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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
2-year Event-free Survival
Gerhard Ehninger, Prof. Dr. med.
Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, 01307 Dresden
Germany: Federal Institute for Drugs and Medical Devices