Clinical trial NCT00911066: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndrome
Lead sponsor: Millennium Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2009-06-01
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements
timeFrame: 12 months
Secondary outcomes:
measure: Pharmacokinetic parameters
timeFrame: 12 months
measure: Pharmacodynamic effects
timeFrame: 12 months
measure: Assess disease response
timeFrame: 12 months
measure: Heart corrected QT intervals
timeFrame: During screening and during Cycle 1, Days 1 and 15
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: San Antonio
country: United States
facility: Institute for Drug Development
state: Texas
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
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.
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.