Trametinib With or Without GSK2141795 in Treating Patients With Recurrent or Persistent Endometrial Cancer

- Patients must have recurrent or persistent endometrial carcinoma, which is refractory to curative therapy or established treatments; histologic confirmation of the original primary tumor is required

- Formalin-fixed, paraffin-embedded tumor tissue must be submitted to Baylor College of Medicine (BCM) - Cancer Genetics Laboratory for Clinical Laboratory Improvement Amendments (CLIA)-certified KRAS mutation testing; results must be reported on the eligibility checklist during registration in order to receive treatment assignment

- All patients must have measurable disease; measurable disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 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 at least one "target lesion" to be used to assess response on this protocol as defined by RECIST version 1.1; 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

- Gynecologic Oncology Group (GOG) performance status of 0 or 1

- 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 chemotherapy and immunotherapy, must be discontinued at least three weeks prior to registration; any investigational agent must be discontinued at least 30 days prior to registration

- Any prior radiation therapy must be discontinued at least four weeks prior to registration

- At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: laparotomy, laparoscopy); there is no delay in treatment for minor procedures (e.g., tumor core biopsy)

- Patients must have had one prior chemotherapeutic regimen for management of endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and radiation therapy, 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 cytotoxic regimen for management of recurrent or persistent disease

- Patients MAY HAVE received non-cytotoxic (biologic or targeted) agent(s) as part of initial treatment and/or for management of recurrent or persistent disease, with the below stated exceptions (see NOTE below); prior hormonal therapy is allowed, but must be discontinued at least one week prior to registration

- Absolute neutrophil count (ANC) >= 1,500/mcl

- Platelets >= 100,000/mcl

- Hemoglobin >= 9 g/dl

- Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 ml/min OR 24-hour urine creatinine clearance >= 50 ml/min

- Bilirubin =< 1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

- Alkaline phosphatase =< 2.5 x ULN

- Albumin >= 2.5 g/dL

- Fasting glucose < 160 mg/dL

- Hemoglobin A1C (HbA1C) =< 8 if patient has diabetes

- Thyroid-stimulating hormone (TSH) within institutional/laboratory normal limits

- Left ventricular ejection fraction (LVEF) greater than or equal to institutional/laboratory lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

- International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x ULN

- For patients on Coumadin, INR/prothrombin time (PT)/PTT must be > 1.5 ULN

- Hemodynamic parameters:

- All prior treatment-related toxicities must be CTCAE v4 grade =< 1 (except alopecia) at the time of randomization

- Patients with abnormal fasting glucose values at screening will be excluded (fasting glucose >= 160); in addition, patients with type 1 diabetes will also be excluded; however, patients with type 2 diabetes will be allowed if diagnosed >= 6 months prior to enrollment, and if presenting with hemoglobin A1C (HbA1C) =< 8% at screening

- Patients must be able to swallow and retain orally-administered medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

- Women of child-bearing potential 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 AND for 4 months following discontinuation; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

- Patients must meet pre-entry requirements as specified

- Patients must have signed an approved informed consent and authorization permitting release of personal health information

- Patients who have had prior therapy with GSK2141795 or any other PI3K/AKT/MTOR pathway inhibitor

- Patients who have prior therapy with trametinib or any other MEK inhibitor

- Patients who have mucinous, squamous, sarcomas, or carcinosarcomas

- Patient with a history of other invasive malignancies, with the exception of non-melanoma skin cancer are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol eligibility

- Patients with symptomatic or untreated leptomeningeal or brain metastasis or spinal cord compression

- Patients with a history of interstitial lung disease or pneumonitis

- Patients with known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the trametinib, GSK2141795 or dimethyl sulfoxide (DMSO)

- Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

- Drugs that potently inhibit cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) should be prohibited or used with caution; drugs which are strong inducers of CYP3A and may result in lower exposures of GSK2141795 should also be prohibited; drugs that are substrates of CYP3A4 or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) with a narrow therapeutic index may be prohibited; drugs that are sensitive substrates of CYP3A4 or CYP2C8 should be used with caution

- Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (unless cleared) will be excluded

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

- History or current evidence/risk of retinal vein occlusion (RVO)

- History or evidence of cardiovascular risk including any of the following:

- 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

- Patients who are pregnant or nursing; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; if a patient becomes pregnant while the patient receives trametinib and/or GSK2141795, the potential hazard to the fetus should be explained to the patient