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MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia

Primary Purpose

Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
MLN4924
Azacitidine
Sponsored by
Millennium Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia

Eligibility Criteria

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

Inclusion Criteria:

  • Age greater than or equal to 18 years

  • Have the following diagnosis:

    • AML or ALL (for the dose escalation phase only)including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, who have failed to achieve complete response (CR) or who have relapsed after prior therapy and are not candidates for potentially curative treatment.
    • Acute Promyelocytic Leukemia (APL) patients are not eligible
    • AML or ALL patients who are over age 60 and have not received prior therapy are also eligible if they are not candidates for standard induction chemotherapy
    • High-grade MDS, defined as > 10% blasts on bone marrow examination
    • Low-grade MDS, defined as < 10% blasts on bone marrow examination (Schedule B expansion cohort only)
  • Patients who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male patients) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  • Female patients who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
  • Male patients who agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
  • Voluntary written consent
  • Suitable venous access
  • Adequate clinical laboratory values during the screening period as specified in the protocol
  • Patients who are on hydroxyurea may be included in the study and may continue on hydroxyurea while participating in this study.

Exclusion Criteria:

  • Female patients who are lactating or have a positive serum pregnancy test during the screening period
  • Any serious medical or psychiatric illness
  • Treatment with any investigational products
  • Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea
  • 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
  • Known human immunodeficiency virus (HIV) positive
  • Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
  • Evidence of uncontrolled cardiovascular conditions as specified in the protocol
  • Diarrhea > Grade 1, based on the NCI CTCAE categorization
  • Systemic treatment with prohibited medications
  • Ongoing anticoagulant therapy (eg, aspirin, Coumadin, heparin) that cannot be held to permit bone marrow sampling
  • Use of acetaminophen, acetaminophen-containing products, and statins are not permitted on the day before dosing, day of dosing, and day after dosing with MLN4924

Sites / Locations

  • Stanford University Medical Center
  • Robert H. Lurie Comprehensive Cancer Center Northwestern University
  • Johns Hopkins Kimmel Cancer Center
  • Dana Farber Cancer Institute
  • University of Michigan Comprehensive Cancer Center
  • Institute for Drug Development

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

MLN4924

Azacitidine

Arm Description

Outcomes

Primary Outcome Measures

Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements

Secondary Outcome Measures

Pharmacokinetic parameters
Pharmacodynamic effects
Assess disease response
Heart corrected QT intervals

Full Information

First Posted
May 28, 2009
Last Updated
December 3, 2013
Sponsor
Millennium Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00911066
Brief Title
MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia
Official Title
An Open-Label, Dose Escalation, Phase 1 Study of MLN4924, a Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients With Acute Myelogenous Leukemia,Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
December 2013
Overall Recruitment Status
Completed
Study Start Date
June 2009 (undefined)
Primary Completion Date
August 2013 (Actual)
Study Completion Date
October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
An open-label, multicenter, phase 1, dose escalation study of MLN4924 in adult patients with acute myelogenous leukemia (AML), high-grade myelodysplastic syndrome (MDS). The patient population will consist of adults previously diagnosed with AML including high-grade MDS for which standard curative, life-prolonging treatment does not exist or is no longer effective.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
72 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MLN4924
Arm Type
Experimental
Arm Title
Azacitidine
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
MLN4924
Intervention Description
MLN4924 intravenous (IV) on a 21-day cycle on one of the following schedules: Days 1, 3, and 5, followed by a rest period of 16 days (Schedule A) Days 1, 4, 8, and 11, followed by a rest period of 10 days (Schedule B) Continuous weekly dosing on Days 1, 8, and 15 (Schedule C) Days 1, 4, 11, 15 for Cycle 1 only; Days 1, 4, 8, 11 for all subsequent cycles (Schedule D) Dosing on Days 1, 3, and 5 in patients with high-grade MDS or AML (Schedule E)
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
Azacitidine will be administered (IV or subcutaneous (SC)) on Days 8 to 12 and Days 15 and 16 in Cycle 1, and on Days 1 to 5 and Days 8 to 9 (Schedule D)
Primary Outcome Measure Information:
Title
Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Pharmacokinetic parameters
Time Frame
12 months
Title
Pharmacodynamic effects
Time Frame
12 months
Title
Assess disease response
Time Frame
12 months
Title
Heart corrected QT intervals
Time Frame
During screening and during Cycle 1, Days 1 and 15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age greater than or equal to 18 years Have the following diagnosis: AML or ALL (for the dose escalation phase only)including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, who have failed to achieve complete response (CR) or who have relapsed after prior therapy and are not candidates for potentially curative treatment. Acute Promyelocytic Leukemia (APL) patients are not eligible AML or ALL patients who are over age 60 and have not received prior therapy are also eligible if they are not candidates for standard induction chemotherapy High-grade MDS, defined as > 10% blasts on bone marrow examination Low-grade MDS, defined as < 10% blasts on bone marrow examination (Schedule B expansion cohort only) Patients who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male patients) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Female patients who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse Male patients who agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse Voluntary written consent Suitable venous access Adequate clinical laboratory values during the screening period as specified in the protocol Patients who are on hydroxyurea may be included in the study and may continue on hydroxyurea while participating in this study. Exclusion Criteria: Female patients who are lactating or have a positive serum pregnancy test during the screening period Any serious medical or psychiatric illness Treatment with any investigational products Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea 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 Known human immunodeficiency virus (HIV) positive Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection Evidence of uncontrolled cardiovascular conditions as specified in the protocol Diarrhea > Grade 1, based on the NCI CTCAE categorization Systemic treatment with prohibited medications Ongoing anticoagulant therapy (eg, aspirin, Coumadin, heparin) that cannot be held to permit bone marrow sampling Use of acetaminophen, acetaminophen-containing products, and statins are not permitted on the day before dosing, day of dosing, and day after dosing with MLN4924
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Stanford University Medical Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Robert H. Lurie Comprehensive Cancer Center Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60657
Country
United States
Facility Name
Johns Hopkins Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Michigan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Institute for Drug Development
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
31355467
Citation
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.
Results Reference
derived
PubMed Identifier
25733005
Citation
Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, Hua Z, Blakemore SJ, Faessel H, Sedarati F, Dezube BJ, Giles FJ, Medeiros BC. Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol. 2015 May;169(4):534-43. doi: 10.1111/bjh.13323. Epub 2015 Mar 2. Erratum In: Br J Haematol. 2015 Oct;171(2):294. Br J Haematol. 2015 Oct;171(2):294.
Results Reference
derived

Learn more about this trial

MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia

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