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. |
|
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 versus
placebo (administered with standard induction and consolidation
chemotherapy, then administered as continuation therapy for up to 36
cycles) on the primary endpoint of overall survival (OS) in subjects with
newly diagnosed AML with FLT3-ITD mutations. |
|
E.2.2 | Secondary objectives of the trial |
• Compare the following in subjects treated with quizartinib versus
placebo (administered with standard induction and consolidation
chemotherapy, then administered as continuation therapy for up to 36
cycles):
-Event-free survival (EFS)
-Composite complete remission rate (CRc = CR + CR with incomplete
neutrophil or platelet recovery [CRi]) after Induction;
-Percentage of subjects achieving CRc with FLT3-ITD minimal or
measurable residual disease (MRD) negativity after Induction;
-Complete remission (CR) rate after Induction;
-Percentage of subjects achieving CR with FLT3-ITD MRD negativity after
Induction.
• Further characterize the safety profile of quizartinib administered
with standard induction and consolidation chemotherapy, then
administered as continuation therapy for up to 36 cycles.
• Assess the pharmacokinetics (PK) of quizartinib and its metabolite
(AC886). |
|
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 greater) and
≤75 years (at Screening);
3. Newly diagnosed, morphologically documented primary AML or AML secondary to myelodysplastic syndrome or a myeloproliferative neoplasm 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. Creatinine clearance rate >50 mL/min, as calculated with the modified Cockcroft Gault equation;
8. Adequate hepatic function defined as:
a. Total serum bilirubin ≤1.5 × ULN unless the subject has documented Gilbert`s syndrome or the increase is related to increased unconjugated (indirect) bilirubin due to hemolysis;
b. Serum alkaline phosphatase, aspartate transaminase and alanine transaminase ≤2.5 × ULN;
9. Serum electrolytes within the institution`s normal limits: potassium, calcium (total calcium, calcium corrected for serum albumin in case of hypoalbuminemia, or ionized calcium) and
magnesium. If outside of the institution`s normal range, subject will be eligible when
electrolytes are corrected;
10. If a woman of childbearing potential, must have a negative serum
pregnancy test upon entry into this study and must be willing to use
highly effective birth control upon enrollment, during the treatment
period and for 6 months following the last dose of investigational drug or cytarabine, whichever is later. A woman is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy);
11. If male, must be surgically sterile or willing to use highly effective
birth control upon enrollment, during the treatment period, and for 6
months following the last dose of investigational drug or cytarabine,
whichever is later.
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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); subjects who undergo diagnostic workup for APL and treatment with all-trans retinoic acid (ATRA), but who are found not to have APL, are eligible (treatment with ATRA must be discontinued before starting induction chemotherapy).
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 (within 2 weeks for investigational or approved immunotherapy) or 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 nonmelanoma 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. Left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal per multi-gated acquisition scan (MUGA) or echocardiogram done within 30 days prior to randomization;
j. Complete left 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; |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is OS.
Overall survival is defined as the time from randomization until death
from any cause. |
|
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 or CRi;
- Death from any cause at any time during the study. |
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E.5.2 | Secondary end point(s) |
Event-free survival is defined as the time from Randomization until
the date of the earliest of any of the following:
Secondary efficacy endpoints (ie, secondary outcome measures) are:
-Refractory disease (or treatment failure) which is determined at the
end of the Induction Phase;
-Relapse after CR or CRi;
-Death from any cause at any time during the study.
• Composite complete remission rate which is the percentage of
subjects achieving CR or CRi after Induction;
• Percentage of subjects achieving CRc with FLT3-ITD MRD negativity
below a certain cutoff after Induction. Minimal or measurable residual
disease is the presence of a small number of leukemic cells in the bone
marrow of patients with AML below the level of detection using
conventional morphologic assessment. The FLT3-ITD MRD assay by Next
Generation Sequencing will be used to detect and quantify residual FLT3-
ITD mutations.
• Complete remission rate, which is the percentage of subjects
achieving CR after Induction;
• Percentage of subjects achieving CR with FLT3-ITD MRD negativity
following induction therapy. |
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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 |
|
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 135 |
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
|
Overall End of Study will occur when:
• all subjects have discontinued treatment and discontinued long-term survival follow-up or have died;
• an alternative study becomes available, for subjects continuing to derive benefit from treatment with quizartinib, where the study drug is offered to these subjects;
• the study is discontinued by the Sponsor for other reasons (administrative, program level or class-related);
The subject`s EOS is the date of their last study visit/ contact |
|
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 |