title: Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Bldg 31, Rm 3A44, Bethesda, MD, 20892, USA.
authors: Khanh
authors: K
authors: Do
authors: Giovanna
authors: G
authors: Speranza
authors: Rachel
authors: R
authors: Bishop
authors: Sonny
authors: S
authors: Khin
authors: Larry
authors: L
authors: Rubinstein
authors: Robert J
authors: RJ
authors: Kinders
authors: Manuel
authors: M
authors: Datiles
authors: Michelle
authors: M
authors: Eugeni
authors: Michael H
authors: MH
authors: Lam
authors: L Austin
authors: LA
authors: Doyle
authors: James H
authors: JH
authors: Doroshow
authors: Shivaani
authors: S
authors: Kummar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D045325:HCT116 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014054:Tomography; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206
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