Phase II, randomized, open-label, international, multicenter study to compare efficacy of
standard chemotherapy vs. letrozole plus abemaciclib as neoadjuvant therapy in
HR-positive/HER2-negative high/intermediate risk breast cancer patients
This is an international, multicenter, open-label, randomized phase II study in the
Approximately 200 premenopausal and postmenopausal women with Hormone Receptor
(HR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2) negative Breast Cancer (BC) of
intermediate/high risk determined by Ki67 index ≥ 20% on untreated breast tissue and
centrally assessed, with indication of neoadjuvant treatment, will be included. Patients with
Early Breast Cancer (EBC) on stages II-III (tumor size (T) > 2cm - T3, T4b, and lymph node
involvement (N) N0-2) according to the 8th edition of the Union for International Cancer
Control (UICC) TNM Classification. The subgroup with tumors T2 N0 will include high risk
patients based on Ki67 index > 30% or Ki67 index between 20% and 30% and Progesterone
Receptor (PgR) negative and/or histological grade 3.
Patients will be stratified according to the disease stage (II vs. III), menopausal status
(premenopausal vs. postmenopausal) and Ki67 index (Ki67 < 30% vs. Ki67 ≥ 30%).
Once the screening process (locally at site and at the central laboratory) is completed,
fully eligible patients will be randomized in a 1:1 fashion to the control arm with standard
Chemotherapy (CT) based on anthracyclines and taxanes or to the experimental arm with
letrozole + abemaciclib.
All patients will be treated according to the stipulations below, unless any of the following
occur: unacceptable toxicity, progressive disease, or withdrawal of informed consent,
whatever occurs first.
After the last dose of any of the drugs in the neoadjuvant combinations, in both treatment
arms definitive surgery will be performed. For Arm A not earlier than 21 days and not later
than 42 days after the last dose of chemotherapy, and for Arm B within 7 days from the last
dose of abemaciclib and/or letrozole, unless toxicities are not recovered completely in any
Patients are eligible to be enrolled in the study only if they meet all of the following
1. Written informed consent prior to any specific study procedures.
2. Women ≥ 18 years of age.
3. Documentation of histologically confirmed primary invasive adenocarcinoma of the
4. Availability of a primary tumor tissue sample obtained during the diagnostic process
before treatment for the central assessment of Ki67 index.
5. Documentation of Hormone Receptor (HR) positive and Human Epidermal Growth Factor
Receptor 2 (HER2) negative Breast Cancer (BC) based on local laboratory determination.
- HR positive is defined as more than or equal to 10% positive cells by
Immunohistochemistry (IHC) for ER and/or progesterone receptor (PgR).
- HER2 negative tumor is determined according to recommendations of American
Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018
6. Intermediate and high risk patients based on Ki67 index value (≥ 20%) determined at a
7. Patients should be in the following clinical stages of disease according to the 8th
edition of the TNM Classification of Breast Cancer by the Union for International
Cancer Control (UICC): T2 (> 2cm) - T3, T4b, N0 - N2, M0 (stages IIA, IIB, IIIA or
IIIB). Subpopulation with tumors T2 N0 M0 will include high risk patients based on
Ki67 index > 30% or Ki67 index between 20-30% and PgR negative with or without
histological grade 3.
8. Patients diagnosed with multifocal or multicentric breast cancer will be eligible for
the study if only 2 tumor lesions have been confirmed in the clinical evaluation and
both lesions comply with the characteristics required by the protocol (please, refer
to previous inclusion criteria).
9. Indication of neoadjuvant treatment.
10. At the time of presentation, patients must be candidates for potentially curative
surgery by surgeon's assessment.
11. Sentinel lymph node biopsy (SLNB) will be preferable after the neoadjuvant treatment.
Those patients with SLNB before the neoadjuvant treatment will be eligible for the
study only if the SLNB has a negative result (N0). One Step Nucleic Acid Amplification
(OSNA) method is not allowed.
12. Premenopausal and postmenopausal women. Postmenopausal status is defined as:
- Patient underwent bilateral oophorectomy, or
- Age ≥ 60 years, or
- Age < 60 years and amenorrhea for 12 or more months (in the absence of
chemotherapy, tamoxifen, toremifene or ovarian suppression) and
Folliculostimulating hormone (FSH) and plasma estradiol are in the postmenopausal
ranges per local normal ranges.
All women who do not meet the criteria for postmenopausal status are considered
premenopausal for the purpose of this trial.
13. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
14. Patients are able to swallow oral medications.
15. Adequate organ and bone marrow function:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5x109/L);
- Platelets ≥ 100,000/mm3 (100x109/L);
- Hemoglobin (Hgb) ≥ 8g/dL (80g/L) (erythrocyte transfusions are permitted; initial
treatment must not begin earlier than the day after the erythrocyte transfusion);
- Total serum bilirubin ≤ 1.5x Upper Limit of Normal (ULN) (≤ 2x ULN and direct
bilirubin within normal limits if Gilbert´s disease);
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3x ULN.
16. Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated acquisition
scan (MUGA) or echocardiogram (ECHO).
17. For premenopausal women: agreement to remain abstinent or use single or combined
non-hormonal contraceptive methods that result in a failure rate of < 1% per year
during the treatment period and for at least 3 weeks after the last dose of study
treatment. Abstinence is only acceptable if it is in line with the preferred and usual
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of
contraception. Examples of non-hormonal contraceptive methods with a failure rate of <
1% per year include tubal ligation, male sterilization, and certain intrauterine
devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a
cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier
methods must always be supplemented with the use of a spermicide.
18. Negative serum pregnancy test within 7 days of the first dose of abemaciclib for
premenopausal women, and for women who have experienced menopause onset < 12 months
prior to first dose of therapy.
19. Patients consent to biological sample provision for biomarker exploratory analyses.
20. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests and other study procedures.
Patients will be excluded from the study if they meet any of the following criteria:
1. Previous anti-cancer treatment with therapeutic intent for current breast cancer is
2. Inflammatory breast cancer, multifocal/multicentric breast cancer with ≥ 3 tumor
lesions or synchronous bilateral invasive breast cancers are not eligible.
3. Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of
the investigator, would preclude participation in this study (for example,
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe
renal impairment [e.g. estimated creatinine clearance < 30ml/min], 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 baseline
Grade 2 or higher diarrhea).
4. Patients with rare hereditary problems of galactose intolerance, total lactase
deficiency or glucose- galactose malabsorption.
5. Females who are pregnant or lactating.
6. Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of
initiating study treatment), fungal infection, or detectable viral infection (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
7. 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.
8. Diagnosis of any other malignancy within 5 years prior to randomization, except for
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of
the cervix or colorectal.
9. Prior hematopoietic stem cell or bone marrow transplantation.
10. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.