4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 PO 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.

          Related collections

          Author and article information

          Journal
          8309330
          4372
          Invest New Drugs
          Invest New Drugs
          Investigational new drugs
          0167-6997
          1573-0646
          16 December 2015
          14 December 2015
          April 2016
          01 April 2017
          : 34
          : 2
          : 168-175
          Affiliations
          [1 ]University of Wisconsin–Madison Carbone Cancer Center, Madison, WI, USA
          [2 ]Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA
          [3 ]National Cancer Institute/Medical Oncology Branch, Bethesda, MD, USA
          Author notes
          [* ]Corresponding author and address for reprint requests, Dustin Deming, MD, University of Wisconsin–Madison Carbone Cancer Center, 600 Highland Avenue, K6/544 CSC, Madison, WI 53792, Phone (608) 265-1042, Fax (608) 263-9132, ddeming@ 123456medicine.wisc.edu
          Article
          PMC4788533 PMC4788533 4788533 nihpa744865
          10.1007/s10637-015-0314-7
          4788533
          26666244
          62c4a643-e013-4f53-897f-c944af76d288
          History
          Categories
          Article

          KRAS,colon cancer,phase I,cetuximab,AZD6244,selumetinib
          KRAS, colon cancer, phase I, cetuximab, AZD6244, selumetinib

          Comments

          Comment on this article