Acute Myeloid Leukemia
Conditions
Keywords
AML, Acute Myeloid Leukemia, c-KIT, FLT3-ITD, t(8;21), chemotherapy, midostaurin
Brief summary
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.
Interventions
Midostaurin 50 mg (2 capsules) twice daily days 8-21 in induction II + consolidation I-III; maintenance treatment twice daily continuously for 12 months
Sponsors
Novartis Pharmaceuticals
Technische Universität Dresden
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Event-free Survival | 2-year Event-free Survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | 2-years | — |
| Relapse-free survival | 2-years | — |
| morphologic and molecular CR rate | 2-years | — |
| Time to relapse | 2-years | — |
| MRD kinetics (molecular residual disease) | 2-years | molecular diagnostics of markers in peripheral blood / bone marrow |
| Cumulative incidence of relapse | 2-year | — |
| incidence of AEs/SAEs | until 30 days after end of treatment | — |
Countries
Germany
Outcome results
None listed