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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)

Primary Purpose

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

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Azacitidine

Pevonedistat

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring Drug Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female participants 18 years or older.
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.
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.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
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.
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.
Ability to undergo the study required bone marrow sample collection procedures.
Suitable venous access for the study required blood sampling (that is, including pharmacokinetic (PK) and biomarker sampling).
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).
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:

Previous treatment with decitabine or azacitidine or other hypomethylating agent.
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.
Eligible for allogenic stem cell transplantation.
Participants with MDS, CMML, or low blast AML, whose only site of disease is extramedullary, example, the skin.
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.
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.
Known hypersensitivity to mannitol.
Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
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.
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.
Life threatening illness unrelated to cancer.
Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.
Known human immunodeficiency virus (HIV) seropositive.
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.
Known hepatic cirrhosis or severe pre-existing hepatic impairment.
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.
Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days before the first dose of study drug.
Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 12 months before the first dose of any study drug, except for hydroxyurea.
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.
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).
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).

Sites / Locations

University of Alabama
Greenville Health System
UC San Diego Moores Cancer Center
Compassionate Cancer Care Medical Group Incorporated
Rocky Mountain Cancer Centers
Smilow Cancer Center at Yale New Haven Hospital
University of Miami Miller School of Medicine
H Lee Moffitt Cancer Center and Research Institute
University of Chicago Medical Center
Johns Hopkins University
San Juan Oncology Associates
Monter Cancer Center
Weill Cornell Medical College
Columbia University Medical Center
University of Rochester Medical Center
University of North Carolina at Chapel Hill
Cleveland Clinic
Cancer Care Center of South Texas
Nebraska Cancer Specialists
Texas Oncology - Waco, TX
University of Virginia
Medical Oncology Associates
Yakima Valley Memorial Hospital
AZ Sint-Jan AV
Grand Hopital de Charleroi asbl
Cliniques Universitaires UCL de Mont-Godinne
University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EAD
Specialized Hospital for Active Treatment of Haematological Diseases - Sofia
University Multi-Profile Hospital for Active Treatment Dr Georgi Stranski
Sunnybrook Health Science Centre
Princess Margaret Hospital
Fakultni Nemocnice Brno
Fakultni Nemocnice Kralovske Vinohrady
CHU de GRENOBLE
CHRU Lille
Hopital Saint Louis
Marien Hospital Akademisches Lehrkrankenhaus
Universitatsklinikum Ulm
Tallaght Hospital
University Hospital Galway
Shaare Zedek Medical Center
ZIV Medical Center
Tel Aviv Sourasky Medical Center
Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
Azienda Ospedaliera Universitaria Careggi
Azienda Ospedaliera Bianchi Melacrino Morelli
Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino
Zuyderland Medisch Centrum
Hospital Universitario Son Espases
Hospital Universitario Quironsalud Madrid
Hospital Universitario Germans Trias i Pujol
ICO I'Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet (ICO)
Hospital Clinic de Barcelona
Hospital General Universitario Gregorio Maranon
Hospital Universitario La Paz
Hospital Regional Universitario de Malaga - Hospital Universitario Virgen de la Victoria
Hospital Universitario de Salamanca
Hospital Clinico Universitario de Valencia
Hospital Universitari i Politecnic La Fe de Valencia

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Azacitidine 75 mg/m^2

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

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

Overall Survival (OS)

OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive. The Kaplan Meier estimates was used for the analysis.

Secondary Outcome Measures

Event-Free Survival (EFS)

EFS is defined as the time from the date of randomization to the date of the occurrence of an event. An event is defined as death or transformation to AML for HR MDS/CMML participants, whichever occurs first, or defined as death for low-blast AML participants. HR MDS/CMML participants without documented EFS event will be censored at the date of the last response assessment. HR MDS/CMML participants with no response assessment and no death will be censored at the date of randomization. Low-blast AML participants without documentation of death will be censored at the date the participant was last known to be alive. HR MDS/CMML participants who received alternative antineoplastic therapy before death or transformation to AML will be censored at the date of last adequate assessment prior to starting alternate antineoplastic therapy. The Kaplan-Meier estimate was used for the analysis.

Six-month Survival Rate

Kaplan-Meier estimate of probability of OS at the end of the month 6 from randomization.

One-year Survival Rate

Kaplan-Meier estimate of probability of OS at the end of the first year from randomization.

Time to AML Transformation in HR MDS or CMML Participants

Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants without documented AML transformation at the time of the analysis are censored at the date of the last assessment. Participants who died before progression to AML are censored at the date of death. Transformation to AML is 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%.

Percentage of Participants With Complete Remission (CR)

Disease responses for HR MDS or CMML is based on the modified International Working Group (IWG) response criteria for MDS and for low-blast AML on the revised IWG response criteria for AML. CR for HR MDS or CMML: <= 5% myeloblasts with normal maturation of all cell lines in the bone marrow, and >= 11 gram/deciliter (g/dL) hemoglobin (Hb), >=100*10^9/liter (/L) platelets (plt), >=1.0*10^9/L absolute neutrophil count (ANC) and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). The percentages are rounded off to report the nearest whole numbers.

Percentage of Participants With CR and Partial Remission (PR)

Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow ,>=11 g/dL Hb;>=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood. PR for HR MDS/CMML:considered achieved if all CR criteria is met except for bone marrow blasts decreased by >=50%over pretreatment but still >5%. CR for low-blast AML: morphologic leukemia-free state, ANC of >1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML:fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP(<100*10^9/L). PR for low-blast AML:all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. The percentages are rounded off to report the nearest whole numbers.

Percentage of Participants With Overall Response

Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=100*10^9/L plt,>=1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,>=100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but>=50%less in BM aspirate. The percentages are rounded off to report the nearest whole numbers.

Percentage of Participants With CR in Low-blast AML

Disease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). The percentages are rounded off to report the nearest whole numbers.

Percentage of Participants With CR by Cycle 4

Disease responses for HR MDS or CMML were based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, ANC >=1.0*10^9/L and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). The percentages are rounded off to report the nearest whole numbers.

Percentage of Participants With CR and PR by Cycle 4

Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, >=11 g/dL Hb; >=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML: considered achieved if all CR criteria is met except for bone marrow blasts decreased by>=50% over pretreatment but still>5%.CR for low-blast AML: morphologic leukemia-free state, ANC of>1.0*10^9/L and plt of>=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP (<100*10^9/L). PR for low-blast AML: all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. The percentages are rounded off to report the nearest whole numbers.

Percentage of Participants With Overall Response by Cycle 4

Percentage of Participants With CR in Low-blast AML by Cycle 4

Disease response for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and ptl of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). The percentages are rounded off to report the nearest whole numbers.

Duration of Complete Remission (CR)

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≤5% myeloblasts with normal maturation of all cell lines in the bone marrow,≥11 g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L neutrophils;0% blasts in peripheral blood.CR for low-blast AML:morphologic leukemia-free state,neutrophils of<1.0*10^9/L;pl of≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia.CRi for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (pl<100*10^9/L).

Duration of Complete Remission (CR) and Partial Remission (PR)

Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). Disease responses (HR MDS/CMML) are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. For HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=100*10^9/L plt,>=1.0*10^9/L neutrophils, 0% blasts in peripheral blood;PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still >5%; low-blast AML-CR: morphologic leukemia-free state, >1.0*10^9/L ANC ,plt >=100*10^9/L,transfusion independence, no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia <1.0*10^9/L/TTP <100*10^9/L;PR:all CR hematological values but with a decrease of >=50% in blasts percentage to 5%-25% in bone marrow aspirate.

Duration of Overall Response

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(HR MDS/CMML): modified IWG criteria for MDS;low-blast AML: revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ Cri+PR.HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of BM cell lines,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0%blasts in peripheral blood; PR:CR criteria met except BM blasts≥50%less over pretreatment but still>5%; HI:hb increase(inc)≥1.5g/dL if baseline<11g/dL; plt inc≥30*10^9/L if baseline >20*10^9/L inc from<20*10^9/L->20*10^9/L,ANC inc by100%; absolute inc of >0.5*10^9/L if baseline <100*10^9/L.LB AML-CR: morphologic leukemia-freestate >1.0*10^9 ANC,≥100*1 ^9/Lplt, transfusion independence, no residual evidence of extramedullary leukemia; CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L; PR:all CR hematological values but>=50%less in BM aspirate.

Duration of Complete Remission (CR) in Low-blast AML

Disease responses for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).

Time to First CR or PR

Time to first CR or PR: time from randomization to first documented CR or PR, whichever occurs first. Disease responses (HR MDS/CMML) based on modified IWG response criteria for MDS; low-blast AML on revised IWG response criteria for AML. HR MDS/CMML-CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=100*10^9/L plt,>=1.0*10^9/L ANC, 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, >1.0*10^9/L ANC, plt >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia <1.0*10^9/L/TTP <100*10^9/L; PR: all CR hematological values but with a decrease of >=50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.

Time to Subsequent Therapy

Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study did not be counted as receiving subsequent therapy.

Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

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.

Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

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%. Percentage of participants was calculated as the total number of events divided by the total number of subject-years in each group.

Time to Progressive Disease (PD), Relapse, or Death

Time from randomization until PD/transformation to AML/relapse/death due to any cause, whichever occurs first. Relapse after CR or PR in MDS/CMML: return to pretreatment bone marrow blast % or decrement of >=50% from maximum remission levels in ANC or plt, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence. PD: at least 50% decrement from maximum remission in ANC or plt, or reduction in Hb by>=2g/dL or transfusion dependence;participants with <5% blasts: >=50% increase (inc) in blasts to >5%; 5%-10%: >=50% inc to >10%; 10%-20%: >=50% inc to>20%;20%-30%:>=50% inc to >30%. Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy). If there are no circulating blasts, bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later.

Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. A TEAE was defined as any adverse event occurring after the start of pevonedistat administration of the treatment period.

Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs

Laboratory assessments included clinical chemistry, hematology, and urinalysis.

Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status

Number of participants with change from Baseline in ECOG performance status was measured on 6 point scale to assess participant's performance status, where: Grade 0(Normal activity. Fully active, able to carry on all pre-disease activities without restriction); Grade 1(Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); Grade 2(In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours); Grade 3(In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours); Grade 4(100% bedridden. Completely disabled, cannot carry on any self-care, totally confined to bed or chair); Grade 5(Dead).

Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs

ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF.

Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs

Vital signs assessments included diastolic and systolic blood pressure, heart rate, and body temperature.

Full Information

NCT ID

NCT02610777

First Posted

November 18, 2015

Last Updated

August 24, 2022

Sponsor

Millennium Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02610777

Brief Title

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

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

April 14, 2016 (Actual)

Primary Completion Date

September 4, 2019 (Actual)

Study Completion Date

July 23, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Millennium Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Drug Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

120 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Azacitidine 75 mg/m^2

Arm Type

Active Comparator

Arm Description

Arm Title

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

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Intervention Description

Azacitidine intravenous or subcutaneous formulation.

Intervention Type

Drug

Intervention Name(s)

Pevonedistat

Intervention Description

Pevonedistat intravenous infusion.

Primary Outcome Measure Information:

Title

Overall Survival (OS)

Description

Time Frame

From date of randomization until death (up to 3 years and 5 months)

Secondary Outcome Measure Information:

Title

Event-Free Survival (EFS)

Description

Time Frame

From date of randomization until transformation to AML, or death due to any cause (up to approximately 5 years)

Title

Six-month Survival Rate

Description

Kaplan-Meier estimate of probability of OS at the end of the month 6 from randomization.

Time Frame

Month 6

Title

One-year Survival Rate

Description

Kaplan-Meier estimate of probability of OS at the end of the first year from randomization.

Time Frame

Month 12

Title

Time to AML Transformation in HR MDS or CMML Participants

Description

Time Frame

From date of randomization until transformation to AML (up to approximately 5 years)

Title

Percentage of Participants With Complete Remission (CR)

Description

Time Frame

From date of randomization until CR (up to approximately 5 years)

Title

Percentage of Participants With CR and Partial Remission (PR)

Description

Time Frame

From date of randomization until CR and PR (up to approximately 5 years)

Title

Percentage of Participants With Overall Response

Description

Time Frame

From date of randomization until CR, PR, or hematologic improvement (HI) (up to approximately 5 years)

Title

Percentage of Participants With CR in Low-blast AML

Description

Time Frame

From date of randomization until CR (up to approximately 5 years)

Title

Percentage of Participants With CR by Cycle 4

Description

Time Frame

From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)

Title

Percentage of Participants With CR and PR by Cycle 4

Description

Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, >=11 g/dL Hb; >=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML: considered achieved if all CR criteria is met except for bone marrow blasts decreased by>=50% over pretreatment but still>5%.CR for low-blast AML: morphologic leukemia-free state, ANC of>1.0*10^9/L and plt of>=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP (<100*10^9/L). PR for low-blast AML: all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. The percentages are rounded off to report the nearest whole numbers.

Time Frame

From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)

Title

Percentage of Participants With Overall Response by Cycle 4

Description

Time Frame

From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)

Title

Percentage of Participants With CR in Low-blast AML by Cycle 4

Description

Time Frame

From the date of randomization until CR by Cycle 4 (cycle length=28 days)

Title

Duration of Complete Remission (CR)

Description

Time Frame

From date of randomization until CR (up to approximately 5 years)

Title

Duration of Complete Remission (CR) and Partial Remission (PR)

Description

Time Frame

From date of randomization until CR or PR (up to approximately 5 years)

Title

Duration of Overall Response

Description

Time Frame

From date of randomization until CR, PR or HI (up to approximately 5 years)

Title

Duration of Complete Remission (CR) in Low-blast AML

Description

Time Frame

From date of randomization until CR (up to approximately 5 years)

Title

Time to First CR or PR

Description

Time Frame

From date of randomization until CR or PR (up to approximately 5 years)

Title

Time to Subsequent Therapy

Description

Time Frame

From date of randomization up to approximately 5 years

Title

Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

Description

Time Frame

8 weeks before randomization through 30 days after last dose of any study drug (up to approximately 5 years and 3 months)

Title

Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

Description

Time Frame

From date of randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 5 years)

Title

Time to Progressive Disease (PD), Relapse, or Death

Description

Time Frame

From date of randomization until PD, relapse or death (up to approximately 5 years)

Title

Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Description

Time Frame