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) (+) acute myeloid leukemia (AML) |
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E.1.1.1 | Medical condition in easily understood language |
Acute Myeloid Leukemia (AML) a cancer of the blood. |
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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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare the effect of quizartinib vs placebo (administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 12 cycles) on event-free survival (EFS) in subjects with newly diagnosed FLT3-ITD (+) AML. |
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E.2.2 | Secondary objectives of the trial |
To compare the following in subjects treated with quizartinib vs placebo (administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 12 cycles):
• Overall survival (OS);
• Complete remission (CR) rate;
• Composite complete remission rate (CRc = CR + CRp [Complete Remission with Incomplete Platelet Recovery] + CRi [Complete Remission with Incomplete Neutrophil Recovery]);
• Percentage of subjects achieving CR with no evidence of Minimal Residual Disease (MRD) following induction therapy.
Other Secondary Objectives:
To further characterize the safety profile of quizartinib administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 12 cycles.
To assess the pharmacokinetics (PK) of quizartinib and its metabolite (AC886).
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Up to 100 subjects will have intense pharmacokinetic (PK) sampling for plasma quizartinib (AC220) concentrations and its metabolite (AC886) at Cycle 1 during the Induction phase on Day 8, Day 15, and Day 21, within 10 minutes after the ECG is performed. This will be referred as the “PK-ECG-Biomarker Substudy”.
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E.3 | Principal inclusion criteria |
1. Must be competent and able to comprehend, sign, and date an Ethics Committee or Institutional Review Board approved Informed Consent Form (ICF) before performance of any study-specific procedures or tests;
2. ≥18 years or the minimum legal adult age (whichever is gre
ater) and ≤75 years (at Screening);
3. Newly diagnosed, morphologically documented primary AML or AML secondary to myelodysplastic syndrome, based on the World Health Organization (WHO) 2008 classification (at Screening);
4. Eastern Cooperative Oncology Group performance status 0-2 (at Screening);
5. Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio of ≥3% FLT3-ITD/total FLT3);
6. Subject is receiving standard "7+3" induction chemotherapy regimen as specified in the protocol;
7. Adequate renal function defined as:
a. Serum creatinine ≤1.5 × the upper limit of normal (ULN); or
b. Glomerular filtration rate >50 mL/min/1.73m2, as calculated with the modified Cockcroft Gault equation;
8. Adequate hepatic function defined as:
a.Total serum bilirubin ≤1.5 × ULN;
b.Serum alkaline phosphatase, aspartate transaminase and alanine transaminase ≤2.5 × ULN;
9. Serum electrolytes (potassium, calcium, and magnesium) within normal limits. If outside of normal limits, subject will be eligible when electrolytes are corrected;
10. If female, must be either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or if of childbearing potential, must have a negative serum pregnancy test upon entry into this study and must be willing to use maximally effective double-barrier birth control during the period of therapy and contraception for 3 months following the last investigational drug dose;
11. If male, must be surgically sterile or willing to use an effective double-barrier contraception method upon enrollment, during the course of the study, and for 3 months following the last investigational drug dose.
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E.4 | Principal exclusion criteria |
1. Diagnosis of acute promyelocytic leukemia (APL), French-American-British classification M3 or WHO classification of APL with translocation, t(15;17)(q22;q12), or BCR-ABL positive leukemia (ie, chronic myelogenous leukemia in blast crisis);
2. Diagnosis of AML secondary to prior chemotherapy or radiotherapy for other neoplasms;
3. Prior treatment for AML, except for the following allowances:
a. Leukapheresis;
b. Treatment for hyperleukocytosis with hydroxyurea;
c. Cranial radiotherapy for central nervous system (CNS) leukostasis;
d. Prophylactic intrathecal chemotherapy;
e. Growth factor/cytokine support;
4. Prior treatment with quizartinib or other FLT3-ITD inhibitors;
5. Prior treatment with any investigational drug or device within 30 days prior to Randomization or who are currently participating in other investigational procedures;
6. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts; lumbar puncture is recommended for subjects with symptoms of CNS leukemia to rule out extramedullary CNS involvement;
7. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for at least 2 years;
8. Uncontrolled or significant cardiovascular disease, including any of the following:
a. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
b. QTcF interval >450 msec;
c. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
d. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
e. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);
f. History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker);
g. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;
h. History of New York Heart Association Class 3 or 4 heart failure;
i. Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal;
j. History of complete left or complete right bundle branch block;
9. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy;
10. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
11. Known history of human immunodeficiency virus (HIV). Subjects should be tested for HIV prior to randomization if required by local regulations or EC;
12. History of hypersensitivity to any excipients in the quizartinib/placebo tablets;
13. Females who are pregnant or breastfeeding;
14. Otherwise considered inappropriate for the study by the investigator.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is Event Free Survival in the Intent-to treat (ITT) Analysis Set. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Date of earliest of any of the following:
- Refractory disease (or treatment failure) which is determined at the end of the Induction Phase;
- Relapse after CR, CRp or CRi;
- Death from any cause at any time during the study. |
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E.5.2 | Secondary end point(s) |
1. Overall survival, defined as the time from randomization until death from any cause;
2. Complete remission rate which is the percent of subjects achieving CR after Induction;
3. Composite complete remission rate, which is the percent of subjects achieving CRc after induction;
4. Percent of subjects achieving CR with no evidence of MRD following induction therapy. Minimal residual disease is defined as the presence of leukemic cells in the bone marrow detected above a predefined cut off level by a validated assay in subjects who meet the standard requirements for a CR. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Lost to follow-up
2. Outcome at the end of induction cycle 1 and the induction phase
3. Same as point 2
4. Same as point 2 |
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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 | 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 | 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) | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 |
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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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The study will continue until the target number of EFS events is achieved and at least 14 months have elapsed since completion of enrollment; the end of the trial will be the date of the last subject visit. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |