neoMONARCH: A Phase 2 Neoadjuvant Trial Comparing the Biological Effects of 2 Weeks of Abemaciclib (LY2835219) in Combination with Anastrozole to those of Abemaciclib Monotherapy and Anastrozole Monotherapy and Evaluating the Clinical Activity and Safety of a Subsequent 14 Weeks of Therapy with Abemaciclib in Combination with Anastrozole in Postmenopausal Women with Hormone Receptor Positive, HER2 Negative Breast Cancer

Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] are female and >=18 years of age
[2] have postmenopausal status, defined as meeting one of the following
conditions:
* prior bilateral oophorectomy
* age >=60 years
* age <60 years and amenorrheic (non-treatment-induced amenorrhea
secondary to tamoxifen, toremifene, ovarian suppression, or
chemotherapy) for at least 12 months. Follicle-stimulating hormone
(FSH) and estradiol must be in the postmenopausal range.
[3] histologically or cytologically proven adenocarcinoma of the breast
[4] Clinical Stage I breast tumor >=1 cm in diameter, Stage II, or Stage IIIA or IIIB
breast cancer (according to the AJCC Staging Manual, 7th Edition [Edge et al.
2010]). Multifocal disease is allowed if confined to 1 breast, and if each
tumor is HR+, HER2- and at least 1 tumor is >=1 cm.
[5] at least 1 measureable lesion according to RECIST criteria by physical
examination or imaging tests
[6] breast cancer that is HR+, HER2-
* to fulfill the requirement for HR+ disease, a breast cancer must express,
by immunohistochemistry (IHC), at least 1 of the hormone receptors
(estrogen receptor [ER], progesterone receptor [PgR] as defined in the
relevant American Society of Clinical Oncology [ASCO]/College of
American Pathologists [CAP] Guidelines [Hammond et al. 2010])
* to fulfill the requirement of HER2- disease, a breast cancer must not
demonstrate, at initial diagnosis or upon subsequent biopsy,
overexpression of HER2 by either IHC or in-situ hybridization (ISH), as
defined in the relevant ASCO/CAP guidelines (Wolff et al. 2013)
[7] neoadjuvant endocrine monotherapy is deemed to be a suitable therapy
[8] primary breast cancer that is suitable for baseline core biopsy (provision of
baseline core biopsy specimen is mandatory)
[9] Eastern Cooperative Oncology Group (ECOG) performance status score <=1
[10] patient is willing to comply with treatment, tissue acquisition, and follow-up
[11] patient is able to swallow capsules and tablets
[12] have adequate organ function, including
* hematologic: absolute neutrophil count (ANC) >=1.5 x 109/L, platelets
>100 x 109/L, and hemoglobin >=8 g/dL. Patients may receive
erythrocyte transfusions to achieve this hemoglobin level at the
discretion of the investigator. However, initial study drug treatment
must not begin earlier than the day of the erythrocyte transfusion.
* hepatic: bilirubin <=1.5 times the upper limit of normal (ULN) and
alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
<=3.0 times ULN. Subjects with Gilbert*s syndrome, confirmed by
genotyping or Invader UGTIA1 molecular assay prior to study entry
must have total bilirubin <3.0 times ULN.
* renal: serum creatinine <=1.5 times ULN
[13] have given written informed consent prior to any study-specific procedures

[14] are currently enrolled in a clinical trial involving an investigational product or
non-approved use of a drug or device (other than the study drugs used in this
study), or concurrently enrolled in any other type of medical research judged
not to be scientifically or medically compatible with this study
[15] bilateral invasive breast cancer
[16] metastatic breast cancer (local spread to axillary or internal mammary lymph nodes is permitted)
[17] inflammatory breast cancer, defined as the presence of erythema or induration
involving one third or more of the breast
[18] concurrent therapy with any other non-protocol anti-cancer therapy
[19] history of any other malignancy within the past 5 years, with the exception of
non-melanoma skin cancer or carcinoma-in-situ of the cervix
[20] prior systemic therapy or radiotherapy for invasive or non-invasive breast
cancer in the same breast as currently being treated
[21] prior radiotherapy to the ipsilateral chest wall for any malignancy
[22] prior anti-estrogen therapy with raloxifene, tamoxifen, aromatase inhibitor, or
other selective estrogen receptor modulator (SERM), either for osteoporosis or
prevention of breast cancer. Prior hormone-replacement therapy is permitted.
[23] concurrent treatment with postmenopausal hormone replacement therapy.
Prior treatment must be stopped for at least 28 days prior to first baseline
biopsy.
[24] have received treatment with a drug that has not received regulatory approval
for any indication within 14 days of randomization for a nonmyelosuppressive
or 21 days of randomization for a myelosuppressive agent
[25] have had major surgery within 14 days prior to randomization to allow for
post-operative healing of the surgical wound and site(s)
[26] have received recent (within 28 days prior to randomization) yellow fever
vaccination
[27] have serious preexisting medical conditions that, in the judgment of the
investigator, would preclude participation in this study (for example, history
of major surgical resection involving the stomach or small bowel, or
preexisting Crohn*s disease or ulcerative colitis)
[28] have personal history within the last 12 months of any of the following
conditions: syncope of cardiovascular etiology, ventricular tachycardia,
ventricular fibrillation, or sudden cardiac arrest
[29] have received an autologous or allogeneic stem-cell transplant
[30] have active bacterial or fungal infection or detectable viral infection (for
example, human immunodeficiency virus [HIV] or viral hepatitis). Screening
is not required for enrollment.
[31] male subjects
[32] known hypersensitivity to loperamide hydrochloride or to any of the
excipients