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

Study Drug Administration:

If you are found to be eligible to take part in this study and you are not already taking
metformin, you will take metformin before you begin the regular study cycles (Cycles 1 and
beyond). This will be called "Cycle 0." You will take metformin by mouth 1 time a day on Days
1-4 of Cycle 0 and then 2 times a day (about 12 hours apart) every day after that. You will
take metformin for 7-10 days in Cycle 0 before Cycle 1 begins. If you are already taking
metformin, you will continue your regular dose and start Day 1 of Cycle 1. If you are already
taking metformin but your dose is less than 1000mg/day, your dose will be slowly raised up to
the study dose over the course of 7-10 days and then you will start Cycle 1. In Cycles 1 and
beyond, all participants will take all 3 drugs at a time. You should take metformin with
food.

Starting in Cycle 1, you will take everolimus 1 time a day by mouth at about the same time
every day. You should take it either consistently with food every day or consistently without
food every day.

Starting in Cycle 1, you will take letrozole 1 time a day by mouth at about the same time
every day.

It is very important for you to take the study drugs just as the study doctor tells you. Do
not skip any doses unless your study doctor tells you to skip doses. If you throw up after
taking the study drugs, you should NOT take another tablet that day. Let your study doctor
know that you got sick. If you forget to take the study drugs one day, do not take any extra
doses the next day. Call your study doctor and ask for advice.

There are 4 weeks in each cycle (except Cycle 0).

Study Visits:

Every cycle (+/- 10 days):

- You will have a physical exam, including measurement of your vital signs and weight.

- Your performance status will be recorded.

- You will be asked about any side effects you may have had.

- Blood (about 2 tablespoons) will be drawn for routine tests.

- If the doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to check for
hepatitis.

After Cycles 2, 4, and 6 and then every 3 cycles after that (Cycles 9, 12, 15, and so on)
(+/- 10 days):

- You will have scans such as a CT scan and/or MRI to check the status of the disease.

- If you have chest disease, you will have a CT scan of the chest.

- If the disease could be felt in the pelvis at the beginning of the study, you will have
a pelvic exam

After every other cycle (Cycles 2, 4, and so on), blood (about 1 teaspoon) will be drawn for
routine tests.

Length of Treatment:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Treatment Visit:

Within 4 weeks after the last dose of study drugs:

- You will have a physical exam, including a pelvic exam and measurement of your vital
signs and weight.

- Your performance status will be recorded.

- You will be asked about any side effects you may have had.

- Blood (about 2 tablespoons) will be drawn for routine tests.

- You will have scans such as a CT scan and/or MRI to check the status of the disease.

- If you have chest disease, you will have a CT scan of the chest.

Follow-Up:

You will have follow-up visits as often as the doctor thinks is needed. At every visit:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- You will be asked about any side effects you may have had.

- If the doctor thinks it is needed, you will have scans such as a CT scan and/or MRI to
check the status of the disease.

- If you have chest disease, you will have a CT scan of the chest.

As often as the doctor thinks is needed, the study staff will call you to ask about side
effects you may have had. These calls should last 5-10 minutes.

This is an investigational study. Everolimus is FDA approved and commercially available to
treat kidney, breast, and pancreatic cancers. Letrozole is FDA approved and commercially
available to treat breast cancer and ovarian cancer. Metformin is FDA approved and
commercially available to treat diabetes. The combination of everolimus, metformin, and
letrozole in this study to treat endometrial cancer is investigational.

Up to 64 patients will be enrolled in this study. Up to 59 may take part at MD Anderson. Up
to 5 patients per site may be enrolled at MD Anderson Cooper and Spartanburg Regional
Healthcare System and Harris Health System.

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
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 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 mg/dL 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