A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Participants With Advanced Malignancies
Condition: Advanced Malignancies
MeSH terms: Neoplasms
Intervention: alisertib
Intervention description: Alisertib (MLN8237) capsules
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 59.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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).
    

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).