A Phase II Trial of MLN8237 in Patients With Metastatic Castrate Resistant and Neuroendocrine Prostate Cancer

This is a multi-institutional single-arm, open-label Phase 2 trial evaluating MLN8237 in
patients with histologically confirmed or clinically suspected metastatic neuroendocrine
prostate cancer. Subjects will be treated with MLN8237 at 50 mg twice daily for 7 days
repeated every 21 days. Individual dose reductions will be made on the basis of the AEs
observed. Therapy will continue until disease progression, unacceptable toxicity as a result
of MLN8237, or withdrawal of patient consent. Patients will be followed with history,
physical, and blood tests at each visit to monitor for toxicity. Response and progression
will be evaluated by CT/MRI scan and bone scan after every 3 cycles and determined using
RECIST v1.1. PSA and serum chromogranin A and NSE will be followed every cycle. CTC counts by
CellSearch will be performed at baseline, at 4-6 weeks, and upon progression. Patients will
be followed for survival endpoints following completion of this study until death.

Inclusion Criteria:

- Metastatic prostate carcinoma and at least one of the following:

- Histologic diagnosis of small cell or neuroendocrine prostate cancer

- Histologic diagnosis of prostate adenocarcinoma plus > 50% immunohistochemical
staining for neuroendocrine markers (chromogranin, synaptophysin or neuron
specific enolase)

- Development of liver metastases in the absence of PSA progression as defined by
PCWG2

- Serum chromogranin A level >5 x upper limit of normal and/or serum neuron specific
enolase (NSE) >2x upper limit of normal

- Measurable disease by RECIST 1.1 with PCWG2 modifications

- Patients with pure small cell neuroendocrine carcinoma on histology are not required
to have received prior androgen deprivation therapy (ADT) or castrate levels of
testosterone, but their testosterone state should be maintained for the duration of
the study. Other patients are required to have surgical or ongoing chemical
castration, with baseline testosterone level <50ng/dL.

- Patients capable of fathering children must agree to use an effective method of
contraception for the duration of the trial and should continue use for 4 months after
last dose of study drug

- Subjects must be able to take oral medication and to maintain a fast as required for 2
hours before and 1 hour after MLN8237 administration.

- ANC > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values must be obtained without
need for myeloid growth factor or platelet transfusion support within 14 days,
however, erythrocyte growth factor is allowed as per published ASCO guidelines.

- Total bilirubin ≤ ULN, SGOT (AST) and SGPT (ALT)< 1.5 x ULN. AST and/or ALT may be up
to 5X ULN if with known liver metastases provided bilirubin is normal.

- Adequate renal function as defined by serum creatinine ≤ 1.5 x ULN. If creatinine >1.5
x ULN, calculated or measured creatinine clearance must be ≥ 40 mL/minute
(Cockcroft-Gault).

- ECOG performance status 0-2

- Estimated life expectancy > 3 months

- Voluntary written informed consent 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.

Exclusion Criteria:

- Radiation therapy to 25% of bone marrow within 2 weeks of first dose

- Residual > Grade 2 toxicity from prior treatment must have resolved with the exception
of those explicitly described elsewhere in entry criteria

- Known history of uncontrolled sleep apnea syndrome and other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease; requirement for supplemental oxygen.

- Requirement for constant administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed (see
section 5.5)

- Severe or uncontrolled systemic 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.

- Patient has received other investigational drugs with 14 days before enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Other severe acute or chronic medical or psychiatric condition, including uncontrolled
diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement
for pancreatic enzymes, any condition that would modify small bowel absorption of oral
medications, or laboratory abnormality that may increase the risk associated with
study participation or investigational product administration or may interfere with
the interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for enrollment in this study.

- Currently active other malignancy excluding controlled non-melanoma skin cancer.
Patients are considered NOT to have "currently active" malignancy if they have
completed any necessary therapy and are considered by their physician to be at less
than 30% risk of relapse.

- Treatment with 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

- Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C. Testing is not required in the absence of clinical findings or suspicion.