Clinical trial NCT01830361: Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: AML
Acute Myeloid Leukemia
c-KIT
FLT3-ITD
t(8;21)
chemotherapy
midostaurin
Lead sponsor: Technische Universität Dresden
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2013-04-12
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Event-free Survival
timeFrame: 2-year Event-free Survival
Secondary outcomes:
measure: Time to relapse
timeFrame: 2-years
measure: Overall survival
timeFrame: 2-years
measure: Relapse-free survival
timeFrame: 2-years
measure: morphologic and molecular CR rate
timeFrame: 2-years
measure: incidence of AEs/SAEs
timeFrame: until 30 days after end of treatment
measure: MRD kinetics (molecular residual disease)
timeFrame: 2-years
measure: Cumulative incidence of relapse
timeFrame: 2-year
Other outcomes:
Locations:
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Medizinische Klinik 5
city: Frankfurt Main
country: Germany
facility: Klinikum der Johann-Wolfgang-Goethe Universität
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Klinik für Innere Medizin II
city: Marburg
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Städtisches Klinikum Nord
city: Regensburg
country: Germany
facility: Klinikum der Universität Regensburg
Study officials:
affiliation: Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
name: Christoph Röllig, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: