E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly diagnosed Acute Myeloid Leukemia patients |
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E.1.1.1 | Medical condition in easily understood language |
Newly diagnosed Acute Myeloid Leukemia patients |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000880 |
E.1.2 | Term | Acute myeloid leukaemia |
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 |
To show superiority in terms of overall survival of treatment with pracinostat versus placebo in patients treated with Azacitidine as background therapy |
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E.2.2 | Secondary objectives of the trial |
• To describe the efficacy of pracinostat evaluating additional efficacy variables
• To assess the safety and tolerability
• To evaluate the pharmacokinetics of pracinostat and its main metabolites
• To assess the possible drug interaction of Pracinostat on the PK of Azacitidine
• To perform a health-economic evaluation of treatment and control group |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Assessment of the possible drug interaction of pracinostat on the PK of Azacitidine |
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E.3 | Principal inclusion criteria |
1. Male or female patient ≥ 18 years of age with newly diagnosed, histologically or cytologically confirmed, AML including de novo, secondary to antecedent hematologic disorders, or treatment-related disease with intermediate or unfavorable-risk cytogenetics
2. Unable to receive intensive chemotherapy regimens at enrollment, based on one of the following:
I. Age ≥ 75 years, or
II. Age < 75 years with at least 1 of the following co-morbidities:
a. An ECOG performance status of 2
b. Clinically significant cardiovascular disease defined as:
i. Left ventricular ejection fraction (LVEF) ≤ 50%, measured within 3 months prior to Day 1 confirmed by ECHO/MUGA
ii. Congestive heart failure requiring medical therapy
iii. Chronic stable angina requiring medical therapy
iv. Prior cerebrovascular accident with sequelae
c. Clinically significant pulmonary disease defined as:
i. Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected
ii. Lung diffusing capacity for carbon monoxide (DLCO) ≤ 65% of expected
Confirmed by pulmonary tests within 3months prior to Day1.
d. Diabetes mellitus with symptomatic end-organ damage (e.g., retinopathy, nephropathy, neuropathy, vasculopathy)
e. Autoimmune inflammatory conditions (e.g., rheumatoid arthritis, systemic lupus erythematous, inflammatory bowel disease, or similar) requiring chronic disease modifying therapy (e.g., etanercept, adalimumab, infliximab, rituximab, methotrexate, or similar)
f. Class III obesity defined as a Body Mass Index (BMI) > 40 kg/m2
g. Renal impairment defined as serum creatinine > 1.3 mg/dL (> 115 µmol/L) or creatinine clearance <70 ml/min, but still fulfilling criterion #7
3. > or equal than 20% blasts in bone marrow
4. Peripheral white blood cell (WBC) count 30,000/µL
For cyto-reduction, hydroxyurea is allowed during screening and up to Cycle 1, Days 1-14, to reduce WBC count to < 30,000 µL prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited.
5. ECOG performance status ≤ 2
6. Adequate organ function as evidenced by the following laboratory findings:
a. Total bilirubin ≤ 2 × upper limit of normal (ULN) or < 3 x ULN for patients with Gilbert-Meulengracht Syndrome
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
7. Serum creatinine ≤ 1.5 × ULN according to institutional standards or creatinine clearance ≥ 50 mL/min
8. QT-interval corrected according to Fridericia’s formula (QTcF) ≤ 450 ms on electrocardiogram (ECG) at Screening
9. Male patient who is surgically sterile, or male patient who is willing to agree with the true abstinence (refrain from heterosexual intercourse) or who uses barrier contraceptive measures during the entire study treatment period and for 3 months after the last administration of study drug, and agree to refrain from donating sperm during the entire study treatment period and for 3 month after the last administration of study drug
10. Female patient who is of childbearing potential willing to use a highly effective contraceptive measure while participating on study, OR willing to agree with the true abstinence from heterosexual intercourse during the entire study treatment period and for 3 months after the last administration of study drug
11. Female patient who is of childbearing potential must have a negative serum pregnancy test result within 1 week prior to starting study drugs.
12. Willing to provide voluntary written informed consent before
performance of any study related procedure not part of normal medical care
13. Willing and able to understand the nature of this study and to comply with the study and follow-up procedures. |
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E.4 | Principal exclusion criteria |
1. Able to receive intensive induction chemotherapy
2. AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e. promyelocytic leukemia) with/without secondary aberrations; t(8;21) lacking del (9q) or lacking complex karyotypes
3. Presence of an active malignant disease within the last 12 months, with the exception of adequately treated cervical cancer in-situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]). Other malignancies may be considered after consultation with the Medical Monitor
4. Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction that, in the Investigator’s opinion, could compromise the patient’s safety or put the study outcomes at risk
5. Uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York Heart Association (NYHA) functional classification (Appendix E)
6. Evidence of AML central nervous system (CNS) involvement
7. Previous therapy for AML except for the following, which are allowed:
a. Hydroxyurea for cytoreduction
b. One course of hypomethylating agent therapy (i.e.; up to 7 doses of azacitidine or 3-5 days of decitabine) within 30 days prior to enrollment (Day 1)
8. Use of experimental drugs ≤ 30 days prior to screening
9. Received any prior HDAC inhibitor therapy
10. Received prior treatment with a hypomethylating agent, except as allowed in Exclusion Criterion 7.b
11. Known hypersensitivity to any components of pracinostat, azacitidine, or mannitol
12. Human immunodeficiency virus (HIV) infection or an active and uncontrolled infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
13. Gastrointestinal (GI) tract disease that causes an inability to take oral medication, malabsorption syndrome, or a requirement for IV alimentation; prior surgical procedures affecting absorption; or uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis)
14. Any disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition, that contraindicates the use of pracinostat and/or AZA, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the patient inappropriate for this study
15. Breast-feeding woman.
16. Current smokers (uUse of patches, chewing gums or vaping nicotine containing fluids is permitted). Patients who stopped smoking at least 8 days prior to first pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study.)
17. Prohibited concomitant medications
18. Uncontrolled infections
19. Received more than 1 prior cycle of HMA or bone marrow transplant for any prior hematological disorder antecedent to AML. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the overall survival measured as the time from randomization until death from any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of the study as defined in the protocol |
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E.5.2 | Secondary end point(s) |
1 - Morphologic Complete Remission rate
2 - Cytogenetic Complete Remission (CRc) rate
3 - Complete Remission without minimal residual disease (CRmMRD-)
rate
4- Transfusion independence |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of the study as defined in the protocol |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Argentina |
Australia |
Austria |
Brazil |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Peru |
Poland |
Romania |
Spain |
Taiwan |
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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The end of the trial is defined when 390 events (deaths) have occurred |
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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 | 5 |
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 | 5 |
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 |