| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Newly diagnosed de novo Acute Myeloid Leukemia (AML) or AML secondary to prior myelodysplastic
disease in older subjects with >30% bone marrow blasts and who are not eligible for hematopoietic stem cell transplantation. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute myeloid leukemia, a quickly progressive malignant disease in which there are too many immature blood-forming cells in the blood and bone marrow. |
|
| 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 | 18.0 |
| 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 demonstrate superiority in overall survival (OS) of azacitidine compared with the combined conventional care regimens in subjects ≥ 65 years old who have newly diagnosed AML with > 30% bone marrow blasts. |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the one-year OS rate in the azacitidine treatment arm compared with the combined conventional care regimens
- To determine the effect of azacitidine compared with the combined conventional care regimens on event-free survival
- To determine the effect of azacitidine compared with the combined conventional care regimens on relapse-free survival
- To determine the effect of azacitidine compared with the combined conventional care regimens on overall remission rate (CR + morphologic complete remission with incomplete blood count recovery) and duration of remission
- To determine the effect of azacitidine compared with the combined conventional care regimens on cytogenetic complete remission rate
- To determine the safety and toxicity of azacitidine relative to the conventional care regimens; and
- To determine the effect of azacitidine compared with the combined conventional care regimens on health-related quality-of-life and healthcare resource utilization. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of one of the following:
- Newly diagnosed, histologically confirmed de novo AML or;
-AML secondary to prior myelodysplastic disease not treated with azacitidine, decitabine, or cytarabine or;
- AML secondary to exposure to potentially leukemogenic therapies or agents (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years;
2. Bone marrow blasts > 30%;
3. Male or female subjects ≥ 65 years of age at the time of signing the informed consent document;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
5. Adequate organ function, defined as:
-Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN);
-Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the ULN;
- Serum creatinine ≤ 1.5 times the ULN;
6. Females of childbearing potential must:
- Agree to the use of a physician-approved contraceptive method (oral, injectable, or
implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier
contraceptive with spermicide; or vasectomized partner) while on azacitidine; and for 3 months following the last dose of azacitidine; and
-Have a negative serum pregnancy test within 72 hours prior to starting study therapy.
7. Male subjects with a female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine;
8. Understand and voluntarily sign an informed consent document prior to any study related
assessments/procedures are conducted;
9. Able to adhere to the study visit schedule and other protocol requirements.
|
|
| E.4 | Principal exclusion criteria |
1. Previous cytotoxic (except hydroxyurea which is allowed up to 2 weeks prior to obtaining the hematology sample) or biologic treatment for AML
2. Previous treatment with azacitidine, decitabine, or cytarabine
3. Prior use of targeted therapy agents (eg, FLT3 inhibitors, other kinase inhibitors)
4. Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology, immunophenotype, molecular assay, or karyotype; or AML with prior hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms;
5. AML associated with inv(16), t(8;21), t(16;16), t(15;17), or t(9;22) karyotypes or molecular evidence of such translocations
6. Prior bone marrow or stem cell transplantation
7. White blood cell (WBC) count > 15 x 10^9/L at screening;
a. Hydroxyurea is not allowed to attain a WBC count ≤ 15 x 10^9/L;
8. Proven central nervous system leukemia
9. Inaspirable bone marrow
10. Candidate for allogeneic bone marrow or stem cell transplant
11. Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, “in-situ” carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure)
12. Malignant hepatic tumors
13. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA)
class 3 or 4 congestive heart failure
14. Pregnant or lactating females
15. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment)
16. Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C
17. Known or suspected hypersensitivity to azacitidine or mannitol
18. Use of any other experimental drug or therapy within 28 days prior to Day 1 of Cycle 1
19. Unwilling or unable to complete patient reported outcome assessments without assistance or with minimal assistance from trained site personnel and/or caregiver
20. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
21. Any significant medical condition, laboratory abnormality, or psychiatric illness that would interfere or prevent the subject from participating in the study
22. Any condition that confounds the ability to interpret data from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study is overall survival (time from randomization to death from
any cause). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- One-year overall survival rate;
- Event-free survival (EFS);
- Relapse-free survival (RFS);
- Overall remission rate (CR + CRi);
- Duration of remission (CR + CRi);
- Cytogenetic complete remission rate (CRc);
- Safety / tolerability (type, frequency, severity, and relationship of adverse events to study treatments; physical examinations, vital signs; clinical laboratory evaluations, and concomitant medication/therapy);
- Patient-reported outcomes utilizing the European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30); and
- Measures of healthcare resource utilization. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
One-year overall survival rate [ Time Frame: 31 months ]
Event free survival [ Time Frame: 31 months]
Overall remission rate and duration of remission [Time Frame: 31 months]
Cytogenetic complete remission rate [ Time Frame: 31 months]
Safety and tolerability [ Time Frame: 31 months ]
Patient reported outcomes of QoL [ Time Frame: 31 months ]
Healthcare resource utilization [ Time Frame: 31 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | 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 | 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Austria |
| Belgium |
| Canada |
| China |
| Czech Republic |
| France |
| Germany |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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