| 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 | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
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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 |
Determination of:
•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 |
Determination of:
•Duration and rates of remission
•Disease-free survival (DFS)
•Overall survival (OS) and treatment related mortality
•Time to treatment (TTR)
•Safety and tolerability with emphasis on ECG changes
•Pharmacokinetic (PK) and pharmacodynamic (PD) parameters
•Impact of AC220 treatment on hematological parameters, improvement 'bridging patients to transplant', disease control, blood and platelet transfusions, infections, days in hospital, performance status (ECOG scale)
• Pharmacogenetic analysis of FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) ie, FLT3-ITD
• Correlation of remission with FLT3-ITD allelic ratio and other parameters using other assays
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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, as determined by pathology review at the treating institution, and confirmed later by the Sponsor-designated 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. Patients with previously known or currently locally determined FLT3-ITD activating mutations prior to study entry, may be considered positive for FLT3-ITD activating mutation for eligibility prior to central laboratory confirmation of such a mutation at the discretion of the Investigator and with the agreement of the Sponsor. (Appropriate blood and bone marrow samples must be taken for FLT3-ITD determination and shipped to the Sponsor-designated laboratory prior to study entry.) However, if such a mutation is not confirmed by the central laboratory, the patient may be permitted to stay on the study if they wish and consent to do so but such patients’ data will be analyzed separately.
6. ECOG performance status of 0 to 2
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. The use of chemotherapeutic or antileukemic agents other than hydroxyurea (as defined in the protocol) is not permitted during the study with the possible exception of intrathecal (IT) therapy for patients with CNS leukemia in remission at the discretion of the Investigator and with the agreement of the Sponsor.
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 x ULN (upper limit of normal)
11. Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits, and every effort should be made to keep potassium concentrations above 4.0 mEq/dL, magnesium concentrations above 1.8 mg/dL, and serum calcium at normal concentration with the administration of oral/IV potassium and/or magnesium and/or calcium replacement during the study. If this is not possible, potassium and magnesium (and calcium) concentrations should at least be kept within institutional normal limits.
12. Total serum bilirubin ≤ 1.5 x ULN (upper limit of normal)
13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5 x 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 in such a manner that the risk of pregnancy is minimized. WOCBP includes any female that has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not post menopausal (defined as amenorrhea >12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level >35 mIU/mL). Additionally, women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or are practicing abstinence or where the partner is sterile (eg, vasectomy), should be considered to be of childbearing potential.
16. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 72 hours prior to the start of study drug.
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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. Donor lymphocyte infusion (DLI) is not permitted during the study or 30 days prior to study entry.
9. Clinically active CNS leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving IT therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor.
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, but only if clinically indicated and must be fully documented in the CRF (recommended washout of 5 half-lives prior to patient’s first dose with AC220).
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, unless an echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA) performed either within 1 month prior to study screening or during screening results in a left ventricular ejection fraction (LVEF) that is ≥ 45% (or institutional lower limit of normal value).
• 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 if their sexual partners are WOCBP for the entire study period and for at least 3 months after completion of the study
20. Active uncontrolled infection
21. Known infection with human immunodeficiency virus (HIV)
22. Known active hepatitis B or C or other active liver disease
23. Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the judgment of the Principal Investigator, could jeopardize patient safety or interfere with the objectives of the study
24. History of cancer, except treated Stage 1 cervix or nonmelanotic skin cancer and with the possible exception of patients in complete remission at the discretion of the Investigator, and with agreement of the Sponsor.
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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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 17 |
| 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 | 2 |
| 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 | 2 |
| 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 |
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