E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000880 |
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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 |
Overall complete remission rate, defined as the confirmed rate of complete remission (CR) plus complete remission with incomplete platelet (CRp) or incomplete hematological recovery (CRi) (ie, CR + CRp + CRi) Complete remission rate, defined as the confirmed rate of CR |
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E.2.2 | Secondary objectives of the trial |
Duration of remission. All patients will be followed until relapse and death. Every effort must be made to capture subsequent antileukemic therapies [if any] and outcomes, which will be documented in the case report form (CRF). Remission rates for all categories of remission, including: CR, CRp, CRi, partial remission (PR), CR + CRp, and CR + CRp + CRi + PR Disease-free survival (DFS) Overall survival (OS) Treatment induction and post induction treatment-related mortality Time to treatment response (TTR) Safety and tolerability with emphasis on electrocardiogram (ECG) changes Pharmacokinetic (PK) and pharmacodynamic (PD) parameters of orally administered AC220 and its active metabolite (AC886) under the conditions of this study Impact of AC220 treatment on: o Hematological improvement o Bridge to transplant ie, patients for whom treatment with AC220 enabled them to become eligible for allogeneic hematopoietic stem cell transplant (HSCT) o Duration of |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females age ≥ 18 years 2. Understand and voluntarily sign the informed consent form for this study 3. Available for periodic follow-up at the investigative site 4. Able to swallow the liquid study drug 5. Morphologically documented primary AML or AML secondary to myelodsyplastic syndrome (MDS) as defined by the World Health Organization (WHO) criteria, central laboratory and must be: ≥ 60 years of age who are relapsed after 1 first-line chemotherapy regimen (with or without consolidation) and after first complete remission (CR1) < 12 months or are primary refractory to first-line chemotherapy, or ≥ 18 years of age who are relapsed or refractory after 1 second line (salvage) regimen or relapsed or refractory after HSCT Positive for FLT3-ITD activating mutation determined during current disease by the Sponsor-designated central laboratory using predefined criteria prior to study entry. 6. ECOG performance status of 0 to 2 (Appendix 4) 7. In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents, including immunosuppressive therapy post HSCT. 8. Persistent chronic clinically significant nonhematological toxicities from prior treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, HSCT, or surgery) must be Grade ≤ 1. 9. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220. 10. Serum creatinine ≤ 1.5  ULN (upper limit of normal) 11. Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits. 12. Total serum bilirubin ≤ 1.5  ULN (upper limit of normal) 13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5  ULN 14. Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). 15. WOCBP must be using an adequate and medically accepted method of contraception to avoid pregnancy throughout the study and for at least 3 months after the study |
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E.4 | Principal exclusion criteria |
1. Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor 2. Diagnosis of acute promyelocytic leukemia 3. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis 4. Do not have FLT3-ITD activating mutation 5. AML in relapse or refractory after 3 or more previous lines of chemotherapy treatment (ie, first-line chemotherapy with or without consolidation [first line], first salvage [second line], and second salvage [third line] or subsequent regimens) 6. AML or antecedent MDS secondary to prior chemotherapy 7. Persistent clinically significant nonhematological toxicity that is Grade > 1 by NCI CTCAE v4 from prior chemotherapy 8. Patients who have had HSCT and are within 100 days of transplant and/or are still taking immunosuppressive drugs and/or have clinically significant graft-versus-host disease requiring treatment and/or have Grade > 1 persistent nonhematological toxicity related to the transplant. 9. Clinically active CNS leukemia. 10. Patients who have previously received AC220 11. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment) 12. Major surgery within 4 weeks prior to enrollment in the study 13. Radiation therapy within 4 weeks prior to, or concurrent with, study 14. Use of concomitant drugs that prolong QT/QTc interval or are CYP3A4 inhibitors are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient, 15. Uncontrolled or significant cardiovascular disease, including : A myocardial infarction within 12 months Uncontrolled angina within 6 months Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, Diagnosed or suspected congenital long QT syndrome Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Sponsor s Medical Monitor prior to patient s entry into the study. Prolonged QTcF interval on pre-entry ECG (≥450 ms) Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker) Heart rate < 50/minute on pre-entry ECG Uncontrolled hypertension Obligate need for a cardiac pacemaker Complete left bundle branch block Atrial fibrillation 16. WOCBP who are unwilling or unable to use an acceptable contraceptive method to avoid pregnancy for the entire study period and for at least 3 months after the study 17. Women who are pregnant or breastfeeding 18. WOCBP with a positive pregnancy test 19. Men who are unwilling or unable to use an acceptable method of birth control 20. Active uncontrolled infection 21. Known infection with human immunodeficiency virus (HIV) 22. Known active hepatitis B or C or other active liver disease |
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E.5 End points |
E.5.1 | Primary end point(s) |
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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 | 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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 67 |
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 | Information not present in EudraCT |
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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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 | 11 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |