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

NCT00911066 | Completed Phase 1

• 1 other identifier: C15003
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 6

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.

Conditions

Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

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

  12 months

Secondary Outcomes (4)

• Pharmacokinetic parameters

  12 months

• Pharmacodynamic effects

  12 months

• Assess disease response

  12 months

• Heart corrected QT intervals

  During screening and during Cycle 1, Days 1 and 15

Study Arms (2)

MLN4924

EXPERIMENTAL

Drug: MLN4924

Azacitidine

EXPERIMENTAL

Drug: Azacitidine

Interventions

MLN4924 DRUG

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)

MLN4924

Azacitidine DRUG

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)

Azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (6)

Stanford University Medical Center

Stanford, California, 94305, United States

Location

Robert H. Lurie Comprehensive Cancer Center Northwestern University

Chicago, Illinois, 60657, United States

Location

Johns Hopkins Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Institute for Drug Development

San Antonio, Texas, 78229, United States

Location

Related Publications (2)

• 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.

  PMID: 31355467 DERIVED

• 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.

  PMID: 25733005 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes

Interventions

pevonedistat; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2009
• First Posted: June 1, 2009
• Study Start: June 1, 2009
• Primary Completion: August 1, 2013
• Study Completion: October 1, 2013
• Last Updated: December 5, 2013

Record last verified: 2013-12

Locations

US (6)