Phase II Study of Intrauterine Device (IUD) Alone or in Combination With Everolimus in Endometrial Cancer

Stage 1 Study Visits:

The Levonorgestrel IUD:

This study will have 2 stages. If you are found to be eligible to take part in this study, in
Stage 1, you will receive the levonorgestrel IUD. The levonorgestrel IUD is a T-shaped birth
control device that is made of flexible plastic. It is designed to prevent pregnancy by
releasing a hormone called levonorgestrel, which is a type of progesterone. Progesterone is a
common type of hormone that is used to prevent pregnancy.

The IUD is placed during an exam of the pelvis. The uterine size is measured and the IUD
placed directly into your uterus. This placement may be done at the time of the dilation and
curettage (D&C, explained below) or during a routine clinic visit.

Removal of the IUD is typically done during a clinic visit during a routine pelvic exam. The
IUD strings are located, grasped, and used to remove the device.

Study Surgery and IUD Placement:

On Day 1 (within 1 week after screening) you will have a standard of care procedure called
dilation and curettage (D&C) to confirm the diagnosis. You would have this procedure even if
you did not take part in this study. For this procedure, you will have a pelvic exam, and
then you will receive general anesthesia to put you to sleep. You may also receive medication
to numb the cervix. During this procedure a small amount of tissue will be scraped from the
uterus. You will sign a separate consent form describing this procedure and its risks in more
detail.

During the D&C, the levonorgestrel IUD will be placed in your uterus. If you have recently
had a D&C, the procedure will not need to be repeated. Instead, the IUD will be placed during
a clinic visit.

About 1 week after surgery, the study staff will review your surgery and pathology results
with you. If the results showed that you had a change in your diagnosis from hyperplasia to
early-stage cancer, the doctor will decide if you are still eligible to take part in this
study. If the pathology results show that there is grade 2 or higher cancer in the uterus,
you will be unable to take part in the study. The levonorgestrel IUD can be removed in the
operating room when you have surgery for removal of disease outside the uterus. You may also
have the levonorgestrel IUD removed in the clinic.

At 4 weeks after surgery, you will have a physical exam, including a pelvic exam. Placement
of the levonorgestrel IUD will be checked during the pelvic exam. This visit may be in our
office or at your local doctor's office, whichever you prefer. In addition, you may have an
ultrasound of your uterus to confirm the location of your IUD. If the IUD is not in the
correct location, it will be replaced at this visit.

Stage 1 Study Visits:

At 3 months after the IUD placement, you will have an endometrial biopsy (a biopsy of the
uterine lining) to check the status of the disease. This is standard care and would be done
even if you did not take part in this study.

If the biopsy shows that the disease has gotten worse, you will be taken off study and other
treatment options will be discussed with you.

If the disease appears to have become stable, you will continue on to Stage 2 of the study
(described below). You will also have a physical exam and blood (about 2 tablespoons) drawn
for routine tests at this visit.

If the disease appears to have responded completely, you will have a standard of care biopsy
3 months later to confirm the response. If confirmed, you will then be followed every 6
months with a standard of care biopsy until the disease appears to get worse or you and/or
your physician decide to remove the IUD and come off study.

If a complete response is not confirmed at the 6-month biopsy visit, you will be taken off
study and the doctor will talk with you about options including surgical or non-surgical
treatment.

Stage 2 Study Groups:

If at 3 months after IUD placement the disease has remained stable, you will be assigned to a
study group. You will be randomly assigned (as in a roll of dice) to 1 of 2 arms. This is
done because no one knows if one arm is better, the same, or worse than the other arm.

- If you are in Arm 1, you will continue on the levonorgestrel IUD alone.

- If you are in Arm 2, you will receive everolimus every day in addition to continuing on
the levonorgestrel IUD.

Stage 2 Study Drug Administration:

If you are in Arm 2, at 3 months after IUD placement, 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. Each cycle in Stage 2 is 28 days.

On Day 1 of Cycles 1-4, you will use a steroid-based mouth wash to help prevent side effects.
You may stop taking this if the doctor thinks it is not needed.

Stage 2 Study Visits--Arm 1 only:

If you are in Arm 1, at 6 Months after IUD placement.

- You will have a physical exam, including a pelvic exam.

- You will have an endometrial biopsy to check the status of the disease.

If the disease appears to get better or stay the same. You will then be followed every 3
months with a standard of care biopsy until the disease appears to get worse or you and/or
your physician decide to remove the IUD and come off study.

You will have a physical exam and biopsy at 9 months and 1 year.

If your disease appears to have gotten worse at the 9-month or 1-year biopsy, or your disease
has stayed the same at the time of the 1-year biopsy, you will come off study and the doctor
will talk with you about options including surgical or non-surgical treatment.

If you have a complete response at the time of the 1-year biopsy, you will have a standard of
care biopsy 3 months later to confirm the response. If confirmed, you will then have a
standard of care biopsy every 6 months until the disease appears to get worse or you and/or
your physician decide to remove the IUD.

Stage 2 Study Visits--Arm 2 only:

If you are in Arm 2, on Day 1 of each Cycle:

- You will have a physical exam, including a pelvic exam.

- 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 or to check your liver function.

If you are in Arm 2, at Cycles 3, 6 and 9:

- You will have a physical exam, including a pelvic exam.

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

- You will have a follow-up endometrial biopsy to check the status of the disease.

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

If you are in Arm 2, on Cycle 1 and every 3rd cycle (Cycles 1, 4, 7, and so on) until the end
of treatment:

°Blood (about 1 tablespoon) will be drawn to check your lipid profile (the level of
cholesterol and triglycerides in your blood).

If the disease appears to have completely responded at the time of the Cycle 9 biopsy, you
will have an endometrial biopsy to confirm the response at Cycle 12. If confirmed, you will
have a biopsy every 6 cycles as long you are on study. You will also have the following tests
and procedures 1 time each cycle starting at Cycle 10:

- You will have a physical exam, including a pelvic exam.

- 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 your
liver function.

If the disease appears to have gotten worse at the time of the Cycle 3, 6, or 9 biopsy, you
will stop taking everolimus and come off study. The doctor will talk with you about surgical
and/or non-surgical treatment options.

If the disease has remained stable at the time of the Cycle 9 biopsy, you will come off study
and the doctor will talk with you about surgical and/or non-surgical treatment options.

Biomarker Testing:

Leftover tissue from a previous procedure will be tested for biomarkers. Biomarkers are found
in the blood/tissue and may be related to your response to levonorgestrel. Biomarker testing
will also be performed on leftover tissue from the Month 3 EMB, Month 6 EMB and Cycle 3 (only
if you are in Arm 2), and if you have a hysterectomy.

End-of-Treatment Visit (Arm 2 only):

After you are no longer receiving the study treatment(s):

- You will have a physical exam.

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

Inclusion Criteria:

1. All patients with a diagnosis of complex atypical hyperplasia OR, grade 1 endometrioid
OR focal grade 2 adenocarcinoma in predominately grade 1 disease endometrial carcinoma
on endometrial biopsy or D& C within three months of study enrollment.

2. Prior progesterone treatment is ALLOWED.

3. Ability to comply with endometrial biopsies every 3 months

4. Age >/= 18 years

5. ECOG performance status
6. Adequate bone marrow function as shown by: absolute neutrophil count (ANC) >/= 1.5 x
10^9/L; Platelets >/=100 x 10^9/L; Hb >9 g/dL;

7. Adequate liver function as shown by: a) Total serum bilirubin Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) Limit of Normal (ULN); c) International Normalized Ratio (INR) if patient on anticoagulant Eliquis

8. Adequate renal function: serum creatinine
9. Fasting serum cholesterol can only be included after initiation of appropriate lipid lowering medication;

10. Signed informed consent obtained prior to any protocol specific procedures.

Exclusion Criteria:

1. Patients with grade 2-3 endometrioid, uterine serous, clear cell, mucinous, squamous,
transitional cell, sarcomas, or carcinosarcoma histology

2. Evidence of extrauterine spread of disease on imaging or during surgical evaluation.

3. Patients who have prior therapy with everolimus or any other mTORC1 inhibitor.

4. Patients currently receiving anticancer therapies (including chemotherapy, radiation
therapy, hormonal, or antibody-based therapy). Prior treatment should have a washout
period of 28 days or 4 1/2 half-lives (7 days), whichever is shorter;

5. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
sirolimus, temsirolimus);

6. Known intolerance or hypersensitivity to progesterone or its excipients

7. Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus (e.g., inability to take oral
medication or a requirement for IV alimentation, prior surgical procedures affecting
absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded.
Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete
small bowel obstruction are also excluded, as are any patients who cannot swallow the
capsule whole.

8. Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate therapy.
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM)
may be included, however blood glucose and antidiabetic treatment must be monitored
closely throughout the trial and adjusted as necessary;

9. Patients who have any severe and/or uncontrolled medical conditions such as: a.
unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
any other clinically significant cardiac disease b. Symptomatic congestive heart
failure of New York heart Association Class III or IV c. active (acute or chronic) or
uncontrolled severe infection (not responding to antibiotics), liver disease such as
cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.
quantifiable hepatitis B virus-deoxyribonucleic acid (HBV-DNA) and/or positive
Hepatitis B surface antigen (HbsAg), quantifiable hepatitis C virus-ribonucleic acid
(HCV-RNA), d. known severely impaired lung function (spirometry and Diffusing capacity
of the Lung for Carbon Monoxide [DLCO] 50% or less of normal and O2 saturation 88% or
less at rest on room air), e. active, bleeding diathesis;

10. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or
inhaled corticosteroids are allowed

11. Patients who have a known history of human immunodeficiency virus (HIV) seropositivity

12. Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study. Patient should also avoid close contact with others
who have received live attenuated vaccines. Examples of live attenuated vaccines
include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus
Calmette-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines

13. Other malignancies within the past 3 years except for basal or squamous cell carcinoma
of the skin

14. Active (acute or chronic) or uncontrolled severe infections (not responding to
antibiotics), including acute pelvic inflammatory disease

15. Congenital or acquired uterine anomaly which distorts the uterine cavity

16. Genital actinomycosis

17. Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study

18. Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing.

19. Women who are pregnant or nursing (lactating) women

20. Women of child-bearing potential (WOCBP), defined as women physiologically capable of
becoming pregnant, must use one additional highly effective methods of contraception
in addition to the LIUD during the study and 8 weeks after. Acceptable effective
contraception methods include combo of the following: a. Barrier methods of
contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/ vaginal suppository; b. Total abstinence or; c.
Male/female sterilization. Women are considered post-menopausal and not of
child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea
with an appropriate clinical profile (e.g. age appropriate, history of vasomotor
symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy)
or tubal ligation > six weeks prior to randomization.