| 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] - Cancer [C04] |
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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:
•Composite 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 FLT3-ITD mutation
• For all patients with detectable FLT3-ITD mutation, cCorrelation of remission with FLT3-ITD allelic ratio and other parameters using other assays
• For all patients, summaries of non-ITD mutations identified, the percent mutant allelic ratio (normalized for blasts), and correlational analyses.
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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. Patients must also meet the
following criteria:
•≥ 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
•Must provide a sample for determination of FLT3-ITD mutation status as outlined in Section 10.6.1.
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. 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 ULN (upper limit of normal) and glomerular filtration rate (GFR) > 30 mL/min (calculated by Cockcroft and Gault formula, Appendix 6).
11. Serum potassium, magnesium, and calcium levels (corrected serum calcium values for hypoalbunemia should be used) 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 (corrected serum calcium values for hypoalbunemia are acceptable) 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. 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)
5. AML or antecedent MDS secondary to prior chemotherapy
6. Persistent clinically significant nonhematological toxicity that is Grade > 1 by NCI CTCAE v4 from prior chemotherapy
7. 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.
8. Clinically active CNS leukemia. If CNS leukemia is controlled and patients are receiving IT therapy at study entry, patients may be considered eligible at the discretion of the Investigator and with agreement of the Sponsor. Patients should continue to receive IT therapy as clinically indicated.
9. Patients who have previously received AC220
10. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)
11. Major surgery within 4 weeks prior to enrollment in the study
12. Radiation therapy within 4 weeks prior to, or concurrent with, study
13. 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).
14. 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
15. 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
16. Women who are pregnant or breastfeeding
17. WOCBP with a positive pregnancy test
18. 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
19. Active uncontrolled infection
20. Known infection with human immunodeficiency virus (HIV)
21. Known active hepatitis B or C or other active liver disease
22. 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
23. 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) |
Efficacy will be primarily evaluated by the confirmed CR and CRc rate (CR + CRp + CRi), duration of remission, DFS, TTR, and OS. Response will be assessed per Cheson criteria [ref], which will be modified for assessment of CRi as indicated in Section.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Bone marrow aspirates and/or biopsies (both bone marrow aspirates and biopsies are preferred, but biopsies may be omitted at the discretion of the Investigator if an adequate aspirate is obtained) are required at Screening (within 14 days prior to first dose of AC220), Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1 (unless the patient has already achieved a complete remission [CR, CRp, or CRi], in which case bone marrow aspirate and/or biopsy will be repeated after every 3 subsequent cycles), and at the Early Termination/End of Study Visit, and as clinically indicated per the conditions mentioned below. These samples will be evaluated as specified in the protocol for assessment of remission.
•Best Response |
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| E.5.2 | Secondary end point(s) |
•Duration of remission, DFS, TTR, and OS
•Hematological improvement will also be assessed as well as impact of treatment with AC220 on blood and platelet transfusions, infections, days of hospitalization (including days in intensive care), performance status (ECOG scale), providing a “bridge to transplant,” and duration of leukemia/disease control.
•Pharmacogenetic analysis of FLT3-ITD mutation |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Duration of Remission: Time from first fully documented remission until documented relapse. Every effort must be made to capture subsequent antileukemic therapies (if any) and outcomes, which will be documented in the CRF.
•Disease Free Survival (DFS): Same as duration of remission not censored at death.
•Time to Treatment Response (TTR): Time from the first dose of AC220 (Cycle 1 Day 1) until the first measured response (CR, CRp, CRi, or PR). Time to best response will also be assessed, and is the time from the first dose of AC220 (Cycle 1 Day 1) until best response.
•Overall Survival (OS): Time from patient’s first dose of study drug until death. |
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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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 4 |
| 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 | 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 |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| United States |
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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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| Last visit of the last subject |
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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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