This is an open-label, multicenter, phase 1, dose escalation study that will evaluate the safety profile, establish Maximum Tolerated Dose (MTD), and inform the recommended phase 2 dose of MLN4924 as well as evaluate antitumor activity in patients with metastatic melanoma.

Inclusion Criteria:

Each patient must meet all of the following criteria to be enrolled in the study:

• Diagnosis of metastatic melanoma
• Measurable disease
• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse
• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
• Willing and able to give written informed consent
• Suitable venous access for study-required blood sampling
• Appropriate functional status, including the recovery from the effects of prior antineoplastic therapy, and acceptable organ function as described in the protocol

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

• Major surgery or, serious infections, or infections that required systematic antibiotic therapy within 14 days before the first dose of study drug
• Systemic antineoplastic or radiation therapy within 14 days or treatment with any investigational products within 21 days before the first dose of study treatment
• CYP3A inducers within 14 days of study treatment. Moderate and strong CYP3A inhibitors and CYP3A inducers are not permitted during the study
• No prior history of amiodarone in the 6 months before the first dose of MLN4924
• Diarrhea that is greater than Grade 1 as outlined in the protocol
• Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
• Other clinical and laboratory assessments that do not meet the criteria specified in the protocol