| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myeloid Leukemia (AML) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Leukemia is cancer of the white blood cells. |
|
| 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 | 21.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024330 |
| E.1.2 | Term | Leukemia acute |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024348 |
| E.1.2 | Term | Leukemia myelogenous |
| 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 |
| To determine whether the combination of pevonedistat + venetoclax + azacitidine improves EFS compared with venetoclax + azacitidine in patients with newly diagnosed AML who are unfit for intensive chemotherapy. EFS is defined as the time from study randomization to the date of failure to achieve CR/CRi (ie, discontinuing treatment without achieving CR/CRi), relapse from CR or CRi, or death from any cause, whichever occurs first. |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objective is to determine whether the combination of pevonedistat + venetoclax
+ azacitidine improves OS when compared with venetoclax + azacitidine in an unfit population of patients with AML.
(Please refer to protocol for detailed list of other secondary objectives) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female patients aged ≥18 years with newly diagnosed AML, morphologically confirmed (World Health Organization [WHO] criteria 2008). Patients may have newly diagnosed primary de novo AML or secondary AML (sAML) defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN), or therapy-related AML (t-AML) following cytotoxic therapy, and/or radiotherapy for a malignant or nonmalignant disease.
• To qualify for this study, a patient must be considered to be unfit for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by 1 of the following:
≥75 years of age
OR
≥18 to <75 years of age with at least one of the following:
- ECOG performance status of 2 or 3.
- Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
- Severe pulmonary disorder (eg, carbon monoxide lung diffusion capacity ≤65% or forced expiratory volume in 1 second.
- Creatinine clearance <45 mL/min (but ≥30 mL/min as part of general eligibility criteria).
- Hepatic disorder with total bilirubin >1.5 times the upper limit of the normal range (ULN)
• Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):
- Total bilirubin ≤1.5 times the upper limit of the normal range (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll with direct bilirubin ≤3 times the ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times the ULN.
- Creatinine clearance ≥30 mL/minute (calculated by the Modification of Diet in Renal Disease Study equation).
- Albumin >2.7 g/dL.
• White blood cell count (WBC) <25 × 10^9/L. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
(Please refer to protocol for complete list of all inclusion criteria) |
|
| E.4 | Principal exclusion criteria |
• History of myeloproliferative neoplasm with BCR-ABL1 translocation or AML with BCR-ABL1 translocation.
• Genetic diagnosis of acute promyelocytic leukemia.
• Extramedullary AML without evidence of bone marrow involvement.
• Prior treatment with hypomethylating agents for AML (treatment with hypomethylating agents for prior myelodysplastic syndromes [MDS] is not exclusionary).
• Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.
• Patients with either clinical evidence of or history of central nervous system involvement by AML.
• Diagnosed or treated for another malignancy (except for adequately-treated carcinoma in situ of any organ or nonmelanoma skin cancer) within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease that may compromise the administration of pevonedistat, venetoclax or azacitidine. Prior MDS is also allowed, but the patient cannot have received treatment for MDS within 14 days before first dose of any study drug.
• Patient has a WBC count ≥25 × 10^9/L.
• Patient with known hypersensitivity to pevonedistat, venetoclax, or azacitidine, and/or their excipients.
• Uncontrolled HIV infection.
• Patient is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months.
• Known hepatic cirrhosis.
• Treatment with strong cytochrome P450 (CYP)3A4 inducers within 14 days before the first dose of the study drug.
• Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or ST elevation myocardial infarction within 6 months before first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Patient who has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, or cardiovascular disease that, in the medical judgement of the investigator, may compromise the delivery of pevonedistat, venetoclax, and/or azacitidine.
• Patients with uncontrolled coagulopathy or bleeding disorder.
(Please refer to protocol for complete list of all exclusion criteria) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is EFS defined as failure to achieve CR/CRi, relapse from CR/CRi, or death. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoint is OS (Overall Survival) defined as the time from randomization to death from any cause.
Other secondary endpoints:
• 6-month, 1-year, and 2-year survival rates.
• 30- and 60-day mortality rates defined as the proportion of patients who survive at most 30/60 days from the first dose of study drug(s).
• Disease response rates as evaluated by IRC:
– CR rate
– CCR (CR + CRi) rate
– ORR (CR + CRi + PR) rate
– CR + CRh rate
– Leukemia response rate (CR + CRi + PR + MLFS [marrow CR])
• Duration of CR, CRi, CCR, and ORR.
• Time to first CR, CRi, and PR.
• Time to relapse from CR/CRi or death, whichever occurs first.
• HRQOL: Measured by the domains from EORTC-QLQ-C30, selected "European Organisation for Research and Treatment of Cancer (EORTC)"
supplemental items, and EQ 5D-5L.
• Pevonedistat plasma concentration data.
• RBC and platelet transfusion independence rates for each arm.
• Hospitalization rates for patients for each arm. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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) | 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 | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| United States |
| France |
| Germany |
| Italy |
| Poland |
|
| 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
|
| The study will be considered complete after the final analysis (FA) for EFS has been completed or the study has been terminated by the sponsor. The estimated time frame for study completion is approximately 30 to 48 months after the first patient is enrolled, depending upon the event size determined for the FA at the interim analysis (IA). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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