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

Based on protocol G version 11 dated 09 April 2019

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 lymph node can be assessed. In case of bilateral breast cancer,
   hormone receptor 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.

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 in this trial must be treated at the participating center which could be
   the Principal Investigator's 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, hypomagnesemia).

   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

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.