Phase II study to assess the efficacy of the combination of at least 5 year endocrine therapy
and 2 year-palbociclib as adjuvant systemic treatment instead of adjuvant chemotherapy
followed by endocrine therapy in older patients with stage II-III ER+/HER2- early breast
The primary objective of this trial is to assess the efficacy of the combination of at least
5 year endocrine therapy and 2 year-palbociclib as adjuvant systemic treatment instead of
adjuvant chemotherapy followed by endocrine therapy in older patients with stage II-III
ER+/HER2- early breast cancer.
This is a two-arm open-label multi-center randomized (2:1) non-comparative phase II study in
elderly patients with stage II/III, ER+, HER2- early breast cancer for whom treatment with
chemotherapy is indicated.
Patients will be randomized with a 2:1 allocation rate to the following treatment arm:
- experimental palbociclib arm: Standard adjuvant endocrine therapy for a duration of at
least 5 years + palbociclib for a total duration of up to 2 years.
- control chemotherapy arm: adjuvant chemotherapy (4 cycles of
docetaxel/doxorubicin/epirubicin-cyclophosphamide; or of weekly paclitaxel D1, D8, and
D15 q3w if a 3 weekly schedule is not desired), followed by standard adjuvant endocrine
therapy for a duration of at least 5 years.
The primary endpoint of the study is the 3-year D-RFI rate in the experimental arm.
- Women or men with stage II or stage III, early invasive breast cancer according to the
UICC 8th edition for TNM classification
- Histologically confirmed Estrogen Receptor ER+ (at least 10 % of cells staining
positive for ER), Human Epidermal Growth Factor Receptor 2 (HER-2) negative, early
invasive breast cancer based on results of local pathology. Testing may be performed
on diagnostic core biopsy or resection specimen.
- In patients with multicentric, multifocal and/or bilateral breast cancer, all
histopathologically examined invasive tumors must meet pathologic criteria regarding
ER and HER2-status described above.
- Adjuvant chemotherapy indicated and feasible according to treating physician and
patient, based on standard clinicopathological parameters (tumor size, lymph node
involvement, general health status, proliferation marker, patient wish) and gene
expression profile if available.
- Adjuvant chemotherapy combining both anthracycline and taxanes considered not
indicated or not feasible according to treating physician.
- No evidence of macroscopic distant metastases, investigated according to local
- Age ≥70 years
- Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
- Patient must have undergone breast +/- axillary surgery with curative intent for the
current malignancy ≤8 weeks before randomization.
- The maximum duration from last surgery to the start of the first adjuvant treatment is
- Patients must have sufficient resolution of any surgical side effects from the last
surgery per physician assessment, with no active wound healing complications at the
time of randomization.
- Incentive to undergo adjuvant radiation therapy when indicated per local institutional
- Note: For patients in the palbociclib arm, radiation therapy when indicated has to
start ≤9 weeks after last surgery. The endocrine therapy can be initiated during or
after the radiation therapy but not later than 3 weeks after the last radiotherapy.
Palbociclib has to start ≤3 weeks after the last radiotherapy. When radiation therapy
is not indicated, endocrine therapy and palbociclib have to be initiated ≤9 weeks
after last surgery.
- Note: For patients in the chemotherapy arm, chemotherapy has to be the first adjuvant
treatment and has to start ≤9 weeks after the last surgery. When radiation therapy is
indicated, this treatment has to start ≤6 weeks after the last chemotherapy
administration. Adjuvant endocrine therapy can be initiated during or after the
radiation therapy but not later than 3 weeks after the last radiotherapy. When
radiation therapy is not indicated, endocrine therapy has to be initiated ≤6 weeks
after last chemotherapy administration.
- Adequate organ function, evidenced by the following laboratory results within 3 weeks
prior to inclusion:
- Hemoglobin ≥ 9 g/dL
- Absolute neutrophil count (ANC) ≥ 1500/mm3
- Platelet count ≥ 100,000/mm3
- Total bilirubin ≤ 1.5 upper limit of normal (ULN), or total bilirubin ≤ 3.0 × ULN in
patients with documented Gilbert's Syndrome.
- Glomerular Filtration Rate (GFR) ≥ 30 ml/min according to Modification of Diet in
Renal Disease (MDRD) formula or Chronic Kidney Disease - Epidemiology Collaboration
(CKD-EPI) formula or Cockcroft and Gault formula
- Serum Glutamic Oxaloacetic Transaminase (Aspartate Transaminase), Serum Glutamic
Pyruvic Transaminase (Alanine Transaminase) and alkaline phosphatase ≤ 2.5 × ULN
- Patients must be able and willing to swallow and retain oral medication without a
condition that would interfere with enteric absorption.
- Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the trial
- Before patient registration/randomization, written informed consent must be obtained
according to ICH/GCP, and national/local regulations.
- Previous history of invasive breast cancer
- Systemic anticancer therapy prior to the breast cancer surgery
- Prior therapy with any Cyclin-Dependent Kinase (CDK)4/6 inhibitor
- Concurrent investigational agent within 28 days of randomization
- Concomitant anticancer treatment with the exception of bone antiresorptive agents or
Luteinizing Hormone-Releasing Hormone agonists in male patients treated with an
- History of allergic reactions attributed to compounds of chemical or biological
composition similar to palbociclib or to chemotherapy components
- Medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes
within 7 days of randomization (see Chapter 5.6.3 for list of CYP3A inhibitors and
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection (including known HIV, active hepatitis B and/or hepatitis C infection),
symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac
arrhythmia, or uncontrolled diabetes.
- Other malignancy within the last 5 years except: adequately treated non-metastatic
non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal
carcinoma in situ of the breast.