The purpose of this study is to determine whether the combination of pevonedistat and
azacitidine improves overall response rate (ORR) by Cycle 6 and whether the combination of
pevonedistat and azacitidine improves event-free survival (EFS) when compared with
The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to
treat people with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic
leukemia (CMML) and low-blast acute myelogenous leukemia (AML) as a combination treatment
with azacitidine. This study will look at the overall survival, event-free survival and
response to treatment in people who take pevonedistat and azacitidine when compared to people
who take single-agent azacitidine.
The study will enroll approximately 450 patients. Once enrolled, participants will be
randomly assigned in 1:1 ratio (by chance, like flipping a coin) to one of the two treatment
groups in 28-day treatment cycles:
- Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination
- Single-agent azacitidine 75 mg/m^2
All participants will receive azacitidine via intravenous or subcutaneous route. Participants
randomized to the combination arm will also receive pevonedistat intravenous infusion.
This multi-center trial will be conducted worldwide. The overall time to participate in this
study is approximately 63 months. Participants will attend the end-of-treatment visit 30 days
after the last dose of study drug or before the start of subsequent anti-neoplastic therapy
if that occurs sooner.
Participants with HR MDS or CMML will have EFS follow-up study visits every month if their
disease has not transformed to AML and they have not started subsequent therapy. Participants
with low-blast AML will have response follow-up study visits every month until they relapse
from CR or meet the criteria for PD. All participants will enter OS follow-up (contacted
every 3 months) when they have confirmed transformation to AML (for participants with HR MDS
or CMML at enrollment) or experienced PD or relapse from CR (for participants with low-blast
AML at study enrollment).
1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or
nonproliferative chronic myelomonocytic leukemia (CMML) (i.e., with white blood cell
[WBC] <13,000/μL) or low-blast acute myelogenous leukemia (AML).
2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories,
based on the Revised International Prognostic Scoring System (IPSS-R):
- Very high (>6 points).
- High (>4.5-6 points).
- 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
3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.
4. Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM)
score >=4 for intensive, induction chemotherapy as calculated using the simplified
model described by Walter and coworkers.
Calculation of TRM score:
- 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years).
- + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
- + 0 for (platelets <50), +1 for (platelets >50).
1. Has previous treatment for higher-risk myelodysplastic syndromes (HR MDS) or low-blast
AML with chemotherapy or other antineoplastic agents including hypomethylating agent
(HMAs) such as decitabine or azacitidine. Previous treatment is permitted with
hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8
weeks before the first dose of study drug.
2. Has 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. Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.
The reason a participant is not eligible for intensive chemotherapy and/or allogeneic
stem cell transplantation may consist of one or more of the following factors:
- Age >75.
- Inability to tolerate intensive chemotherapy (e.g., patients with AML with
20%-30% blasts and TRM ≥4).
- Physician decision (e.g., lack of available stem cell donor).
- The reason a participant is not eligible should be documented in the electronic
case report form (eCRF).
4. Has either clinical evidence of or history of central nervous system involvement by
5. Has active uncontrolled infection or severe infectious disease, such as severe
pneumonia, meningitis, or septicemia.
6. Is diagnosed or treated for another malignancy within 2 years before randomization or
previously diagnosed with another malignancy and have any evidence of residual
7. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they
have undergone resection.
8. Has prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or active
uncontrolled coagulopathy or bleeding disorder. Participants therapeutically
anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors,
or heparin are excluded from enrollment.
9. Has known human immunodeficiency virus (HIV) seropositive.
10. Has known hepatitis B surface antigen seropositive, or known or suspected active
hepatitis C infection. Note: Participants who have isolated positive hepatitis B core
antibody (i.e., in the setting of negative hepatitis B surface antigen and negative
hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
11. Has known hepatic cirrhosis or severe preexisting hepatic impairment.
12. Has known cardiopulmonary disease defined as unstable angina, clinically significant
arrhythmia, congestive heart failure (New York Heart Association Class III or IV),
and/or myocardial infarction within 6 months before first dose, or severe pulmonary
13. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the
first dose of pevonedistat.