Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)



Status:Recruiting
Conditions:Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology
Healthy:No
Age Range:18 - Any
Updated:3/21/2019
Start Date:November 28, 2017
End Date:March 31, 2023
Contact:Takeda Study Registration Call Center
Email:GlobalOncologyMedinfo@takeda.com
Phone:+1-866-835-2233

Use our guide to learn which trials are right for you!

A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia

The purpose of this study is to determine whether the combination of pevonedistat and
azacitidine improves event-free survival (EFS) when compared with single-agent azacitidine
(An event is defined as death or transformation to AML in participants with MDS or CMML,
whichever occurs first, and is defined as death in participants with low-blast AML).

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 participants. 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).

Inclusion Criteria:

1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or 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 participant determined to be in the Intermediate
Prognostic Risk Category is only allowable in the setting of >=5% bone marrow
myeloblasts.

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).

Exclusion Criteria:

1. Has previous treatment for HR MDS or CMML 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. Participants with AML with a WBC count >50,000/ microliter (mcL).. Participants who
are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet
the eligibility criteria.

4. 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.

- Comorbidities.

- Inability to tolerate intensive chemotherapy (e.g., participants 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).

5. Has either clinical evidence of or history of central nervous system involvement by
AML.

6. Has active uncontrolled infection or severe infectious disease, such as severe
pneumonia, meningitis, or septicemia.

7. Is diagnosed or treated for another malignancy within 2 years before randomization or
previously diagnosed with another malignancy and have any evidence of residual
disease.

8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they
have undergone resection.

9. 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.

10. Has known human immunodeficiency virus (HIV) seropositive.

11. 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.

12. Has known hepatic cirrhosis or severe preexisting hepatic impairment.

13. 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
hypertension.

14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the
first dose of pevonedistat.
We found this trial at
118
sites
1448 East Common Street
New Braunfels, Texas 78130
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Chapel Hill, North Carolina 27599
(919) 962-2211
University of North Carolina at Chapel Hill Carolina’s vibrant people and programs attest to the...
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9500 Euclid Avenue
Cleveland, Ohio 44106
216.444.2200
Cleveland Clinic Cleveland Clinic is committed to principles as presented in the United Nations Global...
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1601 Northwest 12th Avenue
Miami, Florida 33136
(305) 243-6545
University of Miami Miller School of Medicine The University of Miami Leonard M. Miller School...
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2950 Cleveland Clinic Blvd.
Weston, Florida 33331
866.293.7866
Cleveland Clinic Florida Cleveland Clinic Florida, located in Weston, West Palm Beach, Palm Beach Gardens...
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Altamonte Springs, Florida 32701
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1365 Clifton Rd NE
Atlanta, Georgia 30322
(404) 778-1900
Winship Cancer Institute at Emory University Winship Cancer Institute of Emory University is Georgia
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40 Chasely Street
Auchenflower, Queensland 4066
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1700 South Potomac Street
Aurora, Colorado 80012
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901 West 38th Street
Austin, Texas 78705
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6204 Balcones Drive
Austin, Texas 78731
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4101 James Casey Street
Austin, Texas 78745
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Bethlehem, Pennsylvania 18015
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2600 Research Center Drive
Blacksburg, Virginia 24060
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1055 N Curtis Rd
Boise, Idaho 83706
(208) 367-2121
Saint Alphonsus Regional Medical Center Saint Alphonsus Health System is a four-hospital regional, faith-based Catholic...
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Bonita Springs, Florida 34135
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4715 Arapahoe Avenue
Boulder, Colorado 80303
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Bradenton, Florida 34209
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Brandon, Florida 33511
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Caldwell, New Jersey 83605
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Cape Coral, Florida 33914
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Charlottesville, Virginia 22903
(434) 924-0311
University of Virginia The University of Virginia is distinctive among institutions of higher education. Founded...
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1653 W. Congress Parkway
Chicago, Illinois 60612
(312) 942-5000
Rush University Medical Center Rush University Medical Center encompasses a 664-bed hospital serving adults and...
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4350 Malsbary Road
Cincinnati, Ohio 45242
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5053 Wooster Rd
Cincinnati, Ohio 45226
(513) 751-2273
Oncology Hematology Care Our more than 60 physicians and advanced practice providers throughout neighborhood offices...
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Clearwater, Florida 33761
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2312 North Nevada Avenue
Colorado Springs, Colorado 80907
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7777 Forest Lane
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1801 Inwood Rd
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University of Texas Southwestern Medical Center UT Southwestern is an academic medical center, world-renowned for...
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Daphne, Alabama 36526
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1721 East 19th Ave., Suite #200 & #300
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Colorado Blood Cancer Institute When patients come to the Colorado Blood Cancer Institute, the entire...
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Dickson, Tennessee 37055
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4371 Veronica S Shoemaker Boulevard
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Goodyear, Arizona 85338
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Hackensack, New Jersey 07601
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Independence, Missouri 64057
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4500 San Pablo Road South
Jacksonville, Florida 32224
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2316 E Meyer Blvd
Kansas City, Missouri 64132
(816) 276-4000
Research Medical Center Research Medical Center offers hospital and health clinic services across three Kansas...
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Kansas City, Missouri 64131
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3855 Health Sciences Dr,
La Jolla, California 92093
(858) 822-6100
UC San Diego Moores Cancer Center Established in 1978, UC San Diego Moores Cancer Center...
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11750 West 2nd Place
Lakewood, Colorado 80228
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22 West Dry Creek Circle
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Lone Tree, Colorado 80124
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2030 Mountain View Avenue
Longmont, Colorado 80501
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910 East Houston Street
Longview, Texas 75601
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1100 Charlotte Avenue
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5721 W 119th St
Overland Park, Kansas 66209
(913) 498-6000
Menorah Medical Center Menorah Medical Center (MMC), a full-service, acute care hospital located on the...
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9397 Crown Crest Boulevard
Parker, Colorado 80138
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Port Charlotte, Florida 33980
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3676 Parker Boulevard
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Redlands, California 92373
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2013 Jefferson Street Southwest
Roanoke, Virginia 24014
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Rochester, New York 14642
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2410 Round Rock Ave
Round Rock, Texas 78681
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Saint Petersburg, Florida 33705
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5206 Research Drive
San Antonio, Texas 78240
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