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

• ClinicalTrials.gov Identifier: NCT01830361
• Recruitment Status: Completed
• First Posted: April 12, 2013
• Last Update Posted: August 6, 2020
• Sponsor: Technische Universität Dresden
• Collaborator: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Technische Universität Dresden

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

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: midostaurin (PKC412)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 13, 2013
• Actual Primary Completion Date: October 30, 2019
• Actual Study Completion Date: October 30, 2019

Arms and Interventions

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 Name: Rydapt

Outcome Measures

Primary Outcome Measures :

1. Event-free Survival [ Time Frame: 2-year Event-free Survival ]

Secondary Outcome Measures :

1. Time to relapse [ Time Frame: 2-years ]
2. Overall survival [ Time Frame: 2-years ]
3. Relapse-free survival [ Time Frame: 2-years ]
4. morphologic and molecular CR rate [ Time Frame: 2-years ]
5. incidence of AEs/SAEs [ Time Frame: until 30 days after end of treatment ]
6. MRD kinetics (molecular residual disease) [ Time Frame: 2-years ]
   molecular diagnostics of markers in peripheral blood / bone marrow
7. Cumulative incidence of relapse [ Time Frame: 2-year ]

Eligibility Criteria

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

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

Contacts and Locations

Locations

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, Germany

Sponsors and Collaborators

Technische Universität Dresden

Novartis Pharmaceuticals

Investigators

• Principal Investigator: Christoph Röllig, Prof. Dr.; Medizinische Fakultät der TU Dresden, Medizinische Klinik und Poliklinik I

More Information

Additional Information:

Website Study Alliance Leukemia (coordinating study group) 

• Responsible Party: Technische Universität Dresden
• ClinicalTrials.gov Identifier: NCT01830361
• Other Study ID Numbers: TUD-MIDOKI-052; 2011-002567-17 ( EudraCT Number )
• First Posted: April 12, 2013
• Last Update Posted: August 6, 2020
• Last Verified: August 2020

Keywords provided by Technische Universität Dresden:

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

Additional relevant MeSH terms:

Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Neoplasms by Histologic Type; Neoplasms; Midostaurin; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action