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)
Myelodysplastic Syndrome, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute
About this trial
This is an interventional treatment trial for Myelodysplastic Syndrome focused on measuring Drug therapy
Eligibility Criteria
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.
Sites / Locations
- Southern Cancer Center - USOR
- Southern Cancer Center - USOR
- Southern Cancer Center - USOR
- Southern Cancer Center- USOR
- Southeastern Regional Medical Center - CTCA - PPDS
- Arizona Oncology Associates (Orange HOPE) - USOR
- Arizona Oncology Associates (Rudasill HOPE) - USOR
- Arizona Oncology Associates (Wilmot HOPE) - USOR
- Compassionate Care Research Group Inc. at Compassionate Cancer Care Medical Group, Inc
- Compassionate Cancer Care Medical Group Inc
- UC San Diego Moores Cancer Center
- Emad Ibrahim, MD, Inc
- Compassionate Care Research Group Inc. at Compassionate Cancer Care Medical Group, Inc
- Rocky Mountain Cancer Centers (Aurora) - USOR
- Rocky Mountain Cancer Centers (Boulder) - USOR
- Rocky Mountain Cancer Centers (Colorado Springs) - USOR
- Quest Diagnostics, INC
- Colorado Blood Cancer Institute - PPDS
- Presbyterian Saint Lukes Medical Center Laboratory
- Presbyterian/St. Luke's Medical Center
- Rocky Mountain Cancer Centers (Williams) - USOR
- Rocky Mountain Cancer Centers (Denver) - USOR
- Kaiser Foundation Health Plan
- Laboratory Corporation of America
- Rocky Mountain Cancer Centers (Lakewood) - USOR
- Rocky Mountain Cancer Centers (Littleton) - USOR
- Rocky Mountain Cancer Centers (Lone Tree) - USOR
- Rocky Mountain Cancer Centers (Longmont) - USOR
- Rocky Mountain Cancer Centers (Parker) - USOR
- Rocky Mountain Cancer Centers (Pueblo) - USOR
- Rocky Mountain Cancer Centers (Thornton) - USOR
- Medstar Research Institute
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- SCRI Florida Cancer Specialists South
- SCRI Florida Cancer Specialists South
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- SCRI Florida Cancer Specialists South
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- SCRI Florida Cancer Specialists South
- SCRI Florida Cancer Specialists South
- SCRI Florida Cancer Specialists South
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Mayo Clinic Jacksonville - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- University of Miami Miller School of Medicine
- Baptist Health System (N Kendall) - USOR
- SCRI Florida Cancer Specialists South
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- SCRI Florida Cancer Specialists South
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- SCRI Florida Cancer Specialists South
- SCRI Florida Cancer Specialists South
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- SCRI Florida Cancer Specialists South
- SCRI Florida Cancer Specialists South
- Cleveland Clinic Florida
- Florida Cancer Specialists - NORTH - SCRI - PPDS
- Winship Cancer Institute, Emory University
- Saint Alphonsus Regional Medical Center
- Saint Alphonsus Caldwell Cancer Care Center
- Saint Alphonsus Medical Center
- Rush University Medical Center
- Menorah Medical Center
- Centerpoint Medical Center
- HCA Midwest Health - SCRI - PPDS
- Research Medical Center
- Nebraska Cancer Specialists
- New Jersey Hematology Oncology Associates LLC
- John Theurer Cancer Center
- New Jersey Hematology and Oncology
- Weill Cornell Medical Center - Monitoring Location
- Weill Cornell Medical Center
- Strong Memorial Hospital
- University of North Carolina at Chapel Hill
- Oncology Hematology Care, Inc.
- Oncology Hematology Care, Inc.
- Oncology Hematology Care Inc - USOR
- Oncology Hematology Care Inc - USOR
- Fairview Hospital
- The Cleveland Clinic Foundation
- Oncology Hematology Care, Inc - Fairfield
- Hillcrest Hospital Cancer Care Center
- St. Luke's Hospital
- St. Luke's University Health Network
- Greenville Health System
- Greenville Health System
- Greenville Health System Cancer Institute
- Greenville Health System
- Greenville Health System
- Greenville Health System
- Tennessee Oncology - DICKSON - SCRI - PPDS
- Tennessee Oncology - FRANKLIN - SCRI - PPDS
- Tennessee Oncology - GALLATIN - SCRI - PPDS
- Tennessee Oncology - SUMMIT - SCRI - PPDS
- Tennessee Oncology - LEBANON - SCRI - PPDS
- Tennessee Oncology - MURFREESBORO - SCRI - PPDS
- Sarah Cannon Center for Blood Centers - SCRI - PPDS
- Tennessee Oncolgy - BAPTIST - SCRI - PPDS
- Tennessee Oncology NASH - SCRI - PPDS
- Tennessee Oncology - ST THOMAS WEST - SCRI - PPDS
- Tennessee Oncology SKYLINE - SCRI - PPDS
- Tennessee Oncology - SOUTHERN HILLS - SCRI - PPDS
- Tennessee Oncology - SHELBYVILLE - SCRI - PPDS
- Tennessee Oncology - SMYRNA - SCRI - PPDS
- Texas Oncology (West 38) - USOR
- Texas Oncology (Balcones) - USOR
- Texas Oncology (James Casey) - USOR
- Texas Oncology (Medical City) - USOR
- Baylor Sammons Cancer Center
- University of Texas Southwestern Medical Center
- Texas Oncology (Tyler) - USOR
- Texas Oncology (E Common) - USOR
- Texas Oncology (Round Rock) - USOR
- Texas Oncology - San Antonio Medical Center - USOR
- Texas Oncology (Tyler) - USOR
- Oncology and Hematology Associates of Southwest Virginia (Blacksburg) - USOR
- University of Virginia
- Oncology and Hematology Associates of Southwest Virginia (Low Moor) - USOR
- Oncology and Hematology Associates of Southwest Virginia (Roanoke) - USOR
- Oncology and Hematology Associates of Southwest Virginia Inc
- Oncology and Hematology Associates of Southwest Virginia
- Icon Cancer Care Wesley
- Icon Cancer Care Chermside
- Icon Cancer Care South Brisbane
- Icon Cancer Care
- Icon Cancer Care Southport
- Royal Hobart Hospital
- Liverpool Hospital
- Algemeen Ziekenhuis Klina
- CHU UCL Namur asbl - Site Godinne
- AZ Sint-Jan AV
- Cliniques Universitaires Saint-Luc
- UZ Leuven
- Liga Paranaense de Combate Ao Cancer - Hospital Erasto Gaertner
- Liga Norte Riograndense Contra O Cancer
- Centro de Pesquisas Oncologicas
- Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
- Universidade Federal do Rio de Janeiro - UFRJ
- Hospital Santa Marcelina
- Hospital Santa Marcelina
- Tom Baker Cancer Centre
- University of Alberta
- Kaye Edmonton Clinic
- Saint John Regional Hospital
- Sunnybrook Health Sciences Centre
- Princess Margaret Hospital
- Princess Margaret Hospital
- Xuanwu Hospital Capital Medical University
- Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
- Fakultni nemocnice Hradec Kralove
- Vseobecna Fakultni Nemocnice V Praze
- Fakultni nemocnice Kralovske Vinohrady
- Hopital Cote de Nacre
- CHU Angers
- Centre Hospitalier Le Mans
- Hopital Saint Louis
- Hopital Saint Louis
- Universitatsklinikum Tubingen
- Universitatsklinikum Leipzig
- Universitatsklinikum Carl Gustav Carus an der TU Dresden
- Marien Hospital Akademisches Lehrkrankenhaus
- Laiko General Hospital of Athens
- Athens General Hospital 'G Gennimatas'
- Attikon University General Hospital
- University Hospital of Alexandroupolis
- Laiko General Hospital of Athens
- University General Hospital of Ioannina
- University General Hospital of Larissa
- University General Hospital of Patras
- Georgios Papanikolaou General Hospital of Thessaloniki
- Edith Wolfson Medical Center
- Shaare Zedek Medical Center
- Hadassah Medical Center PPDS -
- Galilee Medical Center
- ZIV Medical Center
- Tel Aviv Sourasky Medical Center PPDS
- Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
- ASST degli Spedali Civili di Brescia - Spedali Civili di Brescia - INCIPIT - PIN
- Azienda Ospedaliera Universitaria Careggi
- IRCCS Centro Di Riferimento Oncologico Della Basilicata
- Istituto Clinico Humanitas
- Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino
- Japan Mutual Aid Association of Public School Teachers Chugoku Central Hospital
- Hokkaido University Hospital
- Fukushima Medical University Hospital
- Kobe City Medical Center General Hospital
- University Hospital, Kyoto Prefectural University of Medicine
- Kindai University Hospital
- Saitama Medical Center
- Juntendo University Hospital
- NTT Medical Center Tokyo
- Kyushu University Hospital
- Dokkyo Medical University Hospital
- Nagasaki University Hospital
- Osaka Metropolitan University Hospital
- Yokohama City University Hospital
- University of Fukui Hospital
- Pusan National University Hospital
- Kyungpook National University Hospital
- Chonnam National University Hwasun Hospital
- Asan Medical Center - PPDS
- Samsung Medical Center - PPDS
- The Catholic University of Korea, Seoul St. Mary's Hospital
- Hematologica Alta Especialidad S.C.
- Capital Humano para Investigacion Clinica SC
- Instytut Hematologii i Transfuzjologii
- Uniwersyteckie Centrum Kliniczne, Klinika Hematologii I Transplantologii, Budynek Centrum Medycyny N
- Uniwersyteckie Centrum Kliniczne
- Swietokrzyskie Centrum Onkologii
- Centrum Onkologii Ziemi Lubelskiej
- Zaklad Diagnostyki Obrazowej SOR
- Szpital Wojewodzki w Opolu
- City Clinical Hospital # 40
- North-West Federal Medical Research Center n.a. V.A. Almazov
- Russian Research Institute of Hematology and Blood Transfusion
- ICO lHospitalet Hospital Duran i Reynals
- Complejo Asistencial Universitario de Leon
- Hospital Universitario Vall d'Hebron - PPDS
- Hospital Universitario de La Princesa
- Hospital General Universitario Gregorio Maranon
- Hospital Universitario Ramon y Cajal
- Hospital Universitario La Paz - PPDS
- Complejo Asistencial Universitario de Salamanca - H. Clinico
- Hospital Clinico Universitario de Valencia
- Hospital Universitari i Politecnic La Fe de Valencia
- Gazi University Medical Faculty Gazi Hospital
- Ege University Medical Faculty
- Mersin University Medical Faculty
- Ondokuz Mayis Universitesi Tip Fakultesi Hastanesi
- Namik Kemal University
- Karadeniz Technical University Faculty of Medicine
- Royal Bournemouth Hospital
- Maidstone Hospital
- St Bartholomew's Hospital
- Singleton Hospital - PPDS
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2 + 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.
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.