title: Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3.
abstract: OBJECTIVE
  Mutations leading to constitutive activation of the FMS-like tyrosine kinase 3 receptor (FLT3) occur in blasts of 30% of patients with acute myeloid leukemia (AML). Midostaurin (PKC412; N-benzoylstaurosporin) is a multitargeted tyrosine kinase inhibitor, with demonstrated activity in patients with AML/myelodysplastic syndrome (MDS) with FLT3 mutations.
  
  
  METHODS
  Ninety-five patients with AML or MDS with either wild-type (n = 60) or mutated (n = 35) FLT3 were randomly assigned to receive oral midostaurin at 50 or 100 mg twice daily. The drug was discontinued in the absence of response at 2 months, disease progression, or unacceptable toxicity. Response was defined as complete response, partial response (PR), hematologic improvement, or reduction in peripheral blood or bone marrow blasts by ≥ 50% (BR).
  
  
  RESULTS
  The rate of BR for the population in whom efficacy could be assessed (n = 92) was 71% in patients with FLT3-mutant and 42% in patients with FLT3 wild-type. One PR occurred in a patient with FLT3-mutant receiving the 100-mg dose regimen. Both doses were well-tolerated; there were no differences in toxicity or response rate according to the dose of midostaurin.
  
  
  CONCLUSIONS
  These results suggest that midostaurin has hematologic activity in both patients with FLT3-mutant and wild-type. The degree of clinical activity observed supports additional studies that combine midostaurin and other agents such as chemotherapy especially in FLT3-mutant AML.
authors: Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
authors: Thomas
authors: T
authors: Fischer
authors: Richard M
authors: RM
authors: Stone
authors: Daniel J
authors: DJ
authors: Deangelo
authors: Ilene
authors: I
authors: Galinsky
authors: Elihu
authors: E
authors: Estey
authors: Carlo
authors: C
authors: Lanza
authors: Edward
authors: E
authors: Fox
authors: Gerhard
authors: G
authors: Ehninger
authors: Eric J
authors: EJ
authors: Feldman
authors: Gary J
authors: GJ
authors: Schiller
authors: Virginia M
authors: VM
authors: Klimek
authors: Stephen D
authors: SD
authors: Nimer
authors: D Gary
authors: DG
authors: Gilliland
authors: Catherine
authors: C
authors: Dutreix
authors: Alice
authors: A
authors: Huntsman-Labed
authors: Jodi
authors: J
authors: Virkus
authors: Francis J
authors: FJ
authors: Giles
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin