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

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

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

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: midostaurin (PKC412)

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Chemnitz, Germany
    • Klinikum Chemnitz gGmbH, Klinik für Innere Medizin III
  • Dresden, Germany
    • Universitätsklinikum Dresden Medizinische Klinik und Poliklinik I
  • Erlangen, Germany
    • Universitätsklinikum Erlangen, Medizinische Klinik 5
  • Frankfurt Main, Germany
    • Klinikum der Johann-Wolfgang-Goethe Universität
  • Heidelberg, Germany
    • Universitätsklinikum Heidelberg
  • Jena, Germany
    • Universitätsklinikum Jena, Klinik für Innere Medizin II
  • Marburg, Germany
    • Universitätsklinikum Giessen und Marburg GmbH
  • Münster, Germany
    • Universitatsklinikum Munster
  • Nürnberg, Germany
    • Städtisches Klinikum Nord
  • Regensburg, Germany
    • Klinikum der Universität Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Rydapt

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event-free Survival	2-year Event-free Survival

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	molecular diagnostics of markers in peripheral blood / bone marrow	2-years
Cumulative incidence of relapse		2-year

Collaborators and Investigators

• Sponsor: Technische Universität Dresden
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Christoph Röllig, Prof. Dr., Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I

Publications and helpful links

Helpful Links

• Website Study Alliance Leukemia (coordinating study group)

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2013
• Primary Completion (Actual): October 30, 2019
• Study Completion (Actual): October 30, 2019

Study Registration Dates

• First Submitted: March 25, 2013
• First Submitted That Met QC Criteria: April 9, 2013
• First Posted (Estimate): April 12, 2013

Study Record Updates

• Last Update Posted (Actual): August 6, 2020
• Last Update Submitted That Met QC Criteria: August 5, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; chemotherapy; AML; FLT3-ITD; midostaurin; t(8;21); c-KIT
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Midostaurin
• Other Study ID Numbers: TUD-MIDOKI-052; 2011-002567-17 (EudraCT Number)