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A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery
Trial ID: NCT01864746
The PENELOPEB study is designed to demonstrate that in the background of standard anti-hormonal therapy palbociclib provides superior invasive disease-free survival (iDFS) compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be an attractive option with a favourable safety profile for these patients.
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"
Based on protocol G version 11 dated 04 May 2017
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. In case of
bilateral breast cancer, tumor tissue of both sides needs to be assessable.
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% ER and/or PR 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 or core biopsy of the breast, or if no other tissue is available the
residual tumor of the lymphnode can be assessed.
In case of bilateral breast cancer hormonreceptor positivity and HER2-normal status
has to be centrally 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 or core biopsy. In case of bilateral breast cancer, tumor
tissue of both sides needs to be assessable.
7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This period
must include 6 weeks of a taxane -containing neoadjuvant therapy (Exception: For
patients with progressive disease that occurred after at least 6 weeks of
taxane-containing neoadjuvant treatment, a total treatment period of less than 16
weeks is also eligible).
8. Adequate surgical treatment including resection of all clinically evident disease and
ipsilateral axillary lymph node 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 or less than 10 weeks from
completing radiotherapy (whichever occurs last) at date of randomization.
10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma,
NCCN) is strongly recommended. If radiotherapy is not performed the reason for this
needs to be documented in the eCRF.
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, or score 2 if nodal
status at surgery is ypN+, calculated using local estrogen receptor status and grade
assessed on either core biopsies taken before start of neoadjuvant treatment or
surgical specimen (see chapter 21.1).
13. Age at diagnosis at least 18 years.
14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see Appendix
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 immediate prior to randomization including: Hemoglobin
<10g/dL (100g/L); ANC < 2000/mm³ (< 2.0 x 109/L); Platelets <100,000/mm³ (< 100 x
109/L); AST or ALT >1.5 x upper limit of normal (ULN); alkaline phosphatase > 2.5 x
ULN, total serum bilirubin > 1.25 x ULN; 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. Evidence for infection including wound infections, Human Immunodeficiency Virus (HIV)
or any type of Hepatitis
4. QTc >480 msec
5. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypo¬magnesemia).
6. 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.
7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any
upper gastrointestinal surgery including gastric resection.
8. 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.
9. Current severe acute or uncontrolled chronic systemic disease (e.g. diabetes mellitus)
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.
10. Recent (within the past year) or active suicidal behavior.
11. Pregnancy or lactation period. Women of childbearing potential must implement adequate
non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive
devices, sterilization) during study treatment and for 90 days after discontinuation.
A serum pregnancy test must be negative in premenopausal women or women with
amenorrhea of less than 12 months.
12. Major surgery within 2 weeks prior to randomization.
13. 10 weeks or more have passed since completion of radiotherapy at day of randomization
and 16 weeks interval since the date of final surgery have passed.
14. Prior treatment with any CDK4/6 inhibitor.
15. Patients treated within the last 7 days prior to randomization and/or concurrent use
of drugs known to be strong CYP3A4 inhibitors or inducers (see appendix 21.3)
16. Concurrent treatment with other experimental drugs. Participation in another clinical
trial with any investigational not marketed drug within 30 days prior to
17. Male patients.
drug: Palbociclib PD-0332991
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