Clinical Trials

Inclusion Criteria: 

• Female (regardless of menopausal status) or male ≥18 years of age (or of an acceptable age according to local regulations, whichever is older).
• The patient has confirmed HR+, HER2-negative (HER2-), early stage resected invasive breast cancer without evidence of distant metastases.
  • To fulfill the requirement for HR+ disease by local testing on primary disease specimen, tumor must be ER or PgR positive defined by immunohistochemistry (IHC) according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for hormone receptor testing (Hammond et al. 2010).
  • To fulfill the requirement of HER2- disease by local testing on primary disease specimen, tumor must be HER2- according to ASCO/CAP guidelines for HER2 testing (Wolff et al. 2018).
  • 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.
• The patient must have undergone definitive surgery of the primary breast tumor(s).
  • With the exception of the situations described below, the margins of the resected specimen must be histologically free of invasive tumor and /or a component of ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins.  If tumor is still present at the resected margin after re-excision(s), the patient must undergo mastectomy to be eligible. Of note, patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.
  • For patients who undergo mastectomy or wide local excision where deep margin abuts the pectoralis fascia, patients with microscopic positive margins are eligible as long as radiotherapy of the chest wall is administered prior to study entry. Patients with positive anterior margins may be eligible if there is no gross disease left behind (radiotherapy as per local guidelines).
  • Where surgical excision of supraclavicular or internal mammary nodes is not feasible, residual nodes should be irradiated in accordance with standard guidelines.
  • If given, radiation therapy (for example, post-mastectomy or postlumpectomy) should be administered according to standard guidelines.
• The patient must have tumor tissue from breast (preferred) or lymph node for exploratory biomarker analysis available prior to randomization.
  • Note: Sites should confirm the availability of tumor tissue for exploratory analysis (Section 9.8.2.2) with the pathological laboratory prior to randomization
• 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
  • 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:
    • 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.
• The patient must be randomized within 16 months from the time of definitive breast cancer surgery.
• 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.
• 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).
• 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.
• 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).
• Omit text; see Criterion [1]
• 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 for definitions of highly effective methods of contraception.
• The patient has a performance status ≤1 on the Eastern Cooperative Oncology Group (Appendix 11) scale (Oken et al. 1982).
• The patient has adequate organ function for all of the following criteria, as defined below.

SYSTEM

Hematologic

• ANC ≥ 1.5 × 109/L
  • Note: G-CSF cannot be administered to meet ANC eligibility criterion.
• Platelets ≥ 100 × 109/L
• Hemoglobin ≥ 8 g/dL
  • Note: Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.

HEPATIC

• Total bilirubin ≤ 1.5 × ULN
  • Patients with Gilbert’s syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted.
• ALT and AST ≤ 3 × ULN

Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal.

• The patient is able to swallow oral medications.
• 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.

Exclusion Criteria: 

• Metastatic disease (including contralateral axillary lymph nodes) or node-negative disease. 
• Participants with inflammatory breast cancer. 
• Participants with a history of previous breast cancer, with the exception of ipsilateral ductal carcinoma in situ (DCIS) treated by locoregional therapy alone ≥5 years ago. Participants with a history of contralateral DCIS treated by local regional therapy at any time may be eligible. Participants 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. - Females who are pregnant or lactating. 
• The participant has previously received treatment with any CDK4 and CDK6 inhibitor.
• The participant is receiving concurrent exogenous reproductive hormone therapy (for example, birth control pills, hormone replacement therapy, or megestrol acetate). 
• The participant has previously received endocrine therapy for breast cancer prevention (tamoxifen or raloxifene or aromatase inhibitors). 
• The participant has serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study. 
• The participant has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin or sudden cardiac arrest. Any participant with a history of venous thromboembolism (VTE).
• The participant has active systemic infections or viral load. 
• The participant has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer.