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

About one third of patients with hormone-receptor (HR)-positive, HER2- normal breast cancer
and residual disease after neoadjuvant chemotherapy have a substantial risk of relapse. The
clinical-pathologic stage - estrogen/grade (CPS-EG)1 combining clinical stage before
neoadjuvant treatment, pathological stage after neoadjuvant treatment, grading and
estrogen-receptor status can be used to identify these high-risk patients. The CPS-EG score
was additionally validated in 2454 patients with HRpositive/ HER2-normal tumors from the
German neoadjuvant studies' metadatabase. Patients who had a score of 3 or higher or Score 2
and ypN+ disease show a 3-years iDFS of 77% despite adequate local therapy and adjuvant
endocrine treatment. Cyclin dependent kinases (CDK), a group of serine/threonine kinases,
play a key role in regulating cell cycle progression by interacting with specific cyclin
proteins in luminal-type tumors.2,3 PD-0332991 (palbociclib) is an oral, highly selective
inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by prohibiting
progression of the cell cycle from G1 to S phase through blocking retinoblastoma (Rb)
phosphorylation.4 Preclinical studies identified luminal ER subtype, elevated expression of
cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to
palbociclib.

Based on protocol G version 11 dated 04 May 2017

Inclusion Criteria

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
breast.

4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal
invasion.

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 21.2).

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
cancer.

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.

Exclusion Criteria

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
randomization.

17. Male patients.