Inclusion Criteria:
1. Patients must have signed an approved informed consent.
2. Histologically confirmed endometrial cancer (endometrioid, serous, or clear cell, or mixed histology; any grade) which is considered progressive or recurrent.
3. Patients may have failed no more than two prior chemotherapeutic regimens for recurrent or advanced disease (including adjuvant therapy). Chemotherapy administered in conjunction with radiation as a radio-sensitizer is not counted as a prior treatment for recurrent or advanced disease.
4. All patients must have measurable disease as defined by RECIST 1.1.
5. 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.
6. Patients must have a Zubrod performance status of 0, 1, or 2.
7. Patients must not be of child bearing potential. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal for greater than 12 months. Patients in whom ovaries are present and were not previously menopausal at the time of hysterectomy, should have a serum estradiol \< 10 pg/mL to confirm ovarian senescence.
8. Patients must have a pretreatment granulocyte count (i.e., segmented neutrophils + bands) of \>1,500/Fl, a hemoglobin level of \>/=9gm/dL and a platelet count of \>100,000/Fl. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
9. Patients must have an adequate renal function of \>50cc/min as documented by the Cockcroft Gault creatinine clearance formula: Estimated GFR = (140 - age) x (weight kg) divided by 72 x serum Creatinine (non-IDMS) x 0.85 (female)
10. Patients must have adequate hepatic function as documented by a serum bilirubin \</=2.5 mg/dL, regardless of whether patients have liver involvement secondary to tumor. Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
11. Alanine aminotransferase (SGPT) must be \</= 3x institutional upper limit of normal unless the liver is involved with tumor, in that case, the alanine aminotransferase must be \</= 5 x institutional upper limit of normal.
12. Prior to beginning therapy, at least 4 weeks must have elapsed since prior chemotherapy, surgery, radiation therapy, hormonal therapy or investigational therapy. Patients receiving palliative radiation therapy are exempt from the 4 week waiting period.
13. Baseline lipid levels (triglycerides, cholesterol) must be \</= grade 1. Patients are allowed to be on lipid lowering drugs.
14. Patients must be \>/= 18 years of age.
Exclusion Criteria:
1. Patients with intact ovarian function.
2. Patients who have previously received RAD001 or another mTOR inhibitor or letrozole or another aromatase inhibitor. Use of progestational or other hormonal agents are permitted provided they have not been administered within the previous 4 weeks.
3. Patients who have uterine sarcomas or mixed malignant mullerian tumors.
4. Patients who have isolated recurrences (vaginal, pelvic, or paraaortic) that are amenable to potentially curative treatment with radiation therapy or surgery.
5. Patients with any other severe concurrent disease, which would make the patient inappropriate for entry into this study, including significant hepatic, renal, or gastrointestinal diseases.
6. Patients currently receiving chemotherapy or radiotherapy or those in whom anti-cancer treatment has occurred within the preceding 4 weeks.
7. Chronic treatment with systemic steroids or another immuno-suppressive agent.
8. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.
9. Patients with a history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least five years
10. Patients with active infection that requires systemic antibiotics.
11. Patients with a known history of cardiac disease; i.e., uncontrolled hypertension (systolic B/P \>/= 140 mm Hg and/or diastolic B/P \>/= 90 mm Hg) or unstable angina. Patients with a history of myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure, or symptoms suspicious for congestive heart failure are not eligible unless a left ventricular ejection fraction in the past 6 months is documented to be 50% or greater. Patients who have had a LVEF (performed for any reason) of less than 50% in the past 6 months are ineligible.
12. Patients with a known history severely impaired lung function (patients who are oxygen dependent).
13. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients.
14. Patients who are pregnant or breast-feeding.
15. Presence of clinically apparent untreated central nervous system metastases.
16. Patients with carcinomatous meningitis.
17. Patients with deep venous or arterial thrombosis (including pulmonary embolism) within 6 weeks of study entry. Patients may be on maintenance anticoagulation therapy.
18. Patients with previously documented human immunodeficiency virus (HIV) infection.
19. Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
