Study of MLN4924 Plus Azacitidine in Treatment-naive Participants With Acute Myelogenous Leukemia (AML) Who Are 60 Years or Older

Study Overview
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Brief Summary
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The purpose of this study is to establish the maximum tolerated dose (MTD), and to assess the safety and tolerability of MLN4924 (pevonedistat) in combination with azacitidine in treatment naive participants with AML who were 60 years of age or older.

Official Title
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A Phase 1b, Open-Label, Dose-Escalation Study of MLN4924 Plus Azacitidine in Treatment-Naïve Patients With Acute Myelogenous Leukemia Who Are 60 Years or Older

Conditions
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Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: MLN4924
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with world health organization (WHO)-defined AML, 60 years of age or older, who are unlikely to benefit from standard induction therapy, defined as having at least 1 of the following: Greater than or equal to 75 years of age. Antecedent hematologic disease. Known adverse cytogenetic risk. Eastern Cooperative Oncology Group (ECOG) PS = 2. Participant must not have received definitive treatment for AML, defined as any prior chemotherapy with antileukemic activity. ECOG PS 0 to 2. Expected survival longer than 3 months from enrollment in the study. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence. Male participants who agree to practice effective barrier contraception or agree to practice true abstinence. Voluntary written consent must be given before performance of any study-related procedure. Suitable venous access for the study-required blood sampling. Clinical laboratory values as specified below within 3 days before the first dose of any study drug: •Total bilirubin must be less than or equal to (<=) the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be<=2.5*ULN. Serum creatinine <=1.5*ULN. Albumin greater than or equal to (>=) 27 grams per liter (g/L). Hemoglobin >9 grams per deciliter (g/dL). Note: It was permissible to transfuse participants with red blood cells to achieve this criterion. White blood cell (WBC) count less than (<) 50,000 per microliter (/mcL) before administration of pevonedistat on Days 1, 3, and 5 of Cycle 1. Note: Hydroxyurea could be used to control the level of circulating leukemic blast cell counts to no lower than 10,000/mcL while on pevonedistat. Able to undergo bone marrow aspiration and biopsy at screening. Exclusion Criteria: Previous treatment with azacitidine or decitabine. Known favorable cytogenetic risk. Any serious medical or psychiatric illness. Treatment with any investigational products. Known hypersensitivity to azacitidine or mannitol. 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. Active uncontrolled infection or severe infectious disease. Major surgery within 14 days before the first dose of study drug. Life-threatening illness unrelated to cancer. Clinically uncontrolled central nervous system (CNS) involvement. WBC count greater than (>) 50,000/ mcL. Prothrombin time (PT) or activated partial thromboplastin time (aPTT) >1.5* ULN or a history of coagulopathy or bleeding disorder Known human immunodeficiency virus (HIV) positive. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection Known hepatic cirrhosis or severe pre-existing hepatic impairment. Known cardiac/cardiopulmonary disease defined as 1 of the following: Uncontrolled high blood pressure (that is, systolic blood pressure >180 milliliter per mercury (mm Hg), diastolic blood pressure >95 mm Hg). Congestive heart failure New York Heart Association (NYHA) Class III or IV, or Class II with a recent decompensation that required hospitalization or referral to a heart failure clinic within 4 weeks before screening (see Section 15.4 of the protocol in Appendix 16.1.1). Cardiomyopathy or history of ischemic heart disease Participants with ischemic heart disease who had acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization (example, coronary artery bypass graft, stent) in the past 6 months were excluded. However, participants with ischemic heart disease who had ACS, MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms could be enrolled. Arrhythmia (example, history of polymorphic ventricular fibrillation or torsade de pointes). However, participants with <Grade 3 atrial fibrillation (a fib) for a period of at least 6 months could enroll. Grade 3 a fib is symptomatic and incompletely controlled medically, or controlled with device (example, pacemaker), or ablation. Participants with paroxysmal a fib were permitted to enroll. Implantable cardioverter defibrillator. Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing). Pulmonary arterial hypertension. Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines Left ventricular ejection fraction Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis. Body mass index >40 kilogram per square meter (kg/m^2). Treatment with CYP3A inducers within 14 days before the first dose of MLN4924. Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN4924 and Azacitidine<br> | Drug: MLN4924<br>* MLN4924 intravenously (IV) in AML participants in a 28-day cycle: MLN4924 on Days 1, 3, and 5 for Cycle 1 and all subsequent cycles<br>* Other names: Pevonedistat;Drug: Azacitidine<br>* Azacitidine (IV) or subcutaneously in AML participants in a 28-day cycle: - Azacitidine Days 1, 2, 3, 4, 5, 8, 9 in Cycle 1 and for all subsequent cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Baseline up to 30 days after the last dose of study drug (up to 5 years) | 
| Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings |  | Baseline up to 30 days after the last dose of study drug (up to 5 years) | 
| Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings |  | Baseline up to 30 days after the last dose of study drug (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length is equal to [=] 28 days) | 
| Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, AUC0-tau: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (Tau) for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, AUC0-tau: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (Tau) for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, CLp: Systemic Clearance for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, CLp: Systemic Clearance for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924 |  | Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days) | 
| Best Overall Response Rate | Disease response was based on best overall response as determined by an investigator based on revised recommendations of the International Working Group (IWG) Response Criteria for AML. Best overall response rate was defined as percentage of participants who had complete response (CR), partial response (PR), or CR/remission with incomplete blood count recovery (Cri). CR: free of leukemia-related symptoms, absolute neutrophil count (ANC) greater than (>)1.0*10^9 per liter (/L), platelet count greater than or equal to (>=) 100*10^9/L, normal bone marrow with <5 percent (%) blasts and no Auer rods. CRi: As per CR but with residual thrombocytopenia (platelet count <100*10^9/L) or residual neutropenia (ANC <1.0*10^9/L). PR: >=50% decrease bone marrow blasts to 5 to 25% abnormal cells, or CR with less than or equal to (<=) 5% blasts if Auer rods present. | Cycle(C)1Day(D)22 and at C2 between D20 and 28 and at C4 and beyond C4 after completion of every 3rd C between D15 and 28 up to 30 days after last dose of study drug/before start of subsequent antineoplastic therapy, if that occurred sooner(up to 5 years) | 
| Duration of Response | The duration of response was defined in participants with disease response (CR, CRi, or PR) as the time between the first documentation of response and disease progression. Duration of response was determined by an investigator based on revised recommendations of the IWG Response Criteria for AML. CR: free of leukemia-related symptoms, absolute neutrophil count (ANC) greater than (>)1.0*10^9 per liter (/L), platelet count greater than or equal to (>=) 100*10^9/L, normal bone marrow with <5 percent (%) blasts and no Auer rods. CRi: As per CR but with residual thrombocytopenia (platelet count <100*10^9/L) or residual neutropenia (ANC <1.0*10^9/L). PR: >=50% decrease bone marrow blasts to 5 to 25% abnormal cells, or CR with less than or equal to (<=) 5% blasts if Auer rods present. | From the date of first documented CR, PR or CRi up to the date of first disease progression (Up to 5 years) | 
| Overall Survival | Overall survival was defined as the time from the first dose of study drug to the date of death. The Kaplan-Meier method was used to estimate overall survival, along with the corresponding 95% confidence interval. | From the first dose of study drug up to date of death (up to 5 years) | 
| Thirty-day Mortality Rate |  | 30 days after the first dose of study drug in Cycle 1 (Cycle Length=28 days) | 
| Sixty-day Mortality Rate |  | 60 days after the first dose of study drug on Cycle 1 (Cycle Length=28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy