Phase III Study Evaluating Palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in Patients With Hormone-receptor-positive, HER2-normal Primary Breast Cancer With High Relapse Risk After Neoadjuvant Chemotherapy "PENELOPEB"
1. Written informed consent prior to beginning specific protocol procedures, including
expected cooperation of the patients for the treatment and follow-up, must be
obtained and documented according to the local regulatory requirements.
2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue
block or a partial block from surgery after neoadjuvant chemotherapy and from
core-biopsy before start of neoadjuvant chemotherapy, which will be used for
centralized retrospective confirmation of hormone- and HER2-status and to evaluate
correlation between genes, proteins, and mRNAs relevant to the endocrine and cell
cycle pathways and sensitivity/resistance to the investigational agents.
3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the
4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal
5. Centrally confirmed hormone-receptor-positive (>=1% positive stained cells) and
HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH) ratio <=2.0
status assessed preferably on tissue from post-neoadjuvant residual invasive disease
of the breast, or if not possible, of residual nodal invasion. In case of bilateral
breast cancer status has to be confirmed for both sides.
6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on
post-neoadjuvant residual invasive disease of the breast, or if not possible, of
residual nodal invasion.
7. Patients must have received neoadjuvant chemotherapy of at least 6 cycles at a
minimum duration of 16 weeks including a taxane. (Exception: Patients with
progressive disease that occurred after at least 6 weeks of taxane-containing
neoadjuvant treatment which will also be eligible).
8. Adequate surgical treatment including resection of all clinically evident disease and
ipsilateral axillary lymphnode dissection. Histologically complete resection (R0) of
the invasive and ductal in situ tumor is required in case of breast conserving
surgery as the final treatment. No evidence of gross residual disease (R2) is
required after total mastectomy (R1 resection is acceptable). Axillary dissection is
not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic))
or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.
9. Less than 16 weeks interval since the date of final surgery and date of randomization
(including the radiotherapy period).
10. Completion of adjuvant radiotherapy. Radiotherapy is indicated to the breast in all
patients treated with breast conserving surgery and to chest wall in all patients
with cT3/cT4, R1 or ypN+ disease treated by mastectomy.
11. No clinical evidence for locoregional or distant relapse during or after preoperative
chemotherapy. Local progression during chemotherapy is not an exclusion criterion.
12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of >=3
13. Age at diagnosis at least 18 years.
14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
15. Resolution of all acute toxic effects of prior anti cancer therapy or surgical
procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not
considered a safety risk for the patient at investigator's discretion).
16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast
17. The patient must be accessible for scheduled visits, treatment and follow-up.
Patients registered on this trial must be treated at the participating center which
could be the Principal or a Co- investigator's site.
1. Known severe hypersensitivity reactions to compounds similar to palbociclib or
palbociclib/placebo excipients or to endocrine treatments.
2. Inadequate organ function including: Hemoglobin <9g/dL (90g/L) ANC < 1,500/mm³ (< 1.5
x 109/L); Platelets <100,000/mm³ (< 100 x 109/L); AST and/or ALT >3 x upper normal
limits (UNL); alkaline phosphatase > 2.5 x UNL, total serum bilirubin > 1.25 x UNL;
serum creatinine >1.25 x ULN or estimated creatinine clearance < 60 mL/min as
calculated using the method standard for the institution; severe and relevant
co-morbidity that would interact with the participation in the study
3. Current severe or uncontrolled systemic disease
4. Evidence for infection including wound infections, HIV, Hepatitis
5. QTc >480 msec or a family or personal history of long or short QT syndrome, Brugada
syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
6. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
drug (eg, hypocalcemia, hypokalemia, hypo-magnesemia).
7. Any of the following within 6 months of randomization: myocardial infarction,
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade
≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident including transient
ischemic attack, or symptomatic pulmonary embolism.
8. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any
upper gastrointestinal surgery including gastric resection.
9. Prior malignancy (including invasive or ductal in-situ breast cancer) within 5 years
prior to randomization, except curatively treated basal cell carcinoma of the skin
and carcinoma in situ of the cervix.
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.
11. Recent (within the past year) or active suicidal behavior.
12. Pregnancy or lactation period. Patients of childbearing potential must implement
adequate non-hormonal contraceptive measures (barrier methods, intrauterine
contraceptive devices, sterilization) during study treatment. A serum pregnancy test
must be negative in premenopausal women or women with amenorrhea of less than 12
13. Major surgery within 2 weeks prior to randomization.
14. Prior neoadjuvant endocrine treatment. Adjuvant endocrine treatment might have been
started before randomization.
15. Prior treatment with any CDK4/6 inhibitor.
16. Patients treated within the last 7 days prior to randomization with drugs known to be
CYP3A4 inhibitors or inducers or drugs that are known to prolong the QT interval.
17. Concurrent treatment with other experimental drugs. Participation in another clinical
trial with any investigational not marketed drug within 30 days prior to study entry.
18. Male patients.