|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Subjects diagnosed with FLT3/ITD acute myeloid leukemia (AML) in CR1, including CRp and CRi, for whom a decision not to proceed with transplantation has been made, or a suitable donor could not be identified.
|Medical condition in easily understood language
|AML is cancer of myeloid line of blood cells characterized by rapid growth of abnormal white blood cells that accumulate in bone marrow and interfere with production of normal blood cells.
|Diseases [C] - Cancer [C04]
|E.1.2 Medical condition or disease under investigation
|Acute myeloid leukemia
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary objective is to compare relapse-free survival (RFS) between subjects with FLT3/ITD AML in first complete remission (CR1) without transplant and who are randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a 2-year period.
|Secondary objectives of the trial
|Key Secondary Objective:
●Compare overall survival (OS) in subjects treated with gilteritinib as maintenance therapy after induction/consolidation with those treated with placebo.
Additional Secondary Objectives:
●Event-free survival (EFS), AEs, clinical laboratory, vital signs, electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance scores.
● Examine the relationship of minimal residual disease (MRD), as determined using a next-generation sequencing (NGS) platform specific to FLT3/ITD mutations, with RFS and OS.
|Trial contains a sub-study
|Full title, date and version of each sub-study and their related objectives
|Retrospective Pharmacogenomics Substudy (Optional)
The PGx research that may be conducted in the future with acquired blood samples and/or buccal swab is exploratory. The objective of this research will be to analyze or determine genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. By analyzing genetic variations, it may be possible to predict an individual subject’s response to treatment in terms of efficacy and/or toxicity.
Pharmacokinetic sampling substudy:
Sparse (predose) pharmacokinetic samples will be collected in all subjects.
Additional ECGs and/or time-matched plasma samples will be collected in a subset of approximately 90 subjects (targeting approximately 60 subjects in the gilteritinib arm and 30 subjects in the placebo arm) at the following visits and time points:
● Day 15 – 4 hours (± 1 hour) postdose
● Day 29 – 4 hours (± 1 hour) postdose
|Principal inclusion criteria
|1. Written informed consent must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is considered an adult according to local regulation at the time of signing informed consent form (ICF).
3. Subject consents to allow access to his or her diagnostic bone marrow aspirate or peripheral blood sample and/or the DNA derived from that sample, if available, that may be used to validate a companion diagnostic
test for gilteritinib.
4. Subject has confirmed morphologically documented AML, excluding acute promyelocytic leukemia (APL), in CR1 (including CRp and CRi). For the purposes of enrollment, CR will be defined as < 5% blasts in the
bone marrow with no morphologic characteristics of acute leukemia (e.g., Auer rods) in the bone marrow with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma.
5. Subject will not proceed with transplantation as either a decision not to proceed with transplantation has been made either on the recommendation of the treating physician or by the patient or a suitable donor could not be identified.
6. Subject is < 2 months from the start of the last cycle of consolidation and should have completed the recommended number of consolidations per local practice.
7. Subject has had no use of investigational agents, with the exception of FLT3 inhibiting agents during induction and/or consolidation therapy, within the prior 4 weeks.
8. Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or peripheral blood as determined by the local institution at diagnosis.
9. Subject has an ECOG performance status 0 to 2.
10. Subject must meet the following criteria as indicated on the clinical laboratory tests:
● Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m2 as calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation.
● Serum total bilirubin ≤ 2.5 mg/dL (43 µmol/L), except for subjects with Gilbert’s syndrome.
● Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN.
● Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN).
● Absolute neutrophil count (ANC) ≥ 500/μl and platelets ≥ 20000/μl (unsupported by transfusions).
11. Subject is suitable for oral administration of study drug.
For Inclusion Criteria 12-17 see Protocol
|Principal exclusion criteria
|1.Subject has had prior allogeneic transplant.
2. Subject has QTcF interval > 450 msec (average of triplicate determinations based on central reading).
3. Subject with Long QT Syndrome.
4. Subject with hypokalemia and hypomagnesemia at screening (defined as values below LLN).
5. Subject has clinically active central nervous system leukemia.
6. Subject is known to have human immunodeficiency virus infection.
7. Subject has active hepatitis B or C.
8. Subject has an uncontrolled infection. If a bacterial or viral infection is present, the subject must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to randomization. If a fungal infection is present, the subject must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to randomization.
9. Subject has progressing infection defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
10. Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
11. Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A.
12. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject.
13. Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
For Exclusion Criteria 14-16 see Protocol
|E.5 End points
|Primary end point(s)
|Relapse-free survival (RFS)
Leukemia relapse will be defined as bone marrow blasts 5% or higher (not attributable to regenerating bone marrow), any circulating blasts, any extramedullary blast foci as per Revised International Working Group (IWG) criteria.
|Timepoint(s) of evaluation of this end point
|RFS: the time from randomization until relapse or death from any cause, whichever comes first.
|Secondary end point(s)
|Key Secondary Endpoints:
● Overall survival (OS)
Additional secondary efficacy endpoints:
● Event-free survival (EFS)
● Minimal residual disease (MRD)
● Serum chemistry, hematology, coagulation and urinalysis
● Vital signs
● Physical examination findings
● Eastern Cooperative Oncology Group (ECOG) performance status
|Timepoint(s) of evaluation of this end point
|OS: the time from randomization until death from any cause.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Democratic People's Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of trial in all participating countries is defined as the last subject’s last contact.
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days