Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: midostaurin (PKC412)

• Registration Number: NCT01830361
• Lead Sponsor: Technische Universität Dresden

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.

Study Timeline

• Study Start: 2013-03-13
• Study First Submitted: 2013-03-25
• Study First Submitted QC: 2013-04-09
• Study First Posted: 2013-04-12
• Primary Completion: 2019-10-30
• Study Completion: 2019-10-30
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-05
• Last Update Posted: 2020-08-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
midostaurin (PKC412), capsules	midostaurin (PKC412)	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.

Primary Outcome Measures

Name	Time	Method
Event-free Survival	2-year Event-free Survival

Secondary Outcome Measures

Name	Time	Method
Overall survival	2-years
Time to relapse	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

Trial Locations

Locations (10)

Universitätsklinikum Münster; 🇩🇪 Münster, Germany

Klinikum der Johann-Wolfgang-Goethe Universität; 🇩🇪 Frankfurt Main, Germany

Klinikum der Universität Regensburg; 🇩🇪 Regensburg, Germany

Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III; 🇩🇪 Chemnitz, Germany

Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I; 🇩🇪 Dresden, Germany

Universitätsklinikum Erlangen, Medizinische Klinik 5; 🇩🇪 Erlangen, Germany

Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Germany

Universitätsklinikum Jena, Klinik für Innere Medizin II; 🇩🇪 Jena, Germany

Universitätsklinikum Gießen und Marburg GmbH; 🇩🇪 Marburg, Germany

Städtisches Klinikum Nord; 🇩🇪 Nürnberg, Germany