This phase II trial studies how well Akt inhibitor MK2206 works in treating patients with recurrent or advanced endometrial cancer. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To assess the activity of MK-2206 (Akt inhibitor MK2206) in patients with recurrent or persistent endometrial cancer classified by phosphoinositide-3-kinase catalytic alpha (PIK3CA) mutation. Activity will be ascertained by the proportion of patients who survive progression-free for at least 6 months after initiating therapy or who have objective tumor response.

II. To evaluate the efficacy of MK2206 in patients with serous tumors using a composite endpoint of complete and partial response by Response Evaluation Criteria In Solid Tumors (RECIST) and progression-free interval of 6 months or longer.

SECONDARY OBJECTIVES:

I. To determine the duration of progression-free survival and overall survival. II. To determine the nature and degree of toxicity of MK-2206 as assessed by version 4 of the National Cancer Institute (NCI) Common Terminology Criteria For Adverse Events (CTCAE) in these cohorts of patients.

III. To explore the associations between select biomarkers and response to MK-2206 such as progression-free survival, objective tumor response, and overall survival as well as patient characteristics such as histological cell type.

IV. To explore the development of feed-back loop activation (post-treatment biopsy biomarker analysis) and target inhibition using MK-2206 via analysis of pre-treatment and post-treatment biopsies in select patients enrolled in the trial.

V. To determine the duration of progression-free and overall survival, following initiation of therapy with MK-2206.

VI. To determine the toxicities of MK-2206, as assessed with the revised NCI CTCAE version 4.

VII. To explore the association between select biomarkers and response to MK-2206 such as progression-free survival, objective tumor response.

OUTLINE:

Patients receive Akt inhibitor MK2206 orally (PO) once weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Inclusion Criteria:

• Participants must have histologically confirmed recurrent or persistent high grade endometrial carcinoma with a serous component, which is refractory to curative therapy or established treatments; histologic confirmation of the original primary tumor is required
• All patients must have measurable disease as defined by RECIST 1.1; measurable disease is defined as at least one lesion 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), 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 had one prior chemotherapeutic regimen for management of endometrial carcinoma initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy; chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen
• Patients are allowed to receive, but are not required to receive, one additional prior treatment regimen (including a single chemotherapeutic, a combination of chemotherapeutics, or an anti-angiogenic drug such as bevacizumab) for management of their recurrent or persistent disease; prior hormonal therapy is allowed and does not count towards this prior regimen
• Patients must have NOT received any class of drugs targeted to the PI3K pathway (such has PI3K inhibitors or mTOR inhibitors) for management of recurrent or persistent disease
• Life expectancy of greater than 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Creatinine within normal institutional limits or creatinine clearance >= 60 mL/min/1.73 m^2 for subjects with creatinine levels about institutional normal
• Hemoglobin A1c (HgA1c) =< 7.5% and fasting blood glucose less than 130mg/dL
• Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue from the original or most recent biopsy for mutational analysis
• Women of childbearing potential must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a patient become pregnant or suspect she is pregnant while she is participating in this study, she should inform the treating physician immediately
• Toxicities of prior therapy (excepting alopecia) should be resolved to =< grade 1 per the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4
• MK-2206 is an oral medication; patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of MK-2206
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to =< grade 1 (excepting alopecia) from adverse events (as per the revised NCI CTCAE version 4) due to agents administered more than 3 weeks earlier
• Participants may not be receiving any other study agents
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; should patients develop brain metastases while on trial and have clinical benefit from MK-2206 otherwise, patients may continue on drug after clinical management of the brain metastases with the permission of the principal investigator. MK-2206 should be restarted between 3 and 6 weeks after the last radiation treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206
• Patients requiring any medications or substances that are strong inhibitors or inducers of CYP 450 3A4 are ineligible
• Preclinical studies demonstrated the potential of MK-2206 for induction of hyperglycemia in all preclinical species tested; patients with diabetes or in risk for hyperglycemia should not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial. HgbA1c > 7.5% or fasting glucose greater than 130mg/dL will exclude patients from entry on study; patients requiring insulin for control of their hyperglycemia are excluded from entry on this study
• Preclinical studies indicated transient changes in QTc interval during MK-2206 treatment; prolongation of QTc interval is potentially a safety concern while on MK-2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female) will exclude patients from entry on study
• Due to a high incidence of bradycardia by Holter monitor, preexisting bundle branch block or baseline bradycardia due to cardiac disease will exclude patients from treatment with MK-2206
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; mother with MK-2206 breastfeeding should be discontinued if the mother is treated with MK-2206; these potential risks may also apply to other agents used in this study
• MK-2206 is an oral medication; patients who are unable to tolerate oral medication are not eligible; patients with signs and symptoms of bowel obstruction or with uncontrolled, persistent diarrhea will be excluded
• Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: breast cancer in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
• Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible
• Patients may not use natural herbal products or other "folk remedies" while participating in this study