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A Single-arm Phase II Trial to Assess the Efficacy of Midostaurin (PKC412) Added to Standard Primary Therapy in Patients With Newly Diagnosed c-KIT or FLT3-ITD Mutated t(8;21) AML

Phase 2
18 Years
65 Years
Open (Enrolling)
Acute Myeloid Leukemia

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Trial Information

A Single-arm Phase II Trial to Assess the Efficacy of Midostaurin (PKC412) Added to Standard Primary Therapy in Patients With Newly Diagnosed c-KIT or FLT3-ITD Mutated t(8;21) AML

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.

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

- Therapy-related AML after prior radiotherapy or chemotherapy

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

- Inability to swallow oral medications

- Symptomatic congestive heart failure

- Bilirubin >2.5 x upper limit of normal

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free Survival

Outcome Time Frame:

2-year Event-free Survival

Safety Issue:


Principal Investigator

Gerhard Ehninger, Prof. Dr. med.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, 01307 Dresden


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

April 2012

Completion Date:

September 2018

Related Keywords:

  • Acute Myeloid Leukemia
  • AML
  • Acute Myeloid Leukemia
  • c-KIT
  • FLT3-ITD
  • t(8;21)
  • chemotherapy
  • midostaurin
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid