Study of Ribociclib (LEE011), Everolimus, and Letrozole, in Patients With Advanced or Recurrent Endometrial Carcinoma

Study Drug Administration:

Each study cycle is 28 days.

Participant will take everolimus, letrozole and ribociclib by mouth and should be swallowed
whole without opening, chewing, or crushing 1 time every day at the same time. Participant
will take the dose in the morning with a full cup of water (about 8 ounces). Participant
should fast (not eat or drink anything except water) for up to 2 hours before and after each
dose of study drugs.

When participant comes to clinic for a visit, participant should wait to take participant's
drugs until the study team tells participant to take them.

Length of Treatment:

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

Participation on the study will be over after follow-up.

Study Visits:

On Day 1 of Each Cycle:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) and urine will be collected for routine tests.

- If the doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to check for
hepatitis. If participant has had the hepatitis screening test during screening, it will
not be repeated.

- On Day 1 of Cycles 2 and beyond, participant will have an EKG.

- On Day 1 of Cycle 3 and every 3 cycles after that (Cycles 6, 9, 12, and so on), part of
the routine blood draw will be used to check the level of fat in participant's blood.

On Day 15 of Cycle 1:

- Blood (about 3 ½ tablespoons) will be drawn for routine and pharmacodynamic PD testing.

- Participant will have three EKGs 5 minutes apart before the dose and then 2-4 hours
after.

On Day 15 of Cycle 2, participant will have an EKG before and then 2-4 hours after the dose.

At the end of Cycles 2, 4, 6 and every 3 cycles after that (Cycles 9, 12, 15, and so on) (+/-
7 days):

- Participant will have an MRI and/or CT scan. If participant has signs of disease in the
chest chest disease, participant will have a CT scan of the chest.

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

End-of-Treatment Visit:

Within 4 weeks after the last dose of study drugs:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) and urine will be collected for routine tests.

- Participant will have an MRI and/or CT scan. If participant has signs of disease in the
chest, participant will have a CT scan of the chest.

Follow-Up:

At 30 days after participant's last dose of study drugs and then every 3 months (+/- 1 month)
after that, a member of the study staff will contact participant by phone or at a regularly
scheduled clinic visit to ask how participant is doing and about any side effects participant
may have had. These calls or visits should last about 5-10 minutes each time.

Inclusion Criteria:

1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being
performed and is able to comply with protocol requirements.

2. Patients must have histologically-confirmed endometrial carcinoma (endometrioid and
mixed endometrioid tumors, any grade).

3. Patients must have advanced or recurrent disease that is refractory to curative
treatment based on imaging or clinical exam.

4. Patient must consent to allow for a baseline tumor biopsy. Tumor material from
biopsies done before the screening period are acceptable if the biopsy was performed
within 3 months prior to the planned treatment start and no other systemic cancer
therapy was administered in the interim. If a biopsy is performed and the specimen is
considered non-diagnostic or dose not have enough tissue, this does not prevent the
patient from proceeding with the treatment.

5. Patients must have had no more than two prior chemotherapeutic regimens for recurrent
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.

6. Prior radiation therapy of any kind is allowed.

7. Prior treatment with letrozole is allowed if the patient meets the washout period of
10 days.

8. All patients must have measurable disease per RECIST version 1.1 defined as at least
one "target lesion" that can be accurately measured in at least one dimension (>/= 10
mm 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.

9. Patients must not be pregnant, breastfeeding or 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 (If patient is
uncertain of amenorrhea for 12 months, a pregnancy test will be done to confirm
pregnancy status). 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

10. Patients must be off all other anti-tumor therapies (including immunologic agents) for
at least four weeks prior to study registration. Patients on hormonal agents require a
washout for 10 days.

11. Age >/= 18 years

12. GOG performance status of 0 to 1

13. Patient has adequate bone marrow and organ function as defined by the following
laboratory values at screening: a. Absolute neutrophil count >/=1.5 × 109/L b.
Platelets >/=100 × 10^9/L c. Hemoglobin >/=9.0 g/dL d. INR /=50 mL/min f. In the absence of liver
metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x
ULN. If the patient has liver metastases, ALT and AST <5 x ULN g. Total bilirubin <
ULN; or total bilirubin well-documented Gilbert's Syndrome. h. i.h. Fasting serum cholesterol these thresholds are exceeded, the patient can only be included after initiation of
appropriate lipid lowering medication.

14. Patient with available standard 12-lead ECG with the following parameters at
screening: a. QTcF interval at screening <450msec (using Fridericia's correction). b.
Resting heart rate 50-100bpm

Exclusion Criteria:

1. Patients who have uterine sarcomas, carcinosarcomas, serous tumors (any component) 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. Patient has not recovered from all toxicities related to prior anticancer therapies to
NCI-CTCAE version 4.03 Grade grade of alopecia are allowed to enter the study).

4. Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects (tumor biopsy is not considered as major surgery).

5. Participation in a prior investigational study within 30 days prior to enrollment or
within 5 half-lives of the investigational product, whichever is longer.

6. Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

7. 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.

8. Patients with central nervous system (CNS) involvement unless they meet ALL of the
following criteria: a. At least 4 weeks from prior therapy completion (including
radiation and/or surgery) to starting the study treatment. b. Clinically stable CNS
tumor at the time of screening and not receiving steroids and/or enzyme-inducing
anti-epileptic medications for brain metastases.

9. Patient has a concurrent malignancy or malignancy within 3 years prior to starting
study drug, with the exception of adequately treated, basal or squamous cell
carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.

10. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment, may cause unacceptable safety risks,
contraindicate patient participation in the clinical study or compromise compliance
with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active
untreated or uncontrolled fungal, bacterial or viral infections, etc.)

11. Patient has a known history of HIV infection (testing not mandatory).

12. Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormalities, including any of the following: a.History of acute coronary syndromes
(including myocardial infarction, unstable angina, coronary artery bypass grafting,
coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior
to screening. b. History of documented congestive heart failure (New York Heart
Association functional classification III-IV). c.Documented cardiomyopathy. d. Left
Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition
(MUGA) scan or echocardiogram (ECHO) at screening. e. clinically significant cardiac
arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block,
high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV
block)

13. Cont. from #12. Long QT syndrome or family history of idiopathic sudden death or
congenital long QT syndrome, or any of the following: a. Risk factors for Torsades de
Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac
failure, or history of clinically significant/symptomatic bradycardia. b.Concomitant
use of medication(s) with a known risk to prolong the QT interval and/or known to
cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days
prior to starting study drug) or replaced by safe alternative medication. c. Inability
to determine the QT interval on screening (QTcF, using Fridericia's correction). d.
Systolic blood pressure (SBP) >160 mmHg or <90mmHg at screening.

14. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of study medication (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection associated with malabsorption)

15. Patient is currently receiving any of the following medications and cannot be
discontinued 7 days prior to starting study drug: a. Known strong inducers or
inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos,
star-fruit, and Seville oranges. b. That have a narrow therapeutic window and are
predominantly metabolized through CYP3A4/5. c. Herbal preparations/medications,
dietary supplements. d. Hormone replacement therapy, topical estrogens (including any
intra-vaginal preparations), megestrol acetate and selective estrogen-receptor
modulators (e.g. raloxifene)

16. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH) or fondaparinux is allowed.

17. Liver disease such as cirrhosis or severe hepatic impairment (Patient with a
Child-Pugh score B or C). 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.

18. Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus,
temsirolimus, everolimus).

19. Patients with a known hypersensitivity to ribociclib or everolimus or to its
excipients.

20. History of noncompliance to medical regimens.

21. Patients unwilling to or unable to comply with the protocol.