Phase I Open-Label Study of Decitabine in Combination With Midostaurin (PKC412) for Elderly (Age ≥ 60) Newly Diagnosed or Relapsed/Refractory Adult Patients With Acute Myeloid Leukemia
The development of a primarily outpatient treatment option for AML that is also capable of
providing significant disease control is a priority for most clinicians. To address the
need for less toxic, more effective treatments for older patients with AML, the purpose of
this Phase 1 single institution study is to evaluate the safety and efficacy of midostaurin
and decitabine administered in combination.
Decitabine is an epigenetic modifier of gene expression that has been shown to be
well-tolerated in this population at the dose schedule proposed in this study, with
reasonable efficacy. Although its precise mechanism of action is incompletely understood, it
is postulated to work by reactivating the expression of key tumor suppressor genes silenced
in tumor cells by reversing a pattern of hypermethylation of promotor elements.
Midostaurin is an oral agent that has been shown to inhibit FLT3 kinase in preclinical in
vitro and in vivo studies, as well as clinically in patients with both ITD and TKD FLT3
mutations (FLT3mut). Both directly and indirectly, midostaurin also potently inhibits
multiple other molecular targets thought to be important for the pathogenesis of AML. These
targets include VEGFR-1, a VEGF receptor; c-kit; H- and K-ras; as well as the multidrug
resistant gene, MDR.
The addition of midostaurin to a decitabine regimen of previously established efficacy and
tolerability will allow us to evaluate the hypothesis that two drugs that are believed to
work through distinct mechanisms of action may act together to improve the responses of
patients treated with decitabine alone, without significant additional toxicity.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine a tolerated dose of the combination of decitabine and midostaurin as induction and consolidation in patients ≥ 60 years with newly diagnosed AML not eligible for standard induction or adult patients with relapsed/refractory disease.
3 months per patient
Casey Williams, PharmD
University of Kansas
United States: Food and Drug Administration
|University of Kansas Medical Center, Westwood Campus||Kansas City, Kansas 66205|