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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Acute Myelogenous Leukemia
• Intervention / Treatment: Drug: MLN4924; Drug: Azacitidine

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60657
      • Robert H. Lurie Comprehensive Cancer Center Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Kimmel Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • Institute for Drug Development

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azacitidine	Drug: Azacitidine; 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)
Experimental: MLN4924	Drug: MLN4924; 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: May 28, 2009
• First Submitted That Met QC Criteria: May 28, 2009
• First Posted (Estimate): June 1, 2009

Study Record Updates

• Last Update Posted (Estimate): December 5, 2013
• Last Update Submitted That Met QC Criteria: December 3, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; Pevonedistat
• Other Study ID Numbers: C15003