Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML (MIDOKIT)
Primary Purpose
Acute Myeloid Leukemia
Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
midostaurin (PKC412)
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring AML, Acute Myeloid Leukemia, c-KIT, FLT3-ITD, t(8;21), chemotherapy, midostaurin
Eligibility 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
- Plus cytogenetic diagnosis of aberration t(8;21)/AML1-ETO
- 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
Sites / Locations
- Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III
- Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
- Universitätsklinikum Erlangen, Medizinische Klinik 5
- Klinikum der Johann-Wolfgang-Goethe Universität
- Universitätsklinikum Heidelberg
- Universitätsklinikum Jena, Klinik für Innere Medizin II
- Universitätsklinikum Gießen und Marburg GmbH
- Universitätsklinikum Münster
- Städtisches Klinikum Nord
- Klinikum der Universität Regensburg
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
midostaurin (PKC412), capsules
Arm Description
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.
Outcomes
Primary Outcome Measures
Event-free Survival
Secondary Outcome Measures
Time to relapse
Overall survival
Relapse-free survival
morphologic and molecular CR rate
incidence of AEs/SAEs
MRD kinetics (molecular residual disease)
molecular diagnostics of markers in peripheral blood / bone marrow
Cumulative incidence of relapse
Full Information
NCT ID
NCT01830361
First Posted
March 25, 2013
Last Updated
August 5, 2020
Sponsor
Technische Universität Dresden
Collaborators
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01830361
Brief Title
Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
March 13, 2013 (Actual)
Primary Completion Date
October 30, 2019 (Actual)
Study Completion Date
October 30, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Technische Universität Dresden
Collaborators
Novartis Pharmaceuticals
4. Oversight
Data Monitoring Committee
Yes
5. 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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
AML, Acute Myeloid Leukemia, c-KIT, FLT3-ITD, t(8;21), chemotherapy, midostaurin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
midostaurin (PKC412), capsules
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
midostaurin (PKC412)
Other Intervention Name(s)
Rydapt
Intervention Description
Midostaurin 50 mg (2 capsules) twice daily days 8-21 in induction II + consolidation I-III; maintenance treatment twice daily continuously for 12 months
Primary Outcome Measure Information:
Title
Event-free Survival
Time Frame
2-year Event-free Survival
Secondary Outcome Measure Information:
Title
Time to relapse
Time Frame
2-years
Title
Overall survival
Time Frame
2-years
Title
Relapse-free survival
Time Frame
2-years
Title
morphologic and molecular CR rate
Time Frame
2-years
Title
incidence of AEs/SAEs
Time Frame
until 30 days after end of treatment
Title
MRD kinetics (molecular residual disease)
Description
molecular diagnostics of markers in peripheral blood / bone marrow
Time Frame
2-years
Title
Cumulative incidence of relapse
Time Frame
2-year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Plus cytogenetic diagnosis of aberration t(8;21)/AML1-ETO
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christoph Röllig, Prof. Dr.
Organizational Affiliation
Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I
Official's Role
Principal Investigator
Facility Information:
Facility Name
Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III
City
Chemnitz
Country
Germany
Facility Name
Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
City
Dresden
Country
Germany
Facility Name
Universitätsklinikum Erlangen, Medizinische Klinik 5
City
Erlangen
Country
Germany
Facility Name
Klinikum der Johann-Wolfgang-Goethe Universität
City
Frankfurt Main
Country
Germany
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
Country
Germany
Facility Name
Universitätsklinikum Jena, Klinik für Innere Medizin II
City
Jena
Country
Germany
Facility Name
Universitätsklinikum Gießen und Marburg GmbH
City
Marburg
Country
Germany
Facility Name
Universitätsklinikum Münster
City
Münster
Country
Germany
Facility Name
Städtisches Klinikum Nord
City
Nürnberg
Country
Germany
Facility Name
Klinikum der Universität Regensburg
City
Regensburg
Country
Germany
12. IPD Sharing Statement
Links:
URL
http://www.sal-aml.org
Description
Website Study Alliance Leukemia (coordinating study group)
Learn more about this trial
Trial to Assess the Efficacy of Midostaurin (PKC412) in Patients With c-KIT or FLT3-ITD Mutated t(8;21) AML
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