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

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

The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced malignancies. This study determined the dose-limiting toxicity, maximum tolerated dose, safety and pharmacokinetics (how the drug moves through the body) for alisertib when given once or twice a day for 7 to 21 days.

This open label study enrolled 59 patients. Participants were enrolled in one of 10 dose escalation arms:

* Alisertib 5 mg once daily (QD) for 7 Days (D)
* Alisertib 80 mg QD 7D
* Alisertib 150 mg QD 7D
* Alisertib 50 mg twice daily (BID) 7D
* Alisertib 60 mg BID 7D
* Alisertib 75 mg BID 7D
* Alisertib 100 mg BID 7D
* Alisertib 50 mg QD 14D
* Alisertib 50 mg QD 21D
* Alisertib 70 mg QD 21D

All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity.

This multi-center trial was conducted in Spain. The overall time to participate in this study was 730 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
2. Aged 18 years or more.
3. Eastern Cooperative Oncology Group performance status 0 or 1.
4. Have an expected survival longer than 3 months from enrollment in the study.
5. Radiographically or clinically evaluable tumor.
6. Suitable venous access for the conduct of blood sampling.
7. 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. Participants 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. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva® \[erlotinib\], and hormonal agents, such as Femara® \[letrozole\]) must not have received treatment with these drugs for at least 2 weeks before the first dose of alisertib was given.
8. Male participants 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.
9. Female participants 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.
10. Able to give written consent.

Exclusion Criteria:

1. Pregnant or lactating.
2. Major surgery or serious infection within the 28 days preceding the first dose of study treatment.
3. Life-threatening or uncontrolled medical illness unrelated to cancer.
4. Ongoing nausea or vomiting of any severity.
5. \>Grade 1 diarrhea. Participants 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.
6. Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237.
7. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease.
8. Difficulty swallowing capsules.
9. Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237.
10. Received more than 4 previous cytotoxic chemotherapeutic regimens, including regimens used as adjuvant or neo-adjuvant therapies (in participants with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted).
11. Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution.
12. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow for the distribution of active bone marrow in adults).
13. Clinical and/or radiographic evidence of cerebral metastases. However, participants 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.
14. Absolute neutrophil count(ANC) \< 1500/mm\^3; platelet count\< 100,000/mm\^3.
15. Serum creatinine \>1.6 mg/dL or a measured or estimated (Cockcroft-Gault formula) creatinine clearance \<40 mL/min
16. 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 could be elevated up to 5 times the ULN if their elevation could be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT in all circumstances must have been \<2.5 times the ULN.
17. 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).
18. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C.
19. Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237.
20. 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.
21. Activated partial thromboplastin time (aPTT) and/or prothrombin time (PT) exceeding the upper limit of the normal range.
22. Known bleeding diathesis or history of abnormal bleeding.
23. Ongoing therapy with an anticoagulant (e.g., aspirin, plavix, coumadin).