Clinical trial NCT00677170: Study of MLN4924 in Adult Patients With Nonhematologic Malignancies
Official title: An Open-Label, Dose Escalation, Phase I Study of MLN4924, a Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients With Nonhematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Nonhematologic Malignancies
Lead sponsor: Millennium Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2008-05-14
Enrollment: 62
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: This study is an open-label, multicenter, Phase 1, dose escalation study of MLN4924 in adult patients with nonhematologic malignancies. This study will be the first to administer MLN4924 in humans. The patient population will consist of adults with any form of nonhematologic malignancy for which standard, curative, life prolonging, or palliative treatment does not exist or is no longer effective.


Eligibility criteria: Inclusion Criteria:

* Male or female patients 18 years or older
* Eastern Cooperative Oncology Group performance status 0-2
* Patients must have a diagnosis of a nonhematologic malignancy for which standard curative, life-prolonging, or palliative treatment does not exist or is no longer effective.
* Expected survival longer than 6 weeks from enrollment in the study
* Radiographically or clinically evaluable tumor
* Suitable venous access for the conduct of blood sampling for MLN4924
* Tumor tissue that, in the opinion of the investigator, can be safely biopsied using a core needle
* Male patients must use an appropriate method of barrier contraception
* Female patients must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control
* Voluntary written consent

Exclusion Criteria:

* Pregnant or lactating
* Major surgery within 14 days prior to the first dose of study treatment
* Serious infection within 14 days prior to the first dose of study treatment
* Receiving antibiotic therapy within 14 days prior to the first dose of study treatment
* Life-threatening illness unrelated to cancer
* Diarrhea that is greater than Grade 1 in severity
* Systemic antineoplastic therapy within 21 days preceding first dose of study treatment
* Radiotherapy within 21 days preceding first dose of study treatment
* Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow
* CYP3A inducers within 14 days before the first dose of MLN4924. Moderate and strong CYP3A inhibitors and CYP3A inducers are not permitted during the study.
* Clinically significant central nervous system metastases
* Absolute neutrophil count \<1,500/mm3; platelet count \<100,000/mm3
* Patients with a prothrombin time or aPTT \> 1.5 x the upper limit of the normal range, or with a history of a coagulopathy or bleeding disorder
* Ongoing anti-coagulant therapy that can not be held to permit tumor biopsy
* Calculated creatinine clearance \<50 mL/minute
* Bilirubin \>1.5 times the upper limit of normal; aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase \>2.5 times the upper limit of normal.
* Uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months
* Abnormalities on 12-lead electrocardiogram including, but not limited to, changes in rhythm and intervals that in the opinion of the investigator are considered to be clinically significant
* Known human immunodeficiency virus positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
* Treatment with any investigational products within 28 days preceding the first dose of study treatment

Primary outcomes:
measure: Determine the safety profile, MTD and PK/pharmacodynamics of MLN4924
timeFrame: Maximum duration of therapy for 12 months
Secondary outcomes:
measure: Disease response
timeFrame: Day 21, every other cycle and end of study
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: San Antonio
country: United States
facility: Cancer Therapy & Research Center at the UT Health Science Center
state: Texas
city: San Antonio
country: United States
facility: Institute for Drug Development
state: Texas
Study officials:
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, Watts J, Erba HP, Altman JK, Maris M, Anwer F, Hua Z, Stein H, Faessel H, Sedarati F, Dezube BJ, Giles FJ, Medeiros BC, DeAngelo DJ. Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood Cancer J. 2017 Feb 3;7(2):e520. doi: 10.1038/bcj.2017.1. No abstract available.