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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
"**PENELOPE**  
  
  
  
  
B"
GBG-78 - BIG 1-13 - **NSABP-B-54-I**
EudraCT No.: 2013-001040-62 FDA IND: 123239 Protocol G (Version 11 - 9 th April 2019)
CONFIDENTIAL: Information and data included in this protocol contain trade secrets and privileged or confidential information which is the property of the GBG Forschungs GmbH. No person is authorized to make it public without the written permission of the GBG Forschungs GmbH. These restrictions on disclosure will apply equally to all future information supplied to you which is indicated as privileged or confidential. This material may be disclosed to and used by your staff and associates as may be necessary to conduct the clinical study.  
  
  
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"
GBG-78 - BIG 1-13 - NSABP-B-54-I
EudraCT No.: 2013-001040-62 FDA IND: 123239 The following Amendment(s) and Administrative Changes with Administrative letters (DIL) have been made to this protocol since the date of preparation: **Protocol A (Version** 6-23.09.2013)  
| Country                                 | Amendment No.                                                                                                                                                                                                                                                                                                                                                               | Date of Amendment th April 2019 9   |
|-----------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|
| Global                                  | Administrative Amendment th April 2019) Protocol G (Version 11 - 9 Summary of changes Update of GBG Subboard Neoadjuvant, and International  Steering Committee members, resp. (chapter 1). Change of International Principal Investigator /  Coordinating Investigator (chapter 1). Adding of new position "Unblinded independent  statistician" (chapter 1).              | 04th May 2017                       |
| Protocol G (Version 11 - 04th May 2017) |                                                                                                                                                                                                                                                                                                                                                                             |                                     |
| Global                                  | Summary of Changes Specification of potential outcomes of the efficacy  interim analysis (Futility, sample size re-estimation up to  a new total number of 1250 patients, efficacy) have been  added to statistical section in synopsis, section 11.1 and  15 ff. Rationale: Adaptive design of the trial does allow  st adjustment of patient number based on outcome of 1 |                                     |  
efficacy interim analysis. New information on Human Pharmacokinetic (PK) Data based on IB 2017 added:  
| o                                                                                           | no dose adjustment for patients with  Asian race required   |                                    |
|---------------------------------------------------------------------------------------------|-------------------------------------------------------------|------------------------------------|
|                                                                                            | section 6.3.4                                               | - palbociclib does not prolong the |
| QT interval to a clinically meaningful extent at the  recommended clinical dose (125 mg QD) |                                                             |                                    |
| Administrative and corrective changes:  Update of steering committee member and study  contacts  Correction of typo Inclusion criteria #9  Alignment of wording of exclusion criterion #13  with inclusion criterion #9  Table "Schedule of acitivities" : o Windows updated for treatment visit and  added for "end of treatment" and followup visit o Wording and timing for disease assements specified  o Wording for SAE reporting aligned with  wording in SAE section 17.7 o Wording for PK-DDI sampling updated  since collection finished o ctDNA sampling table corrected  Procedure for unblinding in case of progressive  disease specified in section 12.2  Administrative window for IP intake added to  section 12.3.3  Reporting timelines for pregnancy after end of  treatment updated in section 12.7  Contraception method wording updated in  section 13.1  Wording and timing for disease assements aligned in section 13.1 to "schedule of activities"  IDMC recommendation regarding frequency of  interim safety analysis added to section 15.5.7                                                                                             |                                                             |                                    |  
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Wording for SAE reporting in section 13.1 aligned  with wording in SAE section 17.7   |               |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------|---------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Back-up time points for general Palbociclib-PK  sampling added in section 13.3 and closure of PKDDI sampling comment added in same section                                                                                       |               |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Protocol E (Version 10 - 12th April 2016)                                             | 12 April 2016 |
| Summary of Changes: Substantial   Inclusion Criterion #2: Specification for bilaterial  breast cancer added  Inclusion Criterion #5: Specification which tissue  can be used for central testing added  Inclusion Criterion #6: Specification for bilaterial  breast cancer added  Inclusion Criterion #10: Radiotherapy  requirements adjusted to standard guidelines  Exclusion Criterion #4: QTc criterion adjusted due  to new information in Palbociclib IB versions Feb  2015 and Dec 2015  Exclusion Criterion #5: Specified to electrolyte  disorders in general  Exclusion Criterion #13: Removal of endocrine  treatment timing which was a description but not  an exclusion criterion. Was replaced with  definition of radiotherapy window  Exclusion Criterion #15: Drugs known to prolong  QTc interval are no longer considered prohibited  due to new information in Palbociclib IB versions  Feb 2015 and Dec 2015  Exclusion Criterion #16: Study entry time was  specified as date of randomization.   Endocrine treatment options updated. Patients  may now be receiving either tamoxifen or  aromatase inhibitor (AI: letrozole, anastrozole, or  exemestane). For premenopausal patients,  concurrent LHRH agonist use is allowable (section  12.8.1)  Patients may now concurrently receive  bisphosphonates or rank ligand inhibitors while |                                                                                       |               |  
| on this study if necessary for treatment or  prevention of osteopenia or osteoporosis (section  12.5.3)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                  |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|-------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Safety Monitoring Frequency adjusted to IDMC  recommendation in section 15.5.7                                                   |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Opthamologic assessment removed due to new  information in Palbociclib IB versions Dec 2015                                      |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Optional samples for CTC, RNAlater and FreshFrozen tissue removed.                                                                                                                                  |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Optional ct-DNA sample collection time-point at  detection of progressive disease added                                          |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Specification of relevant overdose definition in  section 17.5.2 and removal notification  requirement for non-relevant overdose |             |
| Administrative and corrective changes:  Updated contact addresses and contacts section  Updated reference data in rationale  Alignment of table "schedule of activities" and  tables "assessments and schedules" with current  protocol  Updated reference data in section 6.3.7  Added internet reference for appendix 3   Labelled appendix 4 as no longer applicable in  order to align with updated eligibility criteria  Addition of additional time points for PK-DDI  samples in case a sample was missed for a  patient.  Specification wording on CRF documentation and  signing in section 17.8 and 18.5- |                                                                                                                                  |             |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Protocol D (Version 9 - 09th February 2015)                                                                                      | 09 Feb 2015 |
| Summary of Changes: Substantial   Inclusion criteria #5: Clarification for testing in  case of bilateral breast cancer   Inclusion criteria #6: Centrally testing possibility  extended to core biopsy  Inclusion criteria #12: allows now patients with a CPS-EG Score of 2 if ypN+ to participate                                                                                                                                                                                                                                                                                                                      |                                                                                                                                  |             |  
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Exclusion criteria #15: Proton Pump Inhibitors no  longer disallowed                    |             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|-------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Addition of additional stratification criteria: CPSEG score 3 vs 2&ypN+                                                                                         |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Update of section 6.3.3 Human Pharmacokinetic  (PK) Data                                |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Update of section 12.5.1 Prohibited Medication  Proton Pump Inhibitors removed          |             |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Update of section 15.5 ff Statistical Analysis due  to change of inclusion criteria #12 |             |
| Administrative and corrective changes:  Clarifications / correction of schedule of activities table   Clarification of dose modification schedule in  Table 3  Clarification of endocrine treatment starting  points in section 10 and 11.3   Specification of PK sample set requirements in  section 13.3  Update to section 6.3.3 regarding the use of PPIs  Update of Section 7 rationale of the study  Deletion of "Interim Efficacy Analyses" from  section 15.5.1 since already in section 15.5.8  Update on IDMC compostion - Section 16.1  Incorporation of French protocol version B  (Version 7 - 14 Jun 2014) in order to generate a  global document Update of references |                                                                                         |             |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Protocol C (Version 8-06.08.2014)                                                       | 06.Aug.2014 |
| Substantial Amendment Summary of Changes: Prognostic Marker Inclusion Criterion #12 with score  CPS-EG, allows now the use of surgical biopsy: … using  local estrogen receptor status and grade assessed on  core biopsies taken before start of neoadjuvant  treatment either / or surgical biopsy. Predictive Marker Inclusion Criterion #5, must be PR  positive in residual tissue or with the core biopsy: …  (>=1% ER and/or PR positive stained cells). Retreatment (12.3.7) and dose reduction (12.3.8)  chapter: Increased clarifications to guidance provided                                                                                                                       |                                                                                         |             |  
| based on gained experience in the Palbociclib program. Exclusion Criterion #14 allows now prior neoadjuvant  treatment to allow entry patients from ADAPT and  similar trials: Prior neoadjuvant treatment is acceptable. Editorial changes to Exclusion criteria: #3 (Curent severe or uncontrolled..) was merged with #9  (Other severe acute..) due to repetition. Better wording  of #11 (Pregnancy and lactation….) and #15 not  recommended medications Chapter 6.3.3 Human Pharmacokinetik Data, Chapter  6.3.4 QTc Evaluation Data, Chapter 6.3.7 Comination  with other endocrine agents and 6.3.8 Long Term toxicity  Data were updated with the most recent nonclinical and  clinical information.  The blood sample for ctDNA was increased from 10 ml to  20 ml. Furthermore occasional text clarifications and  typographic errors were corrected. Editorial Amendment to update the protocol Version C  with Administrative Letter 5 (DIL), FDA-IND number amended   |                                                      |             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|-------------|
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Protocol B (Version 7-12.06.2014)                    | 12.Jun.2014 |
| Editorial Amendment to update the protocol version B with the Administrative letters 1-4 (DIL) into the  protocol, correct typographic errors, update Appendix 10  the Declaration of Helsinki Administrative Letter No.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Date of Letter (DIL)                                 |             |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 5, Appendix 17, chapter 21.17                        | 21.Jul.2014 |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 4, Appendix 16, chapter 21.16                        | 7.Mar.2014  |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 3, Appendix 15, chapter 21.15                        | 30.Jan.2014 |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 2, Appendix 14, chapter 21.14                        | 14.Jan.2014 |
| Global                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 1, Appendix 13, chapter 21.13                        | 15.Jan.2014 |
| Local Amendment No                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Date of local  Amendment                             |             |
| Korea                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Translation into local language                      | n/a         |
| Spain                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Translation into local language                      | n/a         |
| France                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | French Appendix introducing visual acuity testing at | 05.Aug.2014 |
| Baseline, Cyclus 7, EOT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                      |             |  
| Local Administrative Letter No   | Date of local  Amendment                              |            |
|----------------------------------|-------------------------------------------------------|------------|
| Germany                          | 1 (Global Administrative letter sent to German sites) | 28.10.2014 |
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1. addresses responsibilities and signatures

GBG Forschungs GmbH D-63263 Neu-Isenburg, Martin-Behaim-Straße 12 Phone:+49 (0) 6102 / 7480-0 Fax: +49 (0) 6102 / 7480-440 Email: PENELOPE@GBG.de Members of the various boards and responsible persons for special protocol tasks are listed as of the date of final protocol.
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gbg subboard neoadjuvant

Jens-Uwe Blohmer, Berlin Peter Fasching, Erlangen Carsten Denkert, Marburg (Pathology) Claus Hanusch, Munich Jens Huober, Ulm Christian Jackisch, Offenbach Theresa Link, Dresden Sibylle Loibl, Neu-Isenburg / Frankfurt/Main Kerstin Rhiem, Cologne Andreas Schneeweiss, Heidelberg Christine Solbach, Frankfurt/Main Michael Untch, Berlin
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international steering committee

Gunter von Minckwitz (GBG, Germany - Chair)
Harry Bear (NSABP, USA) Hervé Bonnefoi (Unicancer, France) Nicole Burchardi (GBG, Germany - blinded study statistician) Marco Colleoni (IBCSG, Italy)
Karen Gelmon (CCTG, Canada)
Michael Gnant (ABCSG, Austria) Cathy Kelly (ICORG, Ireland) Sung-Bae Kim (Korean BC group) Sibylle Loibl (GBG, Germany) Andreas Makris (ICR-CTSU, UK) Miguel Martin (GEICAM, Spain) Jorge-Luis Martinez (BIG, Belgium) Nicole McCarthy (ANZBCTG, Australia) Hope Rugo (I-Spy, USA) Masakazu Toi (JBCRG, Japan) Jennifer Tursi (Pfizer representative) Michael Untch (AGO-B, Germany)
Gustavo Werutzky (LACOG, Brazil)
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coordinating investigator

Sibylle Loibl German Breast Group Centre for Haematology and Oncology / Bethanien Frankfurt am Main c/o GBG Forschungs GmbH D-63263 Neu-Isenburg, Martin-Behaim-Straße 12 Phone:+49 (0) 6102 / 7480-426 Fax: +49 (0) 6102 / 7480-126 Email: Sibylle.Loibl@GBG.de
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project management randomisation and safety/sae

Mathias Uhlig GBG Forschungs GmbH, D-63263 Neu-Isenburg, Martin-Behaim-Straße 12 Phone:+49 (0) 6102 / 7480-414 Fax: +49 (0) 6102 / 7480-440 Email: PENELOPE@GBG.de
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statistics

Nicole Burchardi (blinded GBG Statistician) GBG Forschungs GmbH, D-63263 Neu-Isenburg, Martin-Behaim-Straße 12 Phone:+49 (0) 6102 / 7480-303 Fax: +49 (0) 6102 / 7480-440 Email: Nicole.Burchardi@GBG.de Valentina Nekljudova (Head of GBG Statistics) GBG Forschungs GmbH, D-63263 Neu-Isenburg, Martin-Behaim-Straße 12 Phone:+49 (0) 6102 / 7480-467 Fax: +49 (0) 6102 / 7480-440 Email: Valentina.Nekljudova@GBG.de
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monitoring coordination

Carmen Schmidt-Rau / Nadine Jesche GBG Forschungs GmbH, D-63263 Neu-Isenburg, Martin-Behaim-Straße 12 Phone:+49 (0) 6102 / 7480-316 Fax: +49 (0) 6102 / 7480-440 Email: Carmen.Schmidt-Rau@GBG.de / Nadine.Jesche@GBG.de
2. approval signatures
monitoring coordination

Study Title:
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"
GBG-78 - **BIG 1-13**
EudraCT no.: 2013-001040-62 FDA IND: 123239  
  
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it accurately describes the planned conduct of the study.  
Signature: **Date**:  
_______________________________________________ __________________   
_______________________________________________ __________________  
  
  
 Dr. Nicole Burchardi (GBG Forschungs GmbH) Study Biostatistician  
| 3.              | PROTOCOL SYNOPSIS                                                                                                                                                                                                                                      |
|-----------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study Title     | 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 "PENELOPE-B" |
| Study Code      | GBG-78 - BIG 1-13 - NSABP-B-54-I                                                                                                                                                                                                                       |
| EudraCT         | 2013-001040-62                                                                                                                                                                                                                                         |
| Number Sponsor  | GBG Forschungs GmbH, Neu-Isenburg                                                                                                                                                                                                                      |
| Development     | Phase III                                                                                                                                                                                                                                              |
| Phase Rationale | 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  4 Preclinical studies identified luminal  retinoblastoma (Rb) phosphorylation. ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced  p16 expression as being associated with sensitivity to palbociclib. Final results from a randomized phase II study (Paloma-1/TRIO-18) 5 in 165 postmenopausal, ER+/HER2- metastatic breast cancer patients revealed a  progression-free survival of 20.2 months when palbociclib was given in  combination with letrozole compared to 10.2 months when letrozole was  given alone (HR 0.49 (95% CI 0.32-0.75) (p<0.001). Patients preselected by  CCND1 (the gene encoding for cyclin-D1) amplification and/or loss of p16 in  the primary tumor did not show different results. Uncomplicated  neutropenia (48% grade 3, 6% grade 4), anemia (4% grade 3, 1% grade 4),  and fatigue (2% grade 3, 2% grade 4) were the most common grade 3 and 4                                                                                                                                                                                                                                                        |  
| adverse events. 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.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
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| Primary                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | To compare invasive disease free survival (iDFS) for palbociclib vs. placebo in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Objectives                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | patients with residual invasive breast cancer and high CPS-EG score - after  neoadjuvant chemotherapy receiving standard adjuvant endocrine therapy  for HR-positive/HER2-normal primary breast cancer.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Secondary and  other Objectives                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Secondary objectives: To compare between the two arms:  iDFS excluding second primary of non-breast cancers  overall survival (OS)   distant disease free survival (DDFS)  locoregional recurrences-free (LRRFS) survival  iDFS per treatment group in patients with luminal-B tumors (as  determined by e.g. PAM50 or any other commercially available test  at the time of analysis)  compliance and safety according to NCI-CTCAE Version 4.0  patients reported outcomes  health economic outcomes  to explore drug-drug interaction (DDI) potential for each palbociclib - endocrine combination therapy in a subset of this patient population   to explore correlations between exposure and efficacy and/or safety  findings; Other objectives: Scores and markers for their prognostic value in this specific trial setting and  their predictive information on the efficacy and/or safety of palbociclib:  pRB immunoreactive score in residual tumor after neoadjuvant  treatment  Cyclin D immunoreactive score in residual tumor after neoadjuvant  treatment   residual cancer burden (RCB)6  clinical response to neoadjuvant chemotherapy (assessed according  to chapter 21.1)  incidence and alterations in genes, proteins, and RNAs relevant to |  
| the cell cycle (eg, CCND1 amplification, CDKN2A deletion), drug  targets (eg, CDK 4/6), and tumor sensitivity and/or resistance (Ki67,  pRb, tRB, cyclin E, pi3k, p16, and other markers, measured by  optimal test available at the time of analysis) in tumor tissues and/or  peripheral blood.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |    |
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|                                                                                                                                                                                                                                                                                                    | Low and high risk groups (defined by Endopredict®, ROR or other any  other available test at the time of analysis)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |    |
|                                                                                                                                                                                                                                                                                                    | low and high risk groups defined by a standardized image analysis  system for Ki67                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |    |
|                                                                                                                                                                                                                                                                                                    | circulating tumor DNA (ctDNA)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |    |
| Study Design                                                                                                                                                                                                                                                                                        | This is a prospective, international,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | multicenter, randomized, double    |
| blinded, placebo-controlled, parallel-group Phase III study comparing the                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |    |
| and Treatment                                                                                                                                                                                                                                                                                       | efficacy and the safety of thirteen cycles (1 year) adjuvant treatment with  palbociclib versus placebo in high risk (CPS-EG score 3-6 or CPS-EG score 2  and ypN+) patients without pathological complete response after neoadjuvant chemotherapy for hormone-receptor-positive / HER2-normal  primary breast cancer. Patient will receive standard adjuvant endocrine  treatment after completion of adequate local surgical and radiotherapeutic  treatment. Prior endocrine treatment as part of neoadjuvant treatment is  acceptable. Adjuvant endocrine treatment might have been started before  randomization can be started anytime post-surgery. The study has an adaptive design with two interim analyses including sample  size re-estimation and non-binding stopping of the trial due to futility in the  first and early stopping of the trial prematurely due to overwhelming  efficacy in the second efficacy interim analysis.  Due to the adaptive design sample size will be at least 1100 patients. The  sample size can be increased to a maximum of 1250 patients depending on  the result of the first efficacy interim analysis. Patients will be randomized in a 1:1 ratio to:  Arm A: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles;  Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7  days off treatment in a 28-day cycle for thirteen cycles.  Randomization will be stratified using block randomization by:  histological lymph node status at surgery (ypN 0-1 vs ypN2-3)  age at first diagnosis (<=50 vs >50 yrs)  centrally measured Ki-67 (>15% vs <=15%)  global region of participating site (Asian vs non Asian)  risk status (CPS-EG Score >=3 vs CPS-EG Score = 2 and ypN+) Due to the prognostic impact of the randomization criterion risk status,  randomization to the stratum CPS-EG score =2 and ypN+ will be limited to |    |  
| 50% of the patients. Palbociclib/Placebo will be given for thirteen 28-day cycles or until diagnosis  of invasive local, regional or distant recurrence, diagnosis of secondary  malignancy, unacceptable toxicity, or withdrawal of consent of the patient or  study termination by the Sponsor, whichever occurs first.  Patients in both arms shall receive standard endocrine treatment for at least 5 years.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
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| Inclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                  | Patients will be eligible for study participation only if they comply with the  following 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   | 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Known severe hypersensitivity reactions | to compounds similar to |            |    |    |           |
| Criteria    | 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 (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.                                    |                                                                                                                                                                                                                                                                                                                                                                                                                             |     |           |           |       |             |       |
| Investigational                                       | Palbociclib/placebo at a dose of 125 mg will be administered orally once a                                                                                                                                                                                                                                                                                                                                                  |     |           |           |       |             |       |
| product and                                           | day at the same day time for 21 days followed by 7 days off treatment of                                                                                                                                                                                                                                                                                                                                                    |     |           |           |       |             |       |  
| formulation   | every 28-day cycle. A total of thirteen 28-day cycles palbociclib/placebo  capsules should be administered together with endocrine treatment. Patients should take Palbociclib/placebo with food.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|---------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Noninvestigational  product and  formulation               | Current treatment guidelines recommend adjuvant endocrine treatment for  5 to 10 years after surgery for patients with hormone-receptor-positive  disease. Adjuvant endocrine treatment might have already started before  the patient enters the study.  Patients may be receiving either tamoxifen or aromatase inhibitor (AI:  letrozole, anastrozole, or exemestane). For premenopausal patients,  concurrent LHRH agonist use is allowable. PK-DDI sampling was done for patients receiving Tamoxifen or  Gosereline+Tamoxifen or Anastrozole as endocrine treatment (collection  closed in meantime).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Analysis      | Randomized patients consist of all patients who have given their written                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| populations   | informed consent and for whom there is confirmation of successful  allocation of a randomization number through the web-based data collection  interface. Intent to treat (ITT) efficacy population: all randomized patients (including  those not starting treatment). This population provides the basis for the  main efficacy analyses. Patients will be analyzed according to the treatment  group they were randomized to.  Evaluable patients (EP) efficacy population: subset of the ITT population,  this population includes all treated patients with at least 80% of the planned  number of doses of palbociclib/placebo. This population is for supportive  efficacy analyses. Patients will be analyzed according to the treatment group  they were randomized to. All randomized and treated patients safety (SP) population: all randomized  patients (excluding those not starting treatment). Patients will be analyzed  according to the treatment actually received. This is the only population for  all safety analyses. Translational Research sub-study population: a subset of randomized and  treated patients with available molecular-biological parameters before first  study drug administration. All analyses using this population will be based on  the treatment received. |
| Sample size   | Sample size was determined based on the analysis of the primary endpoint,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| calculation   | iDFS. The sample size was calculated based on the following assumptions:  Time to iDFS event follows an exponential distribution.   3-year iDFS rates for placebo arm and for the palbociclib arm are 0.77  and 0.836, respectively. The rates are equivalent to a HR (palbociclib/  placebo) of 0.685.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
| Based on these assumptions, a minimal number of 255 iDFS events will be  required to give 85% power to detect a HR (palbociclib/ placebo) of 0.685 at  the 0.05 significance level (2-sided) on iDFS using a stratified log-rank test.  Assuming time to dropout follows exponential distribution with a common  hazard rate (0.04383 subjects per year) for both arms. Applying a 1:1  randomization and a non-uniform enrollment rate of 40 subjects per month  at the peak, it was estimated that 1100 subjects will need to be enrolled. The  total enrollment period is estimated to be 3.6 years.  The final analysis will take place when 255 iDFS events are observed which is  estimated to occur about 6.5 years after first patient.  Power calculation is also done for the secondary endpoint of iDFS excluding  second primary of non-breast cancer. Assuming that not more than 15% of  iDFS events are second primary of non-breast cancer, there is 79% power to  detect statistical significance between the 2 arms with a 2-sided significance  level of 0.05.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Safety                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Safety interim analysis (SIA) reviewed by the IDMC have a special focus on                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Monitoring                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | safety and reasons for treatment discontinuations (including progressive  disease) and are scheduled regarding the number of patients having  completed 2 cycles of treatment or discontinued study treatment  prematurely: after the first 25 patients, two more SIAs after approximately  further 50 patients each, then after further 150 patients and whenever the  next 300 patients have completed 2 cycles or discontinued study treatment  prematurely. SIA frequency may be adjusted due to the IDMCs  recommendations. In subsets of at least 24 evaluable patients each starting with the  combination of palbociclib and tamoxifen, palbociclib and anastrozole, and  palbociclib and goserelin and tamoxifen plasma PK samples will be collected  to explore DDI between palbociclib and the combination drug. No significant  DDI between Palbociclib and Letrozole were observed and no samples need  to be collected to explore DDI for the Letrozole combination. Review of the PK data will be done by the IDMC once all planned PK samples  from the complete subset of 24 measurable patients of each assessed  combination have been analyzed. The study will continue while PK analysis  and data review are ongoing. The PK analysis and DDI assessment will  require unblinded analysts, details regarding the unblinded analysis and the  prospective plan for how the blind will be maintained during this process for  all study team members can be found in the PK unblinding plan. Details of  the analysis (along with other safety data included in the early safety review)  will be provided in the IDMC charter. The IDMC will review the data from the  early safety lead-in as soon as available in an ad-hoc meeting. |
| Statistical                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Primary efficacy endpoint is invasive disease-free survival (iDFS) which is  defined according to Hudis7 as the time period between randomization and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Analyses                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
| Analysis of  Primary  Endpoint   | first                                                                         | event   | (ipsi-   | or   | contralateral   | invasive   | in-breast   | or   | loco-regional   |
|----------------------------------|-------------------------------------------------------------------------------|---------|----------|------|-----------------|------------|-------------|------|-----------------|
| recurrence, distant recurrence, death from breast cancer, death from nonbreast cancer cause, death from unknown cause, invasive contralateral  breast cancer, second primary invasive cancer (non-breast)). The primary analysis for iDFS will be the comparison between treatment  arms in the ITT population with a 2-sided stratified log-rank test at the  overall significance level 0.05. The factors used in the stratified log-rank test  will be histological lymphnode status at surgery (ypN 0-1 vs ypN 2-3), age at  first diagnosis (<=50 vs >50 yrs), Ki-67 (>15% vs <=15%), and risk status (CPSEG score >= 3 vs. CPS-EG score = 2 and ypN+). Global region will not be  included. The nominal significance level for the final analysis of iDFS is  0.0463 because of the two planned interim analyses. In addition, iDFS curve  will be estimated in each treatment arm using the Kaplan-Meier method.  Cox regression model stratified by the factors used in the stratified log-rank  test will be used to estimate the treatment hazard ratio. The iDFS rates at 3  years will also be estimated for each arm. Final efficacy analysis Final analysis of the primary endpoint and secondary efficacy endpoints  (except for OS) will be conducted when the target number of iDFS events for  the final analysis have been observed. The minimum number of iDFS events  is 255. Due to the adaptive design of the trial this number can be increased  to a maximum of 290 iDFS events depending on the result of the efficacy  interim analysis. The final analysis is estimated to be performed  approximately 6.5 years after first patient randomized.                                  |                                                                               |         |          |      |                 |            |             |      |                 |
| Efficacy Interim                 | Two efficacy interim analyses (EIA) will be performed in the study. O'Brien - |         |          |      |                 |            |             |      |                 |
| Analyses:                        | Fleming type stopping boundaries based on the Lan-DeMets spending  function will be applied. Futility criteria are not used to calculate the  nominal alphas (non-binding method) in order to control the overall Type-Ierror. The objectives of the first EIA will be:  To re-estimate the sample size.   To assess safety, including any unexpected toxicity.   To allow for early stopping of the trial due to futility.  The objectives of the second EIA will be:  To assess safety, including any unexpected toxicity.   To allow for early stopping of the trial due to futility.   To allow for early stopping of the trial due to overwhelming efficacy.  The first EIA was originally planned to be performed after the first 85 events  (1/3 of the total events) have occurred or prior to the last patient  randomized to allow for the continuation of the enrollment in case of SSR.  According to an estimation in February 2017 the planned fraction of events                                                                               |         |          |      |                 |            |             |      |                 |  
would have occurred one month after last patient randomized. It was estimated that approximately two months are required to perform the EIA
and to implement potential changes. Therefore, the EIA is scheduled to be performed in April 2017. The second EIA will be performed on the basis of 2/3 of the total events. It was estimated that 2/3 of 255 events (170 events) will have occurred <5 years from the first patient randomized. In case of sample size re-estimation, 2/3 of 290 events (194 events) must have been documented, which is estimated to have occurred 5.1 years from first patient randomized. The unblinded results of the EIA will be provided to the IDMC to receive recommendation regarding the efficacy interim analysis' objectives. All staff at GBG will remain blinded to the treatment allocation of the patients with exception of the independent statistician (unblinded statistician).  
| Number  of events     | Futility   | Sample size   | Efficacy   |     |         |
|-----------------------|------------|---------------|------------|-----|---------|
| min/max               | (HR)       | re-estimation | (-level)  |     |         |
| st EIA                | April 2017 | 67            | ≥1.0       | Yes | <0.0002 |
| 1 2 nd EIA            | 2/3        | 170/194       | ≥0.90      | No  | <0.0120 |
| FA*                   | 3/3        | 255/290       | N/A        | N/A | <0.0463 |
| Time /                |            |               |            |     |         |
| Information  Fraction |            |               |            |     |         |
| Analysis              |            |               |            |     |         |  
The following table displays the decision rules regarding the objectives of the two EIA and the final analysis.  
* Final Analysis The actual nominal  levels for the EIA and for the final analysis will depend on the fraction of total events occurred at the time of analysis, in order to control the overall type I error for the endpoint of iDFS. At EIA statistical hypothesis tests will be performed only for the primary efficacy parameter, iDFS. The secondary endpoint of iDFS excluding second primary of non-breast cancer will also be taken into consideration when performing sample size re-estimation (SSR).  
Cui, Hung and Wang 8 method will be used for adaptive sample size  
modification. The decision about SSR will be made on the basis of the  
favorable zone concept by Mehta and Pocock9. In case the conditional power  
calculated on the basis of the efficacy interim analysis' treatment effect fell in the favorable zone, increase of sample size to the maximum of 1250 patients and increase of the number of iDFS events to the maximum of 290 events is planned. The definition of the favorable zone is only laid down in the addendum to the IDMC charter and must be kept secret to avoid "reverse engineering" of the treatment effect.  
| in the favorable zone, increase of sample size to the maximum of 1250  patients and increase of the number of iDFS events to the maximum of 290  events is planned. The definition of the favorable zone is only laid down in  the addendum to the IDMC charter and must be kept secret to avoid  "reverse engineering" of the treatment effect.   |                                                                                         |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|
| Analysis of  Secondary  Efficacy                                                                                                                                                                                                                                                                                                                   | Secondary efficacy endpoints are:  iDFS excluding second primary of non-breast cancers |  
| Endpoints                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                    | overall survival (OS)   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|-------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | distant disease free survival (DDFS)                                                |                         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | locoregional recurrences-free (LRRFS) survival                                      |                         |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | iDFS per treatment group in patients with luminal-B tumors as  determined by PAM50. |                         |
| Overall survival (OS) is defined as the time period between randomization  and death of any cause. An interim OS analysis will be conducted at the time  of final iDFS analysis and final OS analysis will be conducted at a later time  after the final analysis for iDFS endpoint. Details will be described in  Statistical Analysis Plan. Locoregional recurrences-free survival (LRRFS) is defined as the time period  between randomization and diagnosis of any loco-regional (ipsilateral breast  (invasive or DCIS), local/regional lymph nodes) recurrence of disease, any  invasive contralateral breast cancer or death due to any cause whichever  occurs first. Distant disease free survival (DDFS) is defined as the time period  between randomization and diagnosis of any distant recurrence of disease,  any second primary invasive cancer (non-breast) or death due to any cause  whichever occurs first. LRRFS and DDFS will be analyzed at the time of final  iDFS analysis. Time-to-event curves will be estimated using the Kaplan-Meier method and  compared between 2 arms with a two-sided stratified log-rank test.  Univariate Cox-proportional hazards model will be used to calculate hazard  ratios for the overall population as well as for subgroups predefined by the  stratification factors. Multivariate Cox-proportional hazards model will be performed for event  free data, to adjust for all stratification factors, as well as clinical stage  before neoadjuvant chemotherapy, pathological stage after neoadjuvant  chemotherapy, and grade. |                                                                                     |                         |
| Analysis of  Other Secondary  Endpoints Tolerability and Safety: Descriptive statistics for the 2 treatments will be  given on the number of patients whose treatment had to be reduced,  delayed or permanently stopped. The reason for termination includes  aspects of efficacy (e.g. termination due to tumor progression), safety (e.g.  termination due to adverse events) and compliance (e.g. termination due to patient's withdrawal of consent). Reasons for premature termination will be  categorized according to the main reason and will be presented in frequency  tables. Safety by toxicity grades will be defined by the NCI-CTCAE v4.0.  Patients reported outcome and health economic analyses: data will be  captured using the following questionnaires: the EORTC QLQ-C30, the breast  cancer module QLQ-BR23, QLQ fatigue, GAD7 patient self-rating mood scale  and the EQ-5d instruments. Summary statistics (mean, standard deviation,  median, 25th and 75th percentiles, and range) of absolute scores and their  changes from baseline will be summarized at each assessment time point for                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                     |                         |  
| the 2 treatment arms. Only patients with a baseline assessment and at least  one post-baseline assessment will be included in this analysis. Repeatedmeasures mixed-effects models will be used to explore the treatment effect  changes over time and treatment-by-time interaction.  Translational research: Exploratory analyses will be performed to identify  possible relationships between biomarkers and iDFS and OS. Patients with  missing biomarker data will not be included in the respective analysis                                       |                                                                                                                                                                                                                                                                                                        |            |
|---------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|
| Number of sites                       | Approx. 300 sites are necessary to recruit approximately 40 patients per  month at full speed recruitment.  Annual recruitment per site has to be 3.1- 3.6 patients in average, which  requires annual neoadjuvant treatment in at least 10 patients of all breast  cancer subtypes (35% uptake rate). |            |
| Study Timelines                       | First patient in:                                                                                                                                                                                                                                                                                      | QI 2014    |
| - original design                     | Last patient in                                                                                                                                                                                                                                                                                        | QIII 2017  |
| (after  sample size  re-estimation)   | First efficacy interim analysis:                                                                                                                                                                                                                                                                       | April 2017 |
| Second efficacy interim analysis:     | QI 2019 (QII 2019)                                                                                                                                                                                                                                                                                     |            |
| Final iDFS (and interim OS) analysis: | QIII 2020                                                                                                                                                                                                                                                                                              |            |
| Final OS analysis:                    | QIII 2023                                                                                                                                                                                                                                                                                              |            |
| Study duration                        | QIV 2013 - QIII 2020. No interventional procedures after final iDFS (and  interim OS) analysis.                                                                                                                                                                                                        |            |
2. approval signatures
schedule of activities

The Schedule of Activities table provides an overview of the protocol visits and procedures. Refer to Study Procedures and Assessments (Section 13) for detailed information on each procedure and assessment required for compliance with the protocol. The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct evaluations or assessments required to protect the wellbeing of the patient.  
| Penelope Schedule of Activities I: Routine assessments prior to study entry (Prescreening, Prior to any protocol investigations or procedures) Breast ultrasound(<13 month) and either bilateral mammography (< 13 months) or bilateral breast MRI (<13 months) data needs to be available . For women treated with mastectomy only imaging data of contralateral breast is required ; for women with bilateral mastectomy an imaging assessment as recommended per national  guidelines should be available. Other instrumental examinations only in case of symptoms suspicious for locoregional or distant relapse. Reports of  these examinations within <13 month year prior to enrollment must be available then. Bone scan, CT, MRI, and/or  PET-CT scans may be performed as clinically indicated according to the investigator. Imaging test for staging <13 Months Surgery (breast-conserving surgery or ablation) excising the initial tumor bed. Subsequent secondary  surgical interventions do not count regarding this time interval. All surgery reports and all pre- and  postneoadjuvant histopathology reports including information on the components of residual cancer burden (RCB)  (primary tumor bed area, overall cancer cellularity (%), percentage of cancer that is in situ disease, number of positive  nodes, diameter of largest metastases) have to be provided. Less than 16 weeks  prior to randomization Less than 10 weeks  prior to randomization Completion of radiotherapy after surgery according to guidelines (IORT allowed). Adequate radiotherapy reports including information of time period of radiotherapy, irradiated region and dose per region, dose per day have to be  provided   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Active Treatment Phase a - (1 cycle = 28 days)                                                                                                                                                  | End of Treatment /                                                         |                                            |                                                          |                                    |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------------------|------------------------------------|----|
| Protocol Activity                                                                                                                                                                               | Screening                                                                  | Withdrawal of treatment  c                 | Post-Treatment Follow-Up  according to ASCO-guidelines d |                                    |    |
| Cycles 1 and 2                                                                                                                                                                                  | Cycles 3-13                                                                |                                            |                                                          |                                    |    |
| Day 1 b                                                                                                                                                                                         | Day 14                                                                     | Day 1                                      | Thereafter until                                         |                                    |    |
| Year 2-5 twice                                                                                                                                                                                  | end of study                                                               |                                            |                                                          |                                    |    |
| *Time Window for procedures if required due                                                                                                                                                     | a year (+/-14d)                                                            |                                            |                                                          |                                    |    |
| +/-2 days*                                                                                                                                                                                      | +/-2 days*                                                                 | +3 days *                                  | (+3 days for EOT)                                        | yearly (+/- 14d)                   |    |
| to administrative reasons Study Day                                                                                                                                                             | Within 30 days prior to  randomization unless  specified otherwise 1 visit | 11 visits in total during active treatment | 1 visit                                                  | site visit, written or tel contact |    |
| Clinical Documentation/Clinical History                                                                                                                                                         | or telephone                                                               |                                            |                                                          |                                    |    |
| Written Informed Consent Process e                                                                                                                                                              | before any study related  procedure                                        |                                            |                                                          |                                    |    |
| History including diagnosis of breast cancer,  menopausal status, general medical history  including cardiac history and allergy,  concurrent illness, response to neoadjuvant  therapy CPS-EGf | X                                                                          |                                            |                                                          |                                    |    |
| Concomitant Medications/Clinical History s                                                                                                                                                      | X                                                                          | Cycle 1, 2, 3, 5, 7, 9, 11,13              | X                                                        | X                                  |    |
| ECOG Performance Status                                                                                                                                                                         | X                                                                          | Cycle 1, 2                                 | Cycle 1, 2                                               | Cycle 3, 4, 5, 7, 9, 11, 13        | X  |
| Physical Examination/Vital signs l                                                                                                                                                              | X                                                                          | Cycle 1, 2 b                               | Cycle 1, 2                                               | Cycle 3, 4, 5, 7, 9, 11, 13        | X  |
| Drug Compliance and dispensing q                                                                                                                                                                | ◄ ►, dispensing Cycle 1, 2,3,4,5,7,9,11,13                                 |                                            |                                                          |                                    |    |
| Adverse Event Reporting r                                                                                                                                                                       | X                                                                          | X                                          | X                                                        | X                                  |    |
| Laboratory  Hematology m                                                                                                                                                                        | Cycle 3, 4, 5, 6,7, 8,9,                                                   |                                            |                                                          |                                    |    |
| <8 days                                                                                                                                                                                         | Cycle 1, 2                                                                 | Cycle 1, 2                                 | 10,11, 12 and 13 and if                                  | X                                  |    |
| (Information on hematology lab results g m)                                                                                                                                                     | clinically indicated                                                       |                                            |                                                          |                                    |    |
| Blood chemistry with liver function tests m                                                                                                                                                     | <8 days                                                                    | Cycle 1, 2                                 | Cycle 3, 7, 11                                           | X                                  |    |
| HbA1C y                                                                                                                                                                                         | X                                                                          | Cycle 3,7,11                               | X                                                        |                                    |    |
| Serum pregnancy test (if applicable) m                                                                                                                                                          | <14 days                                                                   | (X)                                        |                                                          |                                    |    |  
| Active Treatment Phase a - (1 cycle = 28 days)                                                   | End of Treatment /                                                                            |                                            |                                                          |                                                  |
|--------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------------------|--------------------------------------------------|
| Protocol Activity                                                                                | Screening                                                                                     | Withdrawal of treatment  c                 | Post-Treatment Follow-Up  according to ASCO-guidelines d |                                                  |
| Cycles 1 and 2                                                                                   | Cycles 3-13                                                                                   |                                            |                                                          |                                                  |
| Day 1 b                                                                                          | Day 14                                                                                        | Day 1                                      | Thereafter until                                         |                                                  |
| Year 2-5 twice                                                                                   | end of study                                                                                  |                                            |                                                          |                                                  |
| *Time Window for procedures if required due                                                      | a year (+/-14d)                                                                               |                                            |                                                          |                                                  |
| +/-2 days*                                                                                       | +/-2 days*                                                                                    | +3 days *                                  | (+3 days for EOT)                                        | yearly (+/- 14d)                                 |
| to administrative reasons Study Day                                                              | Within 30 days prior to  randomization unless  specified otherwise 1 visit                    | 11 visits in total during active treatment | 1 visit                                                  | site visit, written or tel contact  or telephone |
| SH and E2 in patients aged <55 with history  of hysterectomy                                     | X                                                                                             |                                            |                                                          |                                                  |
| Cardiac Monitoring 12 Lead ECG n                                                                 | X                                                                                             | cycle 1                                    |                                                          |                                                  |
| Biomaterials Liquid biomaterial samples i                                                        | X                                                                                             | Prior to Cycle 7                           | X                                                        |                                                  |
| Full blood for SNP (pharmacogenomic blood  sample) h                                             | X                                                                                             | predose                                    |                                                          |                                                  |
| Cycle1 Day 14  and                                                                               |                                                                                               |                                            |                                                          |                                                  |
| Pharmacokinetics for all patients j                                                              | Cycle 2 Day 14                                                                                |                                            |                                                          |                                                  |
| from surgery and core                                                                            |                                                                                               |                                            |                                                          |                                                  |
| biopsy for central testing of  biomarkers used for  stratification after ICF  signature          |                                                                                               |                                            |                                                          |                                                  |
| Tumor Tissue k                                                                                   | In case of disease progression according to the current guidelines from the metastatic lesion |                                            |                                                          |                                                  |
| Disease Assessment Clinical disease assessment, relapse and  survival status, imaging V          | Cycle 7 X                                                                                     | EoT X                                      | At least yearly X                                        |                                                  |
| Other Investigations: thoracic or abdominal CT /  MRI, bone scans, x-rays, biopsies and others o | In case of symptoms suspect for disease progression or as clinically indicated                |                                            |                                                          |                                                  |
| PRO / Health Economics  General Quality of Life (Qol) questionnaire  (EORTC-QLQ-C30) t           | <14d                                                                                          | X                                          | X                                                        |                                                  |  
| Active Treatment Phase a - (1 cycle = 28 days)                                                                                                                                                                    | End of Treatment /                                                         |                                            |                                                          |                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------------------|------------------------------------|
| Protocol Activity                                                                                                                                                                                                 | Screening                                                                  | Withdrawal of treatment  c                 | Post-Treatment Follow-Up  according to ASCO-guidelines d |                                    |
| Cycles 1 and 2                                                                                                                                                                                                    | Cycles 3-13                                                                |                                            |                                                          |                                    |
| Day 1 b                                                                                                                                                                                                           | Day 14                                                                     | Day 1                                      | Thereafter until                                         |                                    |
| Year 2-5 twice                                                                                                                                                                                                    | end of study                                                               |                                            |                                                          |                                    |
| *Time Window for procedures if required due                                                                                                                                                                       | a year (+/-14d)                                                            |                                            |                                                          |                                    |
| +/-2 days*                                                                                                                                                                                                        | +/-2 days*                                                                 | +3 days *                                  | (+3 days for EOT)                                        | yearly (+/- 14d)                   |
| to administrative reasons Study Day                                                                                                                                                                               | Within 30 days prior to  randomization unless  specified otherwise 1 visit | 11 visits in total during active treatment | 1 visit                                                  | site visit, written or tel contact |
| Cycle 1, 3, 5, 7, 9, 11                                                                                                                                                                                           | or telephone                                                               |                                            |                                                          |                                    |
| Qol breast cancer questionnaire                                                                                                                                                                                   | (EORTC                                                                            |                                            |                                                          |                                    |
| QLQ-BR23) t                                                                                                                                                                                                       | (+/-2 days cycle 1,3)                                                      |                                            |                                                          |                                    |
| Fatigue questionnaire (EORTC QLQ FA-13  Fatigue) t                                                                                                                                                                | (+/-7 days thereafter)                                                     |                                            |                                                          |                                    |
| Mood questionnaire (GAD7) t Health economics questionnaire (EuroQol  (EQ)-5D) t Use of medical resources (Patient diary) Study Treatment Randomization after all baseline  documentation entered and CPS-EG score | X                                                                          |                                            |                                                          |                                    |
| calculated                                                                                                                                                                                                        | ◄--►w                                                                      |                                            |                                                          |                                    |
| Palbociclib or placebo dosing w; a                                                                                                                                                                                | Once Daily on Day 1 to Day 21of each Cycle followed by 7  days off         |                                            |                                                          |                                    |
| Prior endocrine treatment  acceptable. Adjuvant  endocrine treatment can be  started anytime postsurgery.                                                                                                                                                                                                                   |                                                                            |                                            |                                                          |                                    |
| Endocrine treatment x                                                                                                                                                                                             | at least 5years                                                            |                                            |                                                          |                                    |  
a **Active Treatment Phase:** All assessments should be performed prior to dosing with study medications on the visit day unless otherwise indicated. Acceptable time windows for performing each assessment are described in the column headers.  
b Cycle **1/Day 1:** Blood chemistry, hematology, 12-lead ECG and physical examination are not required if acceptable screening assessment was performed within 7 days prior to randomization.  
c End of **Treatment/Withdrawal:** Assessments have to be done at End of Treatment (EOT) visit. End of Treatment is defined as **30d after last intake** of IP. If a laboratory assessment is done after D1 of of cycle 13 but before EOT visit, it needs to documented as additional lab assessement in the eCRF for cycle 13.  
d Post Treatment **Follow-up:** Patients who discontinue study treatment for any reason other than objective disease progression or death will continue to have tumor assessments performed according to ASCO guidelines. See Tumor Assessment Requirements Flowchart for details. For patients who discontinue study treatment due to objective disease progression, survival data (i.e., patient status, onset and type of new anticancer therapy will still be collected approximately every 6 months
(+/- 14 days) from the last dose of study treatment. See section 13.8 on details of documenting imaging, first palliative treatment and clinical disease assessment.  
e Informed **Consent:** Informed consent may be obtained greater than 30 days before randomization; however, must be obtained prior to any protocol specific assessments.  
f History **(Medical/Oncological):** To include information on prior anticancer treatments. The clinical-pathologic stage - estrogen/grade (CPS-EG) score and grade assessed according to Appendix 21.1). Baseline tumor therapy related signs and symptoms will be recorded at baseline visit together with the Medical history prior to initiating treatment and then reported as adverse events during the trial if they worsen in severity or increase in frequency. Patients should have recovered from toxic effects of prior treatment, see inclusion criterion 15.  
g **Information based on external results** at Day 1 of Cycles 6, 8, 10 and 12 are allowed per protocol. However investigator must ensure repeated site labs are provided if external labs are significant and would require a dose reduction based on the CBC count and as per the investigator's discretion. See footer m
(Hematology) and Table 3 (Dose modifications) for details.  
h Retained Pharmacogenomic Blood **Sample:** A 10 ml full blood sample for SNP (whole blood collection optimized for DNA analysis) will be collected from all patients, unless prohibited by local regulations, at the screening (or at any timepoint after randomization) visit to be retained for potential pharmacogenomic analyses (SNP) related to drug response. For example, putative safety biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to the mechanism of drug action may be examined.  
i **Liquid biomaterial samples**: Two de-identified blood samples (10 ml full blood for serum and 10 ml full blood for plasma) will be collected from all patients at baseline, prior to Cycle 7 and at the end of treatment, unless prohibited by local regulations. The baseline samples must be drawn prior to the first dose of study drug (Cycle 1, Day 1). (see biomaterial management manual for additional details).  
j **Pharmakokinetics**: Mandatory plasma PK samples must be drawn predose on Day 14 of Cycle 1 and Cycle 2 for all patients.  
k Tumor Tissue for Biomarker **Assessments:** Tumor tissue is required for patient participation, and patients must agree to provide tissue from the metastatic or recurrent site at the time of study entry. For the purpose of eligibility, documentation of ER-positive and/or PR-positive tumor and HER2 negative tumor will be performed based on local results utilizing an assay consistent with local standards. For retrospective biomarker assessments, archived formalin-fixed paraffin embedded (FFPE) specimen will be collected. Every effort should be made to collect a tumor biopsy from the site of progression. Tissue samples from all patients will be used for additional biomarker analyses. Details on preparation of these samples including processing, storage, and shipment will be provided in the biomaterial management manual. .  
l Physical Examination **/Vital signs:** A full physical examination including an examination of all major body systems (palpation of breast/chest wall, axillae, supraand infraclavicular region), height (at screening only), weight, blood pressure and pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, will be required at screening. Symptom-directed physical examinations, blood pressure and pulse rate will be performed at subsequent visits.  
m **Laboratory tests:** Hematology includes hemoglobin, WBC, absolute neutrophils, platelet count. Acceptable Blood Chemistry and Hematology Labs must be provided prior randomization (< 8 days prior randomization). Blood chemistry includes AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, total calcium, total bilirubin, serum creatinine, and albumin. Additional hematology/chemistries panels may be performed as clinically indicated.  
Laboratory assessments will be performed whenever possible by the same laboratory ("site lab"). The exception are hematology labs on Day 1 of Cycles 6, 8, 10 and 12 which can be done at any laboratory conveniently located for the patient and if accepted per local EC/IRB with protocol approval. Results have to be sent immediately to the site for review. Abnormal external lab results (neutropenia <1000/mm³, thrombocytopenia <50.000/mm³ or anemia grade ≥3) obtained on those dates and at a lab different from the site lab, must be repeated at the site lab within 2 days (=extra, but clinically indicated hematology lab), and the Investigator must immediately determine the impact on study drug dosing and further medical management of the patient based on site lab results (See Table 3 Dose modifications). Serum pregnancy test for women of childbearing potential (<14 days prior randomization). A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months. Testing may be repeated as per request of IRB/IECs or if required by local regulations.  
n 12-Lead ECG **including automated calculation of PR interval, QT interval, RR interval, and QRS complex:** To be performed during screening, Day14 Cycle1 and as clinically indicated.  
o **Other Investigations:** Thoracic or abdominal CT / MRI, bone scans, x-rays, biopsies and others in case of symptoms suspect for disease progression or as clinically indicated.  
q Drug Compliance **and dispensing:** IWRS is used for IP dispense. Palbociclib, placebo bottle(s) including any unused medication will be returned to the clinic for drug accountability. Drug accountability will be performed after completion of intake for a cycle and prior to dispensing new drug supply for the next cycle(s) and prior dispensing drug for a dose reduction. Starting with Cycle 5 drug compliance will be documented retrospectively by the site. Patient needs to be advised to start a new bottle with each cycle.  
r **Adverse Events:** The worst grade for each AE in each cycle will be documented. For SAEs, the active reporting period begins from the time that the patient took the first dose of IMP and including 30 calendar days after the last administration of the investigational product. Following the active safety reporting period, newly occurred serious adverse reactions (SARs) have to be documented on the SAE form (e-CRF MedCodes) and have to be submitted to the Sponsor within 24 h after becoming aware of the event. Serious adverse events occurring to a patient after the active reporting period has ended (=post treatment follow up) have to be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all serious adverse events that the investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor. AEs (serious and non serious) should be recorded on the CRF from the time the patient has taken at least one dose of study treatment through last patient visit.  
s Concomitant **Medications/Treatments:** Concomitant medications and treatments will be recorded from 30 days prior to randomization and up to 28days after the last dose of study treatment. Entries in the patient diary can be used as Medical resources in the post-treatment follow up.  
t Patient Reported Outcomes **Assessments:** All self-assessment questionnaires should be completed by the patients while in the clinic. However they can be posted home (< 14 days), especially during post-treatment follow-up. Interviewer administration in clinic may be used under special circumstances.  
u Survival **Follow-Up:** After discontinuation of study treatment, post-study survival status (including start and type of post-study anticancer therapies) will be collected every 6 months (±14 days) from the last dose of study treatment. Telephone contact is acceptable for visits when no imaging is required..  
v Imaging (mammograph **or MRI):** Imaging should be performed at Cycle 7 and EOT. During follow-up, imaging tests for should be performed according to national guidelines but at least once a year. In patients with mastectomy only contralateral mammography / MRI is required; patients with bilateral mastectomy should be assessed as per national guidelines recommended imaging examination.  
w Palbociclib or **Placebo dosing:** To be taken orally once daily from Day 1 to Day 21 (21 days) of every 28-day cycle. Patients will be required to return all bottles of palbociclib/placebo as well as the completed patient diary at the beginning of each second cycle for drug accountability. Every patient should complete 13 cycles. See details for administration chapter 12.3.3, for recommended dose modifications chapter 12.3.5, for dose interruptions chapter 12.3.6, for dose delays chapter 12.3.7 and for dose reductions chapter 12.3.8.  
x **Endocrine treatment (required for all study patients):** While on study, treatment will continue as per local standard of care. Generics are allowed, if available. y HbA1c **measurements** can be done at a local laboratory convenient for the patient. In case of an abnormal value, please refer the patient to a diabetologist or a diabetes nurse for further diagnostic tests and to introduce medication if necessary (which has to be reported on the concomitant medication CRF).  
1 Liquid biomaterial samples: One de-identified blood samples (20ml plasma for ctDNA) will be collected from patients who gave additional consent for blood sampling of ctDNA at baseline (latest before 1" dosing with IP), prior to Cycle 7,  at the end of treatment and when progressive disease was detected, unless prohibited by local regulati The baseline samples must be drawn prior to the first dose of study drug (Cycle 1, Day 1). (See biomaterial management manual for additional details.). If a baseline sample i missed during screening it should be collected after randomization before first patient dosing at the latest.  
2 The samples must be frozen immediately at -20°C to -80°C and stored at the center until pick up by a courier service.  
For a subset of the patients enrolled in the following cohorts an additional mandatory blood samples was  taken for additional PK analysis
(see section 13.3 Pharmacokinetic measurements - collection completed in meantime  
| Whithin 4 weeks of detection   |
|--------------------------------|
| of progressive disease         |
| 2x 10 ml                       |  
| cycle 1        | cycle 2   | cycle 3   |          |          |          |         |          |          |          |          |          |
|----------------|-----------|-----------|----------|----------|----------|---------|----------|----------|----------|----------|----------|
| Plasma PK 2    | day 14    | day 14    |          |          |          |         |          |          |          |          |          |
| dy 1           | dy 1      | day 14    |          |          |          |         |          |          |          |          |          |
| for subset of  |           |           |          |          |          |         |          |          |          |          |          |
| 24 pts.        | 1h post-  | 2h post-  | 4h post- | 6h post- | 8h post- | 2h post | 2h post- | 4h post- | 6h post- | 8h post- | 2h poste |
| pre-dose       | pre-dose  | pre-dose  | pre-dose | pre-dose |          |         |          |          |          |          |          |
| dose           | dose      | dose      | dose     | dose     | dose     | dose    | dose     | dose     | dose     | dose     |          |
| placebo/       |           |           |          |          |          |         |          |          |          |          |          |
| palbociclib ÷  | x         | x         | x        | x        | X        | x       |          |          |          |          |          |
| tamoxifen      |           |           |          |          |          |         |          |          |          |          |          |
| placebo/       |           |           |          |          |          |         |          |          |          |          |          |
| palbociclib +  | X         | x         | x        | x        | x        | X       | x        |          |          |          |          |
| an as tratozol |           |           |          |          |          |         |          |          |          |          |          |
| placebo/       |           |           |          |          |          |         |          |          |          |          |          |
| palbociclib ÷  | x         | x         | x        | x        |          |         |          |          |          |          |          |
| gosereline ✦   |           |           |          |          |          |         |          |          |          |          |          |
| tamoxifen      |           |           |          |          |          |         |          |          |          |          |          |  
| screening   | before cycle 7   | EOT   |
|-------------|------------------|-------|
| 2x 10 ml    | 2x 10 ml         |       |
| ctDNA 1     | 2x 10 ml         |       |