MIDOKIT: Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: midostaurin (PKC412), capsules midostaurin 50 mg (two 25 mg capsules) is given in combination with the second of two induction cycles and in combination with three cycles of high-dose cytarabine (HiDAC) consolidation chemotherapies and maintenance treatment in patients with c-kit or FLT3-ITD positive t(8;21) AML in an open-label one-arm design. The first cycle of induction is not part of the study. |
Drug: midostaurin (PKC412)
Midostaurin 50 mg (2 capsules) twice daily days 8-21 in induction II + consolidation I-III; maintenance treatment twice daily continuously for 12 months
Other Names:
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Outcome Measures
Primary Outcome Measures
- Event-free Survival [2-year Event-free Survival]
Secondary Outcome Measures
- Time to relapse [2-years]
- Overall survival [2-years]
- Relapse-free survival [2-years]
- morphologic and molecular CR rate [2-years]
- incidence of AEs/SAEs [until 30 days after end of treatment]
- MRD kinetics (molecular residual disease) [2-years]
molecular diagnostics of markers in peripheral blood / bone marrow
- Cumulative incidence of relapse [2-year]
Eligibility Criteria
Criteria
Inclusion Criteria:
- Diagnosis of c-KIT mutated t(8;21) AML i.e.
-
20% myeloid blasts in bone marrow and/or peripheral blood at initial diagnosis
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Plus cytogenetic diagnosis of aberration t(8;21)/AML1-ETO
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Plus mutation of c-KIT gene (mut-KIT17 or mut-KIT8) or FLT3-ITD mutation or both c-KIT and FLT3-ITD mutations
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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
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Age 18-65 years
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ECOG performance status of 0-2
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Life expectancy of at least 12 weeks
Exclusion Criteria:
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Primary refractory or previously relapsed AML
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Non-eligibility for high-dose cytarabine based consolidation, e.g. intolerance to cytarabine
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Inability to swallow oral medications
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Symptomatic congestive heart failure
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Bilirubin >2.5 x upper limit of normal
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III | Chemnitz | Germany | ||
| 2 | Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I | Dresden | Germany | ||
| 3 | Universitätsklinikum Erlangen, Medizinische Klinik 5 | Erlangen | Germany | ||
| 4 | Klinikum der Johann-Wolfgang-Goethe Universität | Frankfurt Main | Germany | ||
| 5 | Universitätsklinikum Heidelberg | Heidelberg | Germany | ||
| 6 | Universitätsklinikum Jena, Klinik für Innere Medizin II | Jena | Germany | ||
| 7 | Universitätsklinikum Gießen und Marburg GmbH | Marburg | Germany | ||
| 8 | Universitätsklinikum Münster | Münster | Germany | ||
| 9 | Städtisches Klinikum Nord | Nürnberg | Germany | ||
| 10 | Klinikum der Universität Regensburg | Regensburg | Germany |
Sponsors and Collaborators
- Technische Universität Dresden
- Novartis Pharmaceuticals
Investigators
- Principal Investigator: Christoph Röllig, Prof. Dr., Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- TUD-MIDOKI-052
- 2011-002567-17