Aurora A Kinase Inhibitor MLN8237 in Treating Patients With Unresectable Stage III-IV Melanoma
Condition: Recurrent Melanoma; Stage IIIc Melanoma; Stage IV Melanoma
MeSH terms: Melanoma
Intervention: laboratory biomarker identification and analysis; biopsy; immunohistochemistry/tissue microarrays; TdT-mediated dUTP nick end labeling assay; mass spectrometry
Intervention description: Correlative studies; Correlative studies; Correlative studies; Correlative studies; Correlative studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      RATIONALE: Aurora A kinase inhibitor MLN8237 may stop the growth of tumor cells by blocking
      some of the enzymes needed for cell growth.

      PURPOSE: This phase II trial is studying how well Aurora A kinase inhibitor MLN8237 works in
      treating patients with unresectable stage III-IV melanoma

      Funding Source - FDA OOPD
    

Eligibility criteria:

        Inclusion Criteria:

          -  Stage IIIc or IV histologically proven melanoma (confirmed by Vanderbilt
             pathologists), that is not curable by standard surgery, radiation therapy, or
             chemotherapy. No available effective therapy (i.e.; therapy known to be curative,).
             Non-biopsied (resected) tumor sites must be measurable for therapy.

          -  Patients on stage 2 of the enrollment must have tumor sites that are easily biopsied
             and be willing to undergo pre- and post-treatment (around day 8 +/- 3 days) tumor
             biopsies.

          -  Adequate performance status for the study, ECOG 0-1

          -  Adequate baseline organ system function, including

               1. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 without growth factor support

               2. Hemoglobin ≥ 9.0g/dL (without need for transfusion support within 30 days; growth
                  factor allowed)

               3. Platelet count ≥100,000 cells/mm3 without transfusion or growth factor
                  requirement

               4. INR<1.5,

               5. Creatinine < 1.5x institutional upper limit of normal (IULN), and/or an adequate
                  renal function as defined by: Calculated creatinine clearance must be ≥ 40
                  mL/minute (Cockcroft-Gault).

               6. Aspartate and alanine aminotransferase < 2.5 x institutional upper limit of
                  normal (IULN), bilirubin < 1.5x IULN

          -  Female subject is either post-menopausal or surgically sterilized or willing to use an
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study and for 3 months after the completion of the study. Male subject
             agrees to use an acceptable method for contraception for the duration of the study and
             for 3 months after the completion of the study

          -  A single regimen of prior chemotherapy for metastatic melanoma is allowed. Patients
             also may have received other immunotherapy or biologic therapy (including kinase
             inhibitors, antibodies to checkpoints CTLA4, PD1, PDL1, etc.) for metastatic melanoma
             and there is a limit of three therapy regimens

          -  No prior Aurora kinase inhibitor

          -  Completed prior chemotherapy a minimum of 4 weeks previously (6 weeks for BCNU and/or
             mitomycin C), 4 weeks for prior immune therapy, 6 weeks for antibodies to checkpoints
             CTLA4, PD1, PDL1, etc, and 2 weeks for targeted agents (i.e. inhibitors of MEK, BRAF,
             Akt, PI3K, mTORC1/2) or localized radiation therapy. All treatment All treatment
             related toxicity must have resolved to grade 2 or less or to a baseline level as well.

          -  Patients cannot receive concomitant radiation therapy at enrollment. While on protocol
             limited palliative radiotherapy extending over a small bone marrow field (10%) is
             allowed.

          -  Patients with brain metastases are allowed only if they are off systemic
             corticosteroids and stable for a minimum of 8 weeks.

          -  Patients must be 18 years of age or above and voluntary written informed consent must
             be obtained before performance of any study-related procedure not part of normal
             medical care, with the understanding that consent may be withdrawn by the subject at
             any time without prejudice to future medical care.

          -  Subject must be able to take oral medication and to maintain a fast as required before
             and after MLN8237 administration.

        Exclusion Criteria

          -  Uncontrolled or serious infection

          -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia or active conduction system abnormalities. Prior to study entry, any ECG
             abnormality at Screening has to be documented by the investigator as not medically
             relevant.

          -  Patients with thromboembolic disease cannot be on coumadin, but low molecular heparins
             are allowed.

          -  Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
             considered to be over 25%.

          -  Prior allogeneic bone marrow or organ transplantation.

          -  Concurrent therapy for cancer.

          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

          -  Inability to comply with protocol-specified procedures (i.e., treatment, monitoring,
             or follow-up)

          -  Female subject is pregnant or breast-feeding. Confirmation that the subject is not
             pregnant must be established by a negative serum β-human chorionic gonadotropin
             (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
             required for post-menopausal or surgically sterilized women.

          -  Patients with GI absorptive problems making it unlikely to absorb study medication or
             more likely to experience GI toxicities.

          -  Patient is HIV-positive and is receiving combination antiretroviral therapy.

          -  Treatment with clinically significant enzyme inducers, such as the enzyme-inducing
             antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin,
             rifapentine or St. John's wort within 14 days prior to the first dose of MLN8237 and
             during the study

          -  Other serious medical problem that in the view of the investigator makes therapy
             difficult to comply with or difficult to interpret toxicity

          -  If applicable, patient has ≥ Grade 2 peripheral neuropathy within 14 days before
             enrollment.

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

          -  Patient has received other investigational drugs with 14 days before enrollment