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Acute Myelogenous LeukemiaPhase 1NCT01814826

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

A Phase 1 study testing MLN4924 and Azacitidine in people with Acute Myelogenous Leukemia, run by Millennium Pharmaceuticals, Inc. at 8 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 60 years and older
Conditions the study is for
Acute Myelogenous Leukemia
What is being tested?
MLN4924 and Azacitidine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
64 participants
Where
8 sitesUnited States
Study dates
10 Apr 2013to 8 Apr 2018
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • UNC-Chapel Hill School of Medicine

    Chapel Hill, North Carolina, 27599

  • Hospital Corporation of America-HealthOne, LLC

    Denver, Colorado, 80218

  • Mayo Clinic - Jacksonville, FL

    Jacksonville, Florida, 32224

  • University of Miami School of Medicine

    Miami, Florida, 33136

  • Sarah Cannon Research Institute

    Nashville, Tennessee, 37203

  • Methodist Hospital

    San Antonio, Texas, 78229

  • Stanford University

    Stanford, California, 94305-5826

Other trials in United States

About this study

Official title: 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

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.

Being tested
MLN4924, Azacitidine
Keywords
Drug Therapy
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MLN4924Drug

    Also called Pevonedistat

    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

  • AzacitidineDrug

    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
Study groups in NCT01814826
Study groupRoleWhat they receive
MLN4924 and AzacitidineExperimentalNot described
Receives: Drug: MLN4924; Drug: Azacitidine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

    Measured: Baseline up to 30 days after the last dose of study drug (up to 5 years)

  2. Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings

    Measured: Baseline up to 30 days after the last dose of study drug (up to 5 years)

  3. Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings

    Measured: Baseline up to 30 days after the last dose of study drug (up to 5 years)

Secondary outcomes (27)

  1. Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924

    Measured: 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)

  2. Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924

    Measured: 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)

  3. Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924

    Measured: 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)

  4. MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924

    Measured: 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)

  5. Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924

    Measured: 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)

  6. MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924

    Measured: 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)

  7. 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

    Measured: 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)

  8. 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

    Measured: 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)

  9. Dose-escalation Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924

    Measured: 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)

  10. MTD Expansion Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924

    Measured: 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)

  11. Dose-escalation Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924

    Measured: 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)

  12. MTD Expansion Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924

    Measured: 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)

  13. Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924

    Measured: 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)

  14. MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924

    Measured: 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)

  15. Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924

    Measured: 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)

  16. MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924

    Measured: 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)

  17. Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924

    Measured: 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)

  18. MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924

    Measured: 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)

  19. Dose-escalation Phase, CLp: Systemic Clearance for MLN4924

    Measured: 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)

  20. MTD Expansion Phase, CLp: Systemic Clearance for MLN4924

    Measured: 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)

  21. Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924

    Measured: 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)

  22. MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924

    Measured: 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)

  23. 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.

    Measured: 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)

  24. 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.

    Measured: From the date of first documented CR, PR or CRi up to the date of first disease progression (Up to 5 years)

  25. 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.

    Measured: From the first dose of study drug up to date of death (up to 5 years)

  26. Thirty-day Mortality Rate

    Measured: 30 days after the first dose of study drug in Cycle 1 (Cycle Length=28 days)

  27. Sixty-day Mortality Rate

    Measured: 60 days after the first dose of study drug on Cycle 1 (Cycle Length=28 days)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Mar 2013 (estimated)
  2. Study start10 Apr 2013
  3. Primary completion3 May 2016
  4. Study completion8 Apr 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Other
Intervention model
Sequential
Masking
None (open label)
Enrolment
64 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01814826
Sponsor's protocol ID
C15009
Other IDs
U1111-1221-2792
Status last verified
Feb 2020
First submitted
18 Mar 2013
Last updated
3 Mar 2020
Data monitoring committee
No
Individual data sharing
Yes: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Publications

  • Swords RT, Coutre S, Maris MB, Zeidner JF, Foran JM, Cruz J, Erba HP, Berdeja JG, Tam W, Vardhanabhuti S, Pawlikowska-Dobler I, Faessel HM, Dash AB, Sedarati F, Dezube BJ, Faller DV, Savona MR. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018 Mar 29;131(13):1415-1424. doi: 10.1182/blood-2017-09-805895. Epub 2018 Jan 18.

    PubMed 29348128

  • Faessel HM, Mould DR, Zhou X, Faller DV, Sedarati F, Venkatakrishnan K. Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies. Br J Clin Pharmacol. 2019 Nov;85(11):2568-2579. doi: 10.1111/bcp.14078. Epub 2019 Sep 4.

    PubMed 31355467

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing MLN4924 and Azacitidine in people with Acute Myelogenous Leukemia, run by Millennium Pharmaceuticals, Inc. at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01814826, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2020.

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