Alisertib, Abiraterone Acetate and Prednisone in Treating Patients With Hormone-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

1. Phase I: To determine the safe dose of alisertib when given in combination with
abiraterone (abiraterone acetate) and prednisone in metastatic castration resistant
prostate cancer (mCRPC) patients with disease progression on abiraterone and prednisone.

2. Phase II: To determine the proportion of patients who have no disease progression after
alisertib is added to abiraterone and prednisone.

SECONDARY OBJECTIVES:

1. Phase II: To determine the prostate specific antigen (PSA) kinetics after alisertib is
added to abiraterone and prednisone regimen (this includes the proportion of patients
with PSA progression free at 3 months, proportion of patients with 50% PSA reduction
after study treatment, maximum PSA decline from baseline during the first 12 weeks).

2. Phase II: To compare baseline circulating tumor cells (CTCs) enumeration to 12 week
post-therapy CTC enumeration.

3. Phase II: To compare baseline neuroendocrine marker (chromogranin A and neuron-specific
enolase [NSE]) levels to 12 week post therapy neuroendocrine marker levels.

4. Phase II: To further assess overall safety of combination of alisertib with abiraterone
and prednisone in the phase 1 portion of the study.

OUTLINE: This is a phase I, dose escalation study of alisertib followed by a phase II study.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7, abiraterone acetate PO
daily, and prednisone PO BID. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

1. Age >/= 18 years and are capable of giving informed consent. 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medical care, with the understanding that consent may be withdrawn by the subject at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.

2. Patients must have a pathologically confirmed diagnosis of prostate adenocarcinoma.
Features of neuroendocrine phenotype are allowed.

3. Patients must have evidence of metastatic disease.

4. Patients are currently on Abiraterone treatment and the treatment dose has been stable
for at least 4 weeks. There will be no further dose adjustment per treating physician.

5. Patients with evidence of any of the following disease progression based on PCWG2
criteria while on abiraterone acetate and prednisone:

- Clinical progression (such as symptoms related to prostate cancer) with PSA
progression (defined as 25% increase over baseline value with an increase in the
absolute value of at least 2 ng/mL and a baseline PSA of 2 ng/ml or above).

- Progression of one dimension measurable soft tissue (nodal or visceral
metastasis) assessed within 30 days prior to registration by a CT scan or MRI of
the abdomen and pelvis as per RECIST criteria.

- Progression of bone disease (evaluable disease) or ( ≥ 2 new bone lesion(s)) by
bone scan.

6. Patients must have and ECOG performance status of ≤ 2.

7. Patients must be on continuous LH-RH agonist or antagonist treatment or surgically
castrated with castrate levels of testosterone (< 20 ng/dl).

8. For Phase I: any number of prior chemotherapy regimens are allowed, but patient needs
to be on abiraterone acetate at the time of progression. Chemotherapy naïve patients
are allowed only in the phase I part of the trial.

9. For Phase I: Patients must have either failed, are intolerant to, or have refused
treatment with docetaxel.

10. For Phase II: Patients must have received 1 but no more than 2 prior chemotherapy
regimen for prostate cancer.

11. Patients may have had androgen receptor targeted therapy (including second and third
line antiandrogens) or other investigational drugs. Patient must have discontinued
flutamide or nilutamide or other antiandrogens (including Enzalutamide) for at least 4
weeks and bicalutamide for at least 6 weeks prior to day1 treatment.

12. Patients receiving treatment with bisphosphonates or denosumab must remain on
treatment during the study.

13. Patients must not require concurrent radiation or other chemotherapy while receiving
protocol therapy. Patients may have received previous radiation but must have
completed radiation at least 4weeks (8 weeks for radiation to the brain) prior to
registration.

14. Patients must have recovered to grade ≤ 1 from all acute toxicity of previous
radiation or hormonal or chemotherapy.

15. Patient agrees to use an acceptable method for contraception during the entire study
treatment period through 4 months after the last dose of Alisertib. 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).

16. 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.

17. 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 mets

Exclusion Criteria:

1. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first
dose of study drug, or other severe infection.

2. Major surgery within 28 days or serious infection requiring IV antibiotics within 14
days preceding the first dose of study treatment.

3. Patient has received other investigational drugs within 14 days before enrollment.

4. Known GI disease or GI procedure that could impact drug absorption in the upper bowel,
or tolerance of Alisertib. Examples include but are not limited to partial
gastrectomy, small bowel resection, pancreatectomy, malabsorption or celiac disease.

5. Patient requires constant administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed (to
manage gastric acidity or reflux) during the study day 8 - 20. [Histamine-2 (H2)
receptor antagonists are not permitted from the day prior (Day -1) through to the end
of Alisertib dosing (Day 7)]

6. Ongoing nausea or vomiting of any severity without improvement after appropriate
treatment.

7. > Grade 1 diarrhea, not controlled with appropriate treatment.

8. History of uncontrolled sleep apnea syndrome and other conditions that could result in
excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease
requiring supplemental oxygen.

9. Clinical and/or radiographic evidence of cerebral metastases. However, patients who
have a history of central nervous system (CNS) 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.

10. Radiation therapy to more than 25% of the active bone marrow. Whole pelvic radiation
is considered to be over 25%.

11. 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.

12. Serious medical or psychiatric illness 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.

13. 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.

14. 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 Alisertib and
during the study.

15. 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.