An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)

NCT ID: NCT02610777

Last Updated: 2022-09-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-14
• Study Completion Date: 2021-07-23

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.

Detailed Description

The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with MDS or CMML, or low-blast 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 120 participants. Once enrolled, participants will be randomly assigned (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 44 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 will enter event-free survival follow-up or response follow-up (study visits every 3 months) if their disease has not transformed to AML (for participants with HR MDS or CMML) or progressed (for participants with low-blast AML), and they have not started subsequent therapy. Participants will also enter overall survival follow-up (contacted every 3 months to document subsequent therapies and survival status).

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Azacitidine 75 mg/m^2

Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

Group Type: ACTIVE_COMPARATOR

Azacitidine

Intervention Type: DRUG

Azacitidine intravenous or subcutaneous formulation.

Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2

Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m\^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Azacitidine intravenous or subcutaneous formulation.

Pevonedistat

Intervention Type: DRUG

Pevonedistat intravenous infusion.

Interventions

Azacitidine

Azacitidine intravenous or subcutaneous formulation.

Intervention Type: DRUG

Pevonedistat

Pevonedistat intravenous infusion.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Male or female participants 18 years or older.

2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cells [WBC] <20,000 per microliter [/mcL]) or low blast AML based on 1 of the following:

French American British (FAB) Classifications:

• Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20% myeloblasts in the bone marrow.
• CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

OR

WHO Classifications:

• RAEB 1 - defined as having 5% to 9% myeloblasts in the bone marrow.
• RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
• CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
• CMML 1 (Although CMML 1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%.
• WHO defined AML with 20% to 30% myeloblasts in the bone marrow and <30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine based therapy.

3. For MDS and CMML participants, prognostic risk category, based on the Revised International Prognostic Scoring System (IPSS R), of:

• Very high (>6 points),
• High (>4.5 to 6 points), or
• Intermediate (>3 to 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.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

5. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):

• Albumin >2.7 g/dL.
• Total bilirubin <upper limit of normal (ULN) except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin <=1.5*ULN of the direct bilirubin.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5*ULN.
• Creatinine clearance >=50 milliliter per minutes (mL/min).
• Hb >8 g/dL. Participants may be transfused to achieve this value. Elevated indirect bilirubin due to post transfusion hemolysis is allowed.

6. For CMML participants: WBC count <20,000/mcL before administration of the first dose of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at least 1 week prior to WBC count assessment.

7. Ability to undergo the study required bone marrow sample collection procedures.

8. Suitable venous access for the study required blood sampling (that is, including pharmacokinetic (PK) and biomarker sampling).

9. Female participants who:

• Are postmenopausal for at least 1 year before the Screening visit , or
• Are surgically sterile, or
• If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

Male participants, even if surgically sterilized (that is, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

10. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria

1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.

2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.

3. Eligible for allogenic stem cell transplantation.

4. Participants with MDS, CMML, or low blast AML, whose only site of disease is extramedullary, example, the skin.

5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures or could limit participant expected survival to less than 6 months.

6. Treatment with any anti leukemic/anti MDS therapies (example, lenalidomide, cytarabine, anthracyclines, purine analogs) or with any investigational products within 14 days before the first dose of any study drug.

7. Known hypersensitivity to mannitol.

8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.

9. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (example, catheter, port) is not considered major surgery.

10. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.

11. Life threatening illness unrelated to cancer.

12. Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.

13. Known human immunodeficiency virus (HIV) seropositive.

14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (that is, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

16. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or IV) and/or myocardial infarction within 6 months prior to first dose, or severe pulmonary hypertension. As an example, well controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.

17. Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days before the first dose of study drug.

18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 12 months before the first dose of any study drug, except for hydroxyurea.

19. Female participants who are lactating and breast feeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

20. Female participants who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).

21. Male participants who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Millennium Pharmaceuticals, Inc.

Locations

University of Alabama

Birmingham, Alabama, United States

Greenville Health System

Little Rock, Arkansas, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

Compassionate Cancer Care Medical Group Incorporated

Riverside, California, United States

Rocky Mountain Cancer Centers

Aurora, Colorado, United States

Smilow Cancer Center at Yale New Haven Hospital

New Haven, Connecticut, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

San Juan Oncology Associates

Farmington, New Mexico, United States

Monter Cancer Center

Lake Success, New York, United States

Weill Cornell Medical College

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

Cancer Care Center of South Texas

New Braunfels, Texas, United States

Nebraska Cancer Specialists

The Woodlands, Texas, United States

Texas Oncology - Waco, TX

Tyler, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Medical Oncology Associates

Spokane, Washington, United States

Yakima Valley Memorial Hospital

Yakima, Washington, United States

AZ Sint-Jan AV

Bruges, West-Vlaanderen, Belgium

Grand Hopital de Charleroi asbl

Charleroi, , Belgium

Cliniques Universitaires UCL de Mont-Godinne

Yvoir, , Belgium

University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EAD

Sofia, , Bulgaria

Specialized Hospital for Active Treatment of Haematological Diseases - Sofia

Sofia, , Bulgaria

University Multi-Profile Hospital for Active Treatment Dr Georgi Stranski

Sofia, , Bulgaria

Sunnybrook Health Science Centre

Toronto, Ontario, Canada

Princess Margaret Hospital

Toronto, Ontario, Canada

Fakultni Nemocnice Brno

Brno, , Czechia

Fakultni Nemocnice Kralovske Vinohrady

Prague, , Czechia

CHU de GRENOBLE

Grenoble, , France

CHRU Lille

Lille, , France

Hopital Saint Louis

Paris, , France

Marien Hospital Akademisches Lehrkrankenhaus

Düsseldorf, , Germany

Universitatsklinikum Ulm

Ulm, , Germany

Tallaght Hospital

Dublin, , Ireland

University Hospital Galway

Galway, , Ireland

Shaare Zedek Medical Center

Jerusalem, , Israel

ZIV Medical Center

Safed, , Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi

Bologna, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Azienda Ospedaliera Bianchi Melacrino Morelli

Reggio Calabria, , Italy

Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino

Torino, , Italy

Zuyderland Medisch Centrum

Sittard, , Netherlands

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

Hospital Universitario Quironsalud Madrid

Pozuelo de Alarcón, Madrid, Spain

Hospital Universitario Germans Trias i Pujol

Badalona, , Spain

ICO I'Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet (ICO)

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital General Universitario Gregorio Maranon

Madrid, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Hospital Regional Universitario de Malaga - Hospital Universitario Virgen de la Victoria

Málaga, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Hospital Clinico Universitario de Valencia

Valencia, , Spain

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, , Spain

Countries

United States; Belgium; Bulgaria; Canada; Czechia; France; Germany; Ireland; Israel; Italy; Netherlands; Spain

References

Sekeres MA, Watts J, Radinoff A, Sangerman MA, Cerrano M, Lopez PF, Zeidner JF, Campelo MD, Graux C, Liesveld J, Selleslag D, Tzvetkov N, Fram RJ, Zhao D, Bell J, Friedlander S, Faller DV, Ades L. Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia. 2021 Jul;35(7):2119-2124. doi: 10.1038/s41375-021-01125-4. Epub 2021 Jan 22. No abstract available.

Reference Type: DERIVED

PMID: 33483617 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U1111-1169-6540

Identifier Type: REGISTRY

Identifier Source: secondary_id

2015-000221-37

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

REec-2016-2145

Identifier Type: REGISTRY

Identifier Source: secondary_id

Pevonedistat-2001CTID

Identifier Type: OTHER

Identifier Source: secondary_id

Pevonedistat-2001

Identifier Type: -

Identifier Source: org_study_id