title: A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer.
abstract: BACKGROUND
  KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC.
  
  
  METHODS
  A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC.
  
  
  RESULTS
  15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease.
  
  
  CONCLUSIONS
  The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA. ddeming@medicine.wisc.edu.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Deming
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Ludmila L
authors.initials: LL
authors.lastname: Cavalcante
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Lubner
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mulkerin
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Noelle K
authors.initials: NK
authors.lastname: LoConte
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.affiliation: National Cancer Institute/Medical Oncology Branch, Bethesda, MD, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Fioravanti
authors.affiliation: National Cancer Institute/Medical Oncology Branch, Bethesda, MD, USA.
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
authors.affiliation: National Cancer Institute/Medical Oncology Branch, Bethesda, MD, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Compton
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Doyle
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.affiliation: National Cancer Institute/Medical Oncology Branch, Bethesda, MD, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Duffy
authors.affiliation: University of Wisconsin-Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI, 53792, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000068818:Cetuximab / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: AZD6244; Cetuximab; Colon cancer; KRAS; Phase I; Selumetinib