title: A phase II evaluation of selumetinib (AZD6244, ARRY-142886), a selective MEK-1/2 inhibitor in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study.
abstract: BACKGROUND
  Activation of the mitogen activated protein kinase pathway plays a pivotal role in cell proliferation and is frequently activated in endometrial cancer. We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer.
  
  
  METHODS
  This was a phase II, single-arm, open-label study evaluating response and 6-month event-free survival (EFS) as primary endpoints. Eligible patients had measurable disease, 1-2 prior cytotoxic regimens, and performance status 0-2. Selumetinib 75mg PO BID was administered daily until progression or intolerance. One cycle was 28days.
  
  
  RESULTS
  Fifty-four patients were enrolled; 2 were excluded due to improper pre-study treatment (1) and never treated (1), leaving 52 evaluable for efficacy/safety. Median age was 62; histology included endometrioid (58%), serous (17%) and mixed (23%). Seventeen patients (33%) had 2 prior cytotoxic regimens. The median number of cycles administered was 2 (1-34). Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively. Drug-attributed grade 3/4 adverse events were observed (≥5%) were fatigue (15%), anemia (10%), pain (10%), extremity edema (8%), and dyspnea (6%). There was 1 grade 4 infection (renal), 1 grade 4 anemia, and 1 death due to hemorrhage (rectum).
  
  
  CONCLUSIONS
  Selumetinib was tolerable in this population but did not meet pre-trial specifications for clinical efficacy.
authors.affiliation: Dept. of Gynecologic Oncology & Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030. Electronic address: rcoleman@mdanderson.org.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: NRG Oncology Statistics & Data Management Center; Roswell Park Cancer Institute, Buffalo, NY 14263. Electronic address: msill@gogstats.org.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.affiliation: Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO 63110. Electronic address: thakerp@wudosis.wustl.edu.
authors.forename: Premal H
authors.initials: PH
authors.lastname: Thaker
authors.affiliation: University of Iowa; Gyn/Onc Division; Iowa City, IA 52242. Electronic address: david-bender@uiowa.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Bender
authors.affiliation: Cancer Care Associates; Tulsa, OK 74136. Electronic address: daron.street@tciok.org.
authors.forename: Daron
authors.initials: D
authors.lastname: Street
authors.affiliation: Franklin Square Hospital; Medical Oncology; Baltimore, MD 21237. Electronic address: wmcguire52@aol.com.
authors.forename: William P
authors.initials: WP
authors.lastname: McGuire
authors.affiliation: Division. of Gynecologic Oncology; University of Michigan; Ann Arbor, MI 48109. Electronic address: johnstob@med.umich.edu.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Johnston
authors.affiliation: Rush-Presbyterian St. Lukes Med. Center; Chicago, IL 60612. Electronic address: jacob_rotmensch@rush.edu.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rotmensch
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: MEK inhibitor; Phase II trial; Selumetinib; endometrial cancer; toxicity