title: Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.
abstract: OBJECTIVE
  The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown.
  
  
  METHODS
  Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation.
  
  
  RESULTS
  Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027).
  
  
  CONCLUSIONS
  Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.
authors.affiliation: Authors' Affiliations: The University of Chicago; Decatur Memorial Hospital, Decatur; Illinois Cancer Care, Peoria; Loyola University Medical Center, Maywood, Illinois; University of California, San Francisco, San Francisco; City of Hope, Duarte, California; University of Michigan Medical Center, Ann Arbor, Michigan; Medical College of Wisconsin, Milwaukee, Wisconsin; and National Cancer Institute, Rockville, Maryland.
authors.forename: Nitin
authors.initials: N
authors.lastname: Jain
authors.forename: Emily
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authors.lastname: Curran
authors.forename: Neil M
authors.initials: NM
authors.lastname: Iyengar
authors.forename: Ernesto
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authors.lastname: Diaz-Flores
authors.forename: Rangesh
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authors.lastname: Kunnavakkam
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kirschbaum
authors.forename: Theodore
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authors.lastname: Karrison
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
authors.forename: Margaret
authors.initials: M
authors.lastname: Green
authors.forename: Xavier
authors.initials: X
authors.lastname: Poire
authors.forename: Greg
authors.initials: G
authors.lastname: Koval
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Poluru L
authors.initials: PL
authors.lastname: Reddy
authors.forename: Loren
authors.initials: L
authors.lastname: Joseph
authors.forename: Ehab L
authors.initials: EL
authors.lastname: Atallah
authors.forename: Philip
authors.initials: P
authors.lastname: Dy
authors.forename: Sachdev P
authors.initials: SP
authors.lastname: Thomas
authors.forename: Scott E
authors.initials: SE
authors.lastname: Smith
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D011905:Genes, ras; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases