Aurora A Kinase Inhibitor MLN8237 in Treating Patients With Unresectable Stage III-IV Melanoma

PRIMARY OBJECTIVES:

I. Estimate the degree of clinical benefit based primarily on objective clinical responses
with AURKA inhibitor, MLN8237 in patients with metastatic melanoma in a phase II, 2-stage
trial for patients with measurable unresectable disease.

SECONDARY OBJECTIVES:

I. Assess the progression-free survival and overall survival for all patients enrolled.

II. Define toxicities due to MLN8237 and characterize their severity both over a short and
prolonged duration of administration.

III. In patients entered on stage 1 of clinical trial whenever possible through
pre-treatment biopsy and post-treatment surgical specimen, we will define target inhibition
at tumor sites based on: AURKA autophosphorylation (AURKAThr288/AURKA), intra-tumoral drug
levels, expression of p53-induced NOXA and PUMA expression, TPX2, (by IHC) and TUNEL as
markers of apoptosis, cell cycle changes (mitotic index), proliferation (Ki-67), aneuploidy,
and AKT phosphorylation.

IV. All phase II trial patients enrolled on the 2nd stage will have pre- and post-treatment
biopsies (post-day 7+/-3 days) to demonstrate that AURKA is inhibited based on
autophosphorylation AURKA/AURKA^Thr 288, Histone H3 (at S10) phosphorylation, AKT
phosphorylation, cell cycle changes (mitotic index), TPX2 (by IHC), proliferation (Ki-67),
aneuploidy, and p53-induced NOXA and PUMA expression, and TUNEL as markers of apoptosis.

V. Demonstrate any correlation between MLN8237 induced target inhibition at tumor sites and
clinical benefit of MLN8237.

VI. Characterize the de novo molecular mutational profile of the melanomas from all patients
entered using a developed SNaPshot assay for melanoma in addition loss of regulatory
proteins (i.e., PTEN), DNA copy numbers and gene expression (AURKA), and autophosphorylation
of AURKA as well as AURKA localization by IHC.

OUTLINE: Patients receive oral Aurora A kinase inhibitor MLN8237 every 12 hours on days 1-7.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for 5 years.

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