A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Patients With Advanced Malignancies

• To describe the pharmacokinetics of MLN8237. [ Time Frame: Duration of therapy ] [ Designated as safety issue: Yes ]
• To evaluate the relationship between MLN8237 exposure and inhibition of Aurora A Kinase in tumor tissue and in the proliferating basal epithelial cells of the skin. [ Time Frame: Duration of therapy ] [ Designated as safety issue: Yes ]
• To describe any antitumor activity that may be observed with MLN8237 treatment. [ Time Frame: Duration of therapy ] [ Designated as safety issue: No ]

This is a multicenter, dose escalation, phase 1 study of MLN8237 in adult patients with advanced malignancies (excluding those with primary bone marrow involvement, such as leukemias and multiple myeloma).

Inclusion Criteria:

• Have a histologically or cytologically confirmed metastatic and/or advanced malignancy (including lymphomas but excluding malignancies with extensive bone marrow involvement such as leukemias and multiple myeloma) for which standard treatment does not offer curative or life-prolonging potential
• Aged 18 years or more
• Eastern Cooperative Oncology Group performance status 0 or 1
• Have an expected survival longer than 3 months from enrollment in the study
• Radiographically or clinically evaluable tumor
• Suitable venous access for the conduct of blood sampling
• 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.
• Male patients must use an appropriate method of barrier contraception and inform any sexual partners that they must also use a reliable method of contraception from the time of informed consent until 3 months after the last dose of study treatment.
• Female patients must be postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse.
• Able to give written consent.

Exclusion Criteria:

• Pregnant or lactating
• Major surgery or serious infection within the 28 days preceding the first dose of study treatment
• Life-threatening or uncontrolled medical illness unrelated to cancer
• Ongoing nausea or vomiting of any severity
• > Grade 1 diarrhea. Patients who require ongoing therapy with an antimotility agent to control diarrhea to a Grade 1 or lower level are not allowed to participate in this trial
• Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237.
• 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 (in patients with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted).
• 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 for the distribution of active bone marrow in adults)
• Clinical and/or radiographic evidence of cerebral metastases. However, patients who have a history of central nervous system 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.
• Abnormalities on 12-lead electrocardiogram 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).
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C.
• 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.
• aPTT and/or PT exceeding the upper limit of the normal range
• Known bleeding diathesis or history of abnormal bleeding
• Ongoing therapy with an anticoagulant (e.g., aspirin, plavix, coumadin).