Clinical trial NCT02610777: 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)
Official title: A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myelogenous Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Acute
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-11-20
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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).

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomization until death (up to 3 years and 5 months)
Secondary outcomes:
measure: Event-Free Survival (EFS)
timeFrame: From date of randomization until transformation to AML, or death due to any cause (up to approximately 5 years)
measure: Six-month Survival Rate
timeFrame: Month 6
measure: One-year Survival Rate
timeFrame: Month 12
measure: Time to AML Transformation in HR MDS or CMML Participants
timeFrame: From date of randomization until transformation to AML (up to approximately 5 years)
measure: Percentage of Participants With Complete Remission (CR)
timeFrame: From date of randomization until CR (up to approximately 5 years)
measure: Percentage of Participants With CR and Partial Remission (PR)
timeFrame: From date of randomization until CR and PR (up to approximately 5 years)
measure: Percentage of Participants With Overall Response
timeFrame: From date of randomization until CR, PR, or hematologic improvement (HI) (up to approximately 5 years)
measure: Percentage of Participants With CR in Low-blast AML
timeFrame: From date of randomization until CR (up to approximately 5 years)
measure: Percentage of Participants With CR by Cycle 4
timeFrame: From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)
measure: Percentage of Participants With CR and PR by Cycle 4
timeFrame: From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)
measure: Percentage of Participants With Overall Response by Cycle 4
timeFrame: From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)
measure: Percentage of Participants With CR in Low-blast AML by Cycle 4
timeFrame: From the date of randomization until CR by Cycle 4 (cycle length=28 days)
measure: Duration of Complete Remission (CR)
timeFrame: From date of randomization until CR (up to approximately 5 years)
measure: Duration of Complete Remission (CR) and Partial Remission (PR)
timeFrame: From date of randomization until CR or PR (up to approximately 5 years)
measure: Duration of Overall Response
timeFrame: From date of randomization until CR, PR or HI (up to approximately 5 years)
measure: Duration of Complete Remission (CR) in Low-blast AML
timeFrame: From date of randomization until CR (up to approximately 5 years)
measure: Time to First CR or PR
timeFrame: From date of randomization until CR or PR (up to approximately 5 years)
measure: Time to Subsequent Therapy
timeFrame: From date of randomization up to approximately 5 years
measure: Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence
timeFrame: 8 weeks before randomization through 30 days after last dose of any study drug (up to approximately 5 years and 3 months)
measure: Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
timeFrame: From date of randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 5 years)
measure: Time to Progressive Disease (PD), Relapse, or Death
timeFrame: From date of randomization until PD, relapse or death (up to approximately 5 years)
measure: Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
measure: Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs
timeFrame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
measure: Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
measure: Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs
timeFrame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
measure: Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs
timeFrame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Little Rock
country: United States
facility: Greenville Health System
state: Arkansas
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Riverside
country: United States
facility: Compassionate Cancer Care Medical Group Incorporated
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Center at Yale New Haven Hospital
state: Connecticut
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: New Braunfels
country: United States
facility: Cancer Care Center of South Texas
state: Texas
city: The Woodlands
country: United States
facility: Nebraska Cancer Specialists
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Waco, TX
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Spokane
country: United States
facility: Medical Oncology Associates
state: Washington
city: Yakima
country: United States
facility: Yakima Valley Memorial Hospital
state: Washington
city: Brugge
country: Belgium
facility: AZ Sint-Jan AV
state: West-Vlaanderen
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi asbl
city: Yvoir
country: Belgium
facility: Cliniques Universitaires UCL de Mont-Godinne
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EAD
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Haematological Diseases - Sofia
city: Sofia
country: Bulgaria
facility: University Multi-Profile Hospital for Active Treatment Dr Georgi Stranski
city: Toronto
country: Canada
facility: Sunnybrook Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Brno
country: Czechia
facility: Fakultni Nemocnice Brno
city: Praha 10
country: Czechia
facility: Fakultni Nemocnice Kralovske Vinohrady
city: Grenoble
country: France
facility: CHU de GRENOBLE
city: Lille
country: France
facility: CHRU Lille
city: Paris
country: France
facility: Hopital Saint Louis
city: Dusseldorf
country: Germany
facility: Marien Hospital Akademisches Lehrkrankenhaus
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Dublin
country: Ireland
facility: Tallaght Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Safed
country: Israel
facility: ZIV Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi Melacrino Morelli
city: Torino
country: Italy
facility: Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino
city: Sittard
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Baleares
city: Pozuelo De Alarcon
country: Spain
facility: Hospital Universitario Quironsalud Madrid
state: Madrid
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: Barcelona
country: Spain
facility: ICO I'Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet (ICO)
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga - Hospital Universitario Virgen de la Victoria
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.