A Randomized, Open-Label, Phase 3 Study of Abemaciclib Combined with Standard Adjuvant Endocrine Therapy versus Standard Adjuvant Endocrine Therapy Alone in Patients with High-Risk, Node-Positive, Early -Stage, Hormone Receptor-Positive, Human Epidermal Receptor 2-Negative, Breast Cancer

1. Female (regardless of menopausal status) or male >=18 years of age (or of an
acceptable age according to local regulations, whichever is older).
2. The patient has confirmed HR+, HER2-negative (HER2-), early stage resected
invasive breast cancer without evidence of distant metastases. For local
HR+/HER2-confirmation considerations, please refer to section 6.1(2) of the
Clinical Protocol.
Patients with bilateral breast cancer (diagnosis of invasive tumors in both
breasts simultaneously or within 6 months of each other) can be eligible if all
lesions tested on both sides are HR+/HER2- and adequate surgery has been
performed in both breasts (see inclusion criterion [3]). The Lilly Clinical
Research Physician and Clinical Research Scientist (CRP/CRS) must be consulted
for all cases of bilateral breast cancer.
3. The patient must have undergone definitive surgery of the primary breast
tumor(s). For details around surgery, please see protocol page 29/30.
4. The patient must have tumor tissue from breast (preferred) or lymph node for
exploratory biomarker analysis available prior to randomization.
5. Patients must be node positive (microscopic and macroscopic tumor
involvement are allowed; ipsilateral internal mammary and supraclavicular lymph
nodes are allowed, but will not count toward the number of positive lymph
nodes) and fulfill one of the following criteria:
A. pathological tumor involvement in >=4 ipsilateral axillary lymph nodes.
OR
B. Pathological tumor involvement in 1 to 3 ipsilateral axillary lymph node(s)
(for patients who received neoadjuvant therapy also cytological tumor
involvement at time of initial diagnosis is allowed) and meet at least 1 of the
following criteria:
1. Grade 3 as defined by a combined score of at least 8 points per the modified
Bloom-Richardson grading system (Elston and Ellis 1991), also known as the
Nottingham scale, or equivalent following discussion with the Lilly CRP/CRS
- pathological primary invasive tumor size >=5 cm (for patients who received
neoadjuvant therapy primary tumor size >=5 cm on breast imaging is allowed).
Note: if tumor size is needed to meet eligibility criteria, patients with
multifocal/multicentric tumors may be eligible based on the addition of
diameters of the individual lesions following discussion with the Lilly CRP/CRS.
- Ki-67 index of >=20% (for Cohort 2) on untreated breast tissue as determined
by the investigational assay (described in Section 3.2.1) at the Study JPCF
central laboratory. See Section 9.8.1 for Ki-67 sample requirements.
6. The patient must be randomized within 16 months from the time of definitive
breast cancer surgery.
7. If the patient is currently receiving or initiating standard adjuvant
endocrine therapy at time of study entry, she/he may receive up to 12 weeks of
endocrine therapy until randomization following the last non-endocrine therapy
(surgery, chemotherapy, or radiation), whichever is last.
Use of GNRH analogues for ovarian suppression is not considered endocrine
therapy for the purposes of this criterion. Note: Adjuvant treatment with
fulvestrant is not allowed.
8. Patients who received or will be receiving adjuvant chemotherapy must have
completed adjuvant chemotherapy prior to randomization and patients must have
recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade <=1)
from the acute effects of chemotherapy except for residual alopecia or Grade 2
peripheral neuropathy prior to randomization. Patients who are not candidates
for adjuvant chemotherapy or decline chemotherapy are permitted. Patients may
also have received neoadjuvant chemotherapy. A washout period of at least 21
days is required between last adjuvant chemotherapy dose and randomization
(provided the patient did not receive radiotherapy).
9. Patients who received or will be receiving adjuvant radiotherapy must have
completed radiotherapy prior to randomization, and patients must have recovered
(Grade <=1) from the acute effects of radiotherapy. A washout period of at least
14 days is required between end of radiotherapy and randomization.
10. The patient has recovered from surgical side effects following definitive
breast surgery based on investigator discretion (for example, adequate wound
healing complications or seroma complications).
11. Text was omitted with protocol(a); see Criterion [1]]
12. Women of reproductive potential must have a negative blood pregnancy test
at baseline (within 14 days prior to randomization) and agree to use highly
effective contraceptive methods to prevent pregnancy during the study and for
12 weeks following the last dose of study treatment. Males must agree to use an
acceptable method of birth control and to not donate sperm during the study and
for at least 12 weeks following the last dose of study treatment. Refer to
Appendix 4 of the clinical protocol for definitions of highly effective methods
of contraception.
13. The patient has a performance status <=1 on the Eastern Cooperative Oncology
Group Scale
14. The patient has adequate organ function for all of the following criteria,
as defined in section 6.1(14) of the Clinical Protocol. Please refer to the
revisions in the Protocol section.
15. The patient is able to swallow oral medications.
16. The patient has given written informed consent prior to any study-specific
procedures and is willing and able to make herself/himself available for the
duration of the study and amenable and able to follow study schedule during
treatment and follow-up.

17. The patient has metastatic disease (including contralateral axillary lymph
nodes) or lymph node-negative breast cancer. Patients with inflammatory breast
cancer are excluded. Inflammatory carcinoma should not apply to a patient with
neglected locally advanced breast cancer presenting late in the course of their
disease (American Joint Committee on Cancer [AJCC] staging system for breast
cancer 8th edition, Hortobagyi et al. 2017). The investigator should consult
with the Lilly CRP/CRS regarding eligibility of patients with neglected
inflammatoid disease.
18. Patients with a history of previous breast cancer are excluded, with the
exception of ipsilateral DCIS treated by locoregional therapy alone >=5 years
ago. Patients with a history of contralateral DCIS treated by local regional
therapy at any time may be eligible. Patients with a history of any other
cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix),
unless in complete remission with no therapy for a minimum of 5 years from the
date of randomization are excluded. For patients with a history of other
non-breast cancers within 5 years from the date of randomization and considered
of very low risk of recurrence per investigator*s judgment (for example,
papillary thyroid cancer treated with surgery), eligibility is to be discussed
with the Lilly CRP/CRS.
19. Females who are pregnant or lactating.
20. The patient has previously received treatment with any CDK4 and CDK6
inhibitor.
21. The patient is receiving concurrent exogenous reproductive hormone therapy
(for example, birth control pills or hormone replacement therapy, or megestrol
acetate). Appropriate washout period between last dose of exogenous hormone
therapy and randomization is up to the investigator*s medical judgment (for
example, applying 5 times the half-life elimination rule). Note: topical
vaginal estrogen therapy is permitted if all other non-hormonal options are
exhausted.
22. The patient has previously received endocrine therapy for breast cancer
prevention (tamoxifen or raloxifene or aromatase inhibitors).
23. The patient has serious preexisting medical condition(s) that, in the
judgment of the investigator, would preclude participation in this study (such
as severe renal impairment, [for example, estimated creatinine clearance <30
mL/min], interstitial lung disease, severe dyspnea at rest or requiring oxygen
therapy, history of major surgical resection involving the stomach or small
bowel, or preexisting Crohn*s disease or ulcerative colitis or a preexisting
chronic condition resulting in clinically significant diarrhea).
24. The patient has a personal history of any of the following conditions:
syncope of cardiovascular etiology, ventricular arrhythmia of pathological
origin (including, but not limited to, ventricular tachycardia and ventricular
fibrillation), or sudden cardiac arrest. Exception: patients with controlled
atrial fibrillation for >30 days prior to randomization are eligible. Any
patient with a history of VTE (for example, DVT of the leg or arm and/or PE)
will be excluded.
25. The patient has active systemic infections (for example, bacterial
infection requiring intravenous [IV] antibiotics at time of initiating study
treatment, fungal infection, or detectable viral infection requiring systemic
therapy) or viral load (such as known human immunodeficiency virus positivity
or with known active hepatitis B or C [for example, hepatitis B surface antigen
positive]). Screening is not required for enrollment.
26. The patient has had major surgery within 14 days prior to randomization.
27. The patient has received an experimental treatment in a clinical trial
within the last 30 days or 5 half-lives, whichever is longer, prior to
randomization, or is currently enrolled in any other type of medical research
(for example: medical device) judged by the sponsor not to be scientifically or
medically compatible with this study. Co-enrollment to other studies may be
allowed following consultation with the Lilly CRP/CRS.