E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
FLT3 mutated Acute Myeloid Leukemia (AML) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000012984 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine if the addition of midostaurin to daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and continuation therapy improves overall survival (OS) in both the mutant FLT3-ITD and FLT-3 TKD AML patients. |
|
E.2.2 | Secondary objectives of the trial |
Key: To compare the event-free survival (EFS) between the two treatment groups.
Other:-To compare OS between the two treatment groups using an analysis in which patients who receive a SCT are censored at the time of transplant.
-To compare the CR rate between the two treatment groups.
-To compare the DFS of the two treatment groups.
-To compare the DFS rate one year after completion of the continuation phase of the two groups.
-To assess the toxicity of the experimental combination.
-To describe the interaction between treatment outcome and pretreatment characteristics such as age, performance status, WBC count, morphology, cytogenetics, and molecular and pharmacodynamic features.
-To assess the population pharmacokinetics (popPK) of midostaurin and its two major metabolites, CGP52421 and CGP62221.The potential association(s) between PK exposure and FLT3 status, OS, EFS and clinical response will be explored.
-To assess and compare the SCT rate between the two treatment groups. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Unequivocal diagnosis of AML (>20% blasts in the bone marrow based on the WHO classification), excluding M3 (acute promyelocytic leukemia).
Documented FLT3 mutation (ITD or point mutation), determined by analysis in a protocol-designed FLT3 screening laboratory.
Age greater than or equal to 18 years.
Age less than 60 years.
AML patients with a history of antecedent myelodyspasia (MDS) remain eligible for treatment on this trial, but must not have had prior cytotoxic therapy (e.g. azacitidine or decitabine).
Bilirubin < 2.5 times upper limit of normal.
Women of childbearing potential must have a negative serum or urine pregnancy test within a sensitivity of at least 50 mIU/ml within 16 days prior to registration and must either commit to continued abstinence from heterosexual intercourse or commit to two acceptable methods of birth control (one highly effective and one additional effective method) at the same time. This should be commenced before receiving midostaurin/placebo therapy and continue for 12 weeks after completion of all midostaurin therapy.
Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking midostaurin/placebo and for 12 weeks after therapy is stopped, even if they have undergone a successful vasectomy.
|
|
E.4 | Principal exclusion criteria |
No prior chemotherapy for leukemia or myelodysplasia with the following exceptions:
- emergency leukapheresis
- emergency treatment for hyperleukocytosis with hydroxyurea for less than or equal to 5 days
- cranial RT for CNS leukostasis (one dose only)
- growth factor/cytokine support
Patients who have developed therapy related AML after prior RT or chemotherapy for another cancer or disorder are not eligible.
Patients with symptomatic congestive heart failure are not eligible.
Pregnant or nursing patients may not be enrolled. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis with a cutoff date of April 1, 2015 after a minimum follow up of approximately 3.5 years after the randomization of the last patient (October 15th 2011).
A supportive (final) analysis at the end of the trial when the 10 year post-randomization follow up period has been completed for all patients, or when 509 events are observed, whichever occurs first. |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoint:
- event free survival
Other secondary endpoints:
- overall survival (OS) where patients who receive a stem cell transplant (SCT) are censored at the time of the transplant
- complete response (CR) rate in the remission induction stage of the study
- disease free survival (DFS)
- DFS rate one year after completing the planned continuation phase
- SCT rates |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Primary analysis with a cutoff date of April 1, 2015 after a minimum follow up of approximately 3.5 years after the randomization of the last patient (October 15th 2011).
A supportive (final) analysis at the end of the trial when the 10 year post-randomization follow up period has been completed for all patients, or when 509 events are observed, whichever occurs first. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |