  CONCLUSIONS
  The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials.
authors.affiliation: Royal Marsden Hospital, Sutton, Surrey, United Kingdom. Udai.Banerji@icr.ac.uk
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Debashis
authors.initials: D
authors.lastname: Sarker
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Desar
authors.forename: Johanna N H
authors.initials: JN
authors.lastname: Timmer-Bonte
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Brown
authors.forename: Mireille V
authors.initials: MV
authors.lastname: Cantarini
authors.forename: Clive
authors.initials: C
authors.lastname: Morris
authors.forename: Sarah M A
authors.initials: SM
authors.lastname: George
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002214:Capsules; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002214:Capsules; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2