An Open-Label, Dose Escalation Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Solid Tumors

Inclusion Criteria:

- Histologically or cytologically confirmed metastatic and/or advanced solid tumors
(including lymphomas) for which no effective standard treatment is available

- Aged 18 years or more

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Expected survival longer than 3 months from enrollment in the study

- Radiographically or clinically evaluable tumor; however, measurable disease as
defined by RECIST criteria is not required for participation in this study

- Suitable venous access for the conduct of blood sampling for MLN8237 PK

- Recovered from the reversible effects of prior antineoplastic therapy (with the
exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the
last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks
elapsed since exposure to nitrosoureas or mitomycin C. Patients treated with fully
human monoclonal antibodies must not have received treatment with such antibodies for
at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have
received treatment with such antibodies for at least 4 weeks. Patients treated with
noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva®,
and hormonal agents, such as Femara®) must not have received treatment with these
drugs for at least 2 weeks before the first dose of MLN8237 is given.

- Male patients must use an appropriate method of barrier contraception (eg, condoms)
and inform any sexual partners that they must also use a reliable method of
contraception (eg, birth control pills) from the time of informed consent until 3
months after the last dose of study treatment.

- Female patients must be postmenopausal, surgically sterilized, or willing to use
reliable methods of birth control (eg, a hormonal contraceptive, an intrauterine
device, diaphragm with spermicide, or abstinence) and inform male sexual partners
that they must also use a reliable method of contraception (eg, condoms) from the
time of informed consent until 3 months after the last dose of study treatment.

- Willing and able to give written informed consent before the conduct of any study
related procedure that is not part of normal medical care, and willing to comply with
the protocol

Exclusion Criteria:

- Pregnant or lactating

- Major surgery or serious infection within the 28 days preceding the first dose of
study treatment

- Life-threatening illness or uncontrolled medical illness unrelated to cancer

- Ongoing nausea or vomiting of any severity

- > Grade 1 diarrhea

- Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of MLN8237. Examples include but are not limited to partial gastrectomy,
history of small intestine surgery, and celiac disease.

- History of uncontrolled sleep apnea syndrome and other conditions that could result
in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease.

- Difficulty swallowing capsules

- Inability to take nothing by mouth except for water and prescribed medications for 2
hours before and 1 hour after each dose of MLN8237

- Received more than 4 previous cytotoxic chemotherapeutic regimens including regimens
used as adjuvant or neo-adjuvant therapies. There is no limit on the number of
noncytotoxic therapies (eg, hormonal and immunologic) that patients may have
received. Tyrosine kinase inhibitors (eg, Tarceva and Iressa®) are considered
noncytotoxic compounds.

- Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the
use of peripheral blood or bone marrow stem cell support for hematopoietic
reconstitution

- Prior treatment with radiation therapy involving ≥25% of the hematopoietically active
bone marrow

- Clinical and/or radiographic evidence of cerebral metastases. However, patients who
have a history of central nervous system (CNS) metastasis but who have no
radiographic or clinical evidence of residual tumor (eg, following complete surgical
resection or stereotactic radiosurgery) are not excluded from participation in this
study

- Absolute neutrophil count <1500/mm3; platelet count <100,000/mm3

- Serum creatinine >1.6 mg/dl or a measured or estimated creatinine clearance <40
mL/minute

- Bilirubin >1.5 times the upper limit of the normal range (ULN); aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 times the ULN, and
alkaline phosphatase (ALP) >2.5 times the ULN. Both the AST and ALP may be elevated
up to 5 times the ULN if their elevation can be reasonably ascribed to the presence
of metastatic disease to liver and/or to bone; however, the ALT must in all
circumstances be <2.5 times the ULN

- Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be
clinically significant or baseline prolongation of the rate-corrected QT interval
(eg, repeated demonstration of QTc interval > 450 milliseconds)

- Left ventricular ejection fraction (LVEF) < 50%

- Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface
antigen-positive status, or known or suspected active hepatitis C infection.

Testing for these agents is not required in the absence of clinical findings or suspicion.

- Less than 4 weeks between the last dose of an investigational agent and the first
dose of MLN8237

- Admission or evidence of benzodiazepine dependence or abuse and/or alcohol abuse or
an inability to restrict consumption of alcohol to no more than 1 standard unit of
alcohol per day during the study and for 30 days from the last dose of study
treatment. A standard unit of alcohol is defined as one 12-oz (150mL) beer, 1.5 oz
(45mL) of 80-proof alcohol, or one 6-oz (175mL) glass of wine.