E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066764 |
E.1.2 | Term | Acute myeloid leukaemia progression |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the Leukemia-free survival (LFS) of patients with molecular relapse or persistent molecular positivity on midostaurin treatment after allogeneic stem cell transplantation |
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E.2.2 | Secondary objectives of the trial |
- To explore molecular response to midostaurin treatment in AML patients with MRD positivity after allogeneic SCT
- To assess the development of graft-versus-host disease (GvHD)
- To evaluate safety and tolerability of midostaurin after allogeneic SCT
- To explore mechanisms of primary or secondary resistance to midostaurin by molecular analysis
- To evaluate quality of life on midostaurin therapy in AML |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with molecular relapse or persistent molecular positivity of AML after allogeneic SCT
• Detection of FLT3-ITD or FLT3-TKD at primary diagnosis or at antecedent relapse of AML prior to allogeneic SCT
• Sensitive MRD assessment based on qPCR (i.e. low PCR “cut off” for each applied MRD marker of at least 0.1% - e.g. NPM1mut/ABL1)
• ANC > 1,0 Gpt/L and Platelets > 50 Gpt/L
• ECOG performance status 0-2
• GFR > 30 ml/min and serum bilirubin < 1.5 x ULN
• Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 3.0 × ULN;
Serum levels of potassium (3.3-4.5 mmol/L), magnesium (0.77-1.03 mmol/L), total calcium (2.2- 2.65 mmol/L) or within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]) of the hospital or local laboratory. Correction of electrolytes levels with supplements to fulfil inclusion criteria is allowed.
• All female patients with reproductive potential and all male patients must agree to use effective methods to prevent pregnancy. Female patients of childbearing potential must agree to use dual methods of contraception (i.e. with progesterone contraceptive implants, intrauterine device with progesterone, pills containing estrogen and progestin, as well as three-month injection with depot progestin) for the duration of the study. Male patients and male partners of female patients must agree to use a barrier method of contraception for the duration of the study if sexually active with a female of childbearing potential. It is required that sexually active men use condom during intercourse while taking the drug and for 2 weeks after stopping treatment and not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Female partners of male patients must be advised to use a highly effective method of contraception. Contraception and a hold on sperm donation for male patients are to be continued for at least 2 weeks after the last dose of midostaurin for safety reasons.
• All women of child-bearing potential have to complete a serum pregnancy test at screening visit. After screening, monthly serum pregnancy tests must be performed by all enrolled women of child-bearing potential from start of midostaurin until stop of midostaurin. If a test result indicates a pregnancy, the patient must stop treatment with midostaurin immediately. Pregnancy testing is not required for women who are determined to be post-menopausal.
• Written informed consent prior to any study procedures being performed
• Age ≥ 18 years |
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E.4 | Principal exclusion criteria |
• Acute promyelocytic leukemia (APL)
• Hematological relapse of AML (bone marrow blasts ≥5% or reappearance of blasts in the blood or development of extramedullary disease)
• Lack of a suitable MRD marker (no detectable MRD marker at diagnosis or low sensitivity of an available MRD marker, e.g. sensitivity > 0.1% MRD transcript/ABL1)
• Impaired left ventricular 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
• 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 enrolment or who have not recovered from side effects of such therapy
• Patients with resting QTcF ≥450 msec prior to enrolment or inability to determine the QTcF interval. Other clinically significant heart disease (e.g. unstable angina, congestive heart failure) Other concurrent uncontrolled medical conditions (e.g., active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
• Substance abuse, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Leukemia-free survival (LFS) – i.e. the proportion of patients without AML relapse |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 12 months after detection of MRD positivity and initiation of midostaurin |
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E.5.2 | Secondary end point(s) |
- Achievement of “low MRD” at 3 months
- Incidence and severity of acute or chronic GvHD
- Incidence of adverse events
- Next-generation sequencing analyses of FLT3 and other genes
- Quality of life |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Achievement of “low MRD” at 3 months
- Incidence and severity of acute or chronic GvHD: end of study
- Incidence of adverse events: end of study
- Next-generation sequencing analyses of FLT3 and other genes: per Study Visit
- Quality of life: end of study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Every patient will be observed for 12 months starting on day of inclusion to the study and initiation of midostaurin treatment or until relapse (whichever occurs first) within the Mauritius trial. The end of study (EOS) is defined as the last assessment and documentation of remission and survival status and treatment change 12 months after inclusion of the last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |