Acute Myelogenous Leukemia
Conditions
Keywords
Drug Therapy
Brief summary
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.
Interventions
DRUGMLN4924
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
DRUGAzacitidine
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
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. ECOG PS 0 to 2. 3. Expected survival longer than 3 months from enrollment in the study. 4. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence. 5. Male participants who agree to practice effective barrier contraception or agree to practice true abstinence. 6. Voluntary written consent must be given before performance of any study-related procedure. 7. Suitable venous access for the study-required blood sampling. 8. 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. 9. Able to undergo bone marrow aspiration and biopsy at screening.
Exclusion criteria
1. Previous treatment with azacitidine or decitabine. 2. Known favorable cytogenetic risk. 3. Any serious medical or psychiatric illness. 4. Treatment with any investigational products. 5. Known hypersensitivity to azacitidine or mannitol. 6. 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. 7. Active uncontrolled infection or severe infectious disease. 8. Major surgery within 14 days before the first dose of study drug. 9. Life-threatening illness unrelated to cancer. 10. Clinically uncontrolled central nervous system (CNS) involvement. 11. WBC count greater than (\>) 50,000/ mcL. 12. Prothrombin time (PT) or activated partial thromboplastin time (aPTT) \>1.5\* ULN or a history of coagulopathy or bleeding disorder 13. Known human immunodeficiency virus (HIV) positive. 14. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection 15. Known hepatic cirrhosis or severe pre-existing hepatic impairment. 16. 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 17. Left ventricular ejection fraction 18. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis. 19. Body mass index \>40 kilogram per square meter (kg/m\^2). 20. Treatment with CYP3A inducers within 14 days before the first dose of MLN4924. 21. Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea.
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
| 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) | — |
| 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 | 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) | 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. |
| Duration of Response | From the date of first documented CR, PR or CRi up to the date of first disease progression (Up to 5 years) | 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. |
| Overall Survival | From the first dose of study drug up to date of death (up to 5 years) | 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. |
| 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) | — |
| 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) | — |
| 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) | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 8 investigative sites in the United states from 10 April 2013 to 08 April 2018.
Pre-assignment details
Participants diagnosed with acute myelogenous leukemia (AML) were enrolled to receive MLN4924 in combination with azacitidine intravenous during dose-escalation phase and MLN4924 in combination with azacitidine intravenous or subcutaneous during expansion phase.
Participants by arm
| Arm | Count |
|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous MLN4924 20 mg/m\^2, infusion, intravenously, once on Days 1, 3, and 5 in combination with azacitidine 75 mg/m\^2, infusion, intravenously, once on Days 1 through 5, 8 and 9 before administration of MLN4924 in a 28-day treatment cycle up to symptomatic deterioration or progressive disease (PD), or until treatment was discontinued for another reason (up to Cycle 53). | 32 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous MLN4924 20 mg/m\^2, infusion, intravenously, once on Days 1, 3, and 5 in combination with azacitidine 75 mg/m\^2, infusion, subcutaneously, once on Days 1 through 5, 8 and 9 before administration of MLN4924 in a 28-day treatment cycle up to symptomatic deterioration or PD, or until treatment was discontinued for another reason (up to Cycle 53). | 29 |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous MLN4924 30 mg/m\^2, infusion, intravenously, once on Days 1, 3, and 5 in combination with azacitidine 75 mg/m\^2, infusion, intravenously, once on Days 1 through 5, 8 and 9 before administration of MLN4924 in a 28-day treatment cycle up to symptomatic deterioration or PD, or until treatment was discontinued for another reason (up to Cycle 53). | 3 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 29 | 24 | 3 |
| Overall Study | Other | 3 | 5 | 0 |
Baseline characteristics
| Characteristic | Total | MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous |
|---|---|---|---|---|
| Age, Continuous | 75.2 years STANDARD_DEVIATION 6.09 | 74.7 years STANDARD_DEVIATION 6.28 | 75.2 years STANDARD_DEVIATION 6 | 80.3 years STANDARD_DEVIATION 3.21 |
| Body Surface Area (BSA) | 1.86 square meter (m^2) STANDARD_DEVIATION 0.257 | 1.88 square meter (m^2) STANDARD_DEVIATION 0.249 | 1.85 square meter (m^2) STANDARD_DEVIATION 0.256 | 1.79 square meter (m^2) STANDARD_DEVIATION 0.428 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 3 Participants | 5 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 28 Participants | 22 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 58 Participants | 27 Participants | 28 Participants | 3 Participants |
| Region of Enrollment United States | 64 Participants | 32 Participants | 29 Participants | 3 Participants |
| Sex: Female, Male Female | 30 Participants | 14 Participants | 14 Participants | 2 Participants |
| Sex: Female, Male Male | 34 Participants | 18 Participants | 15 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 29 / 32 | 24 / 29 | 3 / 3 |
| other Total, other adverse events | 32 / 32 | 29 / 29 | 3 / 3 |
| serious Total, serious adverse events | 21 / 32 | 22 / 29 | 3 / 3 |
Outcome results
Primary
Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings
Time frame: Baseline up to 30 days after the last dose of study drug (up to 5 years)
Population: The safety population was defined as all enrolled participants who receive at least 1 dose of any study drug, MLN4924 or azacitidine.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 15 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 10 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 5 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Renal impairment | 0 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Febrile neutropenia | 7 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 6 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 3 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 5 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 6 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Proteinuria | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood alkaline phosphatase increased | 7 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 6 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 2 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 6 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Proteinuria | 0 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 10 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 2 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 2 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood alkaline phosphatase increased | 0 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Febrile neutropenia | 12 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Renal impairment | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 3 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 3 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood alkaline phosphatase increased | 2 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 2 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Proteinuria | 0 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 0 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 2 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Renal impairment | 0 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 1 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 2 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 1 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 1 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 0 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 1 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Febrile neutropenia | 1 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 0 Participants |
Primary
Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings
Time frame: Baseline up to 30 days after the last dose of study drug (up to 5 years)
Population: The safety population was defined as all enrolled participants who receive at least 1 dose of any study drug, MLN4924 or azacitidine.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Orthostatic Hypotension | 1 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 3 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 4 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Orthostatic Hypotension | 0 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 6 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 1 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 0 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 0 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Orthostatic Hypotension | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to 30 days after the last dose of study drug (up to 5 years)
Population: The safety population was defined as all enrolled participants who receive at least 1 dose of any study drug, MLN4924 or azacitidine.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 32 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 21 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 29 Participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 22 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 3 Participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
Secondary
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.
Time frame: 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)
Population: The response-evaluable population was defined as all participants who received at least 1 dose of study drug, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Participants who were evaluable at a particular time point for this outcome measure were included in the assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Best Overall Response Rate | CRi | 4 percentage of participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Best Overall Response Rate | PR | 14 percentage of participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Best Overall Response Rate | CR | 43 percentage of participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Best Overall Response Rate | CRi | 13 percentage of participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Best Overall Response Rate | CR | 33 percentage of participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Best Overall Response Rate | PR | 13 percentage of participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Best Overall Response Rate | CRi | 0 percentage of participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Best Overall Response Rate | PR | 0 percentage of participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Best Overall Response Rate | CR | 50 percentage of participants |
Secondary
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
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | 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 5 | 1139.67 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 351.423 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | 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 | 1151.20 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 327.445 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | 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 5 | NA hour*nanogram per milliliter (hr*ng/mL) | — |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | 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 | 1805.47 hour*nanogram per milliliter (hr*ng/mL) | Standard Deviation 423.488 |
Secondary
Dose-escalation Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | 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 | 1020.32 hr*ng/mL | Standard Deviation 267.958 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924 | Cycle 1 Day 5 | 1039.54 hr*ng/mL | Standard Deviation 342.33 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | 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 | 1675.41 hr*ng/mL | Standard Deviation 398.425 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924 | Cycle 1 Day 5 | NA hr*ng/mL | — |
Secondary
Dose-escalation Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924 | Cycle 1 Day 1 | 1101.81 hr*ng/mL | Standard Deviation 310.114 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924 | Cycle 1 Day 1 | 1823.68 hr*ng/mL | Standard Deviation 420.948 |
Secondary
Dose-escalation Phase, CLp: Systemic Clearance for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 1 | 35.69 liter per hour (L/hr) | Standard Deviation 10.318 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 5 | 35.27 liter per hour (L/hr) | Standard Deviation 13.701 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 1 | 29.78 liter per hour (L/hr) | Standard Deviation 7.511 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 5 | NA liter per hour (L/hr) | — |
Secondary
Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924
Time frame: 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)
Population: The pharmacokinetic (PK)-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 1 | 173.60 nanogram per milliliter (ng/mL) | Standard Deviation 78.017 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 5 | 177.87 nanogram per milliliter (ng/mL) | Standard Deviation 67.767 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 1 | 306.67 nanogram per milliliter (ng/mL) | Standard Deviation 81.304 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 5 | NA nanogram per milliliter (ng/mL) | — |
Secondary
Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 1 | 2.34 ng/mL | Standard Deviation 1.987 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 5 | 1.40 ng/mL | Standard Deviation 0.208 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 1 | 1.68 ng/mL | Standard Deviation 0.45 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 5 | NA ng/mL | — |
Secondary
Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 1 | 0.09 1 per hour (1/hr) | Standard Deviation 0.013 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 5 | 0.09 1 per hour (1/hr) | Standard Deviation 0.009 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 1 | 0.09 1 per hour (1/hr) | Standard Deviation 0.009 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 5 | NA 1 per hour (1/hr) | — |
Secondary
Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924 | Cycle 1 Day 5 | 0.99 ratio | Standard Deviation 0.145 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924 | Cycle 1 Day 5 | NA ratio | — |
| Unknown | Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924 | Cycle 1 Day 1 | — ratio | — |
Secondary
Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 1 | 7.80 hour | Standard Deviation 1.126 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 5 | 7.98 hour | Standard Deviation 0.818 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 1 | 7.39 hour | Standard Deviation 0.699 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 5 | NA hour | — |
Secondary
Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle 1 Day 1 | 1.06 hour |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle Day 5 | 1.0 hour |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle 1 Day 1 | 1.0 hour |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle Day 5 | NA hour |
Secondary
Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 1 | 352.06 liter (L) | Standard Deviation 148.987 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 5 | 351.82 liter (L) | Standard Deviation 182.744 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 1 | 257.32 liter (L) | Standard Deviation 88.354 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 5 | NA liter (L) | — |
Secondary
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.
Time frame: From the date of first documented CR, PR or CRi up to the date of first disease progression (Up to 5 years)
Population: The response-evaluable population was defined as all participants who received at least 1 dose of study drug, had measurable disease at baseline, and had at least 1 post baseline disease assessment. Participants who were evaluable at a particular time point for this outcome measure were included in the assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Duration of Response | 9.0 months |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Duration of Response | 6.0 months |
Secondary
Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 1 | 168.80 ng/mL | Standard Deviation 80.504 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 5 | 176.65 ng/mL | Standard Deviation 76.628 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 1 | 159.78 ng/mL | Standard Deviation 57.755 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924 | Cycle 1 Day 5 | 158.95 ng/mL | Standard Deviation 60.807 |
Secondary
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
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | 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 | NA hr*ng/mL | — |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | 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 5 | 1125.90 hr*ng/mL | Standard Deviation 276.604 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | 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 | NA hr*ng/mL | — |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | 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 5 | 1122.91 hr*ng/mL | Standard Deviation 244.752 |
Secondary
MTD Expansion Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924 | Cycle 1 Day 5 | 946.91 hr*ng/mL | Standard Deviation 244.081 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | 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 | 891.89 hr*ng/mL | Standard Deviation 261.82 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924 | Cycle 1 Day 5 | 954.07 hr*ng/mL | Standard Deviation 240.098 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | 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 | 926.74 hr*ng/mL | Standard Deviation 280.128 |
Secondary
MTD Expansion Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924 | Cycle 1 Day 1 | 990.58 hr*ng/mL | Standard Deviation 279.282 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924 | Cycle 1 Day 1 | 1026.45 hr*ng/mL | Standard Deviation 310.47 |
Secondary
MTD Expansion Phase, CLp: Systemic Clearance for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 5 | 38.10 L/hr | Standard Deviation 12.407 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 1 | 41.35 L/hr | Standard Deviation 13.924 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 1 | 39.20 L/hr | Standard Deviation 14.191 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, CLp: Systemic Clearance for MLN4924 | Cycle 1 Day 5 | 34.02 L/hr | Standard Deviation 10.01 |
Secondary
MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 1 | 0.87 ng/mL | Standard Deviation 0.974 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 5 | 1.51 ng/mL | Standard Deviation 1.321 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 1 | 0.91 ng/mL | Standard Deviation 1.105 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924 | Cycle 1 Day 5 | 1.30 ng/mL | Standard Deviation 1.01 |
Secondary
MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 1 | 0.10 1/hr | Standard Deviation 0.027 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 5 | 0.09 1/hr | Standard Deviation 0.028 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 1 | 0.10 1/hr | Standard Deviation 0.022 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924 | Cycle 1 Day 5 | 0.09 1/hr | Standard Deviation 0.022 |
Secondary
MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924 | Cycle 1 Day 5 | NA ratio |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924 | Cycle 1 Day 5 | NA ratio |
| Unknown | MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924 | Cycle 1 Day 1 | — ratio |
Secondary
MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 1 | 7.45 hour | Standard Deviation 1.851 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 5 | 8.07 hour | Standard Deviation 2.414 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 1 | 7.30 hour | Standard Deviation 1.762 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924 | Cycle 1 Day 5 | 7.89 hour | Standard Deviation 1.764 |
Secondary
MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle 1 Day 1 | 1.01 hour |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle 1 Day 5 | 1.0 hour |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle 1 Day 1 | 1.00 hour |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924 | Cycle 1 Day 5 | 0.98 hour |
Secondary
MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924
Time frame: 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)
Population: The PK-evaluable population was defined as all enrolled participants who had sufficient dosing in Cycle 1 and MLN4924 concentration-time data to reliably estimate PK parameters. The PK population where data at specified time points was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 1 | 370.53 liter | Standard Deviation 141.396 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 5 | 401.41 liter | Standard Deviation 173.087 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 1 | 348.66 liter | Standard Deviation 128.661 |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924 | Cycle 1 Day 5 | 370.97 liter | Standard Deviation 175.097 |
Secondary
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.
Time frame: From the first dose of study drug up to date of death (up to 5 years)
Population: The safety population was defined as all enrolled participants who receive at least 1 dose of any study drug, MLN4924 or azacitidine.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Overall Survival | 12.25 months |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Overall Survival | 4.93 months |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Overall Survival | 5.22 months |
Secondary
Sixty-day Mortality Rate
Time frame: 60 days after the first dose of study drug on Cycle 1 (Cycle Length=28 days)
Population: No participant was analyzed since this outcome measure was not planned to be assessed but added in the protocol summary by error.
Secondary
Thirty-day Mortality Rate
Time frame: 30 days after the first dose of study drug in Cycle 1 (Cycle Length=28 days)
Population: The safety population was defined as all enrolled participants who receive at least 1 dose of any study drug, MLN4924 or azacitidine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Thirty-day Mortality Rate | 5 percentage of participants |
| MLN4924 20 mg/m^2 + Azacitidine 75 mg/m^2 Subcutaneous | Thirty-day Mortality Rate | 6 percentage of participants |
| MLN4924 30 mg/m^2 + Azacitidine 75 mg/m^2 Intravenous | Thirty-day Mortality Rate | 0 percentage of participants |