A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma

Inclusion Criteria: 1. Patients must have histologically-confirmed advanced or recurrent endometrial carcinoma (endometrioid and mixed tumors, any grade) that is refractory to curative therapy or established treatments 2. Patients must have had no more than two prior chemotherapeutic regimens for recurrent management of endometrial carcinoma. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer is not counted as a prior treatment for recurrent or advanced disease 3. Prior radiation therapy of any kind is allowed 4. All patients must have measurable disease per RECIST 1.1 defined as at least one target lesion that can be accurately measured in at least one dimension (\>/=10mm longest dimension to be recorded; Lymph nodes must be \>/=15 mm per short axis). Each lesion must be \> 20 mm when measured by palpation or conventional imaging techniques (CT or MRI - based on primary physician preference) or \>10 mm with spiral CT scan. Measurable lesions must be at least 2 times the slice thickness in millimeters. Tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented. Ascites and pleural effusions are not considered measurable disease. If the measurable disease is confined to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology 5. 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 total 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 pm/mL to confirm ovarian senescence. 6. Patients must be off all other anti-tumor therapies (including immunologic or hormonal agents) for at least four weeks prior to study registration. 7. Age \>/= 18 years 8. GOG performance status \</= 2 9. Adequate bone marrow function as shown by: ANC \>/= 1.5 x 10\^9/L, Platelets \>/= 100 x 10\^9/L, Hb \>9 g/dL 10. Adequate liver function as shown by: a. serum bilirubin \</= 1.5 x ULN b. ALT and AST \</= 2.5x ULN (\</= 5x ULN in patients with liver metastases); Adequate renal function:serum creatinine \< 1.4mg/dL (per manufacturer, metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine\> 1.4 mg/dL in females and in patients with abnormal clearance) ; Fasting serum cholesterol \</= 240 mg/dL OR \</=7.75 mmol/L AND fasting triglycerides \</= 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication 11. Signed informed consent 12. Prior treatment with letrozole is allowed. Exclusion Criteria: 1. Patients who have uterine sarcomas, carcinosarcomas, any serous histology or pure clear cell carcinomas 2. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.) 3. Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study 4. Prior treatment with any investigational drug within the preceding 4 weeks 5. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed 6. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. 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. 7. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases 8. Other malignancies within the past 3 years except for basal or squamous cell carcinomas of the skin. 9. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: a. Symptomatic congestive heart failure of New York heart Association Class III or IV; b. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease; c. Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air; d. Active (acute or chronic) or uncontrolled severe infections 10. CONTINUED FROM 10 - e. Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). 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; f. A known history of HIV seropositivity; g. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection); h. Patients with an active, bleeding diathesis 11. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus) 12. Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus). 13. Patients with a known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients 14. History of noncompliance to medical regimens 15. Patients unwilling to or unable to comply with the protocol. 16. Patients with isolated recurrences (vaginal, pelvic, or paraaortic) that are amenable to potentially curative treatment with radiation therapy or surgery. 17. Patients with acute or chronic metabolic acidosis, lactic acidosis, or ketoacidosis. Note: during the study, metformin must be discontinued for 24 hours before and 48 hours after imaging involving IV contrast to minimize risk of lactic acidosis. 18. Patients who have hypoglycemia with a value of \</= 50 mg/dL