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) (PANTHER)

January 4, 2024 updated by: Takeda

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).

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with higher-risk myelodysplastic syndromes (HR 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 Spain, Belgium, Brazil, Canada, Czech Republic, France, Germany, Israel, Italy, the United States, Australia, Greece, Japan, Mexico, Poland, Russia, Korea, Turkey, China and United Kingdom. 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 (for participants with low-blast AML at study enrollment).

Study Type

Interventional

Enrollment (Actual)

454

Phase

Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Australia
- - Liverpool, Australia, 1871
    - Liverpool Hospital
- Queensland
  - Auchenflower, Queensland, Australia, 4066
    - Icon Cancer Care Wesley
  - Chermside, Queensland, Australia, 4032
    - Icon Cancer Care Chermside
  - South Brisbane, Queensland, Australia, 4101
    - ICON Cancer Care
  - South Brisbane, Queensland, Australia, 4101
    - Icon Cancer Care South Brisbane
  - Southport, Queensland, Australia, 4215
    - Icon Cancer Care Southport
- Tasmania
  - Hobart, Tasmania, Australia, 7000
    - Royal Hobart Hospital
Belgium
- - Bruxelles, Belgium, 1200
    - Cliniques Universitaires Saint-Luc
  - Leuven, Belgium, 3000
    - UZ Leuven
- Antwerpen
  - Brasschaat, Antwerpen, Belgium, 2930
    - Algemeen Ziekenhuis klina
- Namur
  - Yvoir, Namur, Belgium, 5530
    - CHU UCL Namur asbl - Site Godinne
- West-Vlaanderen
  - Brugge, West-Vlaanderen, Belgium, 8000
    - AZ Sint-Jan AV
Brazil
- - Porto Alegre, Brazil, 90035-903
    - Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
  - Rio De Janeiro, Brazil, 21941-913
    - Universidade Federal do Rio de Janeiro - UFRJ
  - Sao Paulo, Brazil, 08270-120
    - Hospital Santa Marcelina
  - Sao Paulo, Brazil, 08270-270
    - Hospital Santa Marcelina
- Parana
  - Curitiba, Parana, Brazil, 81520-060
    - Liga Paranaense de Combate ao Cancer - Hospital Erasto Gaertner
- Rio Grande Do Norte
  - Natal, Rio Grande Do Norte, Brazil, 59075-740
    - Liga Norte Riograndense Contra O Câncer
- Santa Catarina
  - Florianopolis, Santa Catarina, Brazil, 88034-000
    - Centro de Pesquisas Oncologicas
Canada
- Alberta
  - Calgary, Alberta, Canada, T2N 4
    - Tom Baker Cancer Centre
  - Edmonton, Alberta, Canada, T6G 2B7
    - University of Alberta
  - Edmonton, Alberta, Canada, T6G1Z1
    - Kaye Edmonton Clinic
- New Brunswick
  - Saint John, New Brunswick, Canada, E2L 4L2
    - Saint John Regional Hospital
- Ontario
  - Toronto, Ontario, Canada, M4N3M5
    - Sunnybrook Health Sciences Centre
  - Toronto, Ontario, Canada, M5G 2M9
    - Princess Margaret Hospital
  - Toronto, Ontario, Canada, M5G2M9
    - Princess Margaret Hospital
China
- Beijing
  - Beijing, Beijing, China, 100053
    - Xuanwu Hospital Capital Medical University
- Tianjin
  - Tianjin, Tianjin, China, 300020
    - Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
Czechia
- - Prague, Czechia, 128 08
    - Vseobecna fakultni nemocnice v Praze
  - Praha, Czechia, 100 34
    - Fakultni nemocnice Kralovske Vinohrady
- Kralovehradeck Kraj
  - Hradec Kralove, Kralovehradeck Kraj, Czechia, 500 05
    - Fakultni nemocnice Hradec Kralove
France
- - Le Mans, France, 74000
    - Centre Hospitalier Le Mans
  - Paris, France, 75010
    - Hopital Saint Louis
  - Paris, France, 75475
    - Hopital Saint Louis
- Calvados
  - Caen, Calvados, France, 14033
    - Hopital Cote de Nacre
- Maine-et-Loire
  - Angers, Maine-et-Loire, France, 49100
    - CHU Angers
Germany
- - Dresden, Germany, 1307
    - Universitätsklinikum Carl Gustav Carus an der TU Dresden
  - Dusseldorf, Germany, 40479
    - Marien Hospital Akademisches Lehrkrankenhaus
- Baden-Wurttemberg
  - Tubingen, Baden-Wurttemberg, Germany, 72076
    - Universitätsklinikum Tübingen
- Sachsen
  - Leipzig, Sachsen, Germany, 4103
    - Universitätsklinikum Leipzig
Greece
- - Alexandroupolis, Greece, 68100
    - University Hospital of Alexandroupolis
  - Athens, Greece, 11527
    - Laiko General Hospital of Athens
  - Ioannina, Greece, 45500
    - University General Hospital of Ioannina
  - Larissa, Greece, 41110
    - University General Hospital of Larissa
  - Patras, Greece, 26504
    - University General Hospital of Patras
  - Thessaloniki, Greece, 57010
    - Georgios Papanikolaou General Hospital of Thessaloniki
- Attiki
  - Athens, Attiki, Greece, 115 27
    - Laiko General Hospital of Athens
  - Athens, Attiki, Greece, 11527
    - Athens General Hospital 'G Gennimatas'
  - Athens, Attiki, Greece, 12462
    - Attikon University General Hospital
Israel
- - Holon, Israel, 58100
    - Edith Wolfson Medical Center
  - Jerusalem, Israel, 91031
    - Shaare Zedek Medical Center
  - Jerusalem, Israel, 91120
    - Hadassah Medical Center PPDS -
  - Nahariya, Israel
    - Galilee Medical Center
  - Safed, Israel, 13100
    - Ziv Medical Center
  - Tel Aviv, Israel, 64239
    - Tel Aviv Sourasky Medical Center PPDS
Italy
- - Firenze, Italy, 50134
    - Azienda Ospedaliera Universitaria Careggi
  - Rionero in Vulture, Italy, 85028
    - IRCCS Centro Di Riferimento Oncologico Della Basilicata
  - Rozzano, Italy, 20089
    - Istituto Clinico Humanitas
  - Torino, Italy, 10126
    - Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino
- Emilia-Romagna
  - Bologna, Emilia-Romagna, Italy, 40138
    - Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
- Lombardia
  - Brescia, Lombardia, Italy, 25123
    - ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia - INCIPIT - PIN
Japan
- - Fukuoka-city, Japan, 812-8582
    - Kyushu University Hospital
  - Mibu, Japan, 321-0293
    - Dokkyo Medical University Hospital
  - Nagasaki, Japan, 8528102
    - Nagasaki University Hospital
  - Osaka, Japan, 545-8586
    - Osaka Metropolitan University Hospital
  - Yokohama-shi, Japan, 232-0024
    - Yokohama City University Hospital
  - Yoshida-gun, Japan, 910-1193
    - University of Fukui Hospital
- Hirosima
  - Fukuyama, Hirosima, Japan, 720-0001
    - Japan Mutual Aid Association of Public School Teachers Chugoku Central Hospital
- Hokkaido
  - Sapporo, Hokkaido, Japan, 060 8638
    - Hokkaido University Hospital
- Hukusima
  - Fukushima-shi, Hukusima, Japan, 960-1295
    - Fukushima Medical University Hospital
- Hyogo
  - Kobe-City, Hyogo, Japan, 650-0047
    - Kobe City Medical Center General Hospital
- Kyoto
  - Kyoto-shi, Kyoto, Japan, 602-8566
    - University Hospital, Kyoto Prefectural University of Medicine
- Osaka
  - Osakasayama, Osaka, Japan, 589-8511
    - Kindai University Hospital
- Saitama
  - Kawagoe, Saitama, Japan, 3508550
    - Saitama Medical Center
- Tokyo
  - Bunkyo, Tokyo, Japan, 113-8431
    - Juntendo University Hospital
  - Shinagawa-ku, Tokyo, Japan, 141-8625
    - NTT Medical Center Tokyo
Korea, Republic of
- - Busan, Korea, Republic of, 49241
    - Pusan National University Hospital
  - Daegu, Korea, Republic of, 41944
    - Kyungpook National University Hospital
  - Jeongnam, Korea, Republic of, 58128
    - Chonnam National University Hwasun Hospital
  - Seoul, Korea, Republic of, 6591
    - The Catholic University of Korea, Seoul St. Mary's Hospital
  - Seoul, Korea, Republic of, 5505
    - Asan Medical Center - PPDS
  - Seoul, Korea, Republic of, 6351
    - Samsung Medical Center - PPDS
Mexico
- - Huixquilucan, Mexico, 52787
    - Hematologica Alta Especialidad S.C.
  - Mexico, Mexico
    - Capital Humano para Investigacion Clinica SC
Poland
- - Lublin, Poland, 20-090
    - Centrum Onkologii Ziemi Lubelskiej
  - Opole, Poland, 45-061
    - Zaklad Diagnostyki Obrazowej SOR
  - Opole, Poland, 45-372
    - Szpital Wojewodzki w Opolu
- Mazowieckie
  - Warszawa, Mazowieckie, Poland, 02-776
    - Instytut Hematologii i Transfuzjologii
- Pomorskie
  - Gdansk, Pomorskie, Poland, 80-952
    - Uniwersyteckie Centrum Kliniczne
  - Gdansk, Pomorskie, Poland, 80-214
    - Uniwersyteckie Centrum Kliniczne, Klinika Hematologii I Transplantologii, Budynek Centrum Medycyny N
- Swietokrzyskie
  - Kielce, Swietokrzyskie, Poland, 25-734
    - Swietokrzyskie Centrum Onkologii
Russian Federation
- - Moscow, Russian Federation, 129301
    - City Clinical Hospital # 40
  - Saint Petersburg, Russian Federation, 197341
    - North-West Federal Medical Research Center n.a. V.A. Almazov
  - St. Petersburg, Russian Federation, 191024
    - Russian Research Institute of Hematology and Blood Transfusion
Spain
- - Barcelona, Spain, 8035
    - Hospital Universitario Vall d'Hebron - PPDS
  - Madrid, Spain, 28034
    - Hospital Universitario Ramon Y Cajal
  - Madrid, Spain, 28006
    - Hospital Universitario de La Princesa
  - Madrid, Spain, 28046
    - Hospital Universitario La Paz - PPDS
  - Madrid, Spain, 28009
    - Hospital General Universitario Gregorio Marañon
  - Salamanca, Spain, 37007
    - Complejo Asistencial Universitario de Salamanca - H. Clinico
  - Valencia, Spain, 46010
    - Hospital Clinico Universitario de Valencia
  - Valencia, Spain, 46026
    - Hospital Universitari i Politecnic La Fe de Valencia
- Barcelona
  - LHospitalet de Llobregat, Barcelona, Spain, 8907
    - ICO lHospitalet Hospital Duran i Reynals
- Castilla Y Leon
  - Leon, Castilla Y Leon, Spain, 24071
    - Complejo Asistencial Universitario de León
Turkey
- - Ankara, Turkey, 6500
    - Gazi University Medical Faculty Gazi Hospital
  - Izmir, Turkey, 35100
    - Ege University Medical Faculty
  - Mersin, Turkey, 33343
    - Mersin University Medical Faculty
  - Samsun, Turkey, 55139
    - Ondokuz Mayis Universitesi Tip Fakultesi Hastanesi
  - Tekirdag, Turkey, 59100
    - Namik Kemal University
  - Trabzon, Turkey, 61080
    - Karadeniz Technical University Faculty of Medicine
United Kingdom
- - London, United Kingdom, EC1A 7BE
    - St Bartholomew'S Hospital
  - Swansea, United Kingdom, SA2 8QA
    - Singleton Hospital - PPDS
- Dorset
  - Bournemouth, Dorset, United Kingdom, BH7 7DW
    - Royal Bournemouth Hospital
- Kent
  - Maidstone, Kent, United Kingdom, ME16 9QQ
    - Maidstone Hospital
United States
- Alabama
  - Daphne, Alabama, United States, 36526
    - Southern Cancer Center - USOR
  - Mobile, Alabama, United States, 36607
    - Southern Cancer Center - USOR
  - Mobile, Alabama, United States, 36608
    - Southern Cancer Center - USOR
  - Mobile, Alabama, United States, 36608
    - Southern Cancer Center- USOR
- Arizona
  - Goodyear, Arizona, United States, 85338
    - Southeastern Regional Medical Center - CTCA - PPDS
  - Tucson, Arizona, United States, 85704
    - Arizona Oncology Associates (Orange HOPE) - USOR
  - Tucson, Arizona, United States, 85704
    - Arizona Oncology Associates (Rudasill HOPE) - USOR
  - Tucson, Arizona, United States, 85711
    - Arizona Oncology Associates (Wilmot HOPE) - USOR
- California
  - Corona, California, United States, 92879
    - Compassionate Care Research Group Inc. at Compassionate Cancer Care Medical Group, Inc
  - Fountain Valley, California, United States, 92708
    - Compassionate Cancer Care Medical Group Inc
  - La Jolla, California, United States, 92093
    - UC San Diego Moores Cancer Center
  - Redlands, California, United States, 92373
    - Emad Ibrahim, Md, Inc
  - Riverside, California, United States, 92501
    - Compassionate Care Research Group Inc. at Compassionate Cancer Care Medical Group, Inc
- Colorado
  - Aurora, Colorado, United States, 80012
    - Rocky Mountain Cancer Centers (Aurora) - USOR
  - Boulder, Colorado, United States, 80303
    - Rocky Mountain Cancer Centers (Boulder) - USOR
  - Colorado Springs, Colorado, United States, 80907
    - Rocky Mountain Cancer Centers (Colorado Springs) - USOR
  - Denver, Colorado, United States, 80218
    - Colorado Blood Cancer Institute - PPDS
  - Denver, Colorado, United States, 80218
    - Rocky Mountain Cancer Centers (Williams) - USOR
  - Denver, Colorado, United States, 80218
    - Presbyterian/St. Luke's Medical Center
  - Denver, Colorado, United States, 80209
    - Quest Diagnostics, INC
  - Denver, Colorado, United States, 80218
    - Presbyterian Saint Lukes Medical Center Laboratory
  - Denver, Colorado, United States, 80220
    - Rocky Mountain Cancer Centers (Denver) - USOR
  - Denver, Colorado, United States, 80239
    - Kaiser Foundation Health Plan
  - Englewood, Colorado, United States, 80112
    - Laboratory Corporation of America
  - Lakewood, Colorado, United States, 80228
    - Rocky Mountain Cancer Centers (Lakewood) - USOR
  - Littleton, Colorado, United States, 80120
    - Rocky Mountain Cancer Centers (Littleton) - USOR
  - Lone Tree, Colorado, United States, 80124
    - Rocky Mountain Cancer Centers (Lone Tree) - USOR
  - Longmont, Colorado, United States, 80501
    - Rocky Mountain Cancer Centers (Longmont) - USOR
  - Parker, Colorado, United States, 80138
    - Rocky Mountain Cancer Centers (Parker) - USOR
  - Pueblo, Colorado, United States, 81008
    - Rocky Mountain Cancer Centers (Pueblo) - USOR
  - Thornton, Colorado, United States, 80260
    - Rocky Mountain Cancer Centers (Thornton) - USOR
- District of Columbia
  - Washington, District of Columbia, United States, 20010
    - Medstar Research Institute
- Florida
  - Altamonte Springs, Florida, United States, 32701
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Bonita Springs, Florida, United States, 34135
    - SCRI Florida Cancer Specialists South
  - Bradenton, Florida, United States, 34209
    - SCRI Florida Cancer Specialists South
  - Brandon, Florida, United States, 33511
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Cape Coral, Florida, United States, 33914
    - SCRI Florida Cancer Specialists South
  - Clearwater, Florida, United States, 33761
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Fort Myers, Florida, United States, 33916
    - SCRI Florida Cancer Specialists South
  - Fort Myers, Florida, United States, 33905
    - SCRI Florida Cancer Specialists South
  - Fort Myers, Florida, United States, 33908
    - SCRI Florida Cancer Specialists South
  - Gainesville, Florida, United States, 32605
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Jacksonville, Florida, United States, 32224
    - Mayo Clinic Jacksonville - PPDS
  - Largo, Florida, United States, 33770
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Lecanto, Florida, United States, 34461
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Miami, Florida, United States, 33136
    - University of Miami Miller School of Medicine
  - Miami, Florida, United States, 33176
    - Baptist Health System (N Kendall) - USOR
  - Naples, Florida, United States, 34102
    - SCRI Florida Cancer Specialists South
  - New Port Richey, Florida, United States, 34655
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Ocala, Florida, United States, 34471
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Orange City, Florida, United States, 32763
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Orlando, Florida, United States, 32806
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Port Charlotte, Florida, United States, 33980
    - SCRI Florida Cancer Specialists South
  - Saint Petersburg, Florida, United States, 33705
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Sarasota, Florida, United States, 34232
    - SCRI Florida Cancer Specialists South
  - Sarasota, Florida, United States, 34236
    - SCRI Florida Cancer Specialists South
  - Spring Hill, Florida, United States, 34608
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Tampa, Florida, United States, 33607
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Tavares, Florida, United States, 32778
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - The Villages, Florida, United States, 32159
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
  - Venice, Florida, United States, 34285
    - SCRI Florida Cancer Specialists South
  - Venice, Florida, United States, 34292
    - SCRI Florida Cancer Specialists South
  - Weston, Florida, United States, 33331
    - Cleveland Clinic Florida
  - Winter Park, Florida, United States, 32792
    - Florida Cancer Specialists - NORTH - SCRI - PPDS
- Georgia
  - Atlanta, Georgia, United States, 30322
    - Winship Cancer Institute, Emory University
- Idaho
  - Boise, Idaho, United States, 83706
    - Saint Alphonsus Regional Medical Center
  - Caldwell, Idaho, United States, 83605
    - Saint Alphonsus Caldwell Cancer Care Center
  - Nampa, Idaho, United States, 83687
    - Saint Alphonsus Medical Center
- Illinois
  - Chicago, Illinois, United States, 60612
    - Rush University Medical Center
- Kansas
  - Overland Park, Kansas, United States, 66209
    - Menorah Medical Center
- Missouri
  - Independence, Missouri, United States, 64057
    - Centerpoint Medical Center
  - Kansas City, Missouri, United States, 64132
    - Research Medical Center
  - Kansas City, Missouri, United States, 64132
    - HCA Midwest Health - SCRI - PPDS
- Nebraska
  - Omaha, Nebraska, United States, 68130
    - Nebraska Cancer Specialists
- New Jersey
  - Brick, New Jersey, United States, 08724
    - New Jersey Hematology Oncology Associates LLC
  - Hackensack, New Jersey, United States, 07601
    - John Theurer Cancer Center
  - Toms River, New Jersey, United States, 08755
    - New Jersey Hematology and Oncology
- New York
  - New York, New York, United States, 10021
    - Weill Cornell Medical Center
  - New York, New York, United States, 10021
    - Weill Cornell Medical Center - Monitoring Location
  - Rochester, New York, United States, 14642
    - Strong Memorial Hospital
- North Carolina
  - Chapel Hill, North Carolina, United States, 27599
    - University of North Carolina at Chapel Hill
- Ohio
  - Cincinnati, Ohio, United States, 45230
    - Oncology Hematology Care, Inc.
  - Cincinnati, Ohio, United States, 45211
    - Oncology Hematology Care, Inc.
  - Cincinnati, Ohio, United States, 45236
    - Oncology Hematology Care Inc - USOR
  - Cincinnati, Ohio, United States, 45242
    - Oncology Hematology Care Inc - USOR
  - Cleveland, Ohio, United States, 44195
    - The Cleveland Clinic Foundation
  - Cleveland, Ohio, United States, 44111
    - Fairview Hospital
  - Fairfield, Ohio, United States, 45014
    - Oncology Hematology Care, Inc - Fairfield
  - Mayfield, Ohio, United States, 44124
    - Hillcrest Hospital Cancer Care Center
- Pennsylvania
  - Bethlehem, Pennsylvania, United States, 18015
    - St. Luke's Hospital
  - Easton, Pennsylvania, United States, 18045
    - St. Luke's University Health Network
- South Carolina
  - Easley, South Carolina, United States, 29640
    - Greenville Health System
  - Greenville, South Carolina, United States, 29605
    - Greenville Health System
  - Greenville, South Carolina, United States, 29615
    - Greenville Health System Cancer Institute
  - Greer, South Carolina, United States, 29650
    - Greenville Health System
  - Seneca, South Carolina, United States, 29672
    - Greenville Health System
  - Spartanburg, South Carolina, United States, 29307
    - Greenville Health System
- Tennessee
  - Dickson, Tennessee, United States, 37055
    - Tennessee Oncology - DICKSON - SCRI - PPDS
  - Franklin, Tennessee, United States, 37067
    - Tennessee Oncology - FRANKLIN - SCRI - PPDS
  - Gallatin, Tennessee, United States, 37066
    - Tennessee Oncology - GALLATIN - SCRI - PPDS
  - Hermitage, Tennessee, United States, 37076
    - Tennessee Oncology - SUMMIT - SCRI - PPDS
  - Lebanon, Tennessee, United States, 37090
    - Tennessee Oncology - LEBANON - SCRI - PPDS
  - Murfreesboro, Tennessee, United States, 37129
    - Tennessee Oncology - MURFREESBORO - SCRI - PPDS
  - Nashville, Tennessee, United States, 37203
    - Tennessee Oncology NASH - SCRI - PPDS
  - Nashville, Tennessee, United States, 37203
    - Sarah Cannon Center for Blood Centers - SCRI - PPDS
  - Nashville, Tennessee, United States, 37203
    - Tennessee Oncolgy - BAPTIST - SCRI - PPDS
  - Nashville, Tennessee, United States, 37205
    - Tennessee Oncology - ST THOMAS WEST - SCRI - PPDS
  - Nashville, Tennessee, United States, 37207
    - Tennessee Oncology SKYLINE - SCRI - PPDS
  - Nashville, Tennessee, United States, 37211
    - Tennessee Oncology - SOUTHERN HILLS - SCRI - PPDS
  - Shelbyville, Tennessee, United States, 37160
    - Tennessee Oncology - SHELBYVILLE - SCRI - PPDS
  - Smyrna, Tennessee, United States, 37167
    - Tennessee Oncology - SMYRNA - SCRI - PPDS
- Texas
  - Austin, Texas, United States, 78705
    - Texas Oncology (West 38) - USOR
  - Austin, Texas, United States, 78731
    - Texas Oncology (Balcones) - USOR
  - Austin, Texas, United States, 78745
    - Texas Oncology (James Casey) - USOR
  - Dallas, Texas, United States, 75390
    - University of Texas Southwestern Medical Center
  - Dallas, Texas, United States, 75246
    - Baylor Sammons Cancer Center
  - Dallas, Texas, United States, 75230
    - Texas Oncology (Medical City) - USOR
  - Longview, Texas, United States, 75601
    - Texas Oncology (Tyler) - USOR
  - New Braunfels, Texas, United States, 78130
    - Texas Oncology (E Common) - USOR
  - Round Rock, Texas, United States, 78681
    - Texas Oncology (Round Rock) - USOR
  - San Antonio, Texas, United States, 78240
    - Texas Oncology - San Antonio Medical Center - USOR
  - Tyler, Texas, United States, 75702
    - Texas Oncology (Tyler) - USOR
- Virginia
  - Blacksburg, Virginia, United States, 24060
    - Oncology and Hematology Associates of Southwest Virginia (Blacksburg) - USOR
  - Charlottesville, Virginia, United States, 22903
    - University of Virginia
  - Low Moor, Virginia, United States, 24457
    - Oncology and Hematology Associates of Southwest Virginia (Low Moor) - USOR
  - Roanoke, Virginia, United States, 24014
    - Oncology and Hematology Associates of Southwest Virginia (Roanoke) - USOR
  - Salem, Virginia, United States, 24153
    - Oncology and Hematology Associates of Southwest Virginia Inc
  - Wytheville, Virginia, United States, 24382
    - Oncology and Hematology Associates of Southwest Virginia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Description

Inclusion Criteria:

Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell [WBC] <13,000/microliter [mcL]) or low-blast acute myelogenous leukemia (AML).
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.
Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.
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:

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.
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.
Participants with AML with a WBC count >50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria.
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).
Has either clinical evidence of or history of central nervous system involvement by AML.
Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
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.
Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
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.
Has known human immunodeficiency virus (HIV) seropositive.
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.
Has known hepatic cirrhosis or severe preexisting hepatic impairment.
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.
Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Interventional Model: Parallel Assignment
Masking: None (Open Label)

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azacitidine 75 mg/m^2 Azacitidine 75 milligram per square meter (mg/m^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to approximately 42 months.	Drug: Azacitidine Azacitidine intravenous or subcutaneous formulation.
Experimental: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to approximately 42 months.	Drug: Pevonedistat Pevonedistat intravenous infusion. Drug: Azacitidine Azacitidine intravenous or subcutaneous formulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS) Time Frame: From randomization until transformation to acute myeloid leukemia, or death due to any cause up to data cut-off date: 28 May 2021 (up to approximately 42 months)	EFS was defined as the time from randomization to the date of an EFS event. An EFS event was defined as death or transformation to acute myelogenous leukemia (AML) (World Health Organization [WHO] classification as a participant having greater than 20 % blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurred first, in participants with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemias (CMML). An EFS event was defined as death in participants with low-blast AML.	From randomization until transformation to acute myeloid leukemia, or death due to any cause up to data cut-off date: 28 May 2021 (up to approximately 42 months)

Secondary Outcome Measures

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Takeda

Collaborators

Takeda Development Center Americas, Inc.

Investigators

Study Director: Medical Director, Takeda

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Ades L, Girshova L, Doronin VA, Diez-Campelo M, Valcarcel D, Kambhampati S, Viniou NA, Woszczyk D, De Paz Arias R, Symeonidis A, Anagnostopoulos A, Munhoz EC, Platzbecker U, Santini V, Fram RJ, Yuan Y, Friedlander S, Faller DV, Sekeres MA. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML. Blood Adv. 2022 Sep 13;6(17):5132-5145. doi: 10.1182/bloodadvances.2022007334.

Helpful Links

Related Info

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 28, 2017

Primary Completion (Actual)

May 28, 2021

Study Completion (Estimated)

June 30, 2024

Study Registration Dates

First Submitted

August 30, 2017

First Submitted That Met QC Criteria

August 30, 2017

First Posted (Actual)

August 31, 2017

Study Record Updates

Last Update Posted (Estimated)

January 23, 2024

Last Update Submitted That Met QC Criteria

January 4, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Drug therapy

Other Study ID Numbers

Pevonedistat-3001
2017-000318-40 (EudraCT Number)
U1111-1189-8055 (Other Identifier: World Health Organization)
MOH_2018-02-04_002154 (Other Identifier: CRS)
JapicCTI-183848 (Registry Identifier: JapicCTI)
NCI-2017-02059 (Other Identifier: National Cancer Institute)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD Sharing Access Criteria

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

IPD Sharing Supporting Information Type

STUDY_PROTOCOL
SAP
ICF
CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Time Frame: Up to data cut-off date: 28 May 2021 (up to approximately 42 months)	Overall survival was defined as the time from randomization to death from any cause.	Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
Kaplan-Meier Estimates of Six-Month Survival Rate Time Frame: Up to Month 6	Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented.	Up to Month 6
Kaplan-Meier Estimates of One-Year Survival Rate Time Frame: Up to Year 1	Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of the first year from randomization are presented.	Up to Year 1
Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30 Time Frame: Up to Day 30	30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug.	Up to Day 30
Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60 Time Frame: Up to Day 60	60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug.	Up to Day 60
Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants Time Frame: From randomization until transformation to AML till data cut-off date: 28 May 2021 (up to approximately 42 months)	Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.	From randomization until transformation to AML till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi) Time Frame: From randomization until CR till data cut-off date: 28 May 2021 (up to approximately 42 months)	CR for HR MDS or CMML is defined as <=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to >=11 gram per deciliter (g/dL) hemoglobin (Hgb),>=10010^9/liter (/L) platelets (pl),>=1.010^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.010^9/L and pl of >=10010^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.010^9/L) or thrombocytopenia (pl<10010^9/L).	From randomization until CR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With CR and Marrow CR Time Frame: From randomization until CR or marrow CR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS or CMML are based on the International Working Group (IWG) Response Criteria for MDS. CR for HR MDS or CMML is defined as <=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and >=11 g/dL Hgb, >=10010^9/L platelets (pl), >=1.010^9/L neutrophils and 0% blasts in peripheral blood. Marrow CR: Bone marrow: <=5% myeloblasts and decrease by >=50% over pretreatment.	From randomization until CR or marrow CR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI) Time Frame: From randomization until, CR, PR or HI till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hgb, >=10010^9/L pl, >=1.010^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: <=5% myeloblasts and decrease by >=50% over pretreatment. PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still >5%. HI: Hgb increase >=1.5 g/dL if <11 g/dL; pl increase >=3010^9/L if baseline>2010^9/L or increase from <2010^9/L to >2010^9/L and by at least 100%; neutrophil increase by 100% and absolute increase of >0.510^9/L if baseline <1.010^9/L.	From randomization until, CR, PR or HI till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With CR and Marrow CR and PR Time Frame: From randomization until CR or Marrow CR and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hgb, >=10010^9/L pl, >=1.010^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: <=5% myeloblasts and decrease by >=50% over pretreatment. PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still >5%.	From randomization until CR or Marrow CR and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI) Time Frame: From randomization until CR, marrow CR, PR or HI till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hgb, >=10010^9/L pl, >=1.010^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: <=5% myeloblasts and decrease by >=50% over pretreatment. PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still>5%. HI: Hgb increase >=1.5 g/dL if baseline <11 g/dL; pl increase >=3010^9/L if baseline>2010^9/L or increases from <2010^9/L to >2010^9/L and by at least 100%; neutrophil increases by 100% and absolute increases of >0.510^9/L if baseline <1.010^9/L.	From randomization until CR, marrow CR, PR or HI till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With Overall Response (OR) Time Frame: From randomization until CR and PR or CR, CRi and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR or PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hgb, >=10010^9/L pl, >=1.010^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still>5%. For low-blast AML-CR:morphologic leukemia-free state>1.010^9 neutrophils, >=10010^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia <1.010^9/L or pl <10010^9/L; PR: all CR hematological values but >=50% decrease in bone marrow aspirate.	From randomization until CR and PR or CR, CRi and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With Overall Response 2 (OR2) Time Frame: From randomization until, CR, PR or HI or CR, CRi or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	OR2=participant with best overall response of CR+PR+HI in HR MDS/CMML participants,or of CR+CRi+PR in low-blast AML participants.CR:≤5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,≥11g/dL Hgb,≥10010^9/L pl,≥1.010^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still >5%;HI:Hgb increase(inc) ≥1.5g/dL if baseline(BL)<11 g/dL;pl inc≥3010^9/L if BL>2010^9/L or inc from <2010^9/L to >2010^9/L and by 100%;neutrophil inc by 100%;absolute inc of >0.510^9/L if BL<10010^9/L.For low-blast AML-CR:morphologic leukemia-free state >1.010^9 neutrophils,≥10010^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia <1.010^9/L or pl<10010^9/L;PR:all CR hematological values but ≥50% decrease in BM aspirate.Number of responders determined by independent review committee(IRC) assessment.	From randomization until, CR, PR or HI or CR, CRi or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Duration of Complete Remission (CR) Time Frame: From CR until first documentation of PD or relapse from CR or relapse after CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. CR for HR MDS or CMML is defined as <=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to >=11 g/dL Hgb,>=10010^9/L pl,>=1.010^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.010^9/L and pl of >=10010^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.010^9/L) or thrombocytopenia (pl<10010^9/L).	From CR until first documentation of PD or relapse from CR or relapse after CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi) Time Frame: From CR until first documentation of PD or relapse from CR or relapse after CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). Disease responses for low-blast AML were based on the Revised IWG Response Criteria for AML. CR is defined as <=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to >=11 g/dL hemoglobin (Hgb),>=10010^9/liter (/L) platelets (pl),>=1.010^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.010^9/L and pl of >=10010^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.010^9/L) or thrombocytopenia (pl<10010^9/L).	From CR until first documentation of PD or relapse from CR or relapse after CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Duration of Overall Response (OR) Time Frame: Up to data cut-off date: 28 May 2021 (up to approximately 42 months)	Duration of OR: response to first documentation of PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML. Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR+PR for HR MDS/CMML and CR+Cri+ PR for low-blast AML.CR for HR MDS/CMML:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11 g/dL Hgb,>=10010^9/L pl,>=1.010^9/L neutrophils,0% blasts in peripheral blood and PR:all CR criteria met except bone marrow blasts>=50% decrease over pretreatment but still >5%. For low-blast AML-CR: morphologic leukemia-free state >1.010^9 neutrophils,>=10010^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with CRi: fulfill CR criteria except residual neutropenia <1.010^9/L or pl <10010^9/L; PR: all CR hematological values but >=50% decrease in % of blasts in bone marrow aspirate.	Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
Duration of Overall Response 2 (OR2) Time Frame: Up to data cut-off date: 28 May 2021 (up to approximately 42 months)	Duration of OR2: from date of first documentation of CR+PR+HI to first documentation of PD/relapse after CR/PR for responders of CR+PR+HI for HR MDS/CMML and CR,CRi,PR for low-blast AML. For HR MDS/CMML-CR:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11 g/dL Hgb, >=10010^9/L pl,>=1.010^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts>=50% decrease over pretreatment, still >5%; HI:Hgb inc >=1.5 g/dL if baseline <11 g/dL; pl inc>=3010^9/L if baseline>2010^9/L or inc from<2010^9/L to>2010^9/L by at least 100%; neutrophil inc by 100% and absolute inc of >0.510^9/L if baseline <1.010^9/L.For low-blast AML-CR: morphologic leukemia-free state,>1.010^9 neutrophils,>=10010^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi: fulfill CR criteria except residual neutropenia<1.010^9/L or pl <10010^9/L;PR:all CR hematological values but>=50% decrease in bone marrow aspirate.	Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence Time Frame: Up to data cut-off date: 28 May 2021 (up to approximately 42 months)	A participant was defined as RBC or platelet-transfusion independent if he/she received no RBC or platelet transfusions for a period of at least 8 weeks before the first dose of study drug through 30 days after the last dose of any study drug. Rate of transfusion independence was defined as number of participants who became transfusion independent divided by the number of participants who were transfusion dependent at Baseline.	Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence Time Frame: Up to data cut-off date: 28 May 2021 (up to approximately 42 months)	Duration of RBC and platelet transfusion independence was defined as the longest time between the last RBC and/or platelet transfusion before the start of the RBC and/or platelet transfusion-independent period and the first RBC and/or platelet transfusion after the start of the transfusion-independent period, which occurs >= 8 weeks later.	Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi) Time Frame: From randomization until CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Time to first CR or PR is defined as the time from randomization to first documented CR or PR, whichever occurs first. Disease responses for HR MDS or CMML or low-blast AML cycle 6 are based on Modified IWG Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. For HR MDS or CMML-CR:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11 g/dL Hgb,>=10010^9/L pl,>=1.010^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts>=50% decrease over pretreatment but still>5%; For low-blast AML-CR: morphologic leukemia-free state,>1.010^9/L neutrophils, pl>=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia<1.010^9/L or pl <10010^9/L; PR: all CR hematological values but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.	From randomization until CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With Hematologic Improvement (HI) Time Frame: From randomization until HI till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. HI: Hgb increase >=1.5 g/dL if baseline <11 g/dL; pl increase >=3010^9/L if baseline >2010^9/L or increase from <2010^9/L to >2010^9/L by at least 100%; neutrophil increase by 100% and absolute increase of >0.510^9/L if baseline <1.010^9/L.	From randomization until HI till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML Time Frame: From randomization until transformation to AML or until initiation of subsequent therapy till data cut-off date: 28 May 2021 (up to approximately 42 months)	Inpatient hospital admission data was collected through transformation to AML (HR MDS/CMML participants) or disease progression (low-blast AML participants) or until initiation of subsequent therapy (all participants), whichever occurred first. Transformation to AML is defined, according to WHO Classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.	From randomization until transformation to AML or until initiation of subsequent therapy till data cut-off date: 28 May 2021 (up to approximately 42 months)
Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death Time Frame: From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first till data cut-off date: 28 May 2021 (up to approximately 42 months)	Time to PD, relapse after CR(low-blast AML), relapse after CR or PR(HR MDS/CMML), or death,defined as time from date of randomization until date of first documentation of PD,relapse after CR(low-blast AML),relapse after CR or PR(HR MDS/CMML),or death due to any cause, whichever occurs first. In HR MDS/CMML,PD: Participants with<5% blasts:>=50% inc >5% blasts, with 5%-9% blasts:>=50% inc>10% blasts, with 10%-19% blasts:>=50% inc >20% blasts,with 20%-30% blasts, at least 50% decrement from maximum remission/response in granulocytes or pl or reduction in Hgb by>=2 g/dL/new transfusion dependence.Relapse after CR or PR: return to pretreatment bone marrow blast %/Decrement of >=50% from maximum remission/response levels in granulocytes/pl/reduction in Hgb conc.>=1.5 g/dL/transfusion dependence. In AML,PD:>50% inc in bone marrow blasts to >30% blasts,>50% inc in circulating blasts to>30% blasts in peripheral blood, Development of extramedullary disease/new sites of extramedullary leukemia.	From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first till data cut-off date: 28 May 2021 (up to approximately 42 months)
Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Time Frame: Up to data cut-off date: 28 May 2021 (up to approximately 42 months)	The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL. The percentage of participants for each parameter score were categorized as improved, stable, and worsened. Only categories with at least one participant with event are reported.	Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
Plasma Concentration of Pevonedistat Time Frame: Cycle 1 Day 1 predose and multiple time points (up to 4 hours) post dose; Cycle 1 Days 3 and 5 predose; Cycle 2 and 4 Day 1 at multiple time points (up to 3 hours) post dose; Cycle 4 Day 3 predose (Cycle length= 28 days)		Cycle 1 Day 1 predose and multiple time points (up to 4 hours) post dose; Cycle 1 Days 3 and 5 predose; Cycle 2 and 4 Day 1 at multiple time points (up to 3 hours) post dose; Cycle 4 Day 3 predose (Cycle length= 28 days)
Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group Time Frame: From randomization until CR, CRi and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)	Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR + PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hgb, >=10010^9/L pl, >=1.010^9/L neutrophils,0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts>=50% decrease over pretreatment but still>5%. For low-blast AML-CR: morphologic leukemia-free state, >1.010^9 neutrophils,>=10010^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia<1.010^9/L or pl<10010^9/L; PR: all CR hematological values but>=50% decrease in the percentage of blasts to 5% to 25% in bone marrow aspirate.	From randomization until CR, CRi and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group Time Frame: From randomization until transformation to AML if eligible or death till data cut-off date: 28 May 2021 (up to approximately 42 months)	Event was defined as death or transformation to AML in participants with MDS or CMML, whichever occurred first. Transformation to AML was defined, according to World Health Organization (WHO) Classification as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Event was defined as death in participants with low-blast AML.	From randomization until transformation to AML if eligible or death till data cut-off date: 28 May 2021 (up to approximately 42 months)
Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group Time Frame: From randomization until death till data cut-off date: 28 May 2021 (up to approximately 42 months)	OS was calculated from date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored as of the date the participant was last known to be alive.	From randomization until death till data cut-off date: 28 May 2021 (up to approximately 42 months)
Number of Participants With Overall Response by Cycle 6 Time Frame: Up to Cycle 6 (up to approximately Day 168)	Responses for HR MDS/CMML are based on Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR+CR with incomplete blood count recovery(CRi)+PR for low-blast AML. CR for HR MDS/CMML:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11g/dL hemoglobin (Hgb),>=10010^9/L platelet (pl),>=1.010^9/L neutrophils, 0% blasts in peripheral blood, and PR:all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still >5%. For low-blast AML-CR:morphologic leukemia-free state,>1.010^9 neutrophils, >=10010^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia <1.010^9/L/thrombocytopenia (pl<10010^9/L); PR:all CR hematological values but>=50% decrease in percentage of blasts to 5%-25% in bone marrow aspirate.	Up to Cycle 6 (up to approximately Day 168)

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) (PANTHER)

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

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