title: Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer.
abstract: BACKGROUND
  More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy.
  
  
  METHODS
  Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival.
  
  
  RESULTS
  Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects.
  
  
  CONCLUSIONS
  Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.
authors.affiliation: Yale Cancer Center, 333 Cedar Street, New Haven, CT, 06520, USA, howard.hochster@yale.edu.
authors.forename: H S
authors.initials: HS
authors.lastname: Hochster
authors.forename: N
authors.initials: N
authors.lastname: Uboha
authors.forename: W
authors.initials: W
authors.lastname: Messersmith
authors.forename: P J
authors.initials: PJ
authors.lastname: Gold
authors.forename: B H
authors.initials: BH
authors.lastname: ONeil
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.forename: C
authors.initials: C
authors.lastname: Denlinger
authors.forename: S
authors.initials: S
authors.lastname: Cohen
authors.forename: C G
authors.initials: CG
authors.lastname: Leichman
authors.forename: L
authors.initials: L
authors.lastname: Leichman
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D000077146:Irinotecan; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002166:Camptothecin