Clinical Trials /

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

NCT01830361

Description:

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

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: TUD-MIDOKI-052
  • SECONDARY ID: 2011-002567-17
  • NCT ID: NCT01830361

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
midostaurin (PKC412)Rydaptmidostaurin (PKC412), capsules

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
midostaurin (PKC412), capsulesExperimentalmidostaurin 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.
  • midostaurin (PKC412)

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
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free Survival
Time Frame:2-year Event-free Survival
Safety Issue:
Description:

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Technische Universität Dresden

Trial Keywords

  • AML
  • Acute Myeloid Leukemia
  • c-KIT
  • FLT3-ITD
  • t(8;21)
  • chemotherapy
  • midostaurin

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