title: A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes.
abstract: OBJECTIVE
  Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria.
  
  
  METHODS
  Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.
  
  
  RESULTS
  The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI.
  
  
  CONCLUSIONS
  ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. ggarciam@mdanderson.org.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lancet
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Winski
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: LouAnn
authors.initials: L
authors.lastname: Cable
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Selena
authors.initials: S
authors.lastname: Rush
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Lara
authors.initials: L
authors.lastname: Maloney
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Grant
authors.initials: G
authors.lastname: Hogeland
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Mieke
authors.initials: M
authors.lastname: Ptaszynski
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Monica Cabrero
authors.initials: MC
authors.lastname: Calvo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zach
authors.initials: Z
authors.lastname: Bohannan
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Alan
authors.initials: A
authors.lastname: List
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Rami
authors.initials: R
authors.lastname: Komrokji
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C000602876:pexmetinib; D014508:Urea; D042787:Receptor, TIE-2; D048051:p38 Mitogen-Activated Protein Kinases