Levonorgestrel-Releasing Intrauterine System With or Without Everolimus in Treating Patients With Atypical Hyperplasia or Stage IA Grade 1 Endometrial Cancer

Inclusion Criteria:

• All patients with a diagnosis of complex atypical hyperplasia OR, grade 1endometrioid OR focal grade 2 adenocarcinoma in predominately grade 1 diseaseendometrial carcinoma on endometrial biopsy or dilation and curettage (D & C) withinthree months of study enrollment

• Patients with complex atypical hyperplasia OR grade 1 endometrioid adenocarcinomawith stable/persistent disease with LIUD already in place. LIUD must have been inplace for at least 3 months

• Prior progesterone treatment is ALLOWED, but a 28 day washout period is requiredbefore LIUD placement. If archival tissue is available from prior to anyprogesterone treatment, the washout period is not needed

• Ability to comply with endometrial biopsies every 3 months

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

• Platelets >= 100 x 10^9/L

• Hemoglobin (Hb) > 9 g/dL

• Total serum bilirubin =< 2.0 mg/dL

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upperlimit of normal (ULN)

• International normalized ratio (INR) =< 2; factor 10A drawn if patient onanticoagulant Eliquis

• Serum creatinine =< 1.5 x ULN

• Fasting serum cholesterol =< 300 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, thepatient can only be included after initiation of appropriate lipid loweringmedication

• Signed informed consent obtained prior to any screening procedures

Exclusion Criteria:

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

• Evidence of extrauterine spread of disease on imaging or during surgical evaluation

• Patients who have prior therapy with everolimus or any other mammalian target ofrapamycin (mTOR) inhibitor

• Patients currently receiving anticancer therapies (including chemotherapy, radiationtherapy, hormonal, or antibody-based therapy); prior treatment should have a washoutperiod of 28 days or 4 1/2 half-lives (7 days), whichever is shorter

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

• Known intolerance or hypersensitivity to progesterone or its excipients

• Known impairment of gastrointestinal (GI) function or GI disease that maysignificantly alter the absorption of oral everolimus (e.g., inability to take oralmedication or a requirement for intravenous [IV] alimentation, prior surgicalprocedures affecting absorption, malabsorption syndrome, and active peptic ulcerdisease) are excluded; subjects with ulcerative colitis, inflammatory bowel disease,or a partial or complete small bowel obstruction are also excluded, as are anypatients who cannot swallow the capsule whole

• Uncontrolled diabetes mellitus as defined by glycosylated hemoglobin (HbA1c) > 8%despite adequate therapy; patients with a known history of impaired fasting glucoseor diabetes mellitus (DM) may be included, however blood glucose and antidiabetictreatment must be monitored closely throughout the trial and adjusted as necessary

• Patients who have any severe and/or uncontrolled medical conditions such as: a)unstable angina pectoris, symptomatic congestive heart failure, myocardialinfarction =< 6 months prior to start of everolimus, serious uncontrolled cardiacarrhythmia, or any other clinically significant cardiac disease; b) symptomaticcongestive 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 chronichepatitis (i.e. quantifiable hepatitis B virus-deoxyribonucleic acid [HBV-DNA]and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis Cvirus-ribonucleic acid [HCV-RNA]); d) known severely impaired lung function (spirometry and diffusing capacity of the lung for carbon monoxide [DLCO] 50% orless of normal and oxygen [O2] saturation 88% or less at rest on room air); e)active, bleeding diathesis

• Chronic treatment with corticosteroids or other immunosuppressive agents; topical orinhaled corticosteroids are allowed

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

• Patients who have received live attenuated vaccines within 1 week of start ofeverolimus and during the study; patient should also avoid close contact with otherswho have received live attenuated vaccines; examples of live attenuated vaccinesinclude intranasal influenza, measles, mumps, rubella, oral polio, BacillusCalmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines

• Other malignancies within the past 3 years except for basal or squamous cellcarcinoma of the skin

• Active (acute or chronic) or uncontrolled severe infections (not responding toantibiotics), including acute pelvic inflammatory disease

• Congenital or acquired uterine anomaly which distorts the uterine cavity

• Genital actinomycosis

• Patients with a history of non-compliance to medical regimens or who are consideredpotentially unreliable or will not be able to complete the entire study

• Patients who are currently part of or have participated in any clinicalinvestigation with an investigational drug within 1 month prior to dosing

• Women who are pregnant or nursing (lactating) women

• Women of child-bearing potential (WOCBP), defined as women physiologically capableof becoming pregnant, must use one additional highly effective methods ofcontraception in addition to the LIUD during the study and 8 weeks after; acceptableeffective contraception methods include combo of the following: a) barrier methodsof contraception: condom or occlusive cap (diaphragm or cervical/vault caps) withspermicidal foam/gel/film/cream/ vaginal suppository; b) total abstinence or; c)male/female sterilization; women are considered post-menopausal and not ofchild-bearing potential if they have had 12 months of natural (spontaneous)amenorrhea with an appropriate clinical profile (e.g. age appropriate, history ofvasomotor symptoms) or have had surgical bilateral oophorectomy (with or withouthysterectomy) or tubal ligation > six weeks prior to randomization; in the case ofoophorectomy alone, only when the reproductive status of the woman has beenconfirmed by follow up hormone level assessment is she considered not ofchild-bearing potential

• Women who are on contraindicated medications to everolimus must have confirmationfrom their physician that they may change or discontinue the medication ifrandomized to the LIUD + everolimus arm