title: Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.
abstract: OBJECTIVE
  FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models.
  
  
  METHODS
  Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML.
  
  
  RESULTS
  Responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay.
  
  
  CONCLUSIONS
  Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.
authors.affiliation: Jorge E. Cortes, Hagop Kantarjian, and Gautam Borthakur, the University of Texas, MD Anderson Cancer Center, Houston, TX; James M. Foran, University of Alabama at Birmingham, Birmingham, AL; Darejan Ghirdaladze, Medulla-Chemotherapy and Immunotherapy Clinic; Mamia Zodelava, Hema-Hematology and Chemotherapy Clinic, T'bilisi, GA; Guy Gammon, Denise Trone, Robert C. Armstrong, and Joyce James, Ambit Biosciences, San Diego, CA; and Mark Levis, Johns Hopkins University, Baltimore, MD.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: James M
authors.initials: JM
authors.lastname: Foran
authors.forename: Darejan
authors.initials: D
authors.lastname: Ghirdaladze
authors.forename: Mamia
authors.initials: M
authors.lastname: Zodelava
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Guy
authors.initials: G
authors.lastname: Gammon
authors.forename: Denise
authors.initials: D
authors.lastname: Trone
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052160:Benzothiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012008:Recurrence; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D052160:Benzothiazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C544967:quizartinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3