| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory or Relapsed FLT3-ITD Positive Acute Myeloid Leukemia (AML) |
|
| 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] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 |
|
| 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 of the study is to determine whether quizartinib monotherapy prolongs
overall survival (OS) compared to salvage chemotherapy in subjects with FLT3-ITD positive
AML who are refractory to or have relapsed within 6 months, after first-line AML therapy. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to determine event-free survival (EFS) with quizartinib versus
salvage chemotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) with privacy language in accordance with national regulations (([eg, Health
Insurance Portability and Accountability Act (HIPAA) for US sites]) prior to any study-related procedures, including withdrawal of prohibited medications if applicable.
2. Age ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent.
3. Morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS), as defined by World Health Organization criteria, as determined by pathology review at the study site.
4. In first relapse (with duration of remission of 6 months or less) or refractoryafter prior therapy, with or without HSCT. Induction therapy must have included at least 1 cycle of an anthracycline/mitoxantrone-containing induction block at a standard dose.
• Refractory is defined as:
- After 1 cycle, a reduction in bone marrow blasts of less than 50% and failure to achieve a CR, CRp or CRi.
- After 2 cycles, lack of achievement of CR, CRp, or CRi.
• First relapse (with duration of remission of 6 months or less) is defined as:
- Achievement of CR, CRi, or CRp, as defined by 2003 International Working Group criteria (Section 7.2) after initial AML therapy with or without consolidation or maintenance, and with or without HSCT
- Duration of CR, CRi or CRp is measured from the date of the bone marrow assessment which confirmed response or the date of allogeneic transplantation, to the date of the bone marrow assessment that identified relapse or the appearance of peripheral blasts
5. Presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood (allelic ratio as determined by a central laboratory with a cutoff of ≥3% FLT3 ITD/total FLT3).
6. Eligibility for pre-selected salvage chemotherapy, according to the Investigator’s assessment.
7. ECOG performance score 0-2.
8. Discontinuation of prior AML treatment before the start of study treatment (except hydroxyurea or other treatment to control leukocytosis) for at least 2 weeks for cytotoxic agents, or for at least 5 half-lives for non cytotoxic agents.
9. Serum creatinine ≤1.5×upper limit of normal (ULN), or glomerular filtration rate >25 mL/min, as calculated with the Cockcroft-Gault formula.
10. Serum potassium, magnesium, and calcium (serum calcium corrected for hypoalbuminemia) within institutional normal limits. Subjects with electrolytes outside the normal range will be eligible if these values are corrected upon retesting following any necessary supplementation.
11. Total serum bilirubin ≤1.5×ULN.
12. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5×ULN. |
|
| E.4 | Principal exclusion criteria |
Wording exceeds the limit of 5000 for E4 Exclusion Criteria. Please refer to protocol for full details of exclusion criteria 1 to 21, however, the changes in the Exclusion Criteria for the Protocol Amendment 4.0 have been included below.
4. Persistent, clinically significant > Grade 1 non-hematologic toxicity from prior AML therapy.
5. Clinically significant GVHD or GVHD requiring initiation of treatment or treatment escalation within 21 days, and/or > Grade 1 persistent or clinically significant nonhematologic toxicity related to HSCT.
6. History of, or current, central nervous system involvement with AML.
7. Clinically significant coagulation abnormality, such as disseminated intravascular coagulation.
8. Prior treatment with quizartinib or participated in a prior quizartinib study.
9. Prior treatment with a FLT3 targeted therapy including sorafenib or investigational FLT3 inhibitors (not including the multi-kinase inhibitor, midostaurin).
10. Major surgery within 4 weeks prior to screening.
11. Radiation therapy within 4 weeks prior to screening.
12. Uncontrolled or significant cardiovascular disease, including:
• QT interval corrected using Fridericia's formula (QTcF) interval >450 msec (average of triplicate determinations).
• Subject has bradycardia of less than 50 BPM (as determined by central read) unless the subject has a pacemaker.
• Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome.
• History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or torsade de pointes.
• History of second or third degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers, and have no history of fainting or clinically relevant arrhythmia with pacemakers.
• Myocardial infarction within 6 months prior to screening.
• Uncontrolled angina pectoris within 6 months prior to screening.
• New York Heart Association (NYHA) Class 3 or 4 congestive heart failure.
• Left ventricular ejection fraction (LVEF) ≤45 % or institutional lower limit of normal.
• Uncontrolled hypertension.
• Complete left or right bundle branch block.
13. Active infection not well controlled by antibacterial, antifungal, and/or antiviral therapy.
14. Known infection with human immunodeficiency virus, or active hepatitis B or C, or other active clinically relevant liver disease.
15. Unwillingness to receive infusion of blood products according to the protocol.
16. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability of the man or woman to use a highly effective contraceptive method for the entire study treatment period and for at least 3 months after study treatment completion
• Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and 105 days after the final study drug administration.
17. In a heterosexually active woman of childbearing potential, unwillingness or inability to use a highly effective contraceptive method for the entire study treatment period and for at least 3 months after study treatment completion. Additionally, for women randomized to chemotherapy, unwillingness to adhere to the restrictions respective locally established guidelines and local approved label (prescribing information, Summary of Product Characteristics, or US product insert) from the manufacturer and the Patient Information Leaflet (package insert) as instructed by the Investigator.
• Women are not regarded as of childbearing potential if they are post-menopausal (at least 2 years without menses) or are surgically sterile (at least 1 month before study).
• Highly effective contraception methods include: hormonal methods associated with inhibition of ovulation, intra-uterine device; surgical sterilization (including partner’s vasectomy) or sexual abstinence if this is the preferred and usual lifestyle of the subject.
• Female subjects must not donate or retrieve, for their own use, ova from the time of Screening and throughout the study treatment period, and for 12 weeks after the final study drug administration.
18. Pregnancy.
19. Female subjects must agree not to breastfeed from the time of Screening and throughout the study period, and for 25 days after the final study drug administration.
20. Medical condition, serious intercurrent illness, or other circumstance that, in the Investigator’s judgment, could jeopardize the candidate’s safety as a study subject, or that could interfere with study objectives.
21. For subjects in the UK only: Refusal of permission to allow the subject’s General Practitioner to be notified of their participation in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is overall survival, the time from randomization until death from
any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from enrollment of first subject to the 280th event (death) will be approximately 36 months. |
|
| E.5.2 | Secondary end point(s) |
The secondary variable is event-free survival (EFS), the time from randomization until documented
disease progression/treatment failure, relapse, or death from any cause. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time from enrollment of first subject to the 280th event (death) will be approximately 36 months. |
|
| 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 | No |
| 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 | No |
| 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 | 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 | No |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Italy |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Serbia |
| Singapore |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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