Study of MLN4924 in Adult Patients With Nonhematologic Malignancies

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label, Dose Escalation, Phase I Study of MLN4924, a Novel Inhibitor of Nedd8-Activating Enzyme, in Adult Patients With Nonhematologic Malignancies

Conditions
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Advanced Nonhematologic Malignancies

Intervention / Treatment
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* Drug: MLN4924


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>MLN4924 | Drug: MLN4924<br>* IV dose escalation for 5 consecutive days followed by a rest period of 16 days for a 21 day cycle. Treated may continue until disease progression or unacceptable toxicity develops.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the safety profile, MTD and PK/pharmacodynamics of MLN4924 |  | Maximum duration of therapy for 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease response |  | Day 21, every other cycle and end of study |