E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the White Blood Cells |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
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 objectives are to evaluate the rate of Grade 2 or higher QTcF prolongation and to
evaluate the composite complete remission rate (CRc), defined as the confirmed rate of
complete remission (CR) plus complete remission with incomplete platelet recovery (CRp) or
incomplete hematological recovery (CRi) at different doses of AC220. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are the following for AC220:
Characterize the pharmacokinetics (PK) of AC220 and the active metabolite AC886
Evaluate the electrocardiogram (ECG) effects of AC220 in relation to plasma drug
concentration
Evaluate the CR rate, overall survival (OS), event-free survival (EFS), leukemia-free
survival (LFS), and duration of remission
Assess overall safety
Exploratory objectives are the following for AC220:
Evaluate the pharmacodynamic (PD) effect of AC220
Evaluate the mechanism of acquired resistance to AC220
Evaluate PK-PD relationships |
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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 |
There will be an optional sub-study as described in Appendix 10, Final Protocol 19Dec 2011, page 90.
The pharmacogenomic research that will be conducted in the future with acquired blood samples is exploratory. The objective of this research is to comprehensively analyze:
• Genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, to be identified in a precautionary/retrospective setting
By analyzing differing genetic polymorphisms, it may be possible to predict genetic influence on an individual subject’s response to ASP2689 [AC220] in terms of efficacy and/or toxicity.
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E.3 | Principal inclusion criteria |
1. Subject has provided an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved signed Informed Consent and privacy disclosure as per national regulations (e.g., HIPAA Authorization for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Subject is male or female ≥ 18 years of age.
3. Subject has morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS) as defined by the World Health Organization (WHO) criteria, as determined by pathology review at the treating institution and has relapsed or is refractory after 1 second line (salvage) regimen or after HSCT (Appendix 8).
4. Subject is positive for FLT3-ITD activating mutation in bone marrow or peripheral blood (>10% allelic ratio as determined by central lab).
5. ECOG performance status of 0 to 2 (Table 4).
6. In the absence of rapidly progressing disease clearly documented by the investigator, the interval from prior treatment to time of AC220 administration will be at least 2 weeks (14 days) for prior cytotoxic agents or at least 5 half-lives for prior noncytotoxic agents, including immunosuppressive therapy post HSCT.
7. Persistent chronic clinically significant nonhematological toxicities from prior treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, HSCT, or surgery) must be Grade ≤ 1.
8. Patients - both males and females - with reproductive potential are eligible if the following criteria is met:
female subject is:
- post-menopausal (defined as at least 2 years without menses) prior to Screening visit; or
- surgically sterile (at leats 1 month) prior to Srceening visit; or
- childbearing potential without contraception
female subject of childbearing potential has negative pregnancy test at Screening visit and agrees to use contraception consisting of two forms of birth control (one of which must be a barrier method) throughout the study period
male subject with partner(s) of childbearing potential must agree to use contraception consisting of two forms of birth control (one of which must be a barrier method) and agrees to no sperm donation throughout the study period
9. Subject must have adequate renal, hepatic, and coagulation parameters as indicated by the following laboratory values:
Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit of normal (ULN)
Total bilirubin ≤ 1.5 x institutional ULN
Serum creatinine ≤ 1.5 x institutional ULN and glomerular filtration rate (GFR) > 30mL/min (calculated by Cockcroft and Gault formula, Appendix 9).
10. Subject is able to comply with study procedures and follow-up examinations. |
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E.4 | Principal exclusion criteria |
1. Subject received previous treatment with AC220.
2. Subject has a diagnosis of acute promyelocytic leukemia.
3. Subject has a diagnosis of chronic myelogenous leukemia (CML) in blast crisis.
4. Subject has AML or antecedent MDS secondary to prior chemotherapy.
5. Subject has had HSCT and has either of the following:
Is within 100 days of transplant
Is still taking immunosuppressive drugs
Has clinically significant graft-versus-host disease requiring treatment
Has Grade > 1 persistent nonhematological toxicity related to the transplant.
Donor lymphocyte infusion (DLI) is not permitted during the study or < 30 days prior to study entry.
6. Subject has clinically active CNS leukemia. If CNS leukemia is controlled and subject is receiving intrathecal (IT) therapy at study entry, subjects may be considered eligible at the discretion of the Investigator and with agreement of the Sponsor. Subjects should continue to receive IT therapy as clinically indicated.
7. Subject has received concurrent chemotherapy, immunotherapy, or radiotherapy within 14 days prior to the first dose of AC220, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
8. Subject requires treatment with concomitant drugs that prolong QT/QTc interval or with strong inhibitors or inducers of cytochrome P450-isozyme3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care posttransplant or to prevent or treat infections and other such drugs that are considered
absolutely essential for the care of the subject. (See Appendix 1)
9. Subject requires treatment with anticoagulant therapy.
10. Subject has a known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen.
11. Subject had major surgery within 4 weeks prior to first dose of AC220.
12. Subject has uncontrolled or significant cardiovascular disease,
including
A myocardial infarction within 12 months prior to the start of study drug;
Uncontrolled angina within 6 months prior to the start of study drug;
History of congestive heart failure (CHF) New York Heart Association (NYHA) class 3 or 4, if a screening echocardiogram (ECHO) or Multiple Gate Acquisition Scan (MUGA) is performed either within 1 month prior to or during study screening and the result is a left ventricular ejection fraction (LVEF) that is ≥ 45% (or institutional lower limit of normal value); then this is not exclusionary
Heart rate < 50 beats per minute at Screening ECG;
Diagnosed or suspected congenital long QT syndrome;
Known family history of congenital long QT syndrome;
QTc interval calculated by Fridericia's correction factor (QTcF) at
Screening and Day 1 (before AC220 dose) ≥ 450 ms. The QTcF will be derived from the average QTcF in triplicate;
Any history of second or third degree heart block;
Uncontrolled hypertension defined as systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg;
Obligate need for a cardiac pacemaker or defibrillator;
Complete left bundle branch block;
Atrial fibrillation documented within 2 weeks prior to first dose of
study drug; or
History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia) that was symptomatic or required treatment (CTCAE Grade 3).
13. Subject has a pre-existing disorder predisposing the subject to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder or cytopenias not related to AML).
14. Subject has an active uncontrolled acute or chronic systemic fungal, bacterial, viral or other infection.
15. Subject has any of the following laboratory values:
Serum potassium < 4.0 mmol/L despite supplementation, or > 5.5 mmol/L.
Serum magnesium below the institutional normal limit despite supplementation, or > 3 mg/dL (1.23 mmol/L).
Serum calcium >11.5 mg/dL (2.9 mmol/L) or ionized calcium >1.5 mmol/L.
16. Subject is a female with a positive pregnancy test, pregnant, or breastfeeding.
17. Subject has any medical, psychiatric, addictive or other kind of disorder which compromises the ability of the subject to give written informed consent and/or to comply with procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy variable is the rate of composite complete response (CRc).
Definition of CRc:
Composite Complete Remission Rate (CRc): Defined as the confirmed remission rate of all
complete and incomplete CRs (i.e., CR + CRp + CRi).
Complete Remission (CR): For subjects to be classified as being in CR, they must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an absolute neutrophil count (ANC) > 1x10e9/L and platelet count > 100 x 10e9/L, and normal marrow differential with < 5% blasts, and they
will be red blood cell (RBC) and platelet transfusion independent (defined as 4 weeks without RBC transfusions and 1 weeks without platelet transfusion). There should be no evidence of extramedullary leukemia.
Complete Remission with Incomplete Platelet Recovery (CRp): For subjects to be classified as being in CRp, they must achieve CR except for incomplete platelet recovery (< 100 x10e9/L).
Complete Remission with Incomplete Hematologic Recovery (CRi): For subjects to be classified as being in CRi, they must achieve CR except for incomplete hematological recovery with residual neutropenia <1 x 10e9/L with or without complete platelet recovery.
RBC and platelet transfusion independence is not required.
Primary safety variable is the rate of Grade 2 or higher QTcF prolongation.
Definition of QTcF prolongation, Grade ≥ 2 ECGs will be recorded in triplicate (3 separate 12-lead ECGs at least 5 minutes apart per time
point) and the Fridericia’s correction of the QT interval (QTcF) will be calculated based on the average of all the ECGs obtained around that time point.
QTcF grading will be done according to CTCAE v. 4.03, and the definition of greater than Grade 2 prolongation is QTcF ≥ 480 ms.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
These end points will be evaluated at the end of the study |
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E.5.2 | Secondary end point(s) |
Secondary safety variables are:
Adverse Events (AEs)
Serum chemistry, hematology, and urinalysis
Vital sign measurements
ECGs
ECOG performance scores
Secondary efficacy variables are:
Complete remission (CR)
Overall survival (OS)
Event free survival (EFS)
Leukemia free survival (LFS)
Duration of remission
Pharmacokinetics
Subjects with sufficient PK samples on Cycle1 Day 1 and Cycle 1 Day 15, NCA will be
performed for to obtain PK parameter estimates for AC220 and AC886 PK parameters
including AUC24, Cmax, Ctrough and tmax
Population PK of AC220 and its active metabolite (AC866)
Pharmacogenetics
FLT3-ITD status and allelic ratio will be measured.
Mutations in the JM and TK domains of FLT3, FLT3-ITD and C-KIT sequences will be
determined using bone marrow or whole blood samples.
Exploratory Variables
Inhibition of phosphorylation of FLT3 and STAT5 will be determined using whole blood
samples. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These end points will be evaluated at the end of the study |
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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 | No |
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 | Yes |
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 |
The pharmacogenomic assessment will be made. This is an optional sub-study. Appendix 10, Final protocol 19Dec2011, page 90. |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 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 | 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 | No |
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 end of the trial will be the last visit of the last subject undergoing the trial (after long-term follow-up phase). |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |