Combination of Decitabine and Midostaurin in Patients Older Than 60 With Newly Diagnosed or Relapsed Refractory Acute Myeloid Leukemia
|Acute Myeloid Leukemia||Drug: combination therapy using decitabine and midostaurin||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- 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. [ Time Frame: 3 months per patient ]
- Explore potential association between clinical response and FLT-3 status in patients treated in each cohort; assess toxicity of combination in each dosing cohort [ Time Frame: 3 months per patient ]
|Study Start Date:||March 2010|
|Study Completion Date:||October 2011|
|Primary Completion Date:||October 2011 (Final data collection date for primary outcome measure)|
|Experimental: Decitabine Midostaurin combination||
Drug: combination therapy using decitabine and midostaurin
Decitabine 20mg/m2 IV daily on days 1-5 to be repeated every 28 days. Midostaurin 25mg bid days 8-21 of each cycle.
Decitabine 20mg/m2 IV daily on days 1-5 to be repeated every 28 days. Midostaurin 50mg bid days 8-21 of each cycle.
Decitabine 20mg/m2 IV daily on days 1-5 to be repeated every 28 days. Midostaurin 50mg bid x 28 days of each cycle.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01130662
|United States, Kansas|
|University of Kansas Medical Center, Westwood Campus|
|Kansas City, Kansas, United States, 66205|
|Principal Investigator:||Casey Williams, PharmD||University of Kansas Medical Center|