E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Higher-risk myelodysplastic syndromes (MDS),
Chronic myelomonocytic leukemia (CMML),
Low-blast acute myelogenous leukemia (AML) |
|
E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndromes (MDS) are characteristed by changes to blood composition including reductions in red and white blood cells and platelets.
Leukaemia 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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054350 |
E.1.2 | Term | Chronic myelomonocytic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10024348 |
E.1.2 | Term | Leukemia myelogenous |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067387 |
E.1.2 | Term | Myelodysplastic syndrome transformation |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009018 |
E.1.2 | Term | Chronic myelomonocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 in patients with higher-risk myelodysplastic syndrome (HR MDS), chronic myelomoncytic leukemia (CMML), and low-blast acute myelogenous leukemia (AML) whether the combination of pevonedistat and azacitidine improves event-free survival (EFS), when compared to single-agent azacitidine; for patients with HR MDS or CMML, an event is defined as death or transformation to AML; for patients with low-blast AML, an event is defined as death. |
|
E.2.2 | Secondary objectives of the trial |
To determine in patients with HR MDS, CMML, and low-blast AML, whether the combination of pevonedistat and azacitidine improves overall survival (OS) when compared to single-agent azacitidine.
To determine in patients with HR MDS, CMML, and low-blast AML whether the combination of pevonedistat and azacitidine improves 6month and 1-year survival rates when compared to single-agent azacitidine. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients 18 years or older.
2. Morphologically confirmed diagnosis of MDS, nonproliferative CMML (ie, with WBC <20,000/μL), or low-blast AML based on 1 of the following:
French-American-British (FAB) Classifications:
- Refractory anemia with excess blasts (RAEB – defined as having 5% to 20%
myeloblasts in the bone marrow).
- CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19%
blasts in the blood.
OR
World Health Organization (WHO) Classifications:
- Refractory anemia with excess blasts-1 (RAEB-1 – defined as having 5% to 9%
myeloblasts in the bone marrow).
- Refractory anemia with excess blasts-2 (RAEB-2 – defined as having 10% to
19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
- Chronic Myelomonocytic Leukemia-2 (CMML-2 – defined as having 10% to
19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
- Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having
<10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these
patients may enroll only if bone marrow blasts ≥5%).
- WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined in this protocol as “Low-Blast AML”) and < 30% myeloblasts in peripheral blood who are considered by investigator to be appropriate for azacitidine-based therapy.
3. For MDS and CMML patients, prognostic Risk Category, based on the Revised International Prognostic Scoring System (IPSS-R):
- Very high (>6 points),
- High (>4.5 - 6 points), or
- Intermediate (>3 – 4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of ≥5% bone marrow myeloblasts.
Patients with indeterminate cytogenetics findings at Screening should be assigned a cytogenetics prognostic variable of 2 points (ie, intermediate) for determining overall Prognostic Risk Category/Score
4. ECOG performance status of 0 to 2
5. 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):
- Albumin >2.7 g/dL.
- Total bilirubin <upper limit of normal (ULN) except in patients with Gilbert’s
syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤ 1.5 x
ULN of the direct bilirubin.
- ALT and AST <2.5 × ULN.
- Creatinine clearance >50 mL/min
- Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion hemolysis is allowed.
6. For CMML patients: WBC count <20,000/μL before administration of the first dose of study drug on Cycle 1 Day 1; patients must have been off hydroxyurea for at least 1 week prior to WBC count assessment.
7. Ability to undergo the study-required bone marrow sample collection procedures.
8. Suitable venous access for the study-required blood sampling (ie, including PK and biomarker sampling).
9. Female patients who:
- Are postmenopausal for at least 1 year before the Screening visit, or
- Are surgically sterile, or
- If they are of childbearing potential, agree to practice 1 highly effective method
and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the
preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the
female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. |
|
E.4 | Principal exclusion criteria |
1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.
2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
3. Eligible for allogenic stem cell transplantation.
4. Patients with MDS, CMML, or low-blast AML, whose only site of disease is extramedullary, eg, the skin.
5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures or could limit patient expected survival to less than 6
months.
6. Treatment with any anti-leukemic/anti-MDS therapies (eg, lenalidomide, cytarabine, anthracyclines, purine analogs) or with any investigational products within 14 days before the first dose of any study drug.
7. Known hypersensitivity to mannitol.
8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
9. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (eg, catheter, port) is not considered major surgery.
10. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
11. Life-threatening illness unrelated to cancer.
12. Prothrombin time (PT) or aPTT > 1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.
13. Known human immunodeficiency virus (HIV) seropositive.
14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
16. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or IV; see Section 15.3), and/or myocardial infarction within 6 months prior to first dose, or severe pulmonary hypertension. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.
17. Treatment with strong CYP3A inhibitors or inducers within 14 days before the first dose of pevonedistat.
18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 12 months before the first dose of any study drug, except for hydroxyurea.
19. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
20. Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
21. Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
EFS;
for patients with HR MDS or CMML, an event is defined as death or transformation to AML;
for patients with low-blast AML, an event is defined as death |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
EFS is defined as the time from randomization to the occurrence of an event. |
|
E.5.2 | Secondary end point(s) |
- OS.
- Six-month and 1-year survival rates.
- Time to AML transformation in HR MDS and CMML patients.
- CR, CR+PR, overall response (CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML).
- CR, CR+PR, overall response (CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML) by Cycle 4.
- Duration of CR, duration of CR+PR, duration of overall response (CR+PR+HI for HR MDS and CMML; CR+PR for low-blast AML).
- Time to first CR or PR.
- Time to subsequent therapy.
- RBCs and platelet-transfusion independence.
- Percent of patients with at least one inpatient hospital admissions related to HR MDS or CMML (collected through transformation to AML or until initiation of subsequent therapy, whichever occurs first) or low-blast AML (collected through AML progression or until initiation of subsequent therapy, whichever occurs first).
- Time to PD, relapse, or death.
- AEs and serious adverse events (SAEs), abnormal clinical laboratory values, Eastern Cooperative Oncology Group (ECOG) performance status, ECGs, and vital sign measurements. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS will be calculated from date of randomization to the date of patient death.
Six-month survival rate is defined as the percentage of patients who are still alive six months after randomization.
One-year survival rate is defined as the percentage of patients who are still alive one year after randomization.
Time to AML transformation is defined as time from randomization to documented AML transformation.
Time to first CR or PR is defined as time from randomization to first documented CR or PR, whichever occurs first.
Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy.
Time to PD, relapse, or death is defined as the time from randomization until disease progression, or relapse, or death. |
|
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
Belgium |
Brazil |
Bulgaria |
Canada |
Czech Republic |
France |
Germany |
Ireland |
Israel |
Italy |
Netherlands |
Spain |
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
|
LPLV - Patients will be considered to have completed the study if they are followed until death or until the sponsor terminates the study. |
|
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 | 4 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |