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Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.

Publication ,  Journal Article
Jain, N; Curran, E; Iyengar, NM; Diaz-Flores, E; Kunnavakkam, R; Popplewell, L; Kirschbaum, MH; Karrison, T; Erba, HP; Green, M; Poire, X ...
Published in: Clin Cancer Res
January 15, 2014

PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

January 15, 2014

Volume

20

Issue

2

Start / End Page

490 / 498

Location

United States

Related Subject Headings

  • fms-Like Tyrosine Kinase 3
  • Treatment Outcome
  • Proto-Oncogene Proteins c-kit
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Mitogen-Activated Protein Kinase Kinases
  • Middle Aged
  • Male
  • Leukemia, Myeloid, Acute
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jain, N., Curran, E., Iyengar, N. M., Diaz-Flores, E., Kunnavakkam, R., Popplewell, L., … Odenike, O. (2014). Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res, 20(2), 490–498. https://doi.org/10.1158/1078-0432.CCR-13-1311
Jain, Nitin, Emily Curran, Neil M. Iyengar, Ernesto Diaz-Flores, Rangesh Kunnavakkam, Leslie Popplewell, Mark H. Kirschbaum, et al. “Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.Clin Cancer Res 20, no. 2 (January 15, 2014): 490–98. https://doi.org/10.1158/1078-0432.CCR-13-1311.
Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014 Jan 15;20(2):490–8.
Jain, Nitin, et al. “Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.Clin Cancer Res, vol. 20, no. 2, Jan. 2014, pp. 490–98. Pubmed, doi:10.1158/1078-0432.CCR-13-1311.
Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, Kirschbaum MH, Karrison T, Erba HP, Green M, Poire X, Koval G, Shannon K, Reddy PL, Joseph L, Atallah EL, Dy P, Thomas SP, Smith SE, Doyle LA, Stadler WM, Larson RA, Stock W, Odenike O. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014 Jan 15;20(2):490–498.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

January 15, 2014

Volume

20

Issue

2

Start / End Page

490 / 498

Location

United States

Related Subject Headings

  • fms-Like Tyrosine Kinase 3
  • Treatment Outcome
  • Proto-Oncogene Proteins c-kit
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Mitogen-Activated Protein Kinase Kinases
  • Middle Aged
  • Male
  • Leukemia, Myeloid, Acute