Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

被引：95

作者：

Jain, Nitin ^{[1
]}

Curran, Emily ^{[1
]}

Iyengar, Neil M. ^{[1
]}

Diaz-Flores, Ernesto ^{[5
]}

Kunnavakkam, Rangesh ^{[1
]}

Popplewell, Leslie ^{[6
]}

Kirschbaum, Mark H. ^{[6
]}

Karrison, Theodore ^{[1
]}

Erba, Harry P. ^{[7
]}

Green, Margaret ^{[1
]}

Poire, Xavier ^{[1
]}

Koval, Greg ^{[1
]}

Shannon, Kevin ^{[5
]}

Reddy, Poluru L. ^{[1
]}

Joseph, Loren ^{[1
]}

Atallah, Ehab L. ^{[8
]}

Dy, Philip ^{[2
]}

Thomas, Sachdev P. ^{[3
]}

Smith, Scott E. ^{[4
]}

Doyle, L. Austin ^{[9
]}

Stadler, Walter M. ^{[1
]}

Larson, Richard A. ^{[1
]}

Stock, Wendy ^{[1
]}

Odenike, Olatoyosi ^{[1
]}

机构：

[1] Univ Chicago, Chicago, IL 60637 USA

[2] Decatur Mem Hosp, Decatur, GA USA

[3] Illinois Canc Care, Peoria, IL USA

[4] Loyola Univ, Med Ctr, Maywood, IL 60153 USA

[5] Univ Calif San Francisco, San Francisco, CA 94143 USA

[6] City Hope Natl Med Ctr, Duarte, CA USA

[7] Univ Michigan, Med Ctr, Ann Arbor, MI USA

[8] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[9] NCI, Rockville, MD USA

来源：

CLINICAL CANCER RESEARCH | 2014年 / 20卷 / 02期

关键词：

ACUTE MYELOID-LEUKEMIA; INTERNATIONAL WORKING GROUP; CELL LUNG-CANCER; N-RAS MUTATIONS; AZD6244; ARRY-142886; OPEN-LABEL; MEDIATES RESISTANCE; GROWTH-INHIBITION; RESPONSE CRITERIA; KINASE INHIBITOR;

D O I：

10.1158/1078-0432.CCR-13-1311

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C)2013 AACR.

引用

页码：490 / 498

页数：9