Enzalutamide in Combination With Carboplatin and Paclitaxel in Endometrial Cancer

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to either
the Safety Lead-in or the Phase 2 portion. The study group you are in will depend on when you
join the study.

In the Safety Lead-in, each study cycle is 21 days. In Phase 2, the first study cycle (Cycle
0) will be 28 days, and all other study cycles will be 21 days.

If you are enrolled in the Safety Lead-in phase, you will receive carboplatin and paclitaxel
on Day 1 of Cycles 1-9. You will also take enzalutamide every day.

If you are enrolled in Phase 2, you will take enzalutamide every day by itself during the
first cycle (called Cycle 0). You will then receive paclitaxel and carboplatin by vein on Day
1 of Cycles 1-9. You will also continue taking enzalutamide every day during this time.

In both phases, the study drug doses may be lowered if you have side effects. The dose that
was found to be appropriate in the safety lead-in will be used in Phase 2.

Study Drug Administration:

Paclitaxel will be given by vein over 3 hours.

Carboplatin will be given by vein over 1 hour.

You will take 4 enzalutamide capsules by mouth at the same time every morning with 1 cup
(about 8 ounces) of water. You may take your dose with or without food. The capsules should
be swallowed whole and not crushed or cut. If you forget to take a dose, you may take it
within 12 hours of the usual dosing time. If you vomit within 30 minutes of taking a dose,
you should take the dose again. If you have side effects, your doctor may decide to lower
your dose.

You will be given a study drug diary to write down when you take each dose of study drug and
if you miss any doses. You should bring the study drug diary and any unused study drugs with
you to each clinic visit.

Study Visits:

Cycle 0 Study Visits (Phase 2 participants only):

At Week 1 of Cycle 0:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine tests.

At Week 4 of Cycle 0:

- Blood (about 3 tablespoons) will be drawn for biomarker testing. If blood was not
collected for genetic research during your screening, some of this blood will also be
used for genetic research.

- You will have the same type of biopsy you had at screening.

Study Visits for All Participants:

At Week 1 of Cycles 1-9:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine tests.

At Weeks 2 and 3 of Cycles 1-9, blood (about 3 tablespoons) will be drawn for routine tests.

At Week 1 of Cycle 2, blood (about ½ teaspoon each time) will be drawn for pharmacokinetic
(PK) testing before the dose and 8 more times over the next 7 hours after the start of the
dose. PK testing measures the amount of study drug in the body at different time points.

At Week 3 of Cycle 3 and then every 9 weeks, you will have an x-ray, CT scan, PET-CT scan, or
MRI to check the status of the disease.

Anytime the doctor thinks it is needed, part of the routine blood sample will be used to
check how well your blood clots.

Length of Treatment:

You may continue to receive the study drugs until Cycle 9. You will no longer be able to take
the study drugs if the disease gets worse, if intolerable side effects occur, or if you are
unable to follow study directions.

Your participation on the study will be over after the follow-up visits (described below).

Follow-Up Visits:

After you stop taking the study drugs, you will return to the clinic every 3 months for 1
year, and then as often as the doctor thinks it is needed after that. At each visit:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine tests.

- You will have an x-ray, CT scan, PET-CT scan, or MRI to check the status of the disease

Inclusion Criteria:

1. Patients must have a histologically confirmed diagnosis (by either primary surgical
specimen or biopsy for recurrence) of advanced stage (stage III or IV) or recurrent
endometrioid endometrial cancer.

2. Measurable disease (at least one measurable lesion) IS required. A measurable lesion
is one that can be accurately measured in at least one dimension (longest diameter to
be recorded). Each lesion must be > 10 mm when measured by CT scan, MRI, or caliper
measurement by clinical exam; or > 20 mm when measured by Chest X-Ray. Lymph nodes
must be > 15 mm in short axis when measured by CT or MRI.

3. Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST. Tumors within a previously irradiated field will be
designated as "non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of radiation
therapy.

4. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status
5. Life expectancy of greater than 3 months in the opinion of the principal investigator.

6. Recovery from effects of recent surgery, radiotherapy, or chemotherapy.

7. Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated UTI).

8. Any hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration.

9. Any other prior therapy directed at the malignant tumor, including immunologic agents,
must be discontinued at least three weeks prior to registration.

10. PRIOR THERAPY: Patients should have had NO prior chemotherapy agents for advanced or
recurrent endometrial cancer. Prior chemotherapy administration in conjunction with
primary radiation therapy as a radiosensitizer would NOT exclude a patient from
participation in this trial.

11. Patients must have adequate: (1) Bone marrow function: Absolute neutrophil count (ANC)
>/= 1,500/mcl, equivalent to Common Terminology Criteria (CTCAE v4.03) grade 1;
Platelets >/= 100,000/mcl; (2) Renal function: calculated creatinine clearance
(Cockcroft-Gault formula) > 50 ml/min OR 24-hour urine creatinine clearance > 50
ml/min; (3) Hepatic function: Bilirubin patients with known Gilbert Syndrome, a total bilirubin bilirubin grade 1; AST and ALT (4) Neurologic function: Neuropathy (sensory and motor) [Continued in Criterion 12]

12. [Continued from Criterion 11] (5) PT such that international normalized ratio (INR) is
of therapeutic warfarin) and a PTT normal. Patients receiving low molecular weight heparin for the prevention or
treatment of venous thromboembolic disease are eligible if considered clinically
stable on their regimen.

13. Patients must have signed an approved informed consent.

14. Age >/=18 years. Because no dosing or adverse event data are currently available on
the use of enzalutamide in combination with carboplatin and paclitaxel in patients <18
years of age, children are excluded from this study.

15. The effects of enzalutamide on the developing human fetus are unknown. For this reason
and because therapeutic agents used in this trial may be teratogenic, women of
child-bearing potential and their partners must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation. Women of child-bearing potential (intact uterus)
should have a negative serum pregnancy test. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately. Patients must be able to swallow whole tablets.

16. With the exception of alopecia, any unresolved toxicities from prior chemotherapy
should be no greater than CTCAE v4 Grade 1 at the time of starting study treatment.

17. Patients on the Phase II portion only must be willing to undergo pre- and
post-treatment biopsies and have at least one lesion amenable to biopsy.

Exclusion Criteria:

1. Patients who have isolated recurrences (vaginal, pelvic, or paraaortic) that are
amenable to potentially curative treatment with radiation therapy or surgery.

2. Patients with the following histologies of endometrial cancer are not eligible for
enrollment: papillary serous adenocarcinoma, clear cell carcinoma, adenosquamous
carcinoma, mucinous adenocarcinoma, carcinosarcoma, sarcoma.

3. Prior Therapy: Prior Chemotherapy: Patients who have had a prior chemotherapy regimen
for advanced or metastatic disease are excluded. Prior Radiation Therapy: Patients may
have received prior radiation therapy for treatment of endometrial carcinoma. Prior
radiation therapy may have included pelvic radiation therapy, extended field
pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy, alone or with
chemotherapy as a radiation sensitizer. All radiation therapy must be completed at
least 4 weeks prior to the first date of study therapy. The prior radiation field,
radiation dose, number of fractions and prior radiation start and stop dates must be
provided at registration.

4. Patients who have previously received enzalutamide. Patients may have received prior
hormonal therapy for treatment of endometrial carcinoma. All hormonal therapy must be
discontinued at least one week prior to the first date of study therapy.

5. Patients who have had radiotherapy within 4 weeks prior to entering the study or those
who have not recovered from adverse events (CTCAE v4.03 grade 2 or greater, excluding
alopecia) due to agents administered more than 4 weeks earlier.

6. Patients may not receive any other anti-neoplastic or investigational agents within 3
weeks of study enrollment. Patients may not be receiving any other investigational
agents during treatment on protocol.

7. Patients may not receive strong CYP2C8 inhibitors, CYP2C8 inducers, or CYP3A4
inducers. In addition, patients should not receive drugs that are metabolized by
CYP3A4 or CYP2C9.

8. Patients who are pregnant or nursing. The effects of enzalutamide on the developing
human fetus are unknown. For this reason women of childbearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. Should a
woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately.

9. Patient had major surgery within 28 days prior to starting study drug or has not
recovered from major side effects of the surgery.

10. Patients may not have a history of other malignancies except for basal cell or
squamous cell skin cancer, in situ cervical cancer, unless they have been disease-free
for at least five years.

11. Patients with predisposing factors for seizure including history of seizure,
underlying brain injury with loss of consciousness, transient ischemic attack within
the past 12 months, cerebral vascular accident, brain metastasis, and brain
arteriovenous malformation.

12. Patient with history of allergic reactions or hypersensitivity attributed to compounds
of similar chemical or biologic composition to enzalutamide, carboplatin, or
paclitaxel.

13. Patients may not have symptomatic, uncontrolled spinal cord compression and/or brain
metastases. A scan to confirm absence of brain metastasis is not required. Patients
can receive a stable dose of corticosteroids before/ during study if these were
started at least 28 days prior to entry.

14. As judged by the Investigator, any evidence of severe or uncontrolled systemic
diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral,
diffuse, parenchymal lung disease], uncontrolled chronic renal diseases
[glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis]),
or current unstable or uncompensated respiratory or cardiac conditions, or
uncontrolled hypertension (blood pressure >/= 160/90), active bleeding diatheses or
active infection including hepatitis B, hepatitis C, and human immunodeficiency virus.
Screening for chronic conditions is not required.

15. As judged by the Investigator, the patient is unsuitable to participate in the study
and the patient is unlikely to comply with study procedures, restrictions, and
requirements.