title: A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma.
abstract: OBJECTIVE
  AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma.
  
  
  METHODS
  AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles.
  
  
  RESULTS
  Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138(+) cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation.
  
  
  CONCLUSIONS
  Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population.
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. beata.holkova@vcuhealth.org stgrant@vcu.edu.
authors.forename: Beata
authors.initials: B
authors.lastname: Holkova
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zingone
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.affiliation: Department of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland.
authors.forename: Ashraf Z
authors.initials: AZ
authors.lastname: Badros
authors.affiliation: Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Voorhees
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Rachid
authors.initials: R
authors.lastname: Baz
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Neha
authors.initials: N
authors.lastname: Korde
authors.affiliation: Department of Biostatistics and Biomedical Informatics, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jin-Qiu
authors.initials: JQ
authors.lastname: Chen
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Department of Biostatistics and Biomedical Informatics, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Wen
authors.initials: W
authors.lastname: Wan
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Tombes
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Ellen
authors.initials: E
authors.lastname: Shrader
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Caryn
authors.initials: C
authors.lastname: Weir-Wiggins
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Heidi
authors.initials: H
authors.lastname: Sankala
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Hogan
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Austin
authors.initials: A
authors.lastname: Doyle
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Martha
authors.initials: M
authors.lastname: Wellons
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: John D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sullivan
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ola
authors.initials: O
authors.lastname: Landgren
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia. Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia. beata.holkova@vcuhealth.org stgrant@vcu.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)