Evaluating Cancer Response to Treatment With Abemaciclib and Fulvestrant in Women With Recurrent Endometrial Cancer

Inclusion Criteria:

- Patients must have signed an approved informed consent and authorization permitting
release of personal information.

- Patient must consent to the collection of archival tumor tissue for biomarker testing.
Availability of archival tissue for biomarker testing must be confirmed by the site
prior to screening of patient. Suitability of archival tissue that was not FFPE must
be discussed with the Principal Investigator. Archival tissue consists of either a
minimum of 10 FFPE slides or FFPE tissue block. Patients with no available archival
tissue (or if the sample is difficult to obtain) may undergo a tumor biopsy to meet
eligibility criteria, as long as the patient consents to this procedure and the biopsy
can be obtained with minimal risk and discomfort to the patient.

- Age ≥ 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 AND Karnofsky
Performance Status (KPS) ≥ 80

- Patients must have had at least one but no more than two prior chemotherapeutic
regimens for management of endometrial carcinoma (including adjuvant chemotherapy).
Initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or
consolidation/maintenance therapy.

- Chemotherapy administered in conjunction with primary radiation as a
radiosensitizer WILL be counted as a systemic chemotherapy regimen.

- Patients are not required to, but may have received a single line of prior hormonal
therapy with either an antiestrogen, anti progesterone (or combination) or an
aromatase inhibitor. Patients may not have received more than 1 line of endocrine
therapy. This will not count toward prior therapy total.

- Resolution of adverse effects of recent surgery, radiotherapy, chemotherapy, or
hormonal therapy to Grade ≤1 prior to first study treatment with the exception of
peripheral neuropathy and alopecia.

- Postmenopausal status due to either surgical or natural menopause. Post menopausal
status due to surgical/natural menopause requires at least 1 of the following:

- History of hysterectomy

- Prior bilateral oophorectomy

- Age ≥ 60

- Age ≤ 60 and amenorrheic for at least 12 months (in the absence of chemotherapy,
hormonal therapy or ovarian suppression) and FSH and estradiol levels in the
postmenopausal range.

- Have a negative serum pregnancy test at baseline (within 7 days prior to
-initiation of treatment) and agree to use medically approved precautions to
prevent pregnancy during the study and for 12 weeks following the last dose of
Abemaciclib.

- For patients of childbearing potential, agreement to use two effective forms of
contraception (e.g., surgical sterilization, a reliable barrier method, birth control
pills, or contraceptive hormone implants) and to continue its use for the duration of
the study and for 30 days after the last abemaciclib dose.

- Disease that is measurable as per RECIST v1.1.

- Tumors within a previously irradiated field wi ll be designated as "nontarget"
lesions unless progression is documented or a biopsy is obtained to confirm
persistence of tumor ≥ 90 days following completion of radiation therapy.

- No active infection requiring antibiotics (with the exception of uncomplicated urinary
tract infection). Any hormonal therapy directed at the malignant tumor must be
discontinued at least 2 weeks prior to the first study treatment.

- Patients must meet all the following criteria to be eligible for study entry:

1. Patients must have recurrent or persistent endometrial carcinoma that is
refractory to curative therapy or established treatments.

2. Histologic confirmation of the original primary tumor is required.

3. Histologic or cytologic confirmation of the recurrent/progressive disease is
desired, but not required.

4. Patients with the following histologic epithelial cell types are eligible:
endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma,
de-differentiated, clear cell adenocarcinoma, mixed epithelial carcinoma,
adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma,
squamous cell carcinoma, and transitional cell carcinoma.

5. Patient must have hormone receptor positive (HR+) endometrial cancer:

- To fulfill the requirement for HR+ disease, tumor must express by
immunohistochemistry (IHC), at least 1 of the hormone receptors (estrogen
receptor [ER] or progesterone receptor [PgR] as defined in the relevant
American Society of Clinical Oncology (ASCO)/College of American
Pathologists (CAP) guidelines (Hammond et al, 2010)

- Any prior therapy directed at the malignant tumor, including immunologic agents and
radiotherapy, must be discontinued at least 21 days prior to first study treatment.

- Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 7 days prior to first study treatment:

- Absolute neutrophil count (ANC) ≥1500/109dL

- Platelet count ≥ 100,000/109dL

- Hemoglobin ≥ 9.0 g/dL

- Albumin ≥ 3.0 g/dL

- Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)

- AST and ALT ≤ 3.0x ULN

- Adequate renal function defined by the following laboratory results obtained within 7
days prior to first study treatment:

Serum creatinine≤1.5x ULN OR creatinine clearance ≥50 mL/min on the basis of the
Cockcroft-Gault glomerular filtration rate :

estimation (140-age)x(weight in kg)x(0.85 if female) 72 x (serum creatinine in mg/dL)

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
≤ 1.5 xULN. For patients requiring therapeutic anticoagulation, a stable INR ≤3 x ULN
is required.

- Are able to swallow capsules

- Are willing to follow study procedures

Exclusion Criteria:

- Patients who are currently receiving an investigational drug in a clinical trial or
participating in any other type of medical research judged not to be scientifically or
medically compatible with this study. If a patient is currently enrolled in a clinical
trial involving non-approved use of a devise, then agreement with the principal
investigator and Lilly is required to establish eligibility

- Patient who is experiencing a visceral crisis, lymphangitic disease spread,
leptomeningeal carcinomatosis. Visceral crisis is not the mere presence of visceral
metastases but implies severe organ dysfunction as assessed by symptoms and signs,
laboratory studies, and rapid progression of disease.

- Patients who have received prior treatment with fulvestrant, everolimus, temsirolimus,
ridaforolimus or another mTor inhibitor, or any CDK4 and CDK6 inhibitor.

- Patients who have received an autologous or allogenic stem-cell transplant.

- Clinically significant history of liver disease, including cirrhosis and current
alcohol abuse.

- Presence of positive test results for hepatitis B (hepatitis B surface antigen
[HBsAGg] and/or total HB core antibody [anti-HBc]) or hepatitis C (hepatitis C virus
[HCV] antibody serology testing)

- Patients positive for anti-HBc are eligible only if also positive for HB surface
antibody (anti-HBs) and polymerase chain reaction (PCR) assay is negative for HBV DNA.

- Patients positive for HCV antibody are eligible only if testing for HCV RNA is
negative.

- Known HIV infection.

- Active autoimmune disease that is not controlled by nonsteroidal anti -inflammatory
drugs.

- Pregnancy, lactation, breastfeeding.

- Current severe, uncontrolled systemic disease (e.g., clinically significant
cardiovascular, pulmonary, or metabolic disease)

- Major surgical procedure or significant traumatic injury within 28 days prior to Day 1
or anticipation of the need for major surgery during the course of study treatment.

- Have initiated biphosphonate or RANK ligand targeted agents (for example,denosumab) <7
days prior to randomization

- Uncontrolled hypomagnesemia or hypokalemia, defined as values below the lower limit of
normal despite optimal electrolyte supplementation or management

- Leptomeningeal disease as a manifestation of cancer

- Known untreated or active central nervous system (CNS) metastases (progression or
requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a
history of treated CNS metastases are eligible, provided that they meet all of the
following criteria:

1. Presence of measurable disease outside the CNS

2. No radiographic evidence of worsening upon the completion of CNSdirected therapy
and no evidence of interim progression between the completion of CNS-directed
therapy and the screening radiographic study

3. No history of intracranial hemorrhage or spinal cord hemorrhage

4. No ongoing requirement for dexamethasone as therapy for CNS disease
(anticonvulsants at a stable dose are allowed)

5. Screening CNS radiographic study is ≤ 6 months after most recent intervention for
CNS metastases (neurological resection, radiotherapy, or brain biopsy) and ≥ 4
months after the discontinuation of corticosteroids

- Inability to comply with study and follow-up procedures

- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that, in the i nvestigator‟s opinion, gives reasonable suspicion of
a disease or condition that contraindicates the use of an investigational drug or that
may affect the interpretation of the results or render the patient at high risk from
treatment complications

- Patients who have:

- History of myocardial infarction, unstable angina, ventricular tachycardia,
ventricular fibrillation or sudden cardiac arrest within 6 months prior to first
study treatment

- New York Heart Association Class II or greater congestive heart failure (see
Appendix A)

- History of malabsorption syndrome or other condition that would interfere with
enteral absorption

- Inability or unwillingness to swallow pills