Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML
Acute Myeloid Leukemia
Conditions: official terms
Leukemia, Myeloid - Leukemia, Myeloid, Acute
Conditions: Keywords
AML, Acute Myeloid Leukemia, c-KIT, FLT3-ITD, t(8;21), chemotherapy, midostaurin
Study Type
Study Phase
Phase 2
Study Design
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: midostaurin (PKC412)
Type: Drug
Overall Status
To assess the efficacy of tyrosine-kinase inhibitor midostaurin in c-KIT or FLT3-ITD mutated t(8;21) AML. To assess the efficacy of midostaurin depending on the type of c-KIT mutation
Detailed Description
AML patients displaying t(8;21) have a relatively favourable outcome. Nevertheless, only approximately 50% of patients carrying this cytogenetic aberration are alive at 5 years. This suggests that some patients have more aggressive leukemic phenotypes and indicates the need for treatment optimization with novel therapies.

The mutated KIT gene as well as the FLT3-ITD mutation have recently been identified as factors most likely to explain the heterogeneous clinical outcomes within the group of t(8;21) AML. The FLT3 and c-KIT genes encode type III receptor tyrosine kinases (RTK) with important and partly redundant functions in early hematopoietic stem cells. Various activating mutations have been described for both genes. For c-KIT, the incidence ranges from 17 to 48% depending on the source population and type of mutations determined. It has been consistently shown that in AMLs with t(8;21), mutated c-KIT is associated with a dramatically increased risk of relapse and reduced overall survival compared to their unmutated counterparts. The FLT3-ITD mutation has a similar negative effect on prognosis in the patient group of t(8;21) mutated AMLs as c-KIT.

PKC412 (midostaurin) is known to inhibit the c-KIT RTK activity as well as the FLT3 kinase, both in patients with ITD and TKD mutations. It should therefore be possible to abrogate the negative impact of pathologically increased c-KIT or FLT3-ITD activity on relapse and overall survival by using midostaurin in this patient population. Aim of the proposed clinical trial is to prove the efficacy of midostaurin in c-KIT or FLT3-ITD mutated t(8;21)- AMLs in an open-label one-arm design.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: 65 Years
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Diagnosis of c-KIT mutated t(8;21) AML i.e.

1. >20% myeloid blasts in bone marrow and/or peripheral blood at initial diagnosis

2. Plus cytogenetic diagnosis of aberration t(8;21)/AML1-ETO

3. Plus mutation of c-KIT gene (mut-KIT17 or mut-KIT8) or FLT3-ITD mutation or both c-KIT and FLT3-ITD mutations

- Chemoresponsive disease as determined by early bone marrow assessment on day 14-16 after first cycle of induction therapy with cytarabine in combination with daunorubicine or idarubicine, or mitoxantrone- Fit for further intensive chemotherapy

- Age 18-65 years

- ECOG performance status of 0-2

- Life expectancy of at least 12 weeks

Exclusion Criteria:

- Primary refractory or previously relapsed AML

- Non-eligibility for high-dose cytarabine based consolidation, e.g. intolerance to cytarabine

- Inability to swallow oral medications

- Symptomatic congestive heart failure

- Bilirubin >2.5 x upper limit of normal
Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III
Chemnitz, Germany
Status: Recruiting
Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
Dresden, Germany
Status: Recruiting
Marien Hospital
Düsseldorf, Germany
Status: Recruiting
Universitätsklinikum Erlangen, Medizinische Klinik 5
Erlangen, Germany
Status: Recruiting
Klinikum der Johann-Wolfgang-Goethe Universität
Frankfurt Main, Germany
Status: Recruiting
Universitätsklinikum Heidelberg
Heidelberg, Germany
Status: Recruiting
Universitätsklinikum Gießen und Marburg GmbH
Marburg, Germany
Status: Recruiting
Universitätsklinikum Münster
Münster, Germany
Status: Recruiting
Städtisches Klinikum Nord
Nürnberg, Germany
Status: Recruiting
Klinikum der Universität Regensburg
Regensburg, Germany
Status: Recruiting
Start Date
April 2012
Completion Date
September 2018
Technische Universität Dresden
Technische Universität Dresden
Record processing date processed this data on July 28, 2015 page