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Midostaurin in MRD (Minimal Residual Disease) Positive Acute Myeloid Leukemia After Allogeneic Stem Cell Transplantation

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ClinicalTrials.gov Identifier: NCT03951961
Recruitment Status : Not yet recruiting
First Posted : May 16, 2019
Last Update Posted : May 16, 2019
Sponsor:
Collaborator:
Ludwig-Maximilians - University of Munich
Information provided by (Responsible Party):
Sebastian Scholl, PD Dr. med., University of Jena

Brief Summary:
The MAURITIUS trial is a single-arm, multicenter phase II study of single treatment with midostaurin being applied to AML (acute myeloid leukemia) patients with activating FLT3 (FMS-like tyrosine kinase3) mutations and either molecular relapse or persistent molecular positivity after allogeneic SCT. The leukemia-free survival (LFS), the achievement of "MRD low" as well as the incidence of GvHD after transplantation reflect the most relevant endpoints of this non-randomized clinical trial.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia, Adult Drug: Midostaurin Phase 2

Detailed Description:

The clinical situation of AML (acute myeloid leukemia) relapse after intensive chemotherapy or even after allogeneic SCT represents a huge challenge in hematology. So far, no FLT3-TKI (Tyrosine kinase Inhibitor) has been approved for the treatment of relapsed or refractory AML with activating FLT3 mutations in the European Union.

For elderly and unfit patients at primary diagnosis and for patients with AML relapse after induction and consolidation chemotherapy (including those with allogeneic SCT) who are not eligible for any further intensive treatment approach, AML therapy with HMA (hypomethylating agents) represents the standard of care and is associated with an even worse prognosis in those patients who relapse with AML after transplantation.

The FLT3-TKI midostaurin has been approved for newly diagnosed AML patients with activating FLT3 mutations who receive intensive induction and subsequent consolidation chemotherapy including midostaurin maintenance restricted to patients who do not undergo allogeneic SCT. So far, there is no approval of FLT3-TKI treatment for patients with FLT3-mutated AML after allogeneic SCT. Recently, preliminary data of the RADIUS trial investigating midostaurin maintenance after allogeneic SCT could demonstrate the feasibility of midostaurin treatment in the setting of post-transplant AML patients. Importantly, only half of patients were able to complete 12 cycles of maintenance and in most cases midostaurin was prematurely ceased due to a higher rate of adverse events than expected. As a consequence of this clinical trial, there is a good rationale to investigate midostaurin maintenance after allogeneic SCT focusing on those AML patients with a high risk of hematologic relapse after transplantation.

In detail, MRD assessment provides a reliable method in the majority of patients with FLT3-mutated AML (e.g. by qPCR) to identify AML patients with the highest risk of relapse following allogeneic SCT. There are consistent data demonstrating that MRD positivity by means of NPM1 (Nuclophosphmin-1)mutation (i.e. 100 to 1000 copies of mutated NPM1 per 10,000 ABL (Abelson Murine Leukemia Viral Oncogene Homolog) transcripts or 1% to 10% NPM1/ABL, respectively, is associated with a 60-90% risk of hematologic relapse.

Thus, this clinically relevant subgroup of AML patients with activating FLT3 mutations who develop a molecular relapse or who are characterized by a persistent MRD positivity after intensive AML treatment represents the target population of this clinical trial. The rationale of this study is to treat AML patients with MRD positivity using single midostaurin treatment and to improve the clinical outcome of these patients by preventing hematologic relapse after allogeneic SCT by "targeted therapy" against activating FLT3 mutations.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Intervention Model: Single Group Assignment
Intervention Model Description: single-arm, multicenter phase II, non-randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Midostaurin in MRD (Minimal Residual Disease) Positive Acute Myeloid Leukemia After Allogeneic Stem Cell Transplantation
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Midostaurin
50 mg Midostaurin bid for 12 months
Drug: Midostaurin
50mg Midostaurin bid for 12 months




Primary Outcome Measures :
  1. proportion of patients without AML relapse [ Time Frame: at 12 months after start of midostaurin treatment ]
    impact of midostaurin single treatment on Leukemia-free survival (LFS)


Secondary Outcome Measures :
  1. number of patients with low MRD (Minimal Residual Disease) [ Time Frame: at 3 months after start of midostaurin treatment ]
    molecular response to midostaurin treatment

  2. Incidence of acute and chronic graft-versus-host disease (GvHD) [ Time Frame: baseline and every 3 months until 12 months after start of midostaurin treatment ]
    Incidence of acute and chronic GvHD

  3. Incidence of adverse events grade 3-5 of midostaurin after allogeneic SCT [ Time Frame: baseline and every 3 months until 12 months after start of midostaurin treatment ]
    Incidence of adverse events grade 3-5

  4. Next-generation sequencing analyses of FLT3-mutation [ Time Frame: baseline and every 3 months until 12 months after start of midostaurin treatment ]
    mechanisms of primary or secondary resistance to midostaurin

  5. quality of life assessment with certified "EORTC QLQ - C30 questionnaire" [ Time Frame: baseline and every 3 months until 12 months after start of midostaurin treatment ]
    quality of life assessment with certified "EORTC QLQ - C30 questionnaire"



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with molecular relapse or persistent molecular positivity of AML after allogeneic SCT (stem cell Transplantation)
  • Detection of FLT3-ITD (Internal tandem duplication) or FLT3-TKD (tyrosine kinase domain) at primary diagnosis or at antecedent relapse of AML prior to allogeneic SCT
  • Sensitive MRD assessment based on qPCR (e.g. by means of NPM1 mutations)
  • absolute neutrophil count > 1,0 Gpt/L and Platelets > 50 Gpt/L
  • ECOG (Eastern Cooperative Oncology Group) performance status 0-2
  • glomerular filtration rate > 30 ml/min and serum bilirubin < 1.5 x upper limit of normal
  • Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 3.0 × ULN
  • Normal serum levels of potassium, magnesium, and corrected calcium
  • Written informed consent prior to any study procedures being performed
  • Age ≥ 18 years

Exclusion Criteria:

  • Acute promyelocytic leukemia (APL)
  • Hematological relapse of AML
  • Lack of a suitable MRD marker
  • Impaired ejection fraction (LVEF) < 45%
  • Patients with midostaurin treatment after allogeneic SCT or with ongoing TKI therapy < 4 weeks prior to inclusion
  • Treatment with an investigational drug within 5 half-lives preceding the first dose of study medication
  • History of acute or chronic pancreatitis
  • Active and uncontrolled infections
  • History of severe lung disease and/or relevant functional impairment
  • Medical indication for treatment with strong CYP3A4 inhibitors (e.g. voriconazole, posaconazole, clarithromycin)
  • Positive PCR for Human Immunodeficiency Virus (HIV) or Hepatitis B or C
  • Patients unable to swallow medication
  • Known hypersensitivity reaction to midostaurin or any excipient of midostaurin
  • Concomitant medications with known induction of CYP3A4 isoenzyme unless they can be discontinued or replaced prior to enrollment
  • Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  • Patients who are pregnant or breast feeding, or females of reproductive potential not employing an effective method of birth control. Female patients must agree to an effective birth control throughout the study and for up to 4 months beyond.
  • Other medical conditions (e.g. corrected QT interval prolongation) that might interfere with midostaurin treatment
  • Substance abuse, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03951961


Contacts
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Contact: Sebastian Scholl, PD Dr. med. +493641 ext 9324573 mauritius@med.uni-jena.de
Contact: Christian Fabisch, Dr. +493641 ext 9396670 mauritius@med.uni-jena.de

Locations
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Germany
Universitätsklinikum Jena Not yet recruiting
Jena, Germany, 07747
Contact: Sebastian Scholl, PD Dr. med.    +49 3641 9324573    sebastian.scholl@med.uni-jena.de   
Sponsors and Collaborators
Sebastian Scholl, PD Dr. med.
Ludwig-Maximilians - University of Munich
Investigators
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Principal Investigator: Sebastian Scholl, PD Dr. med. Universitätsklinikum Jena

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Responsible Party: Sebastian Scholl, PD Dr. med., Principal Investigator, University of Jena
ClinicalTrials.gov Identifier: NCT03951961     History of Changes
Other Study ID Numbers: MAURITIUS
2019-000136-26 ( EudraCT Number )
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: May 16, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Neoplastic Processes
Pathologic Processes
Midostaurin
Staurosporine
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action