This phase II trial studies how well enzalutamide, carboplatin, and paclitaxel work in treating patients with endometrioid endometrial cancer that is stage III-IV or has come back. Androgens can cause the growth of endometrioid endometrial cancer. Antihormone therapy, such as enzalutamide may lessen the amount of androgen made by the body. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving enzalutamide, carboplatin, and paclitaxel may work better in treating patients with endometrioid endometrial cancer.

PRIMARY OBJECTIVES:

I. To determine the clinical activity of combination enzalutamide, carboplatin and paclitaxel represented as:

Ia. Objective tumor response (complete response [CR] + partial response [PR]). Ib. The proportion of patients who survive progression-free for at least 6 months after initiating therapy.

II. To quantify protein and phosphoprotein expression of androgen receptor (AR) and AR-response genes following enzalutamide treatment in match-paired pre and post treatment tumor biopsies.

III. To determine the safety and feasibility of daily enzalutamide given in combination with carboplatin and paclitaxel in women with advanced stage or recurrent endometrial cancer.

SECONDARY OBJECTIVES:

I. Determine median response duration. II. Estimate progression free survival and overall survival. III. Evaluate for presence of pharmacokinetic interaction between enzalutamide and paclitaxel.

EXPLORATORY OBJECTIVES:

I. Correlate molecular results, including AR receptor expression and activation, to clinical endpoints.

II. Identify potential agents to synergize with enzalutamide based on pathways activated after enzalutamide treatment.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD) alone on days 1-28. Patients then receive enzalutamide PO QD on days 1-21, paclitaxel intravenously (IV) over 3 hours on day 1, and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6-9 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 1 year.

Inclusion Criteria:

• 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
• 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 computed tomography (CT) scan, magnetic resonance imaging (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
• Patients must have at least one "target lesion" to be used to assess response on this protocol as defined by Response Evaluation Criteria in Solid Tumors (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
• Patient with an Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Life expectancy of greater than 3 months in the opinion of the principal investigator
• Recovery from effects of recent surgery, radiotherapy, or chemotherapy
• Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection [UTI])
• Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration
• Any other prior therapy directed at the malignant tumor, including immunologic agents, must be discontinued at least three weeks prior to registration
• 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
• Absolute neutrophil count (ANC) >= 1,500/mcl, equivalent to Common Terminology Criteria (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4.03) grade 1
• Platelets >= 100,000/mcl
• Calculated creatinine clearance (Cockcroft-Gault formula) > 50 ml/min OR 24-hour urine creatinine clearance > 50 ml/min
• Bilirubin =< 1.5 x upper limit of normal (ULN) (CTCAE v4.03 grade 1; in patients with known Gilbert syndrome, a total bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN)
• Aspartate aminotransferase (AST) and alkaline phosphatase =< 2.5 x ULN (CTCAE v4.03 grade 1; AST and alanine aminotransferase [ALT] =< 3 x ULN [or =< 5.0 x ULN if hepatic metastases are present])
• Neuropathy (sensory and motor) =< CTCAE v4.03 grade 1
• Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) =< 1.5 times the institutional upper limit of 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
• Patients must have signed an approved informed consent
• 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.
• 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
• 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
• 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:

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

• 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

• 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

• 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

• 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

• 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

• Patients may not receive strong cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) inhibitors, CYP2C8 inducers, or cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers; in addition, patients should not receive drugs that are metabolized by CYP3A4 or cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9)

• Patients who are pregnant or nursing; 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

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

• 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

• 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

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

• 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

• 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

• 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