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01-06-2015 | PHASE II STUDIES

Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer

Authors: Khanh Do, Giovanna Speranza, Rachel Bishop, Sonny Khin, Larry Rubinstein, Robert J. Kinders, Manuel Datiles, Michelle Eugeni, Michael H. Lam, L. Austin Doyle, James H. Doroshow, Shivaani Kummar

Published in: Investigational New Drugs | Issue 3/2015

Summary

Purpose PI3K/AKT/mTOR and RAS/RAF/MEK pathways are frequently dysregulated in colorectal cancer (CRC). We conducted a biomarker-driven trial of the combination of MK-2206, an allosteric AKT 1/2/3 inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with CRC to evaluate inhibition of phosphorylated ERK (pERK) and AKT (pAKT) in paired tumor biopsies. Patients and Methods Adult patients with advanced CRC were enrolled in successive cohorts stratified by KRAS mutation status. Initially, 12 patients received oral MK-2206 90 mg weekly with oral selumetinib 75 mg daily in 28-day cycles. Following an interim analysis, the doses of MK-2206 and selumetinib were increased to 135 mg weekly and 100 mg daily, respectively. Paired tumor biopsies were evaluated for target modulation. Results Common toxicities were gastrointestinal, hepatic, dermatologic, and hematologic. Of 21 patients enrolled, there were no objective responses. Target modulation did not achieve the pre-specified criteria of dual 70 % inhibition of pERK and pAKT levels in paired tumor biopsies. Conclusion Despite strong scientific rationale and preclinical data, clinical activity was not observed. The desired level of target inhibition was not achieved. Overlapping toxicities limited the ability to dose escalate to achieve exposures likely needed for clinical activity, highlighting the challenges in developing optimal combinations of targeted agents.

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Title: Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer
Authors: Khanh Do
Giovanna Speranza
Rachel Bishop
Sonny Khin
Larry Rubinstein
Robert J. Kinders
Manuel Datiles
Michelle Eugeni
Michael H. Lam
L. Austin Doyle
James H. Doroshow
Shivaani Kummar
Publication date: 01-06-2015
Publisher: Springer US
Published in: Investigational New Drugs / Issue 3/2015
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-015-0212-z

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