E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) (FLT3/ITD) acute myeloid leukemia (AML) in first morphologic complete remission (CR1) that has been treated with allogeneic hematopoietic stem cell transplant (HCT)
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E.1.1.1 | 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 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 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 |
The primary objective is to compare relapse-free survival (RFS) between participants with FLT3/ITD AML in CR1 who undergo HCT and are randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two year period |
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E.2.2 | Secondary objectives of the trial |
The key secondary objective is to compare overall survival (OS) in participants treated with gilteritinib as maintenance therapy after HCT compared to those treated with placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Subject is suitable candidate for HCT and has an acceptable source of allogeneic donor cells, as defined per institutional practice (allogeneic HCT for any donor source [matched sibling, unrelated donor (URD), mismatched URD, related haploidentical, or umbilical cord blood] and any graft source [umbilical cord, BM, peripheral blood (PB)], and any conditioning [myeloablative conditioning (MAC), reduced intensity conditioning (RIC), or non-myeloablative conditioning (NMA)] will be permitted). 2.IRB/IEC approved written ICF and privacy language obtained from the participant or legally authorized representative prior to any study-related procedures 3.Subject is legal adult by local regulation at the time of signing ICF 4.Subject consents to allow access to his or her diagnostic BM aspirate or PB sample and/or the DNA derived from that sample, if available. 5.Subject has confirmed, morphologically documented AML in CR1. For the purposes of registration, CR1 will be defined as < 5% blasts in the BM with no morphologic characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma. a.Subject has not received more than 2 cycles of induction chemotherapy to achieve CR1. b.Subjects with CR with incomplete count recovery (CRp or CRi) are allowed. Incomplete platelet recovery (CRp) is defined as CR with platelet count < 100 x 109/L. Incomplete blood count recovery (CRi) is defined as CR with residual neutropenia < 1 x 109/L with or without complete platelet recovery. Red blood cell count (RBC) and platelet transfusion independence is not required. c.The maximum time allowed from establishment of CR1 to registration is 12 months. 6.Subject has presence of the FLT3/ITD activating mutation in the BM or PB as determined by the local institution at diagnosis. 7.Subject must meet the following criteria as indicated on the clinical laboratory tests: a.Serum creatinine within normal range, or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m2 as calculated with the Cockcroft-Gault equation with adjustment if total body weight is ≥ 125% of ideal body weight. b.Total bilirubin (TBL) ≤ 2.5 mg/dL, except for participants with Gilbert’s syndrome. c.Serum AST and/or alanine aminotransferase (ALT) < 3 x institutional upper limit of normal (ULN). 8.Subject has left ventricular ejection fraction at rest ≥ 40%. 9.Subject has diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) ≥ 50% predicted and/or forced expiratory volume in 1 second (FEV1), ≥ 50% predicted.
For all Registration Inclusion Criteria, see protocol. For a list of Randomization Eligibility Criteria and Randomization Inclusion Criteria, see protocol. |
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E.4 | Principal exclusion criteria |
1.Participant has had a prior allogeneic transplant. 2.Participant has Karnofsky performance status score < 70% (APPENDIX F). 3.Participant requires treatment with concomitant drugs that are strong inducers of CYP3A (APPENDIX H) within 14 days of start of study drug. 4.Participant 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 participant. 5.Participant has a Fridericia-corrected QT interval (QTcF) > 450 msec (average of triplicate determinations) per central read. 6.Participant has long QT Syndrome at screening. 7.Participant has a known infection with human immunodeficiency virus (HIV). 8.Participant has active hepatitis B infection as determined by NAAT or surface antigen assay. Participants who have acquired immunity from past exposure (HBcAb positive / HBsAb positive / HBsAg negative) are eligible. 9.Participant has active hepatitis C infection as determined by NAAT. NAAT must be performed if the participant has positive serology for hepatitis C.Participants who have had past exposure and have no detectable virus either through spontaneous clearance or treatment are eligible. 10.Participant has an uncontrolled infection. If a bacterial or viral infection is present, the participant must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to registration. If a fungal infection is present, the participant must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to registration. •Progressing infection is 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. 11.Participant has had a myocardial infarction within 6 months prior to registration or New York Heart Association (NYHA) Class III or IV heart failure (APPENDIX D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
For all Registration Exclusion Criteria, see protocol. For a list of Randomization Exclusion Criteria, see protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is RFS. RFS will be measured from time of randomization to either morphological relapse or death, whichever comes first.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time from randomization to either morphological relapse or death, whichever comes first. |
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E.5.2 | Secondary end point(s) |
Safety and tolerability Overall survival (OS) Non-relapse mortality Event-free survival (EFS) Cumulative incidence of acute graft-versus-host disease (GVHD) Cumulative incidence of chronic GVHD Detection of minimal residual disease (MRD) Incidence and Severity of Infection
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and tolerability - measured from randomization through 30 days after end of study drug. OS - measured from randomization to date of death from any cause. Non-relapse mortality - measured from randomization through death. EFS - measured at 12 and 24 months after randomization. Cumulative incidence of acute GVHD - measured from randomization through 6 months after randomization Cumulative incidence of chronic GVHD - measured from randomization through 12 and 24 months after randomization. Detection of MRD - measured from pre-HCT through 24 months after randomization. Infection assessment - measured from randomization through 12 and 24 months after randomization |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 51 |
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 | No |
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 |
New Zealand |
Taiwan |
Australia |
Belgium |
Canada |
Denmark |
France |
Germany |
Greece |
Italy |
Japan |
Korea, Republic of |
Poland |
Spain |
United Kingdom |
United States |
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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
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End of trial is defined as last-patient-last-contact |
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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 | 7 |
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 | 7 |
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 |