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

Acute Myeloid Leukemia Clinical Trial

— MIDOKIT  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01830361
• Other study ID #: TUD-MIDOKI-052
• Secondary ID: 2011-002567-17
• Status: Completed
• Phase: Phase 2
• Start date: March 13, 2013
• Est. completion date: October 30, 2019

Study information

• Verified date: August 2020
• Source: Technische Universität Dresden
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: October 30, 2019
• Est. primary completion date: October 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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

Locations

Country	Name	City	State
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	Klinikum der Johann-Wolfgang-Goethe Universität	Frankfurt Main
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Jena, Klinik für Innere Medizin II	Jena
Germany	Universitätsklinikum Gießen und Marburg GmbH	Marburg
Germany	Universitätsklinikum Münster	Münster
Germany	Städtisches Klinikum Nord	Nürnberg
Germany	Klinikum der Universität Regensburg	Regensburg

Sponsors (2)

Lead Sponsor	Collaborator
Technische Universität Dresden	Novartis Pharmaceuticals

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free Survival		2-year Event-free Survival
Secondary	Time to relapse		2-years
Secondary	Overall survival		2-years
Secondary	Relapse-free survival		2-years
Secondary	morphologic and molecular CR rate		2-years
Secondary	incidence of AEs/SAEs		until 30 days after end of treatment
Secondary	MRD kinetics (molecular residual disease)	molecular diagnostics of markers in peripheral blood / bone marrow	2-years
Secondary	Cumulative incidence of relapse		2-year

External Links

•   Website Study Alliance Leukemia (coordinating study group)