This is a multicenter, randomized, 2 arm, open label, phase II study. It is designed to
compare the efficacy and safety of abemaciclib combined with ET (letrozole or fulvestrant)
versus a short course with induction chemotherapy with paclitaxel followed by maintenance
therapy with abemaciclib combined with ET (letrozole or fulvestrant) in patients with
previously untreated, unresectable locally advanced, or metastatic HR positive/HER2 negative
breast cancer with aggressive disease criteria.
1. Signed informed consent form (ICF) prior to participation in any study-related
2. Male or female patients ≥18 years at the time of signing the ICF.
3. Eastern Cooperative Oncology Group performance status of 0 or 1.
4. Life expectancy of at least 24 weeks.
5. Pre menopausal or peri menopausal women who are being treated with a luteinizing
hormone-releasing hormone analog for at least 28 days prior to study entry (if
shorter, post-menopausal levels of serum estradiol/follicle-stimulating hormone [FSH]
must be confirmed analytically) or post menopausal women as defined by any of the
1. Documented bilateral oophorectomy;
2. Age ≥60 years;
3. Age <60 years and cessation of regular menses for ≥12 consecutive months with no
alternative pathological or physiological cause; and serum estradiol and/or FSH
level within the laboratory's reference range for post-menopausal females.
6. Unresectable locally advanced or MBC that is not amenable to resection with curative
7. At least one of the following aggressive disease criteria:
1. Presence of visceral disease;
2. Either radiological as per RECIST v1.1 or clinical evidence of progressive
disease (PD) on or within 36 months of completing adjuvant ET;
3. High histological grade and/or PgR-negative status on primary tumor;
4. Lactate dehydrogenase (LDH) >1.5 × the upper limit of normal (ULN).
8. Histologically confirmed estrogen receptor and/or progesterone receptor (PgR) positive
(with ≥1% positive stained cells according to National Comprehensive Cancer Network
and American Society of Clinical Oncology guidelines) and HER2 negative (0 to 1+ by
immunohistochemistry or 2+ and negative by in situ hybridization test) breast cancer
based on local testing on the most recent analyzed biopsy.
9. Measurable disease as per RECIST v 1.1 with at least one site of disease amenable to
biopsy. Patients with bone lesions as the only sites of metastatic disease are not
eligible, except for patients with identifiable soft tissue components, evaluable by
cross sectional imaging techniques such as CT or magnetic resonance imaging (MRI), and
that meet the definition of measurability according to RECIST v1.1.
Note: Previously irradiated lesions can only be considered as measurable disease if
disease progression has been unequivocally documented at that site since radiation.
10. Willingness and ability to provide a tumor biopsy from a metastatic site or the
primary breast tumor at the time of the inclusion to perform exploratory studies. If
not feasible, patient eligibility should be evaluated by Sponsor's qualified designee.
11. Willingness to provide blood samples for exploratory studies at baseline, after two
weeks of study treatment and at progression (or study treatment termination prior to
start alternative anti cancer therapy).
12. Patients relapsing on a cyclin-dependent kinase (CDK) 4/6 inhibitor based regimen in
the neoadjuvant or adjuvant setting will be suitable for the study if disease
progression is confirmed after at least 12 months following CDK 4/6 treatment
13. No prior systemic therapy for unresectable locally advanced or metastatic disease.
14. Radiation therapy for metastatic disease is permitted but the patient must have fully
recovered from the acute effects and at least 14 days must have elapsed between the
last dose and randomization.
Note: For limited-field radiotherapy, at least 7 days must have elapsed between the
last dose and randomization.
15. Resolution of all acute toxic effects of prior anti cancer therapy to Grade ≤1 as
determined by the NCI-CTCAE v 5.0 (except for Grade ≤2 neuropathy, alopecia, or other
toxicities not considered a safety risk for the patient at investigator's discretion)
within at least 14 days prior to study Day 1.
16. Adequate hematologic and organ function within 14 days before the first study
treatment on Day 1 of Cycle 1, defined by the following:
1. Hematological: White blood cell count >3.0 × 109/L; Absolute neutrophil count
≥1.5 × 109/L (without granulocyte colony-stimulating factor support within 2
weeks prior to Cycle 1, Day 1); Platelet count ≥100 × 109/L (without transfusion
within 2 weeks prior to Cycle 1, Day 1); Hemoglobin >9.0 g/dL (without
transfusion within 2 weeks prior to Cycle 1, Day 1).
i. Serum albumin ≥ 3 g/dL; ii. Total bilirubin ≤ 1.5 × ULN (≤2 × ULN in the case of
Gilbert's disease); iii. Aspartate transaminase and alanine transaminase ≤3.0 × ULN
(in the case of liver metastases ≤5 × ULN); iv. Alkaline phosphatase ≤2.5 × ULN (in
the case of liver and/or bone metastases ≤ 5 × ULN).
c. Renal: i. Serum creatinine <1.5 × ULN or creatinine clearance ≥30 mL/min based on
Cockcroft-Gault glomerular filtration rate estimation.
d. Coagulation: i. Partial thromboplastin time (or activated partial thromboplastin
time and international normalized ratio ≤1.5×ULN.
17. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use highly effective contraceptive methods, or two
effective contraceptive methods, as defined in the protocol during the treatment
period and for at least 3 weeks after the last dose of study treatment, and agreement
to refrain from donating eggs during this same period. Women of childbearing potential
must have a negative serum pregnancy test within 7 days before study treatment
18. Male patients should also have their partners who are women of childbearing potential
use highly effective contraceptive methods, or two effective contraceptive methods, as
defined in the protocol during the treatment period and for at least 3 weeks after the
last dose of study treatment and refrain from donating sperm during this period.
19. Able to swallow oral medication.
20. Patients who are reliable, willing to be available for the duration of the study and
are willing to follow study procedures.
1. Known hypersensitivity to abemaciclib, letrozole, fulvestrant, paclitaxel, and/or any
of their excipients.
2. Are currently receiving an investigational drug in a clinical study or participating
in any other type of medical research judged not to be scientifically or medically
compatible with this study.
Note: For patients who stopped receiving an investigational drug in another clinical
study, a washout period of 21 days or 5-half-lives (whichever is shorter) must be
observed before entering the trial.
3. Formal contraindication to ET defined as visceral crisis and rapidly or symptomatic
progressive visceral disease.
4. Known concurrent malignancy or malignancy within 5 years of study enrollment except
for carcinoma in situ of the cervix, non melanoma skin carcinoma, or stage I uterine
cancer. For other cancers considered to have a low risk of recurrence, discussion with
the medical monitor is required.
5. Known active brain metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable for ≥4 weeks by repeat imaging (note that the repeat imaging should be
performed during study screening), clinically stable, and without requirement of
steroid treatment for ≥14 days prior to first dose of study treatment.
6. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the study.
7. Major surgical procedure within 14 days prior to treatment initiation or anticipation
of the need for a major surgical procedure during the course of the study other than
Note: Placement of central venous access catheter(s) (e.g., port or similar) is not
considered a major surgical procedure and is therefore permitted.
8. Active bleeding diathesis, previous history of bleeding diathesis, or chronic
anti-coagulation treatment (the use of low molecular weight heparin is allowed if used
9. Serious and/or uncontrolled pre existing 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 <30 ml/min], history of major
surgical resection involving the stomach or small bowel, or pre-existing Crohn's
disease or ulcerative colitis or a pre existing chronic condition resulting in
baseline Grade 2 or higher diarrhea).
10. Current known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV).
Patients with past HBV infection or resolved HBV infection (defined as having a
negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B core
antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients
positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is
negative for HCV RNA.
11. Active bacterial or fungal infection at the time of enrolment (requiring antibiotics
or antifungal agents at time of initiating study treatment).
12. 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.
13. Pregnant, breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through at least 3
weeks after the last dose of study treatment.