Conditions: Breast Cancer Hormonreceptor Positive Her2-normal Postneoadjuvant Treatment With CDK 4/6 Inhibitor CPS-EG Score
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1250
Healthy volunteers: no

Brief summary:
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.

Detailed description:
Introduction:

Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer who receive chemotherapy as part of their primary treatment are at higher risk of relapse. About a third of the patients with residual invasive disease after neoadjuvant chemotherapy (NACT) will relapse despite adjuvant endocrine therapy (ET). The risk of relapse can be assessed more accurately using the clinical pathological staging-estrogen receptor grading (CPS-EG) scoring system. This involves the tumor stage before treatment start and at surgery, the estrogen receptor (ER) status, and the pathologic grading. A higher score indicates a higher risk of relapse. Patients with a score of three and higher had a disease-free survival of 70% at 5 years despite receiving ET. When combined with the group having a CPS-EG score of two and involved lymph nodes, the disease-free survival increased to 77%. This group comprises about 25% of all patients with residual disease after NACT.

Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) by palbociclib combined with ET demonstrated clinically relevant efficacy in metastatic HR+ and HER2- breast cancer irrespective of biomarker selection. After the pivotal PALOMA-1 trial, which led to accelerated approval of palbociclib in February 2015, further phase III trials demonstrated that the use of CDK4/6 inhibitors in pre- and postmenopausal patients with hormone-sensitive or resistant cancers, in first-line and pretreated metastatic breast cancer, improves progression-free and overall survival (OS).

Thus, we hypothesized that palbociclib may also be active in patients with residual disease after NACT who are at high risk of relapse. Based on the data from PALOMA-1, we designed the PENELOPE-B trial assessing the efficacy of one year palbociclib vs placebo added to any ET in HR+ and HER2- breast cancer patients with residual disease and high risk after NACT, based on the CPS-EG score.

Patient Selection and Study Design:

PENELOPE-B is a prospective, multicenter, multinational, randomized, double-blind, placebo controlled phase III study investigating the addition of palbociclib for one year to standard adjuvant ET for patients with high-risk residual disease according to the CPS-EG score after NACT for early HR+ and HER2- breast cancer.

The trial was sponsored by GBG Forschungs GmbH in collaboration with NSABP Foundation (plus I-SPY and CCTR), ABCSG, AGO-B, ANBCSG, BIG, Geicam, ICR-CTSU, JBCSG, and KCSG. Pfizer Inc funded the trial and provided drug. The trial was conducted according to ICH-GCP guidelines and the Declaration of Helsinki. The clinical trial Protocol (online only) was approved by the respective health authorities and ethics committees or institutional review boards. All patients provided written informed consent for trial participation, data transfer, and biomaterial collection. The trial was overseen by the International Steering Committee and the GBG Boards and supervised by an Independent Data Monitoring Committee (IDMC).

Eligible patients were randomly assigned in a 1:1 manner in permuted blocks of alternating size 4/6 stratified by risk status (CPS-EG sore ≥ 3 v 2/ypN+), nodal involvement after surgery (ypN0-1 v ypN2-3), Ki-67 (≤ 15% v \> 15%), age (≤ 50 v \> 50 years), and global region of participating site (Asian v non-Asian).

Treatment:

Patients received either palbociclib 125 mg orally once daily for 21 days followed by 1 week off treatment for a total duration of 13 4-week cycles or matching placebo in addition to standard adjuvant ET at the discretion of the investigator given for at least 5 years. Dose interruptions, reductions, or delays according to predefined toxicity management were acceptable in the case of significant treatment-related toxicity.

Objectives and End Points:

The primary objective of the study was to compare the invasive disease-free survival (iDFS) defined as the time in months between random assignment and first event (ipsilateral invasive in-breast or locoregional recurrence, distant recurrence, invasive contralateral breast cancer, second primary invasive cancer \[nonbreast\], or death because of any cause) for palbociclib versus placebo. Secondary end points included iDFS excluding second primary invasive nonbreast cancers, distant disease-free survival, OS, locoregional relapse-free interval (LRRFI), safety (which was reported as adverse events (AEs) irrespective of relatedness to study treatment based on National Cancer Institute Common Toxicity Criteria v4.0), and compliance.

All time-to-event end points were analyzed in the intent-to-treat population comprising all randomly assigned patients. Compliance and safety were analyzed in the safety analysis set including all randomly assigned patients who took study medication at least once. For the patients randomly assigned to placebo who received palbociclib at least once during the trial, the treatment group allocation for safety and compliance analyses was the palbociclib arm.

Sample Size and Interim Analyses:

In the initial sample size computation, 233 iDFS events were required to detect a hazard ratio for palbociclib/placebo of 0.67 (from 72% to 80% 3-year iDFS rate) corresponding to a clinically relevant risk reduction of 33% for invasive disease with a power of 85% using a two-sided stratified log-rank test and an overall two-sided significance level of 0.05. Eight hundred patients were planned to be enrolled. To accelerate recruitment after 68 patients had been enrolled, the population was expanded to patients with a CPS-EG score of two and ypN + who were also identified as high-risk patients but with a generally lower risk than the patients with CPS-EG three. Thereafter, the target hazard ratio for palbociclib/placebo was updated to 0.685 (from 77% to 83.6% 3-year iDFS rate), and the iDFS events were increased to 255 and sample size to 1,100 patients.

The study had an adaptive design with two interim efficacy analyses to monitor futility, to test for overwhelming efficacy, and to allow for sample size re-estimation. Safety was assessed at both interim analyses. O'Brien and Fleming type stopping boundaries based on the Lan-DeMets spending function were used in the interim analyses.

Statistical Analysis:

Final analysis of the primary end point iDFS was planned after 290 iDFS events with a nominal significance level of 0.0463 (two-sided). To address the concern of possible inflation of the type I error because of the sample size increase, statistical significance was determined using a weighted statistic of the stratified log-rank test (stratified by risk status, nodal involvement after surgery, Ki-67, age, but not global region of participating site, as prespecified in the Protocol) based on the method of Cui, Hung, and Wang (CHW) with CHW interim monitoring implemented in EAST version 6.5 (Cytel Inc). The 95% repeated CI was reported taking into account the adaptive sample size re-estimation and group sequential nature of the design.

For all other tests, the alpha was set to 0.05 (two-sided). Adjustment for multiple testing in the other tests was not planned. The Kaplan-Meier method was used to estimate the survival probability at specific time points together with a two-sided 95% CI. Univariable Cox-proportional hazards models stratified by the same factors as in the primary analysis were used for time-to-event end points (except LRRFI) to report hazard ratios with 95% CI. LRRFI was analyzed using the cumulative incidence function for rates at specific time points with stratified Gray's test for comparison and stratified univariate Fine-Gray model to report hazard ratio for treatment. Fisher's exact test was used to compare frequencies of AEs between arms.

All statistical analyses were performed using SAS Version 9.4 with SAS Enterprise Guide Version 7.1 on Microsoft Windows 10 Enterprise. Data cutoff date was August 24, 2020.

Arms:
arm 1: 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 2: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles

Interventions: intervention 1: Palbociclib PD-0332991 intervention 2: Placebo
Intervention descriptions: intervention 1: 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 intervention 2: 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

Protocol document:
ICF_002.pdf: 
Model Patient Information and Informed Consent 
for 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 01-13 
NSABP B-54-I 
Document type: 
Model Patient Information and Informed Consent 
Based on: 
PENELOPE Protocol G  (Version 11) 04May2017  
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of GBG  
Informed consent template Version 8.0 dated 04-May 2017 


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NSABP SAMPLE CONSENT 
Consent Form  
for 
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 
[Local institutions may modify the consent form as required by government oversight 
agencies where appropriate throughout the consent form with approval from NSABP. Note 
that "Institutional Review Board" has been used throughout the consent form; institutions 
should replace this with their appropriate oversight committee, e.g., "Research Ethics 
Board" or "Ethics Committee," as necessary.] 
This is a clinical trial, which is a type of research study. You are being asked to take part in this 
study because you have early invasive, hormone receptor (HR) positive, HER2-normal (also 
referred to as "HER2-negative") breast cancer and because you received chemotherapy 
followed by surgery to treat your breast cancer. Examination of the breast tissue and any 
lymph nodes removed during your surgery showed that there were still some cancer cells in 
the breast tissue, in the lymph nodes, or in both the breast tissue and lymph nodes. These 
areas of cancer were removed during your surgery.  
This consent form is to help you understand why the research is being done, what it involves, 
and to help you decide if you want to take part. Please take time to read the information 
carefully. You may want to discuss it with others, for example your family or your treating 
physician. Taking part in this study is entirely voluntary. That means that you should not feel 
influenced by anyone. If you choose not to take part in the study, your medical care will not 
be affected.   
Who is conducting the study? 
This trial is sponsored and conducted by the German Breast Group (GBG), an academic 
research institution specialized in conducting clinical trials in breast cancer.  NSABP 
Foundation, Inc. (NSABP) is conducting this study in the United States (US) and Canada. 
Pfizer Inc., the pharmaceutical company that manufactures and markets palbociclib is 
supporting this trial by providing palbociclib (PD-0332991) and funding this study. 
Why is this study being done? 
Endocrine (hormone) therapy is the standard (usual) treatment for your stage and type of 
breast cancer after chemotherapy and surgery. This study is being done to look at the 
effects, good and bad, of the investigational drug, palbociclib, on you and your breast cancer 
when it is given in combination with endocrine therapy. Palbociclib has been approved in the 
United States (by the US Food and Drug Administration [FDA]) and in several other countries 
for use in combination with aromatase inhibitors (a type of hormonal therapy)  or 
fulvestrant, for the treatment of locally advanced or  metastatic breast cancer. Palbociclib is 


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considered investigational in this study because it has not been approved for the treatment 
of early breast cancer. 
Finding cancer cells in your breast or lymph nodes after treatment with chemotherapy 
increases the risk of cancer returning. The main purpose of this study is to find out if adding  
palbociclib to standard endocrine therapy will prevent breast cancer from returning. More 
research is needed to find additional treatments that will help reduce the risk of cancer 
returning.  In this study, you will be given palbociclib or a placebo (a pill that looks like 
palbociclib but does not contain any active drug) along with standard endocrine therapy. 
Palbociclib is a type of therapy called "targeted therapy" because it targets proteins that help 
cancer cells grow and blocks these proteins, which may prevent the cancer from growing and 
spreading.
Other purposes of this study are:  

to learn if adding palbociclib to standard endocrine therapy will help patients with your 
stage and type of breast cancer live longer,  

to study side effects that might result from taking palbociclib with standard endocrine 
therapy, and to help researchers learn about how the study treatment affects your 
quality of life.  Quality of life is your physical and emotional well-being.
This study also includes special research tests on tumor tissue samples that have already 
been removed and on blood samples that will be collected during the study. In the future, 
the results of these tests may provide researchers with more information about palbociclib. 
Information about these sample collections will be explained to you in more detail later in 
this consent form. 
How many people will take part in the study? 
At least 1100, and up to 1250, women will take part in this study over a 3-year period. The 
study will take place at about 300-350 centers in about 15 countries.  
What will happen if I take part in this research? 
Study treatment 
The type of breast cancer that you have is usually treated after surgery with standard 
endocrine therapy for at least five years. In this study, standard endocrine therapy will be 
given to all patients. In addition to standard endocrine therapy, half of the patients (about 
550 patients) will receive the study treatment, palbociclib, for 1 year and the other half will 
receive a placebo for the same period of time.  
If the tests and exams show that you can be in the study and if you agree to take part, you 
will be randomly assigned (randomized) to one of two Arms (groups): palbociclib or placebo.  
This means that a computer program will put you into an Arm by chance. Neither you nor 
your doctor/study team will know which Arm you are in. You will have an equal chance of 
being placed in either of the two Arms.  


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You will receive appropriate therapy on either Arm of the study. This means that in all cases 
you will be treated with endocrine therapy, which is the standard treatment for your stage 
and type of breast cancer. Your health and well-being will be closely monitored.   
STUDY DESIGN 
PENELOPEB
Neoadjuvant 
Chemotherapy 
  Surgery +/- 
 Radiotherapy 
Randomization 
Palbociclib or placebo 
one capsule by mouth 
daily  
on Days 1 to 21 every 
28 days  
for one year (13 cycles)
(No palbociclib or 
placebo is taken on 
days 22 to 28.)
+
Endocrine therapy  
 (Your doctor will 
prescribe at least  
5 years of standard 
endocrine therapy.) 


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Tests and exams:
During the study therapy period (about 52 weeks), you will need to be seen by your study 
doctor or study team every 2 weeks for the first 2 months, every 4 weeks for the next 3 
months, every 8 weeks for the next 4 months, and then at the end of study therapy.  
You will need to have the following tests and exams before starting, during, and after you 
end study therapy. 

Medical history – Your doctor will ask you questions about your health, general 
condition, symptoms, complaints, and medications that you are taking or have taken in 
up to 30 days before you join the study. It is important that you tell your doctor about 
all the medications that you have been taking, including any medications or herbal 
remedies that you take.  

Physical examinations – Your doctor will periodically examine your body, including a 
breast examination, and will check your height, weight, and vital signs (temperature, 
blood pressure, and pulse rate). Your doctor will also ask you about your ability to carry 
on daily activities. 

HR and HER2 testing – Tumor tissue that was removed during your biopsy and breast 
surgery will be sent to a central laboratory (GBG) to confirm that your breast cancer is 
“HR positive” and “HER2-negative.” Your taking part in the study is dependent on the 
results – if the result shows that your breast cancer is HR negative or HER2-positive you 
will not be allowed to take part in the study, as the study medication is not appropriate 
for you.  

Biomarker testing for research purposes – Before you receive study treatment, your 
tumor samples will also be tested for Ki-67, a marker of how many tumor cells are 
currently in the dividing process, and pRb and cyclin D1,which are two proteins also 
involved in cell division that might be of importance for the treatment effect of 
palbociclib. Your taking part in the study does not depend on the results of these tests. 

Tumor and blood samples for research purposes – If your tumor tissue is confirmed to 
be HR-positive and HER2-negative, tumor tissue remaining from your breast surgery, as 
well as from the diagnostic biopsy taken before chemotherapy, will be sent to a central 
study repository. This is a place where human samples (for example, blood and tissue) 
are stored.  No new removal of tumor tissue is required. Blood samples will be drawn 
before you start, once during study therapy, and when you complete study therapy. 
Your agreement to collect and use these tumor and blood samples is required in order 
to join the PENELOPE study and will be explained to you in detail later in this consent 
form. 

Blood tests – are required before you join the study and on a regular schedule during 
study therapy to check your blood counts, to check how well your kidneys and liver are 
working, and to measure the electrolytes (salts and other substances normally found in 


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the blood), blood sugar levels, and proteins. This is standard medical practice before 
and during cycles of cancer treatment. 
Your blood may be tested to see if you are pregnant and if your ovaries are still actively 
producing sex hormones.  
Additional blood will be collected to test for the concentration of palbociclib in your 
blood.  

Electrocardiogram (ECG) (electrical tracing of your heart) – is required before you join 
the study and 14 days after you start study therapy to ensure that your heart is healthy. 

Breast ultrasound and either a mammogram or MRI of both breasts are required 
within 13 months before you start study therapy. 

Scans and x-rays – If you have new signs or symptoms, your doctor may order 
additional tests, such as a plain X-ray, liver ultrasound, computed tomography (CT), MRI 
scans, or a bone-scan. This is part of regular medical care.  

Quality of Life (QOL) questionnaires – You will be asked to fill in questionnaires that 
will cover your personal and mental well-being at the beginning, several times during 
and at end of study therapy; every six months until year 5; and then every year until the 
study ends, or until you no longer wish to participate in the study. Please note that 
there are no right or wrong answers. You should answer the questions as accurately as 
possible. Also, your doctor will ask you about medical procedures that may have 
become necessary since the last visit.  
How will I take the treatment at home?
You will be asked to take 1 capsule of the study medication (palbociclib 125 mg or placebo) 
once a day for 3 weeks, followed by 1 week of taking only the endocrine therapy. This  
4-week period of taking study medication for 3 weeks on and 1 week off is considered one 
cycle of treatment (4 weeks). In total, 13 cycles of treatment are planned. On the days that 
you take study medication, you can take the endocrine therapy at the same time. The kind of 
endocrine treatment that you take will be prescribed by your study doctor and you will 
continue to take it for at least five years. If you are younger than 50 years and still have your 
menses (periods), your doctor might consider an additional standard endocrine treatment 
with a monthly injection that will switch off the function of your ovaries. Your doctor will talk 
with you about treatment options and about the risks and benefits of this standard 
treatment. This is not part of the clinical trial. 
There are a few instructions you have to follow when taking the study medication at home. 
Study medication (palbociclib or placebo) should be taken: 

with a full meal,  

with a full glass of water and not chewed, 

ideally in the morning at the same time every day. 


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Also: 

Never share your study medication with anyone. 

You must keep track of the palbociclib/placebo capsules that you take by writing each 
dose in the diary that is provided to you and return the diary to your study team at every 
visit.  

You will be asked to bring back the bottles of palbociclib/placebo (empty or containing 
any remaining capsules) at every visit to be counted.  

Grapefruit and products containing grapefruit juice are not allowed starting seven days 
before your first dose and through the entire time that you are taking study treatment.  

There are medications and other substances, such as St. John's Wort, that you should not 
take during the entire study treatment period. Your study doctor or nurse will talk to you 
more about this and will review with you all medications you are taking before you join 
the study. 

If you have forgotten to take your study drug and remember after 6PM, do not take your 
dose that day but continue taking one capsule the following day. At your next study visit, 
let your study doctor or nurse know that this has happened. 

If you have accidentally taken an extra capsule one day, you must skip taking the study 
medication the next day and tell your study doctor that you took an extra dose. 

If you vomit, you should not take another capsule that day, and you should let your 
doctor know. 
It is very important that you take the study drug just as the doctor tells you. Do not miss any 
doses and do not take more than one dose per day.  Write down the study medication that 
you take in the diary that is provided to you. Tell the study staff about any other medications 
you are taking during the study. Talk to your study doctor or nurse before starting any new 
medicines. This includes drugs prescribed by another doctor, over-the-counter medications, 
health supplements, herbal preparations, and vitamins.  Also, please tell your study doctor or 
study staff if you have any unusual symptoms. 
How long will I be in the study? 
You will be in the study for approximately 10 years.  You will receive your study therapy for a 
total of 13 cycles (52 weeks if there are no treatment interruptions). This is considered  
year 1.  After you finish study therapy, we would like to keep track of your health and quality 
of life every 6 months (years 2 to 5), and then every year until approximately 10 years after 
you join the study. This may be done during a visit to your doctor or your study team may 
contact you by writing to you or by telephone. During the follow-up period, information on 
your health status will be collected. If your breast cancer returns (recurs), information such 
as when and where in your body the breast cancer recurs and the type of treatment that 
your doctor prescribes will be collected.  


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Can I stop being in the study?
If you decide to take part in the study and change your mind later, you are free to leave the 
study at any time and without any reason.   
You can choose to withdraw from the study in one of two ways:  

You can stop your study treatment but still allow your study doctor to report about 
your health to NSABP; or

You can stop your study treatment and request that no new information be reported 
to NSABP. Any information collected for this study up to the time you withdraw from 
the study will continue to be used. 
If you decide to leave the study, you should tell your study doctor or study staff. They will 
make sure that proper procedures are followed and a final visit is made for your safety. If 
necessary, further treatment according to your doctor's recommendations may be given to 
you.  
Can anyone else stop me from being in the study? 
Your study doctor may stop you from taking part in this study at any time if he or she 
believes it is in the best interest of your health, if you do not follow the study rules, or if the 
study is stopped by GBG/NSABP. 
What side effects or risks can I expect from being in the study? 
You may have side effects while on the study. Side effects that have been reported from 
other studies with palbociclib are listed here, but there may be other side effects that cannot 
be predicted. Side effects will vary from person to person. 
You will be watched carefully for any side effects. During the study, tests and exams will be 
done to see if the drugs should continue to be given or if the doses of the drugs you are 
receiving should be changed or delayed. The tests will also help to monitor any side affects 
you may have. 
Side effects may be mild or very serious. You may be given medicines to help lessen side 
effects. Many side effects go away soon after you stop taking the study therapy. In some 
cases, side effects can be serious, long lasting, or may never go away. There also is a risk of 
death. Talk to your study doctor about any side effects that you have while taking part in the 
study. 
Problems or side effects that are not known at this time could occur. You will be told of any 
new information that may affect your willingness to start or continue in the study. 


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Risks and side effects related to palbociclib  
The following side effects have been reported in two clinical trials with palbociclib given 
alone and are considered related to treatment: 
These side effects have been reported in 30% or more of patients taking palbociclib: 

decreases in neutrophils (a type of white blood cell) that may increase the risk of 
infection 

fatigue   

decreases in hemoglobin (anemia) that may cause weakness  

diarrhea 

nausea 
These side effects have been reported in 10% to less than 30% of patients taking palbociclib: 

decreases in platelets (may cause bleeding and/or bruising) 

decreases in white blood cells (infection fighting cells) 

decreased appetite 

constipation 

vomiting  

rash 

flatulence (passing gas)  

abdominal pain 

swelling of the hands and feet 

shortness of breath 

joint pain  

fever  

cough 

pain 

back pain 

increases in blood liver markers that indicate liver damage 
These side effects have been reported in 5% to less than 10% of patients taking palbociclib:  

hair loss  

headache  

nosebleed  

muscle spasm 

inflammation of the mucous membranes 

upper respiratory tract infection 

itching 

dizziness 

decreased weight 

abdominal swelling 


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
abdominal discomfort  

chills 

runny nose 

dry mouth 

inability to sleep (insomnia) 

muscle weakness 

pain, including pain of the mouth, throat, side (flank), chest, muscles, hands, feet 

night sweats 

impaired sense of taste 

decreased sense of touch or sensation 

changes in heart rhythm (palpitations) 

indigestion 

disease progression 

common cold 

low blood pressure (hypotension) 

blurred vision 

elevated bilirubin 

feeling of weakness 
The following side effects have been reported in clinical trials with palbociclib when given 
together with hormonal therapy in patients with breast cancer: 
These side effects have been reported in 30% or more of patients taking palbociclib and 
hormonal therapy: 

decreases in neutrophils (may increase the risk for infection) 

decreases in white blood cells (infection fighting cells) 

infections 

fatigue   

increases in blood liver markers that indicate liver damage 
These side effects have been reported in 10% to less than 30% of patients taking palbociclib 
and hormonal therapy: 

decreases in hemoglobin (may cause weakness) 

diarrhea 

hot flush  

pain (including joints, back, , hands and feet, ) 

hair loss 

decreases in platelets (may cause bleeding and/or bruising)  

nausea 

vomiting  

decreased appetite 


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
constipation 

headache 

shortness of breath 

cough 

inflammation of the mouth 

dizziness 

rash 

insomnia (inability to sleep) 
These side effects have been reported in 5% to less than 10% of patients taking palbociclib 
and hormonal therapy:

indigestion 

swelling of the hands and feet 

nosebleed  

irritation of sores in the lining of hollow organs like mouth, throat, stomach, bowels 

pain, abdominal pain, muscle pain, pain in the muscle and bone including around the 
chest, muscle cramps, mouth/throat pain   

dry skin, dry mouth  

fever  

asthenia (general weakness) 

impaired sense of taste 

high blood pressure 

falls 

influenza (flu) like illness 

depression 

itching 
These side effects have been reported in less than 5% of patients taking palbociclib and 
hormonal therapy, but are thought to be important: 

fever associated with dangerously low levels of a type of white blood cells 
(neutrophils) 

decreases in lymphocyte blood cells (infection fighting cells) 

blurred vision 

increased tearing 

dry eye 
Other safety information 
Pulmonary embolism (blood clot in the lungs) has been reported in patients treated with 
palbociclib.  The occurrence of pulmonary embolism and other types of blood clots will 


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continue to be monitored.  You should tell your study doctor immediately if you have chest 
discomfort, pain, or shortness of breath. 
Routine studies in young (2 months) rats revealed that some of the animals developed high 
blood sugar levels and cataracts (clouding of the eye lens) after being given palbociclib for  
3 months or more. These effects were not seen in studies with older (12 months) rats. It is 
currently unknown what these findings mean for patients treated with palbociclib over time. 
As a precaution, your blood will be tested for high sugar levels before, during, and after 
palbociclib therapy.   
There may be other risks that are unknown. All drugs have a potential risk of an allergic 
reaction, which if not treated promptly, could become life threatening. You should get 
medical help immediately and contact your study doctor right away if you think you have any 
of the following symptoms of a serious allergic reaction: trouble breathing, or swelling of the 
face, mouth, lips, gums, tongue or neck. Other allergic reactions may include rash, hives, or 
blisters. 
It is important that you report all symptoms and side effects that you experience as soon as 
they occur, whether or not you think they are caused by the study drug.  
If a serious side effect happens, your study drug might be stopped. You will then be checked 
regularly for the improvement of the side effects. This may require extra visits and additional 
examinations. After the side effects improve or disappear, the study medication may be 
started again at the same or a lower dose, depending on the severity and the duration of the 
events. 
Potential side effects on an unborn fetus: 
Studies in rats have shown that palbociclib can have an effect on chromosomes, with a 
potential risk for the unborn fetus.   
You should not become pregnant while on the study. Women who are pregnant or nursing a 
child are not allowed to participate.   
Side effects of endocrine treatment  
Side effects associated with endocrine therapy depend on the endocrine therapy that your 
study doctor has chosen for you. Your study doctor will inform you about potential risks and 
benefits of that therapy. 
Follow-up of side effects 
If you have a significant side effect during the study, your study doctor may ask you to visit 
the office for follow-up exams until the side effect is resolved. In order to further evaluate 
the side effect, the Sponsor or someone the Sponsor chooses may contact your physician to 
obtain additional information, such as hospital discharge summaries or consultant reports. 


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Biological material (such as biopsies), if already obtained by your physician to evaluate the 
side effect, may be sent for review by an expert chosen by the Sponsor. 
Contraception and pregnancy
Women who are pregnant or nursing a child cannot participate in this trial. You must 
confirm, to the best of your knowledge, that you are not now pregnant and that you do not 
intend to become pregnant during the trial. If you are of child-bearing potential, a pregnancy 
test will be performed within 14 days before you start study treatment.  
It is important that you use a highly effective form of birth control (contraception) if you are 
sexually active and can become pregnant. You and your partner must agree to use highly 
effective contraception during the trial and for a period of 3 months after you discontinue 
study therapy. 
Please discuss with your study doctor the most appropriate birth control methods that also 
respect your cultural and religious situation. You cannot use oral, injected or implanted 
hormonal methods of contraception or other forms of hormonal contraception, for example 
hormone vaginal ring or transdermal (skin patch). 
If you become pregnant or suspect being pregnant during study treatment or up to                
3 months after completing study treatment, you must inform your study doctor and stop 
study treatment immediately. You will not be allowed to continue study treatment if you 
are pregnant. Your study doctor will medically follow your pregnancy until delivery to 
monitor you and your child`s safety.  
What are my responsibilities? 

Keep your study appointments and complete all study assessments.  If you cannot 
keep an appointment, please contact study personnel (your study doctor or study 
staff) as soon as possible to schedule a new appointment. 

Take the study medication as instructed. You will be asked to bring back the bottles 
of palbociclib/placebo (empty or containing any remaining capsules) to your study 
doctor to be counted. At the end of the study (or if you leave the study early), return 
any study treatment still in your possession to your study doctor. 

Inform your study personnel about any symptoms, changes in medications, doctor's 
or nurse's appointments, or hospital admissions that you may have had. 

Agree not to participate in any other research study that includes adjuvant systemic 
chemotherapy. 

Inform study personnel if you think you might be pregnant. 

Inform study personnel if you change your mind about participating in the study. 

Inform your other doctors that you are taking part in this study. 

Complete questionnaires and diaries as instructed. 


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Are there benefits to taking part in the study? 
You will receive standard medical care (endocrine treatment) during the study. The benefits 
of adding palbociclib to standard endocrine treatment in HR positive, HER2-negative early 
breast cancers are not known. You may or may not receive direct benefit from being in this 
study. Information from this study may help you and/or other patients with the same type of 
breast cancer. Therefore, your taking part may help other patients get better care in the 
future. 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 

Getting endocrine therapy alone without being in a clinical trial 

Getting additional chemotherapy followed by endocrine therapy  

Getting treatments or care for your cancer with different drugs through other clinical 
trials  

Getting no additional treatment 
Talk to your study doctor about your choices before you decide if you will take part in this 
study.
Will my medical information be kept private? 
NSABP/GBG will do its best to make sure that the personal information in your medical record 
will be kept private. However, total privacy cannot be guaranteed. Your personal information 
may be given out if required by law. If information from this study is published or presented at 
scientific meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 

NSABP Foundation, Inc. (NSABP); 

The German Breast Group (GBG); 

Pfizer, Inc., the company that makes palbociclib and is providing support for this study; 

Your local Institutional Review Board (IRB) or Research Ethics Board (REB), a group of 
people who review the research study to protect your rights; 

Government agencies, including the United States Food and Drug Administration (FDA), 
the Office for Human Research Protections (OHRP), and similar organizations for other 
countries involved in the study. These agencies may review the research to see that it is 
being done safely and correctly. 

Others responsible for monitoring this research may also review your medical records for 
research quality assurance and analysis, and to see that the research is being done safely 
and correctly. 


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This website will not include information that can identify you.  At most, the website 
will include a summary of the results.  You can search this website at any time. 
What are the costs and compensation if I take part in this study? 
You will not be charged for the study drug (palbociclib/placebo) or any of the tests and 
procedures performed solely for research purposes. The endocrine therapy that is 
prescribed for you is commercially available and you and/or your health plan/insurance 
company will be responsible for its cost and any additional costs from procedures not 
required for this study. You or your insurance company will be responsible for specific 
procedures or tests that are routinely performed in patients with your stage and type of 
breast cancer.  
You will not be paid for taking part in this study. 
What will NSABP and GBG do with the personal medical information they collect? 
NSABP and GBG may use the information that your study doctor gives (i.e., the coded 
information) for the following: 
Storing it electronically and analysing it to find out what this study is telling us. 
Sharing it with Pfizer and regulatory authorities that approve new medicines or with 
groups that check that research is done properly. 
Publishing the results of the study (this will not include any information that directly 
identifies you).  
Sharing it as part of research with other universities, academic partners or companies for 
the purpose of further understanding or developing treatments for breast cancer. 
Sharing it with other universities or academic partners or companies, in this country and 
in other countries. If the information is sent to another country, the same level of 
protection to your information will be applied, to the extent permitted by local law. 
Using it to plan new studies or other types of research or other medical purposes related 
to the development of palbociclib. 
Using it to plan new studies or other types of research or other medical purposes related 
the advancement of breast cancer treatment and related diseases. 
Some of your information may be sent to a public database. 
What happens if I am injured because I took part in this study? 
It is important that you follow carefully all the instructions given by the Study Doctor and 
his/her staff regarding this study. 
If you become ill or are physically injured as a direct result of participation in this study, 
please contact your Study Doctor right away [investigator's name and contact information]; 
he/she will treat you or refer you for treatment. 


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In case such illness or injury results in a monetary loss for you, the Sponsor, GBG Forschungs 
GmbH, has an insurance policy to cover these losses.  The insurer will cover your monetary 
losses: 

if you received reasonable medical care, 

if you have followed instructions, 

if the illness/injury is related to the study drug or to properly performed study 
procedures that are not part of your usual medical care, 

if the illness/injury is not the result of the natural course of any underlying disease 
and/or pre-existing disease process present prior to the proper administration of 
palbociclib/placebo. 
In no way does signing this consent form waive your legal rights nor does it relieve the 
investigators, Sponsor or involved institution from their legal and professional 
responsibilities. 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose to either take part or not take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No 
matter what decision you make, there will be no penalty to you and you will not lose any of 
your regular benefits. Leaving the study will not affect your medical care. You can still get 
your medical care from our institution. 
In case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
REQUIRED TUMOR AND BLOOD SAMPLE COLLECTION FOR THE PENELOPEB STUDY
Collection and testing of your blood for pharmacokinetics is a required part of this study for 
all patients.  
Two blood samples (10 ml blood or about 2 teaspoons) will be collected from all patients and will be 
used to test and compare the concentration of palbociclib in your blood with the occurrence of side 
effects and treatment effects.   
Required collection of tumor and blood samples for the study repository for future 
undefined research that does not include research related to genetic (heritable) factors 
Collection and submission of the following tumor and blood samples is a required part of this 
study for all patients. 
Tumor samples will be taken from the biopsy that you had to diagnose your breast cancer 
and from a sample of the tumor that was removed during surgery after you completed 
chemotherapy. If you have a recurrence of breast cancer during the study and a biopsy is 
taken, a tumor sample from that biopsy will be sent to the researchers at GBG. 


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Blood samples (about 3 tablespoons or less) will be taken at the following times: before you 
start study therapy, before Cycle 7, at the time you finish your study therapy, and in case 
your breast cancer returns. 
What will happen to my tumor and blood samples?
GBG and NSABP are committed to the development of personalized medicine. Currently, 
patients with similar diseases do not always obtain the same benefit from the same 
treatment. The aim is to understand why patients respond differently to treatment, and then 
to develop treatment to provide maximum benefit for individual patients. Therefore, as part 
of the PENELOPE study, your blood and tumor tissue samples will be analyzed by GBG or 
other laboratories to better understand your disease. This is a study requirement.   
Your tumor samples and blood samples will be labeled with a unique code number and 
stored securely in a study repository. Your samples will be kept indefinitely or until they are 
either used up or a request is made for the samples to be returned or destroyed. 
In the future, tumor and blood samples stored in the study repository may be made available 
to scientific researchers who want to improve the understanding and treatment of breast 
cancer. These researchers will need approval of their scientific research by a committee of 
academic researchers representing the groups of doctors participating in the present study. 
All the future scientific research on your tumor and/or blood samples will only be performed 
with approval from an Institutional Review Board/Ethics Committee.  
The proposed research may result in discoveries made that are using, among others, your 
tumor and/or blood samples stored in the study repository, and a company may own such 
discoveries.  
If a commercial product is developed, GBG or its collaborators will own the commercial 
product and you will not profit financially from such product. As a participant in the 
research, you agree to give up all ownership rights to discoveries arising from use of your 
clinical data and results of future scientific research conducted on your tumor and/or blood 
samples.  
In order to participate in this study, you must be willing to allow your tumor and blood 
samples to be stored in a central study repository. GBG is responsible for the central study 
repository. 
Are there any risks or side effects of donating samples? 
Tumor tissue will be collected from existing tissue samples that were taken from previous 
biopsies or surgeries. The blood samples will be taken at the same time as your routine 
blood tests are done. The physical risks of giving a blood sample are the same as those for 
any blood sample taken from a vein. You may feel faint, experience mild pain, bruising, 


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irritation or redness at the site of puncture. In rare cases an infection or nerve damage could 
occur.
There is a risk of loss of privacy. Results from studying your samples may be put into public 
and controlled databases along with information from the other research participants.  
Are there any benefits for me when samples are sent to the study repository? 
You will not get any direct benefit from allowing samples to be sent to the study repository. 
But this research may help patients like you in the future. Because the research will take 
many years, you may not benefit from any results. Neither you nor your doctor will be given 
the results from studying the clinical repository samples. 
Who will have access to my medical information linked to my tumor and blood samples? 
Your privacy will be protected at all times. We understand that information about you and 
your health is confidential and we are committed to protecting the privacy of this 
information by fully anonymizing the information. All information (personal, clinical, 
economic, and data from research on tumor) collected in relation to your samples will be 
treated according to all national applicable laws regarding data protection and privacy. As 
per law, we must obtain your written authorization to use your personal health data linked 
to your samples for future scientific research. By signing this consent form, you are giving 
your permission to your study doctor and staff to use this information and share it with GBG. 
This permission does not automatically end at a particular time, except if you decide to 
withdraw your consent to use your tumor and blood samples and/or to use your medical 
information.  
If you decide you no longer want your samples to be used, you can call the study doctor, 
___________________, (insert name of study doctor for main trial) at 
____________________ (insert telephone number of study doctor for main trial) who will let 
the researchers know.  Then, any samples that remain in the bank will no longer be used.  
(You will still be able to take part in the PENELOPE study.)  Samples or related information 
that have already been given to or used by researchers will not be returned. 
Your medical information and your samples could be shared with other researchers in other 
institutions or hospitals, laboratories, organizations, or private partners, possibly located in 
other countries or continents. However, you will not be identified by name, address, 
telephone number, or any other information that can identify you directly  
(e.g., social security number). Your data will be coded and your identity will not be known by 
third parties. Information about the code will be kept in a secure location and access will be 
limited to research study personnel. Any reports or publication about the scientific research 
done with your samples will not identify you either. 
By signing this consent form, you allow that the coded information related to your tumor 
and blood samples may be used in the following ways: 


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
Storing and analysing it electronically to find out what the scientific research is telling us; 

Publishing the results of the scientific research; 

Sharing it as part of research with other universities, academic organizations, or 
institutions for the purpose of further understanding human biology or developing 
clinical studies; If the information is sent to another country, the same level of 
protection to your information will be applied, to the extent required by local law; 

Sharing your coded health information with other researchers for use in secondary 
research efforts. This research may or may not be focused only on breast cancer. For 
example, your data may be used to study differences between various types of cancers 
or other health problems.  Results from these analyses may not be available to you. 
Please note that personal but coded information (meaning that your name and/or any other 
information that could identify you has been replaced by a code) collected up to the time 
that you withdraw your consent will continue to be used as study data if it is scientifically 
appropriate to do so. 
Sample signature page 
I have read this document or had it read to me.  I have had the opportunity to discuss it with 
my study doctor and my questions have been answered. I understand the purpose of the 
study and what will happen to me during the study. I do freely give my consent to take part 
in this study. I understand that I will receive a copy of this document as signed below. 
In addition, by signing this consent form, I consent to allow my tumor and blood samples to 
be collected for the study repository and submitted for use in the types of research outlined 
in this consent form. I understand that this is a study requirement. 
Contact for future research 
GBG/NSABP may develop clinical trials in the future that are related to the type of breast 
cancer that you have.  Would you like to be re-contacted to discuss such studies?      
YES 
NO  
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number). 
Where can I get more information? 


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You may visit the NCI website at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to 
get the same information at: 1-800-4-CANCER (1-800-422-6237). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at any 
time.
(NSABP institutions may insert or attach a list of materials that they can provide locally to  
patients regarding clinical trials, drug information, the institution/investigator, and/or the  
NSABP.) 
Print patient's name_______________________________ 
Patient’s signature________________________________ 
Date of signature__________________________________ 
Print name of person(s) conducting the informed consent discussion 
_______________________________________ 
Signature of person(s) conducting the informed consent discussion 
_______________________________________ 
Date of signature__________________________________ 
 [Additional signature lines may be added as required by local policies or regulations.]
OPTIONAL BLOOD SAMPLE COLLECTION FOR THE PENELOPEB STUDY 
Collection and submission of the following blood samples are not required in order to 
participate in the PENELOPE study. 
Optional collection of blood samples for the study repository for future undefined research 
that includes research related to genetic (heritable) factors 
Purpose and Description of the Research 
The purpose of this information is to explain what pharmacogenetic/genetic research is and 
to ask you to agree to the collection and use of blood samples that may be used for future 
undefined research that includes research related to genetic (inherited) factors. If you decide 
that you do not want to take part in this portion of the study, you may still take part in the 
PENELOPE study. 


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We ask your permission to use blood samples that will be collected from you for research 
about genetic (inherited) factors of how people respond to the drug or why they experience 
side effects. In order to analyze these factors, researchers will extract DNA, the substance 
that contains the genetic information of cells, from your blood. This type of analysis is called 
pharmacogenetics or genetic research. These studies are run independently of the actual 
trial and you will have no direct benefit from their results. The knowledge gained from these 
studies may result in an improvement of medical knowledge regarding the treatment of 
cancers such as yours. 
If you agree, additional blood samples will be collected before you start study medication, 
before Cycle 7, at the time you finish your study therapy, and in case your breast cancer 
returns. About 4 teaspoons of blood will be taken each time.  
The research results will be kept confidential. The results of the studies cannot be directly 
related to you and may not be accessible. You may cancel your consent at any time during or 
after the trial and your samples will be destroyed. However, all laboratory data and results 
that were obtained from your samples before you cancelled your consent will be used in the 
final study report.  
When the study repository gets your blood samples and health information from the study, 
it will give them a new number. The link between your study number and the new number 
will be stored safely in a database open to very few employees at GBG. This means there is 
an extra layer of privacy. 
Genetic information about you will stay private (confidential). It will not be given to you or 
your study doctor, and it will not be entered in your medical records. Genetic studies of 
these samples will generally only give information about groups of people or about the 
nature of your cancer disease and not necessarily give information on the genetic make-up 
of your body as such. For example, researchers may compare people who respond well to 
the study drug, palbociclib, to those who respond less well. In some cases, these data may be 
used to tell something about you, but you will not be identified. If the results show anything 
about how to treat breast cancer better, researchers will do more studies to confirm this.  
GBG is responsible for storing pharmacogenetic/genetic samples safely and keeping the data 
private. GBG will follow all laws in keeping your health information from the study private. 
Other groups, like health authorities, auditors, and collaborative academic groups may need 
to check the information on the study and how the study was done. GBG may give access to 
personal health information about you to these groups. By signing this optional portion of 
the consent form, you give GBG your consent to give your personal health information to 
other groups.  
GBG or others acting on behalf of, or in collaboration with, GBG may study the samples in 
any country worldwide. They may then send the study results to Health Authorities 
worldwide. They may report results at medical meetings and in medical magazines, so that 


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other doctors can find out about the results of the study; however, you will never be 
identified in such publications.  
Although every effort will be made to keep your information private, there are risks 
associated with storing medical information and results of genetic information: 

There is a risk that someone could get unauthorized access to your personal information 
in your health record or other information stored about you for this study. For example, 
it is possible that there could be violations to the security of the computer systems used 
to store the codes linking your genetic and medical information to you. 

There is a possibility that someone could trace the information in the public or controlled 
databases back to you. Your genetic information is special to you, and you share some 
genetic information with your children, parents, brothers and sisters, and other relatives.  
Although the public or controlled databases will not have information such as your name, 
initials, birthdate, or medical record number, people may find ways in the future that 
would allow someone to link your genetic or medical information from one database 
back to you. For example, someone could compare information from one database with 
information from you (or a relative) in another database and be able to identify you  
(or your relative). 

If genetic information gets out by accident, mistake, or when it wasn't planned to be 
released, a possible harm is that it could be used to make it harder for you to get or keep 
a job or insurance. However, there are laws against the misuse of genetic information 
but they may not give full protection. Information could also include information on 
inherited conditions might affect you or your blood relatives. 
Although chances that these things will happen are very small, GBG/NSABP cannot make 
guarantees. There also may be other unforeseen privacy risks. 
Sample Signature Page
Please read the sentence below and think about your choice. After reading the sentence, 
check "yes" or "no." If you have questions, talk to your study doctor or study team member.
Remember that no matter what you decide about the collection and use of your blood samples, 
you may still take part in the PENELOPE study. 
If you agree, your personal medical information and your personal medical information 
linked to the blood samples will be used for future undefined medical and/or scientific 
pharmacogenetic/genetic research, as explained in this consent form.  
If you agree now but decide, in the future, that you no longer want your samples to be used, 
you can call the study doctor, ___________________, (insert name of study doctor for main 
trial) at ____________________ (insert telephone number of study doctor for main trial) who 
will let the researchers know.  Any samples that remain in the bank will no longer be used; 


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however, samples and related information that have already been given to, or used by, 
researchers up to the time that you notify your study doctor will continue to be used.  
I willingly consent to allow collections and investigations of circulating tumor DNA (ctDNA) 
for future undefined research about genetic (inherited) factors. 
YES 
NO  
You will receive a copy of this form.  If you want more information about this study, ask your study  
doctor. 
(NSABP institutions may insert or attach a list of materials that they can provide locally to  
patients regarding clinical trials, drug information, the institution/investigator, and/or the  
NSABP.) 
Print patient's name_______________________________ 
Patient’s signature________________________________ 
Date of signature__________________________________ 
Print name of person(s) conducting the informed consent discussion 
_______________________________________ 
Signature of person(s) conducting the informed consent discussion 
_______________________________________ 
Date of signature__________________________________ 
[Additional signature lines may be added as required by local policies or regulations.]

Prot_000.pdf: 
GBG 78 - PENELOPEB 
Study Protocol G (Version 11 - 9th April 2019) – Confidential 
1 
  
   
 
 
 
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 
 
Protocol G (Version 11 - 9th 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. 


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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 
“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 
Global 
 
 
 
 
 
 
 
Global 
 
Administrative Amendment 
Protocol G (Version 11 - 9th April 2019) 
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). 
 
Protocol G (Version 11 - 04th May  2017) 
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 
adjustment of patient number based on outcome of 1st 
9th April 2019 
 
 
 
 
 
 
 
04th May 2017 
 


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efficacy interim analysis. 
 
New information on Human Pharmacokinetic (PK) Data 
based on IB  2017 added: 
 Section 6.3.3 updated with further information 
from clinical trials evaluating PK of Palbociclib  
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 follow-
up 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 


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 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 PK-
DDI sampling comment added in same section 
Global 
Protocol E (Version 10 - 12th 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 
12 April 2016 


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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 Fresh-
Frozen 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)  
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 
09 Feb 2015 


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 Exclusion criteria #15: Proton Pump Inhibitors no 
longer disallowed 
 Addition of additional stratification criteria: CPS-
EG 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) 
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 
06.Aug.2014 


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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) 
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 
12.Jun.2014 
 
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 
Baseline, Cyclus 7, EOT 
05.Aug.2014 


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Local Administrative Letter No 
Date of local 
Amendment 
Germany 
1 (Global Administrative letter sent to German sites) 
28.10.2014 
 
 


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9 
1. 
ADDRESSES, RESPONSIBILITIES AND SIGNATURES 
 
Sponsor 
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. 
 
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 
 
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) 
 
 


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Jennifer Tursi (Pfizer representative) 
Michael Untch (AGO-B, Germany) 
Gustavo Werutzky (LACOG, Brazil) 
 
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 
 
Project Management, Randomisation and Safety/SAE Reporting 
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 
 
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 
 
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 
 


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11 
2. 
APPROVAL SIGNATURES 
 
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: 
 
 
 
 
 
_______________________________________________  
__________________ 
   Prof. Dr. Sibylle Loibl (GBG Forschungs GmbH) 
   Coordinating Investigator and Representing the Sponsor 
 
 
 
 
_______________________________________________  
__________________ 
   Dr. Nicole Burchardi (GBG Forschungs GmbH) 
   Study Biostatistician 


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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 
Number 
2013-001040-62 
Sponsor 
GBG Forschungs GmbH, Neu-Isenburg 
Development 
Phase 
Phase III 
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 HR-
positive/HER2-normal tumors from the German neoadjuvant studies’ meta-
database. Patients who had a score of 3 or higher or Score 2 and ypN+ 
disease show a 3-years iDFS of 77% despite adequate local therapy and 
adjuvant endocrine treatment. 
Cyclin dependent kinases (CDK), a group of serine/threonine kinases, play a 
key role in regulating cell cycle progression by interacting with specific 
cyclin proteins in luminal-type tumors.2,3  
PD-0332991 (palbociclib) is an oral, highly selective inhibitor of CDK4/6 
kinase activity that prevents cellular DNA synthesis by prohibiting 
progression of the cell cycle from G1 to S phase through blocking 
retinoblastoma (Rb) phosphorylation.4 Preclinical studies identified luminal 
ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced 
p16 expression as being associated with sensitivity to palbociclib.  
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 


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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. 
Primary 
Objectives 
To compare invasive disease free survival (iDFS) for palbociclib vs. placebo in 
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 


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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.  
 
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 
and Treatment 
This is a prospective, international, multicenter, randomized, double-
blinded, placebo-controlled, parallel-group Phase III study comparing the 
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 


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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.  
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).  


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8. Adequate surgical treatment including resection of all clinically evident 
disease and ipsilateral axillary lymph node dissection. Histologically 
complete resection (R0) of the invasive and ductal in situ tumor is 
required in case of breast conserving surgery as the final treatment. No 
evidence of gross residual disease (R2) is required after total 
mastectomy (R1 resection is acceptable). Axillary dissection is not 
required in patients with a negative sentinel-node biopsy before (pN0, 
pN+(mic)) or after (ypN0, ypN+(mic) neoadjuvant chemotherapy. 
9. Less than 16 weeks interval since the date of final surgery or less than 
10 weeks from completing radiotherapy (whichever occurs last) at  date 
of randomization. 
10. Completion of adjuvant radiotherapy according to standard guidelines 
(e.g. AGO Mamma, NCCN) is strongly recommended. If radiotherapy is 
not performed the reason for this needs to be documented in the eCRF.  
11. No clinical evidence for locoregional or distant relapse during or after 
preoperative chemotherapy. Local progression during chemotherapy is 
not an exclusion criterion. 
12. A clinical-pathologic stage – estrogen/grade (CPS-EG) score of ≥3, or 
score 2 if nodal status at surgery is ypN+, calculated using local 
estrogen receptor status and grade assessed on either core biopsies 
taken before start of neoadjuvant treatment or surgical specimen (see 
chapter 21.1).  
13. Age at diagnosis at least 18 years. 
14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 
or 1 (see Appendix 21.2). 
15. Resolution of all acute toxic effects of prior anti-cancer therapy or 
surgical procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia 
or other toxicities not considered a safety risk for the patient at 
investigator's discretion). 
16. Estimated life expectancy of at least 5 years irrespective of the 
diagnosis of breast cancer. 
17. The patient must be accessible for scheduled visits, treatment and 
follow-up. Patients registered on this trial must be treated at the 
participating center which could be the Principal or a Co- investigator’s 
site.  
Exclusion 
Criteria 
1. Known severe hypersensitivity reactions to compounds similar to 
palbociclib 
or 
palbociclib/placebo 
excipients 
or 
to 
endocrine 
treatments. 
2. Inadequate organ function immediate prior to randomization including: 
Hemoglobin <10g/dL (100g/L); ANC < 2000/mm³ (< 2.0 x 109/L); 
Platelets <100,000/mm³ (< 100 x 109/L); AST or ALT >1.5 x upper limit of 
normal (ULN); alkaline phosphatase > 2.5 x ULN, total serum bilirubin > 
1.25 x ULN; serum creatinine >1.25 x ULN or estimated creatinine 
clearance < 60 mL/min as calculated using the method standard for the 
institution; severe and relevant co-morbidity that would interact with 


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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  
product and 
Palbociclib/placebo at a dose of 125 mg will be administered orally once a 
day at the same day time for 21 days followed by 7 days off treatment of 


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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. 
Non-
investigational 
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 
populations 
Randomized patients consist of all patients who have given their written 
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 
calculation 
Sample size was determined based on the analysis of the primary endpoint, 
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.  


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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 
Monitoring  
Safety interim analysis (SIA) reviewed by the IDMC have a special focus on 
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 
Analyses 
Primary efficacy endpoint is invasive disease-free survival (iDFS) which is 
defined according to Hudis7 as the time period between randomization and 


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Analysis of 
Primary 
Endpoint 
 
first event (ipsi- or contralateral invasive in-breast or loco-regional 
recurrence, distant recurrence, death from breast cancer, death from non-
breast 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 (CPS-
EG 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 
Analyses: 
Two efficacy interim analyses (EIA) will be performed in the study.  O’Brien –
 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-I-
error. 
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 


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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).  
The following table displays the decision rules regarding the objectives of the 
two EIA and the final analysis.  
Analysis 
Time / 
Information 
Fraction 
Number  
of events 
min/max 
Futility 
(HR) 
Sample size  
re-estimation 
Efficacy  
(-level) 
1st EIA 
April 2017 
67 
≥1.0 
Yes 
<0.0002 
2nd EIA 
2/3 
170/194 
≥0.90 
No 
<0.0120 
FA* 
3/3 
255/290 
N/A 
N/A 
<0.0463 
* 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. 
Analysis of 
Secondary 
Efficacy 
Secondary efficacy endpoints are: 
 iDFS excluding second primary of non-breast cancers 


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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 


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the 2 treatment arms. Only patients with a baseline assessment and at least 
one post-baseline assessment will be included in this analysis. Repeated-
measures 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 
- original design 
(after  
sample size  
re-estimation) 
First patient in:  
QI 2014 
Last patient in 
QIII 2017 
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.  
 


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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) 
Imaging test for staging  
<13 Months 
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. 
Less than 16 weeks  
prior to randomization 
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 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 
 
 
 


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Protocol Activity 
Screening 
Active Treatment Phase a – (1 cycle = 28 days) 
End of Treatment / 
Withdrawal of treatment 
c 
Post-Treatment Follow-Up 
according to ASCO-guidelines d 
Cycles 1 and 2 
Cycles 3-13  
Study Day 
Within 30 days prior to 
randomization unless 
specified otherwise 
Day 1 b 
Day 14 
Day 1 
Year 2-5 twice 
a year (+/-14d) 
Thereafter until 
end of study 
yearly (+/- 14d) 
*Time Window for procedures if required due 
to administrative reasons 
+/-2 days* 
+/-2 days*  
+3 days * 
(+3 days for EOT) 
1 visit 
11 visits in total during active treatment 
1 visit 
site visit, written or tel contact 
Clinical Documentation/Clinical History 
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-EG f 
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 
(Information on hematology lab results g m) 
<8 days 
Cycle 1, 2   
Cycle 1, 2   
Cycle 3, 4, 5, 6,7, 8,9, 
10,11, 12 and 13 and if  
clinically indicated 
X 
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) 
 
 


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Protocol Activity 
Screening 
Active Treatment Phase a – (1 cycle = 28 days) 
End of Treatment / 
Withdrawal of treatment 
c 
Post-Treatment Follow-Up 
according to ASCO-guidelines d 
Cycles 1 and 2 
Cycles 3-13  
Study Day 
Within 30 days prior to 
randomization unless 
specified otherwise 
Day 1 b 
Day 14 
Day 1 
Year 2-5 twice 
a year (+/-14d) 
Thereafter until 
end of study 
yearly (+/- 14d) 
*Time Window for procedures if required due 
to administrative reasons 
+/-2 days* 
+/-2 days*  
+3 days * 
(+3 days for EOT) 
1 visit 
11 visits in total during active treatment 
1 visit 
site visit, written or tel contact 
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 
Pharmacokinetics for all patients  j 
predose       
Cycle1 Day 14 
and  
Cycle 2 Day 14 
Tumor Tissue k 
from surgery and core 
biopsy for central testing of 
biomarkers used for 
stratification after ICF 
signature 
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 


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Protocol Activity 
Screening 
Active Treatment Phase a – (1 cycle = 28 days) 
End of Treatment / 
Withdrawal of treatment 
c 
Post-Treatment Follow-Up 
according to ASCO-guidelines d 
Cycles 1 and 2 
Cycles 3-13  
Study Day 
Within 30 days prior to 
randomization unless 
specified otherwise 
Day 1 b 
Day 14 
Day 1 
Year 2-5 twice 
a year (+/-14d) 
Thereafter until 
end of study 
yearly (+/- 14d) 
*Time Window for procedures if required due 
to administrative reasons 
+/-2 days* 
+/-2 days*  
+3 days * 
(+3 days for EOT) 
1 visit 
11 visits in total during active treatment 
1 visit 
site visit, written or tel contact 
Qol breast cancer questionnaire  (EORTC-
QLQ-BR23) t 
Cycle 1, 3, 5, 7, 9, 11 
 
(+/-2 days cycle 1,3) 
(+/-7 days thereafter) 
 
Fatigue questionnaire (EORTC QLQ FA-13 
Fatigue) t 
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 
calculated  
X 
Palbociclib or placebo dosing w; a 
◄--►w 
Once Daily on Day 1 to Day 21of each Cycle followed by 7 
days off 
Endocrine treatment x 
Prior endocrine treatment 
acceptable. Adjuvant 
endocrine treatment can be 
started anytime post-
surgery. 
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. 


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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, supra- 
and 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. 


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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.  


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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).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of the following  samples is optional and encouraged: 


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screening 
before cycle 7 
 
EOT 
Whithin 4 weeks of detection 
of progressive disease  
ctDNA 1 
2x 10 ml 
2x 10 ml 
2x 10 ml 
2x 10 ml 
 
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 1st dosing with IP), prior to Cycle 7,  at the end of treatment and when progressive disease was detected, 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.). If a baseline sample is 
missed during screening it should be collected after randomization before first patient dosing at the latest.  
2 The samples must be frozen immediately at -20oC to -80oC 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 
 
 
 
 


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4. 
TABLE OF CONTENTS 
  
1. 
ADDRESSES, RESPONSIBILITIES AND SIGNATURES ....................................................... 9 
2. 
APPROVAL SIGNATURES ............................................................................................. 11 
3. 
PROTOCOL SYNOPSIS ................................................................................................. 12 
4. 
TABLE OF CONTENTS .................................................................................................. 32 
5. 
LIST OF ABBREVIATIONS ............................................................................................. 37 
6. 
INTRODUCTION .......................................................................................................... 43 
6.1 
Neoadjuvant chemotherapy in breast cancer ........................................................ 43 
6.1.1 
Pathological complete response is a prognostic marker for survival ................. 43 
6.1.2 
Extend of residual disease after neoadjuvant chemotherapy ........................... 43 
6.1.3 
New concepts for post-neoadjuvant systemic treatment .................................. 45 
6.2 
The role of cyclin-dependent kinases in breast cancer .......................................... 46 
6.2.1 
Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer 
Cells ..................................................................................................................... 46 
6.2.2 
Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer .......... 47 
6.3 
INVESTIGATIONAL PRODUCT .................................................................................. 47 
6.3.1 
Overview of palbociclib ...................................................................................... 47 
6.3.2 
Preclinical Data ................................................................................................... 47 
6.3.3 
Human Pharmacokinetic (PK) Data .................................................................... 50 
6.3.4 
QTc Evaluation Data ............................................................................................ 54 
6.3.5 
Palbociclib Dose Rationale .................................................................................. 55 
6.3.6 
Phase I/II Data in Combination with Letrozole in Advanced Breast Cancer ....... 55 
6.3.7 
Combination with other endocrine agents......................................................... 57 
6.3.8 
Long Term toxicity data ...................................................................................... 58 
7. 
RATIONALE OF THE STUDY ......................................................................................... 59 
8. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 60 
8.1 
Control Treatments ................................................................................................ 60 
8.2 
Washout Periods and carry over Effects ................................................................ 60 
8.3 
Selection of Study Population ................................................................................ 60 


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8.4 
Rationale for Biomarker Assessment ..................................................................... 61 
8.5 
Removal of Patients from Therapy or Assessment ................................................ 63 
8.6 
Blinding ................................................................................................................... 63 
8.7 
Rationale for the duration of treatment ................................................................ 64 
8.8 
Treatment Compliance ........................................................................................... 64 
8.9 
Appropriateness of the Primary Efficacy Variable ................................................. 64 
8.10 
Risk-benefit Analysis for the Participants ............................................................... 64 
8.11 
Interpretation of Potential Study Results ............................................................... 65 
9. 
STUDY OBJECTIVES ..................................................................................................... 66 
9.1 
Primary Objectives .................................................................................................. 66 
9.2 
Secondary Objectives ............................................................................................. 66 
10. 
STUDY DESIGN ............................................................................................................ 67 
11. 
STUDY POPULATION ................................................................................................... 68 
11.1 
Number of patients ................................................................................................ 68 
11.2 
Inclusion Criteria ..................................................................................................... 68 
11.3 
Exclusion Criteria .................................................................................................... 70 
11.4 
Removal of Patients from Study ............................................................................. 71 
11.4.1 
Drop-outs without treatment ............................................................................. 71 
11.4.2 
Premature Treatment Discontinuation .............................................................. 71 
12. 
STUDY TREATMENT .................................................................................................... 71 
12.1 
Method of assigning patients to treatment group ................................................. 71 
12.2 
Breaking the Blind by Investigator ......................................................................... 72 
12.2.1 
During treatment with IMP................................................................................. 72 
12.2.2 
After IMP treatment discontinuation ................................................................. 72 
12.3 
Investigational Product ........................................................................................... 73 
12.3.1 
Formulation and Packaging ................................................................................ 73 
12.3.2 
Preparation and Dispensing ................................................................................ 73 
12.3.3 
Administration .................................................................................................... 74 
12.3.4 
Premedication and supportive treatment .......................................................... 74 
12.3.5 
Recommended Dose Modification ..................................................................... 74 


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12.3.6 
Dosing Interruptions ........................................................................................... 75 
12.3.7 
Retreatment ........................................................................................................ 76 
12.3.8 
Dose Reductions ................................................................................................. 76 
12.3.9 
QTc prolongation management .......................................................................... 79 
12.3.10 Medication Errors and Overdose ........................................................................ 81 
12.3.11 Compliance ......................................................................................................... 81 
12.4 
Drug Storage and Drug Accountability ................................................................... 81 
12.5 
Concomitant Medications ...................................................................................... 82 
12.5.1 
Prohibited Medications ...................................................................................... 82 
12.5.2 
Medications Not Recommended ........................................................................ 83 
12.5.3 
Permitted Medications ....................................................................................... 83 
12.6 
Concomitant Radiotherapy or Surgery ................................................................... 84 
12.7 
Pregnancy and Lactation ........................................................................................ 84 
12.8 
Non-investigational Products ................................................................................. 85 
12.8.1 
Description, Formulation, and Handling of the non-investigational 
products .............................................................................................................. 85 
12.9 
Post-study Treatment ............................................................................................. 85 
13. 
STUDY PROCEDURE - ASSESSMENTS AND SCHEDULE................................................ 85 
13.1 
Study Procedures at Screening ............................................................................... 88 
13.2 
Evaluation during active treatment with palbociclib/placebo ............................... 90 
13.3 
Pharmacokinetic measurements ............................................................................ 94 
13.4 
Patient Reported Outcomes (PRO) and health economics .................................... 96 
13.4.1 
EORTC QLQ-C30, EORTC QLQ-FA13, QLQ-BR23 ................................................. 97 
13.4.2 
EQ-5D .................................................................................................................. 97 
13.4.3 
General Anxiety Disorder-7 (GAD-7) .................................................................. 98 
13.5 
Collection of Biomaterials .................................................................................... 100 
13.6 
Biomarker analysis ................................................................................................ 100 
13.7 
End of Treatment (EOT) ........................................................................................ 100 
13.8 
Follow-up Period................................................................................................... 101 
13.9 
Treatment Discontinuation of Individual Patient ................................................. 101 


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13.10 
End of Study (EOS) ................................................................................................ 102 
13.10.1 Regular End of Study ......................................................................................... 102 
13.10.2 Premature Termination of Study ...................................................................... 102 
13.10.3 Premature Termination of Study at a Particular Study Site ............................. 102 
14. 
DATA QUALITY ASSURANCE ..................................................................................... 103 
14.1 
Data Management and Documentation .............................................................. 103 
14.2 
Monitoring and Source Data Verification ............................................................. 104 
14.3 
Computer Systems ................................................................................................ 104 
15. 
STATISTICS ................................................................................................................ 105 
15.1 
Disposition of patient ........................................................................................... 105 
15.2 
Analysis populations ............................................................................................. 105 
15.3 
Sample Size Determination .................................................................................. 106 
15.4 
Treatment Stratification ....................................................................................... 107 
15.5 
Statistical Analyses ............................................................................................... 107 
15.5.1 
Analyses of primary and secondary endpoints................................................. 107 
15.5.2 
Extent of study treatment exposure and compliance ...................................... 109 
15.5.3 
Extent of investigational medicinal product exposure ..................................... 109 
15.5.4 
Analysis of Adverse Events ............................................................................... 110 
15.5.5 
Analyses of laboratory variables ....................................................................... 110 
15.5.6 
Translational research analyses ........................................................................ 111 
15.5.7 
Interim Analysis for Safety ................................................................................ 111 
15.5.8 
Interim Analysis for Efficacy.............................................................................. 112 
15.5.9 
Further Analysis after the End of the Study ..................................................... 113 
16. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ....................................... 113 
16.1 
IDMC Members and Mission ................................................................................ 113 
16.2 
Recommendations of the IDMC ........................................................................... 114 
16.3 
Early Termination of the Trial ............................................................................... 114 
17. 
ADVERSE EVENTS ...................................................................................................... 114 
17.1 
Adverse Event ....................................................................................................... 114 
17.2 
Adverse Reaction .................................................................................................. 115 


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17.3 
Serious Adverse Event/Serious Adverse Reaction ............................................... 115 
17.4 
Suspected Unexpected Serious Adverse Reactions ............................................. 116 
17.5 
Adverse Events of Special Interest ....................................................................... 116 
17.5.1 
Pregnancy: ........................................................................................................ 116 
17.5.2 
Relevant overdose with IMP: ............................................................................ 116 
17.5.3 
Potential Cases of Drug-Induced Liver Injury ................................................... 117 
17.6 
Death on Study ..................................................................................................... 118 
17.7 
SAE and AESI Reporting ........................................................................................ 118 
17.8 
SUSAR Reporting ................................................................................................... 119 
18. 
ADMINISTRATIVE EXECUTION .................................................................................. 119 
18.1 
Monitoring ............................................................................................................ 119 
18.2 
Sponsor’s Responsibilities .................................................................................... 120 
18.3 
Investigator’s Responsibilities .............................................................................. 120 
18.4 
Patient Informed Consent .................................................................................... 121 
18.5 
Confidential Follow-up ......................................................................................... 121 
18.6 
Ethics and Regulatory Considerations .................................................................. 122 
18.7 
Declaration of Helsinki .......................................................................................... 122 
18.8 
Study Documents .................................................................................................. 122 
18.9 
Case Report Forms ................................................................................................ 123 
18.10 
GCP Documents .................................................................................................... 123 
18.11 
Archiving ............................................................................................................... 123 
18.12 
Use of Information and Publication ..................................................................... 124 
18.13 
Finance and Insurance .......................................................................................... 124 
19. 
SUBSTUDIES .............................................................................................................. 124 
19.1 
TBD ........................................................................................................................ 124 
20. 
INVESTIGATOR'S AGREEMENT ................................................................................. 125 
21. 
APPENDICES .............................................................................................................. 126 
21.1 
Appendix 1:  CPS-EG Score / AJCC Breast Cancer Staging .................................... 126 
21.2 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance 
Status .................................................................................................................... 127 


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21.3 
Appendix 3: List of foods and drugs known to be CYP3A4 inhibitors or 
inducers: ............................................................................................................... 127 
21.4 
Appendix 4: List with examples of Drugs Known to Predispose to Torsade de 
Pointes .................................................................................................................. 128 
21.5 
Appendix 5a and Appendix5b:EORTC OLQ-30 to be used in combination with 
Cancer Related Fatigue: EORTC QLQ-FA13........................................................... 129 
21.6 
Appendix 6 EORTC QLQ BR-23 .............................................................................. 131 
21.7 
Appendix 7 GAD7 .................................................................................................. 133 
21.8 
Appendix 8 EQ5D .................................................................................................. 134 
21.9 
Appendix 9: RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines ....................................................................................................... 137 
21.10 
Appendix 10: Declaration of Helsinki ................................................................... 142 
21.11 
Appendix 11: National Cancer Institute Common Terminology Criteria for 
Adverse Events  NCI CTCAE version 4.0 ................................................................ 148 
21.12 
Appendix 12: Assessment of response to neoadjuvant chemotherapy .............. 148 
21.13 
Appendix 13 Administrative Letter 1 .................................................................... 149 
21.14 
Appendix 14 Administrative Letter 2 .................................................................... 150 
21.15 
Appendix 15 Administrative Letter 3 .................................................................... 151 
21.16 
Appendix 16 Administrative Letter 4 .................................................................... 152 
21.17 
Appendix 17 Administrative Letter 5 .................................................................... 153 
22. 
REFERENCES ............................................................................................................. 154 
5. 
LIST OF ABBREVIATIONS 
ABC 
Advanced Breast Cancer 
ASCO 
American Society of Clinical Oncology 
AE 
Adverse Event 
AESi 
Adverse Event of special Interest 
ALT 
Alanine Aminotransferases  
AI 
Aromatase Inhibitor 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferases  
AUC 
Area Under the Curve 


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BC 
Breast Cancer 
CAP 
Chest, Abdomen, Pelvis OR College of American Pathologists 
depending on context. 
CCND1 
Cyclin D1 
CDK 
Cyclin-Dependent Kinase 
CDKN2A, p16Ink4A 
Cyclin-Dependent Kinase Inhibitor 2A 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridization 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Plasma Concentration 
CNS 
Central Nervous System 
cCR 
Clinical Complete Response 
CR 
Complete Response 
CRF 
Case Report Form 
CSA 
Clinical Study Agreement 
CSF 
Colony-Stimulating Factors 
CT 
Computed Tomography 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
DC 
Disease Control 
DCR 
Disease Control Rate 
DFI 
Disease Free Interval 
DFS 
Disease Free Survival 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DR 
Duration of Response 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 


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EDTA 
Ethylenediaminetetraacetic acid 
GnRH 
A gonadotropin-releasing hormone analogue (GnRH analogue or 
analog), also known as a luteinizing hormone releasing hormone 
agonist (LHRH agonist) or LHRH analogue 
eGFR: 
Estimated Glomerular Filtration Rate  
EIU 
Exposure In Utero 
EQ-5D 
Dimension Health State EuroQoL Score 
ER 
Estrogen Receptor 
FDA 
US Food and Drug Administration  
FDA 
US Food and Drug Administration Administration Amendments 
FFPE 
Formalin Fixed Paraffin Embedded 
FIH 
First in Human 
FISH 
Fluorescent In Situ hybridization 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
Hb 
Hemoglobin 
HDPE 
High Density Polyethylene 
HER 
Human Epidermal Growth Factor Receptor 
hERG 
Human Ether-à-Go-Go Related Gene 
HR 
Hazard Ratio or Heart Rate depending on context 
IB 
Investigator’s Brochure 
IC50 
Concentration of 50% Inhibition  
ICH 
International 
Conference 
on 
Harmonisation 
of 
Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IWRS 
Interactive web response system 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 


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INR 
International Normalized Ratio 
IORT 
Intraoperative Radiation Therapy 
IMPAKT 
Improving Care and Knowledge through Translational Research 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
ITT 
Intent-to-treat  
LFT 
Liver Function Test 
LHRH 
A gonadotropin-releasing hormone analogue (GnRH analogue or 
analog), also known as a luteinizing hormone releasing hormone 
agonist (LHRH agonist) or LHRH analogue 
LPD 
Local Product Document 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NACT 
Neoadjuvant chemotherapy 
NCI CTCAE 
National Cancer Institue Common Terminology Criteria 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
OBU 
Oncology Business Unit 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCD 
Primary Outcome Completion Date 
pCR 
pathological Complete Response, pathological Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
pINV 
pathological residual Invasive cancer 


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PK 
Pharmacokinetic  
PR 
Partial Response or Progesterone Receptor (depending on context) 
PR 
The PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex. 
PS 
Performance Status 
PRO 
Patient Reported Outcome 
PT 
Prothrombin Time 
QD 
Quaque Die (once daily) 
QRS 
The QRS complex is a name for the combination of three of the 
graphical deflections seen on a typical electrocardiogram. 
The QRS complex reflects the rapid depolarization of the right and 
left ventricles. 
QT 
Time between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett's fomula 
QTcF 
QT interval corrected for heart rate using Fridericia's fomula 
RANKL 
Receptor Activator of Nuclear Factor Kappa B Ligand 
RB/Rb 
Retinoblastoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
RR 
The interval between an R wave and the next R wave 
Rac 
Accumulation Ratio 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SISH 
Silver in Situ Hybridization 
SD 
Stable Disease or Standard Deviation (depending on context) 
SPC 
Summary of Product Characteristics 
SmPC 
Summary of Product Characteristics 


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t½ 
Terminal Elimination Half-life 
TdP 
Torsade de Pointes 
TEAE 
treatment emergent adverse event 
Tmax 
Time for Cmax 
ULN 
Upper Limit of Normal 
USPI 
United States Package Insert 
Vz/F 
Apparent Volume of Distribution 
WBC 
White Blood Cell 
 
 
 
 
 
 


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6. 
INTRODUCTION 
6.1 
Neoadjuvant chemotherapy in breast cancer 
The concept of moving systemic treatment from after surgery to before surgery was first 
developed based on a hypothesis that the earlier disseminated single tumor cells are being 
killed and the development of metastasis at a later stage is therefore less likely. However, 
trials conducted in the 80’s and 90’s of the last century have not confirmed this concept but 
found a similar outcome of patients treated with chemotherapy before or after surgery.10 
Thereafter neoadjuvant chemotherapy was mainly used to obtain a better operability of 
large operable or even inoperable locally advanced tumors. Today this approach is 
considered as a model to learn not only of the biology of breast cancer in general, but also of 
the treatment sensitivity of an individual patient’s tumor. Tumor tissue obtained by core 
biopsy before treatment allows biological characterization of the tumor and development of 
an individual treatment plan. Early assessment after the first couple of cycles allows to test 
for functional predictors but also to change treatment according to early response. After 
completing all neoadjuvant treatment, histological examination of the surgically removed 
breast and axillary tissue allows precise assessment of tumor response and characterization 
of residual, treatment-resistant disease.  
6.1.1 Pathological complete response is a prognostic marker for survival 
It has been repeatedly shown that patients with a pathological complete response (pCR) after 
neoadjuvant chemotherapy have a better outcome than those without a pCR. However, the 
prognostic value varies for the different breast cancer subtypes.11 12 Especially in patients 
with HR-positive/HER2-normal tumors the association of a pCR with favorable outcome is 
only modest and in lower risk patients having highly or moderately differentiated tumors this 
association is even not existing. In fact, in this subgroup survival improvement was 
demonstrated without any increase in pCR rates.13 
6.1.2 Extend of residual disease after neoadjuvant chemotherapy 
Extent and characterization of residual disease after neoadjuvant chemotherapy raises 
increasingly more interest especially in patients with HR-positive/HER2-normal disease. The 
above mentioned meta-analysis8 showed that the extent of residual disease after 
neoadjuvant chemotherapy in the breast as well in the nodes is associated with survival of 
patients. Worst prognosis with median survival of around 5 years was observed for patients 
with post-treatment persisting inflammatory breast cancer as well as significant (>10) 
involvement of axillary lymph nodes. Further characterization of residual disease included 
examination of Ki-67 on the residual tumor and, together with patients achieving pCR where 
Ki-67 was not detectable, analysis of a total of 1150 patients from the GeparTrio study for 
disease-free and overall survival.14 Patients were subdivided into 4 groups (pCR, Ki-67 0-15%, 
Ki-67 15.1-35%, Ki-67 >35%) having significant different disease-free and overall survival. In 
fact, post-treatment Ki-67 measurements were prognostically more relevant than pre-


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treatment measurements or changes from before to after treatment. When analyzing 
patients separately according to the hormone-receptor status of their tumor, it became 
obvious, that in hormone-receptor-positive disease, patients with low or moderate post-
treatment Ki-67 levels had a comparable outcome to patients with a pCR and only patients 
with high Ki-67 levels showed a very high risk of relapse. In hormone-receptor-negative 
disease, however, patients with a pCR did better than those with low or moderate Ki-67 
levels, and again, patients with highly proliferating tumors had a most unfavorable outcome. 
However, as methodology and cut-offs of Ki-67 is not standardized, prognostic assessment by 
a clinical score post-neoadjuvant chemotherapy might be more appropriate as a risk 
selection tool in a global clinical trial. The clinical-pathologic stage – estrogen/grade (CPS-
EG)1,15combining 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 score was further validated on 2454 patients with HR-positive/HER2-
normal tumors from the German neoadjuvant studies’ meta-database (F. Marmé, 
unpublished manuscript). In an updated version of this meta-database (n=2659) patients who 
have a score of 3 or higher or Score 2 and ypN+ disease show a 3-yrs DFS of 77% despite 
adjuvant endocrine treatment. The CPS-EG score allows identification of patients at 
increased risk of early relapse and allows to isolate a population of patients in whom testing 
of a new agent is indicated. This clinically driven selection approach allows further 
characterization of the tumors into subsets of molecularly different diseases using 
prospectively defined markers. This approach is thought to lead to determination of specific 
population of patients in whom use of palbociclib would be indicated.   
 


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Figure 1: Survival after completion of radiotherapy (iDFS adjusted) in 2659 patients with HR-
positive/HER2-normal tumors from the German neoadjuvant studies’ meta-database by the CPS-EG 
score. The lower curve includes patients with 3 or more score points or score 2 and ypN+ status and 
the upper curve patients with less than 2 score points or score 2 and ypN-. 
 
6.1.3 New concepts for post-neoadjuvant systemic treatment  
Developing treatment strategies for those patients with unfavorable outcome due to residual 
disease after neoadjuvant chemotherapy appears a major task for the future. The NATAN 
study (NCT00512993) has recruited 693 patients with residual disease after anthracycline-
taxane based chemotherapy and randomized them to 5 years treatment with zoledronic acid 
or observation. However, as 80% of the patients had hormone-receptor-positive disease and 
the patients were not otherwise selected for a high relapse-risk, event rate was much lower 
than expected. Results revealed no effect of zoledronic acid on survival with a median DFS of 
73% overall.16. Due to the unfavorable outcome of patients without a pCR after neoadjuvant 
treatment with chemotherapy and trastuzumab, patients with HER2-positive tumors might 
be better candidates for such a post-neoadjuvant approach. A registration trial is currently 
under development with the aim to compare postsurgical treatment with trastuzumab to 
post-surgical treatment with trastuzumab emtansine (T-DM1), a fusion molecule of 
trastuzumab and an anti-microtubule agent derived from maytansine (Katherine study). So 


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far no post-neoadjuvant trial has been conducted for patients with high-risk HR-
positive/HER2-normal tumors. 
6.2 
The role of cyclin-dependent kinases in breast cancer 
6.2.1 Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer Cells 
Studies of ER-positive breast cancer cell lines indicate that estrogens17 and antiestrogens18 
act on sensitive populations of cells in early to mid-G1 phase.  G1/S transition is under the 
control of CDKs activated by specific complex formation with regulatory cyclins.  CDK4 and 
CDK6 are activated by binding to D-type cyclins and act early in G1 phase.19 20 21 22A primary 
target of CDK action in G1 phase is the retinoblastoma susceptibility gene product (Rb), 
which mediates G1 arrest through sequestration of transcriptional factors of the E2F-DP 
family.  Phosphorylation of Rb and other members of the pocket protein family (p107 and 
p130) by active cyclin-CDK complexes leads to release of E2F and DP transcription factors and 
transcription of requisite genes for S-phase entry.23 
 D-type cyclins play an essential role in recognition of extracellular growth stimuli and 
initiation of G1 transit,24 25 and several lines of evidence have linked estrogen regulation of 
cellular proliferation to cyclin D1 expression. Estrogen-induced proliferation of normal 
uterine and breast epithelium in vivo is associated with increased expression of 
cyclin D1 mRNA and protein.26 27 28 29 Expression of cyclin D1 in breast tumor isolates 
correlates with ER-positive status.30 31 32 MCF-7 breast cancer cells treated with estrogen 
exhibit increased expression of cyclin D1 mRNA and protein, formation of active cyclin 
D1-CDK4 complexes, and phosphorylation of Rb leading to G1 /S transition.33 34 35 36 
Estrogen-induced S-phase entry in these cells is inhibited by microinjection of antibodies to 
cyclin D1.37 Anti-estrogen-induced growth arrest of ER-positive breast cancer cells is 
associated with decreased cyclin D1 expression.38 Collectively, these studies are consistent 
with a model of estrogen action in which receptor activation induces increased 
cyclin D1 expression, CDK4 activation, and cell cycle progression. An upstream role for 
cyclin D1 has been suggested by recent reports describing direct physical interactions 
between cyclin D1 and the ER, leading to recruitment of steroid receptor co-activators and 
activation of ER-dependent transcription. This occurs in the absence of hormone and is 
independent of D-type cyclin association with CDK4.39 40 41 42  
Constraint upon CDK activity and G1 progression is provided by the universal CDK inhibitors 
of the Cip-Kip family, including gp21Cip1 and p27Kip1, and the specific CDK4 and CDK6 
inhibitors of the INK4 family, typified by p16INK4a. 43 44 45 46 47 The CDKN2A gene product 
inhibits formation of active D-type cyclin-CDK complexes through specific binding 
interactions with CDK4 or CDK6 that prevent D-type cyclin-CDK association., 48 49 50Over 
expression of p16INK4a in cells with functional Rb results in inhibition of both CDK4-and 
CDK6-associated kinase activity and Rb phosphorylation, with subsequent cell cycle arrest.51 
52 In addition, inhibition of D-type cyclin-CDK4 complex formation by p16INK4a prevents 


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sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of 
cyclin E-CDK2 activity. 53 54 55 
Overexpression of p16INK4a through adenoviral transduction of CDKN2A into MCF-7 cells leads 
to G1 arrest associated with inhibited CDK activity.56 57  Cell cycle progression induced by 
estradiol requires action of the steroid through mid-G1, well beyond the point of cyclin 
D1-CDK4 activation.58 Functional association of cyclin D1-CDK4 is required for 
estrogen-induced CDK2 activation and G1/S transition and estrogen regulates expression of 
p21Cip1, p27Kip1, and Cdc25A independent of D-type cyclin-CDK4 function.59  
6.2.2  Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer 
Cell cycle related genes and proteins are frequently deregulated in breast cancer.  
Approximately 15%–20% of human breast cancers exhibit amplification of the 
cyclin D1 (CCND1) gene,60 61 62 while the majority of human mammary carcinomas over 
express cyclin D1 protein.63 64 65 Over expression of cyclin D1 is seen early in breast cancer, 
and it is maintained at all stages of breast cancer progression, including metastatic lesions.66 
67 Amplification of the CDK4 gene, located at 12q13-q14, has been shown as an alternative 
genetic alteration to CDKN2A inactivation in various human tumor including breast cancer.68 
69 There is a mounting body of evidence linking a specific CCND1 polymorphism (G/A870) to 
increased risk of cancer and outcome in a variety of tumor types including breast cancer.  
This polymorphism results in a splice variant, altered protein structure and enhanced 
oncogenic activity in experimental models.70 The continued presence of CDK4-associated 
kinase activity is actually required to maintain breast tumorigenesis.71 Direct analyses of 
primary tumors have revealed loss of Rb expression in 20–35% of tumors, and loss of 
heterozygosity or other alterations of the Rb locus in 7-37% of tumors.72 73 74 75 
 In preclinical models, Rb depletion appears to be associated with resistance to antiestrogen 
therapy.76 Finally, virtually all ER-positive cell lines harbor loss of p16INK4a 77 78expression, and 
low expression of CDK inhibitors p21 and p27 and high expression level of cyclin E and D1 
have all been associated with resistance to anti-estrogen therapy. 
6.3 
INVESTIGATIONAL PRODUCT 
6.3.1 Overview of palbociclib 
Palbociclib (Molecular Weight free base: 447.53) is an orally active potent and highly 
selective reversible inhibitor of CDK4 and CDK6. The compound prevents cellular DNA 
synthesis by prohibiting progression of the cell cycle from G1 into the S phase. 
6.3.2 Preclinical Data 
Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied 
by the inhibition of specific Rb phosphorylation by CDK4 or CDK6 on residues serine -780 
and -795 of Rb. The IC50 values for reduction of Rb phosphorylation at serine -780 and -795 in 


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MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 µM, respectively. The IC50 values 
for reduction of Rb phosphorylation are similar to the IC50 values of inhibition of thymidine 
incorporation across a range of cultured tumor and normal cells. 
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines.  
Results from these experiments indicate that those cell lines that are more sensitive to 
palbociclib (IC50 < 150 nM) have low levels of CDKN2A (p16) and high levels of Rb1, while 
resistant cell lines show the opposite characteristics. Sensitive cell lines in this panel 
represent mostly the luminal ER+ subtype.79 The combination of palbociclib and aromatase 
inhibitors has been tested in preclinical models.80 Additionally, the combination of palbociclib 
with tamoxifen has been tested in vitro in ER+ human breast cancer cell lines indicating a 
synergistic interaction81. This provides a biologic rationale for evaluating the combination of 
palbociclib with anti-hormonal therapy in the clinic.  
Palbociclib has been evaluated in safety pharmacology, genetic toxicity, reproductive and 
development (fertility and early embryonic development, embryofetal development), and 
repeat-dose toxicity studies of up to 15-weeks duration in the rat and dog.  Based on the 
nonclinical safety studies conducted with palbociclib, the primary palbociclib-related 
systemic toxicities were observed in hematolymphopoietic tissues (decreased cellularity, 
increased iron pigment, decreases in peripheral leukocytes and RBC parameters) and male 
reproductive organs (degeneration of seminiferous tubules, secondary epididymal 
hypospermia and increased intratubular cellular debris).  Partial to complete reversibility of 
toxicities was demonstrated following a 4 week recovery period, with the exception of the 
male reproductive organ findings in the dog.  These toxicities occurred in both rats and dogs, 
and are consistent with the intended pharmacologic effect of palbociclib (i.e., cell cycle 
inhibition) (Fink et al, 2001; Arguello et al, 1998; Bartkova et al, 2003). Palbociclib was also 
identified with the potential to cause QT prolongation (Section 6.3.4 Penelope Protocol), 
developmental effects, and aneugenicity.  Developmental effects that were considered 
adverse included a decrease in fetal body weights in rats and a low incidence of small 
phalanges on the forepaws in rabbits. A no effect level for aneugenicity was observed at 
approximately 7-fold higher than unbound systemic AUC24 exposures associated with the 
human clinical dose of 125 mg QD. 
  
Palbociclib is being further evaluated for chronic toxicity in a 6-month rat and 9-month dog 
repeat-dose toxicity study. (Administrative Letter1, Appendix 13, chapter 21.13) In 
Administrative Letter 1 we informed you, that Palbociclib is being further evaluated for 
chronic toxicity in a 6-month rat and 9-month dog repeat-dose toxicity study. 
Following Data were released by Pfizer on 27th Jan 2014 as Special Safety Concern Report: 
The study entitled “27-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with PD-
0332991 in Rats with a 12-Week Recovery Phase (Study 8282224; Sponsor Reference 
Number 13LJ036). 


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The identification of cataracts in rats following 27-weeks of intermittent dosing represented 
a potential new target organ toxicity. In the previous rat and dog repeat-dose toxicity studies 
up to 15 weeks duration, the primary target organ findings were observed in the 
hematolymphopoietic and male reproductive tissues.  
The minimal dose level for cataract formation has not been identified from the 27-week rat 
toxicity study, based on the histological data (lens degeneration was noted microscopically ). 
Cataracts were identified from ophthalmic evaluations at the lower examined dose of 30 
mg/kg/day in males but at no dose in females. 
While the impact of this nonclinical finding initially was  considered to suggest a potential risk 
to human subjects, the overall benefit-risk for palbociclib remains favorable. (Administrative 
Letter 3, Appendix 21.15). Further data were communicated with Administrative Letter 5 
(Appendix 21.17) that emerged from this toxicity study showing correlation between altered 
glucose metabolism and the formation of cataracts/lens degeneration. In dog toxicity studies 
(15-week and 39-week), no altered glucose levels or cataracts/lens degeneration have been 
observed (lack of lens degeneration not yet confirmed in the 39-week study; histopathology 
pending). Hyperglycemia and diabetes mellitus, are currently (July 2014) not considered to be 
identified clinical risks and are not considered to be adverse drug reactions (ADRs) of 
palbociclib. According to exclusion Criterion #10 a severe acute or chronic medical condition 
that may increase the risk associated with study participation needs to be excluded, which 
includes uncontrolled diabetes melittus. HbA1C levels need to be controlled while patient is 
under palbociclib treatment and in case of a signal the patients need to be refered to a 
diabetologist or a medical advisor to easily control the diabetes. 
Once daily oral administration of palbociclib was well tolerated in rats at levels of 10 
mg/kg/day for males and up to 200 mg/kg/day for females (Sponsor Reference No. 
12LJ025)82.  
Addition of clinical information on glucose and cataracts from Study A5481023 in context of 
discussion of nonclinical data on glucose metabolism and findings of cataracts has been 
provided by the manufacturer via the update of the investigators brochue (Palbociclib IB, 
version December 2015). Given the lack of a signal of hyperglycemia or cataract development 
from the clinical experience and the fact that the finding of cataracts observed in young rats 
is most reasonably, based on now available aged rat toxicity studies, interpreted to be 
secondary to hyperglycemia, the manufacuters Risk Management Committee concluded that 
it was no longer warranted to include monitoring for hyperglycemia and ophthalmic changes 
in planned studies of the manufacturer. For the PenelopeB study, ophthalmic assessments 
have been removed as required study assessment by the sponsor. 
 
 
 


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6.3.3 Human Pharmacokinetic (PK) Data 
 
As of 31 August 2016, twenty-seven clinical studies have evaluated the PK of palbociclib.  
Eight of these trials were conducted in patients with advanced malignant disease.  Nineteen 
Phase 1 clinical pharmacology and biopharmaceutic studies of palbociclib were conducted in 
healthy subjects.  Eleven of these 19 clinical trials were clinical pharmacology studies 
conducted to investigate the absorption, distribution, metabolism, and excretion of 
palbociclib as well as examine the potential for DDI with palbociclib.  The remaining 8 of the 
19 clinical trials were biopharmaceutic studies conducted to examine the bioavailability, 
bioequivalence, and food effect of the palbociclib formulations.   
 
Pharmacokinetic parameters are available from all 74 patients enrolled in Study A5481001 (a 
first-in-human dose-escalation study in patients with advanced cancer) following 
multiple-dose administration (Day 8 of Cycle 1) at daily doses ranging from 25 to 225 mg of 
palbociclib. In addition, PK parameters are also available for nine patients on Day 14 of Cycle 
1 (from patients on Schedule 2/1, i.e., 2 weeks on treatment followed by 1 week off 
treatment) and 4 patients on Day 21 of Cycle 1 (from patients on Schedule 3/1, i.e., 3 weeks 
on treatment followed by 1 week off treatment). The exposure (AUC(0-10) and Cmax) 
increased in a dose proportional manner (i.e. dose linearity) over the dose range of 25 to 225 
mg QD following palbociclib administration on Days 1 and 8 of Cycle 1, although some 
variability (low to moderate) around these doses was observed particularly at the 150 mg QD 
dose level. Following repeated daily dosing to Day 14 and Day 21 palbociclib was absorbed 
with a median Tmax of ~4 hours when fasting 2 hours before and after palbociclib 
administration. The mean palbociclib Vz/F was 3103 L, which is significantly greater than total 
body water (42 L), indicating that palbociclib extensively penetrates into peripheral tissues. 
The ability for palbociclib to cross the blood brain barrier in humans is unknown. In rats, 
palbociclib displayed minimal ability to cross the intact blood brain barrier. Palbociclib was 
eliminated slowly; the mean t½ was 26.5 hours (ranged 15.8 to 36.2 hours) and the mean 
CL/F was 86.1 L/hour. Palbociclib accumulated following repeated dosing with a median Rac 
of 2.4, which is consistent with a half-life of ~27 hours. 
 
Pharmacokinetic data from Study A5481002 indicate that palbociclib exposure at steady 
state in mantle cell lymphoma patients is similar to that observed in solid tumors 
(Protocol A5481001). 
Pharmacokinetic analysis of the Phase 1 portion of Study A5481003 (Paloma-1/Trio-18, 
breast cancer, combination with letrozole) was conducted to evaluate the potential for 
drug-drug interaction between palbociclib and letrozole. The results indicate lack of a 
potential for drug-drug interaction between palbociclib and letrozole when administered in 
combination.  See section 6.3.6 for further details. 
 


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The effect of food on the bioavailability of palbociclib when administered as the commercial 
free base capsule (the formulation being used in the PENELOPE Study), was investigated in 
Study A5481021. The administration of the free base formulation of palbociclib with food 
(including a high fat or a low fat meal given together with palbociclib, or moderate fat meals 
given 1 hour before and 2 hours after palbociclib) resulted in more uniform drug absorption 
and significantly reduced the intersubject variability in drug exposure when compared to the 
administration of the commercial free base formulation of palbociclib in a fasted state. 
Because of these findings, patients should be instructed to take palbociclib/placebo with 
food. This may begin immediately. This change does not significantly affect the study’s scope, 
safety, or scientific quality. (Administrative Letter 2, Appendix 14, chapter 21.14).  
Comparison of the palbociclib isethionate capsule formulation given under both the 
overnight and minimal fasting conditions and the palbociclib commercial free base capsule 
formulation with food was found to be bioequivalent (Study A5481036). 
 
The solubility of the palbociclib free base is pH dependent—palbociclib is water soluble at 
low pH (2.1-4.5), while the solubility dramatically decreases as pH rises above 4.5.  
Concomitant administration of agents which increase gastric pH can alter the solubility and 
absorption of palbociclib free base formulations. 
Study A5481038 evaluated the effects of staggered dosing of the H2-receptor antagonist 
(H2RA) famotidine, and of the staggered dosing of the local antacid Mi-Acid Maximum 
Strength Liquid on the PK of a single oral 125 mg palbociclib free base capsule given with 
food in healthy subjects. The results indicated that administration of palbociclib under fed 
conditions with staggered famotidine and staggered Mi-Acid Maximum Strength Liquid 
dosing had no impact on the exposure of palbociclib.    
Study A5481038 also evaluated the effects the coadministration of a single 125 mg dose of 
the free base capsule of palbociclib following multiple doses of the proton pump inhibitor 
(PPI) rabeprazole under fed conditions in healthy volunteers. Concurrent administration of 
rabeprazole with palbociclib decreased palbociclib Cmax by 41%, but had limited impact on 
AUCinf (13% decrease) compared with a single dose of palbociclib administered alone. This 
13% reduction in overall exposure is not thought to be clinically relevant. 
Given the reduced effect on gastric pH of H2RAs and local antacids compared to PPIs, the 
effect of dosing these classes of acid-reducing agents palbociclib exposure when given 
simultaneously with palbociclib free base capsules under fed conditions is expected to be 
minimal 83 84 .  
In another DDI study (Study A5481018) in healthy subjects, the coadministration of a single 
125 mg dose of the free base capsule of palbociclib with multiple doses of the PPI 
rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 
80%, respectively, when compared with a single dose of palbociclib administered alone.  This 
study readout during the conduct of the PENELOPE study, resulting in an administrative letter 
prohibiting the use of PPIs and recommending the use of alternative treatments (such as 


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H2RAs or local antacids given by staggered dosing) when required (Administrative Letter 3, 
Appendix 15, chapter 21.15). This study also prompted the design and conduct of another 
clinical study evaluating the effects of gastric acid-reducing agents on palbociclib PK when 
palbociclib free base capsules were administered in the fed state (Study A5481038, discussed 
in the preceding paragraphs).   
Collectively, these antacid DDI data further support the requirement that the free base 
capsule of palbociclib should be taken with food. Thus, to decrease inter- and intra-subject 
variability in palbociclib drug exposure as well as to minimize the DDI potential of concurrent 
administration of gastric acid-reducing agents, the palbociclib free base capsule formulation 
should be taken with food. 
Update to Administrative Letter 3, Appendix 15, chapter 21.15: The results from the recently 
performed study A5481038, “A Phase 1, Open-Label Fixed-Sequence 2-Period Crossover 
Study Of Palbociclib In Healthy Subjects To Investigate The Potential Effect Of Antacid 
Treatment On The Pharmacokinetics Of A Single Oral Dose Administered Under Fasted 
Conditions” suggest that coadministration of a single 125 mg dose of pablociliclib  with 
multiple doses of the proton pump inhibitors (PPI) rabeprazole under fed conditions 
decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when 
compared to a single dose of Palbociclib administered alone.  Given the reduced effect on 
gastric pH of H2 receptor antagonists and local antacids compared to PPIs, the effect of these 
classes of acid-reducing agents on palbociclib exposure under fed conditions is expected to 
be minimal.  Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor 
antagonists, or local antacids on palbociclib exposure.  
 
As a result of these findings, the use of proton pump inhibitors is no longer refrained.  
 
Palbociclib is metabolized to multiple metabolites in a qualitatively similar manner in rat, dog 
and human liver microsomes. In vitro, palbociclib is primarily metabolized by CYP3A4 
enzymes. An exploratory evaluation of the circulating metabolites for palbociclib was 
conducted in plasma samples obtained from patients treated with palbociclib 200 mg QD 
(Schedule 2/1) in Study A5481001.  Assessment of the pooled plasma samples on Day 14 of 
Cycle 1 indicated that the glucuronide conjugate of palbociclib and the lactam of palbociclib 
(PF-05089326) were the main metabolites present in plasma. Glucuronide conjugate of 
palbociclib is unlikely to be active vs the intended target (CDK4/6).  Although PF-05089326 
showed similar in vitro activity vs CDK4/6 as with palbociclib, the unbound exposure of this 
metabolite is considerably lower than the parent drug. Therefore, contribution of this 
metabolite to the pharmacologic activity in humans is anticipated to be low. Other 
metabolites observed were the glucuronide conjugates of hydroxylated palbociclib and the 
glucuronide conjugate of reduced palbociclib. PF-05089326 was also observed in the 
circulation of rats following repeated daily oral administration of palbociclib.  Plasma protein 
binding of palbociclib and PF-05089326 is ~85% and 95%, respectively. 


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The effect of multiple dosing of palbociclib (125 mg QD) on the single-dose PK of a sensitive 
CYP3A4/5 probe substrate, midazolam (2 mg), was evaluated in 26 healthy fasted women of 
nonchildbearing potential in Study A5481012.  Coadministration of palbociclib and 
midazolam increased midazolam AUCinf and Cmax by 61% and 37%, respectively, relative to 
midazolam given alone.  The ratios (90% CIs) of the adjusted geometric means for midazolam 
AUCinf and Cmax were 161% (146% 177%) and 137% (124% 152%), respectively, following 
administration of midazolam with multiple doses of palbociclib (Test), relative to midazolam 
administered alone (Reference).  These results indicate that palbociclib is a weak time-
dependent inhibitor of CYP3A. Based on these results, physicians should be aware that the 
dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced 
when given concurrently with palbociclib. 
The effect of multiple doses of itraconazole (200 mg QD), a strong CYP3A inhibitor, on the 
single dose PK of palbociclib (125 mg) was evaluated in 12 healthy fed subjects in Study 
A5481016.  Coadministration of itraconazole and palbociclib increased palbociclib AUCinf and 
Cmax by approximately 87% and 34%, respectively, relative to those when palbociclib dose 
was given alone.  The ratios (90% CIs) of the adjusted geometric means for palbociclib AUCinf 
and Cmax were 187% (173%-202%) and 134% (126%-143%), respectively, when palbociclib 
was administered with multiple doses of itraconazole (Test), relative to palbociclib 
administered alone (Reference). The concomitant use of strong CYP3A inhibitors including, 
but not limited to, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan,  
delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice should 
be avoided. 
The effect of multiple dosing of a strong CYP3A4 inducer, rifampin (600 mg QD), on the 
single-dose PK of palbociclib (125 mg), was evaluated in 15 healthy fasted subjects in Study 
A5481017. Coadministration of rifampin and palbociclib decreased palbociclib AUCinf and 
Cmax by approximately 85% and 70%, respectively, relative to palbociclib given alone.  The 
ratios (90% CIs) of the adjusted geometric means for palbociclib AUCinf and Cmax were 
15.5% (12.0% 19.9%) and 30.2% (23.5% 38.7%), respectively, following administration of 
palbociclib with multiple doses of rifampin (Test), relative to palbociclib administered alone 
(Reference). The concomitant use of strong CYP3A inducers including, but not limited to, 
carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, 
rifampin, rifapentin, and St. John’s wort should be avoided. 
 
The multiple dose PK of palbociclib in patients of the Asian race has been evaluated in 
Studies A5481008, A5481010, A5481019, and A5481023. While palbociclib geometric mean 
AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese healthy subjects 
compared with those in demographic-matched non-Asian healthy subjects, palbociclib 
steady-state AUC, Cmax, and Ctrough values for Japanese and/or Asian (excluding Japanese) 


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patients with advanced breast cancer were comparable with those in non-Asian patients with 
advanced breast cancer in some study populations but were higher in others. 
Notwithstanding, the maximum tolerated dose (MTD) of palbociclib that was determined for 
Japanese advanced cancer patients for both palbociclib monotherapy and in combination 
with letrozole was identical to the MTD determined in the predominantly Caucasian 
advanced cancer patients. Likewise, the same dosing regimen had also been demonstrated to 
be tolerable in Chinese advanced breast cancer patients.  
Based on analysis of the cumulative PK, safety, and efficacy data, no dose adjustment based 
on Asian race is necessary. 
 
 
6.3.4 QTc Evaluation Data 
A pharmacokinetic/pharmacodynamic analysis to evaluate the relationship between 
palbociclib exposure and ECG variables (RR interval and QTc) was developed using data from 
postmenopausal women with ER-positive, HER2 negative advanced breast cancer enrolled in 
the QTc analysis subgroup included in Study A5481008 that was conducted as the definitive 
QT interval prolongation evaluation for the palbociclib program. A total of 125 patients were 
enrolled in this subgroup to evaluate the effect of palbociclib on QT interval. Of these 125 
patients, 77 were randomized to the palbociclib plus letrozole treatment arm and 48 were 
randomized to the placebo plus letrozole arm. A total of 2597 recorded individual QT 
intervals and 322 palbociclib concentrations obtained from 77 palbociclib plus letrozole-
treated patients were included in the analysis dataset. The median (range) age and baseline 
body weight of patients in the analysis dataset was 62.0 (36-86) years and 72.3 (48.1-157) kg, 
respectively. Among the 77 patients, 70 patients provided a total of 320 matched PK-ECG 
pairs to evaluate the relationship between palbociclib exposure and ECG variables (RR 
interval and QTc). Following administration of a therapeutic regimen of 125mg palbociclib QD 
in combination with 2.5 mg letrozole QD, the observed plasma concentrations of palbociclib 
had a median (range) of 88.0 (14.7-210) ng/mL in the PK-ECG matched data. The average 
heart rate, RR interval, QT interval, QT interval corrected for heart rate according to Bazett 
(QTcB), QT interval corrected for heart rate according to Fridericia (QTcF), and QTcS (QT 
interval corrected for heart rate according to a studyspecific correction factor) at baseline for 
PK-ECG matched data were 76.0 beats per minute, 811 msec, 384 msec, 429 msec, 413 msec, 
and 415 msec, respectively. The results of the analysis indicated that palbociclib did not 
appear to have a concentration dependent effect on the heart rate. A slight positive linear 
relationship was observed between palbociclib concentrations and QTcS; however, at the 
mean or median steady-state palbociclib Cmax following administration of the recommended 
clinical dose of Palbociclib (125 mg QD) in patients with cancer, the predicted upper bound of 
the 1-sided 95% CI for the increase in QTcS was less than 10 msec. Palbociclib, when added to 
letrozole, did not prolong the QT interval to a clinically relevant extent at the recommended 


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dosing regimen according to the criteria described in the ICH guidance for Industry E14 (ICH 
E14). Similar results were obtained when QTcF and QTcB were used. 
 
6.3.5 Palbociclib Dose Rationale 
Palbociclib has been tested in a Phase 1 dose escalation Study (A5481001) in 74 patients with 
advanced cancer. Two dosing schedules were evaluated: Schedule 3/1 (3 weeks on 
treatment/1 week off treatment) and Schedule 2/1 (2 weeks on treatment/1 week off 
treatment). 
All DLTs observed in this study were related to myelosuppression and mainly consisted of 
Grade 3 neutropenia lasting more than 7 days after the end of the treatment cycle.  
However, neutropenia was reversible and non-cumulative.  Other most common adverse 
events included fatigue, anemia, diarrhea, constipation, vomiting and dyspnea, all with mild 
to moderate severity. At the MTD, a greater proportion of patients on the 200 mg QD, 2/1 
schedule had treatment-related TEAEs during and after Cycle 1 than patients on the 125 mg 
QD, 3/1 schedule although the proportion of patients with treatment-related neutropenia 
was similar with respect to the 2 dosing schedules, both during and after Cycle 1.  One partial 
response was reported in a patient with testicular cancer. A total of 13/37 patients treated 
with Schedule 3/1 evaluable for efficacy experienced stable disease (SD), including 6 patients 
with SD lasting 40 weeks or longer. One of these patients was a woman with ER+ breast 
cancer who had previously received 7 lines of treatment for her disease. This patient 
remained on treatment for 80 weeks (7 cycles at 50 mg/d and 13 cycles at 75 mg/d) and 
eventually discontinued treatment due to disease progression. Based on the relatively 
improved safety profile of Schedule 3/1, and the efficacy results from this study, the 
Schedule 3/1 has been selected for further clinical development and the RP2D for this 
schedule was determined to be 125 mg/d. This schedule and associated RP2D was further 
explored in combination with letrozole in the Phase I/II study in patients with ABC described 
below.  
6.3.6 Phase I/II Data in Combination with Letrozole in Advanced Breast Cancer 
Based on the preclinical evidence that palbociclib is highly active in ER(+) cell lines and the 
encouraging safety and PK profiles observed in the initial clinical studies, a randomized, 
multicenter active-controlled Phase 1/2 Study (A5481003) was designed to assess the 
efficacy, safety and pharmacokinetics of letrozole 2.5 mg QD (continuously) in combination 
with palbociclib 125 mg QD (schedule 3/1) versus single agent letrozole 2.5 mg QD 
(continuously) for the first-line treatment of ER(+), HER2 (-) advanced breast cancer in 
postmenopausal women. Letrozole was selected as the active control based on its worldwide 
approval and use as standard of care for the first-line hormonal treatment of 
postmenopausal women with ER(+) advanced breast cancer. 
Study A5481003 was comprised of a limited Phase 1 portion, aimed at confirming the safety 
and tolerability of the combination and excluding a PK interaction with the combination, and 


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a randomized Phase 2 portion aimed at evaluating the efficacy and safety of letrozole in 
combination with palbociclib when compared to letrozole alone in the first-line treatment of 
postmenopausal patients with ER(+), HER2(-) advanced breast cancer. The Phase 2 portion 
consisted of 2 parts.  In Part 1, patient selection was based only on ER/HER2 status.  In Part 2, 
patients were prospectively selected also taking into account tumor CCND1 amplification 
and/or p16 loss. In May 2012, 177 patients have been enrolled in this study and enrollment is 
closed.  Twelve (12) were enrolled in the Phase 1 portion and 165 (66 and 99 in Part 1 and 
2, respectively) were enrolled in the Phase 2 portion. 
Results from the Phase 1 portion,85 indicated no PK interaction between palbociclib and 
letrozole with mean AUC(0-24) of 2002 and 2043 ng•hr/mL (n=11) for palbociclib in the 
absence and presence of letrozole, respectively, and 1990 and 1730 ng•hr/mL (n=10) for 
letrozole in the absence and presence of palbociclib, respectively. The RP2D was determined 
to be 125 mg QD on Schedule 3/1 (3 weeks continuous treatment followed by 1 week off 
treatment) in combination with letrozole 2.5 mg QD continuously. Partial responses were 
reported for 3 (33%) out of 9 patients with measurable disease (3 had bone-only disease).  
Another 5 patients (42%) had stable disease for ≥ 6 months and the clinical benefit rate (PR + 
SD ≥ 6 months) was 67%. Eight (8) patients discontinued from the study due to disease 
progression, including 2 patients with clinical progression, 1 patient withdrew consent and 
3 patients are still ongoing.  
Two (2) interim analyses for the Phase 2 portion of the study have been conducted. The 
results of the interim analyses showed consistent trend of clinically meaningful 
improvements in progression-free survival (PFS; primary endpoint). In the first interim 
analysis (Part 1; N=66), the median PFS for the PD 0332991 plus letrozole arm was 18.2 
months  versus 5.7 months for the letrozole alone arm (HR=0.35; 95% CI: 0.17, 0.72; 
p=0.006). The second interim analysis (N=165) continued to demonstrate a statistically 
significant improvement in PFS (26.1 vs. 7.5 months, respectively; HR=0.37; 95% CI: 0.21, 
0.63; p <0.001).   
The combination of palbociclib plus letrozole was generally well tolerated with safety profile 
similar to palbociclib as a single agent. The most frequently reported treatment-related 
adverse events included neutropenia, leukopenia, anemia, and fatigue. There were febrile 
neutropenia reported to date in this study. Overall, 8 patients in the combination arm were 
discontinued from the study treatment due to an adverse event, of which 5 were considered 
treatment-related (grade 3 neutropenia [n=4] and ischemic colitis) and 1 patient from the 
letrozole alone arm.   
These results indicate that the combination of palbociclib with letrozole is well tolerated with 
AEs similar to those seen with either palbociclib or letrozole when administered alone. 
Additionally, the combination demonstrated antitumor activity which was consistent with 
the sensitivity of ER(+) breast cancer observed in the preclinical models. 


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6.3.7 Combination with other endocrine agents 
Palbociclib and Tamoxifen: 
The potential for a DDI between palbociclib and tamoxifen is considered to be probable. 
Multiple enzymes are responsible for the metabolism of tamoxifen and its active metabolites 
including CYP3A4, CYP2C9, and CYP2D6. In vitro evidence suggest that tamoxifen and one of 
its primary active metabolites, 4-hydroxy-tamoxifen, are inducers of CYP3A4 enzymes. In 
clinical trials, co-administration of tamoxifen with letrozole and anastrozole (both CYP3A4 
substrates) has resulted in decreased exposures (AUC) of each by 37% and 27%, respectively. 
Palbociclib is aCYP3A4 substrate and CYP3A4 is thought to be the primary route of the 
oxidative metabolim of pabociclib. Thus, the co-administration of tamoxifen and palbociclib 
may lead to lower circulating levels of palbociclib and require an upward dose adjustment in 
palbociclib if these two compounds are used in conjunction. Additionally, time-dependent 
inhibition of CYP3A4 has been observed in preclinical studies of palbociclib. 
A fixed-sequence 2-period crossover drug-drug interaction (DDI) study to assess the effect of 
steady-state levels of tamoxifen and its active metabolites on the pharmacokinetics of single 
dose palbociclib in healthy volunteers was conducted to rule out a need for palbociclib dose-
adjustments when used in conjuction with tamoxifen. The effect of multiple dosing of 
tamoxifen (60 mg QD for 4 days followed by 20 mg QD for 23 days), on the single-dose PK of 
palbociclib (125 mg), was evaluated in 25 healthy fasted subjects in Study A5481026.  
Administration of palbociclib in the presence of tamoxifen and its metabolites (4-hydroxy-
tamoxifen, N desmethyl tamoxifen, and 4 hydroxy N desmethyl tamoxifen) at steady state 
showed that palbociclib exposure was comparable with that when palbociclib was given 
alone. The ratios (90% CIs) of the adjusted geometric means of palbociclib AUCinf and Cmax 
were 108% (104% 111%) and 116% (105% 129%), respectively, following administration of 
palbociclib with multiple doses of tamoxifen (Test) relative to palbociclib administered alone 
(Reference). These results indicate that it is not necessary to adjust palbociclib starting dose 
when coadministering with tamoxifen. 
 
Prior to opening the PENELOPEB Study, the pharmacokinetics of a single oral dose of 
midazolam, a sensitive CYP3A4 substrate, with and without palbociclib dosed to steady-state 
will be assessed in a healthy volunteer DDI study (A5481012). The results of this study have 
been communicated and are detailed in Section 6.3.3. 
 
Palbociclib and anastrozole: 
The potential for a clinically significant DDI between palbociclib and anastrozole is considered 
to be low. Anastrozole inhibited CYP1A2, 2C8, 2C9, and 3A4 in vitro with Ki values ~30-fold 
higher than the steady-state Cmax values observed following a 1mg daily dose. 
In vitro and in vivo assessments of oxidative metabolism have indicated the route of 
formation of the primary metabolite hydroxyanastrozole is predominantly through CYP3A4.  


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Time dependent inhibition of CYP3A4 has been observed in in vitro studies of palbociclib, 
thus palbociclib has the potential to inhibit the primary clearance pathway of anastrozole. 
Palbociclib and Goserelin: 
The potential for a clinically significant DDI between palbociclib and goserelin is considered to 
be very low. Goserelin is a synthetic decapeptide analogue of gonadotropin releasing 
hormone (GnRH) whose primary route of elimination is the cleavage of C-terminal amino 
acids followed by renal excretion. PK data from Study A5481023 was analyzed to evaluate 
the potential for DDIs between palbociclib and fulvestrant, as well as between palbociclib 
and goserelin, at steady-state. These data indicate a lack of any clinically relevant DDIs 
between palbociclib, fulvestrant, and goserelin when administered in combination.  
The concurrent administration of goserelin did not have clinically relevant impact on the 
plasma PK of palbociclib in Study A5481023. Statistical comparisons of the palbociclib within-
subject mean steady-state Ctrough in the presence and absence of goserelin, both ignoring 
(ANOVA) and accounting for (ANCOVA) demographic differences between the treatment 
groups, confirmed the lack of a clinically significant DDI. The adjusted geometric mean ratios 
ranged from 88.3% to 93.1%, which are not considered clinically relevant. 
Likewise, the concurrent administration of palbociclib did not have a clinically relevant 
impact on the plasma PK of goserelin in Study A5481023. Statistical comparisons (ANOVA) of 
the goserelin within-subject mean steady-state Ctrough in the presence and absence of 
palbociclib confirmed the lack of a clinically significant DDI. The adjusted geometric mean 
ratio was 110%, which is not considered clinically relevant. 
Therefore, there is no clinically relevant DDI between palbociclib and goserelin when the 
two drugs are coadministered. Further pharmacokinetic data will be collected from the initial 
cohorts of 24 participants of the PENELOPEB study each receiving eitherpalbociclib and 
tamoxifen, palbociclib and anastrozole, or palbociclib and goserelin and tamoxifen (see 
Section 13.3 for details). These data will be used to explore the potential for DDIs between 
antihormonal agentsand palbociclib and the result will be used to inform dose adjustment if 
necessary at the PK stop. 
 
6.3.8 Long Term toxicity data  
In order to assess the potential for cumulative toxicity with long term administration of 
palbociclib, an analysis of commonly reported adverse events (neutropenia, leukopenia, 
fatigue, anemia, nausea, arthralgia, alopecia, diarrhea, hot flush) using time interval analysis 
(0-6m, 6-12m, 12-24, and >24m) was performed in Study A5481003 (N=83).  This analysis did 
not show any evidence of cumulative or long-term toxicity with prolonged exposure, since 
there was an almost universal reduction in reporting frequency for these events as treatment 
duration increased.  An additional analysis was done looking at the cumulative percentage of 
reports received following one year, two years, and following any duration of dosing.  This 
analysis indicated that for virtually all adverse events examined (alopecia, anemia, arthralgia, 
asthenia, decreased appetite, diarrhea, dyspnea, epistaxis, fatigue, hot flush, leukopenia, 


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nausea, neuropathy peripheral, neutropenia, pyrexia, stomatitis, thrombocytopenia, URTI, 
and vomiting), the incremental increase of reported events following the initial year of 
exposure was marginal.  Based on these analyses, there does not appear to be any evidence 
of cumulative toxicity.  Long term administration of palbociclib for 2 years and beyond does 
not appears to be associated with an increased rate of adverse events.   
 
7. 
RATIONALE OF THE STUDY 
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) 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 HR-positive/HER2-normal tumors from the 
German neoadjuvant studies’ meta-database. 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.,  
PD-0332991 (palbociclib) is an oral, highly selective inhibitor of CDK4/6 kinase activity that 
prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 to S 
phase through blocking retinoblastoma (Rb) phosphorylation. Preclinical studies identified 
luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 
expression as being associated with sensitivity to palbociclib.  
Final results from a randomized phase II study (Paloma-1/TRIO-18)  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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8. 
DISCUSSION OF THE STUDY DESIGN 
8.1 
Control Treatments 
For patients with residual disease after neoadjuvant chemotherapy no specific alternative 
treatment is recommended except the use of 5-10 years of hormonal agents (tamoxifen, 
aromatase-inhibitors, LHRH agonists). As patients must have received an adequate 
cumulative dose and cycles of chemotherapy before surgery (except for those with tumor 
progression where broad resistance against chemotherapy has to be postulated), no 
additional post-operative chemotherapy is considered indicated. There are no new agents 
that are proven to help improve the outcome in this group of high risk patient. It therefore 
appears reasonable to use a placebo to palbociclib as control treatment. 
8.2 
Washout Periods and carry over Effects 
Based on the available pharmacokinetic data showing a half-life of 27 hours, palbociclib 
should be completely washed out within a period of 7 days. Patients should therefore not 
have elective surgery or new cytotoxic treatment started within this time period after last 
intake of palbociclib. 
8.3 
Selection of Study Population 
The study population was initially selected based on the biological subtype of breast cancer 
as available efficacy data for palbociclib is restricted to patients with HR-positive/HER2-
normal metastatic breast cancer. For patients with this subtype pathological complete 
response after neoadjuvant chemotherapy per se does not provide clinically relevant 
prognostic information. Therefore, a clinical score based on tumor stage before and after 
neoadjuvant chemotherapy, estrogen-receptor status and grade (CPS-EG score) was chosen 
as an enrichment strategy to select patients at highest risk for relapse despite continued 
adjuvant endocrine therapy.1,12 The score was developed and validated by the MD Anderson 
Hospital, Houston, USA, as a prognostic tool to calculate risk of relapse after neoadjuvant 
chemotherapy in all types of breast cancer, and was strongly correlated with prognosis in the 
hormone-receptor-positive subtype as well. However, validation of the score in 2454 patients 
with only HR-positive, HER2-normal disease from neoadjuvant studies of the German Breast 
Group/AGO-Breast group86, confirmed the prognostic value in the subset of patients targeted 
in this trial. The CPS-EG score allows isolation of a population of patients at increased risk of 
early relapse and allows to isolate a population of patients in whom testing of a new agent is 
indicated. This clinically driven selection approach allows further characterization of the 
tumors into subsets of molecularly different diseases using prospectively defined markers. 
This approach is thought to help to potentially further determine the specific, biomarker 
defined population of patients in whom use of palbociclib would be indicated.   


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8.4 
Rationale for Biomarker Assessment 
Today neoadjuvant therapy is considered a model to learn not only about the biology of 
breast cancer and drug effect in general, but also about the treatment sensitivity of an 
individual patient’s tumor. Tumor core biopsy before treatment allows biological 
characterization of the tumor and development of an individual treatment plan. After 
completion of neoadjuvant treatment, histological examination of the surgically removed 
breast and axillary tissue allows precise assessment of tumor response and characterization 
of residual, likely treatment-resistant disease. It also allows confirmation of the presence of 
initially diagnosed subset, as it is known that in rare cases a loss of hormone receptor or 
acquisition of HER2 can be found.8788 
The availability of both the initial diagnosis tissue and most importantly the residual tumor 
tissue for all patients at the time of entry to the PENELOPEB trial provides an opportunity to 
confirm the diagnosis before randomization and compare the molecular profile with the 
tissue from original diagnosis. It also allows prospectively testing of important hypotheses 
regarding the use of the CDK4/6 inhibitor, palbociclib, in combination with anti-hormonal 
therapy in the adjuvant setting. It is believed that the large number of markers analyzed in 
the tissue before entry to the trial will render precious information regarding both anti-
hormonal and palbociclib treatment sensitivity and resistance. The markers will allow for 
further sub-classification of the disease into luminal A and luminal B as well as RB-positive 
and RB-negative disease and define amplification and overexpression of genes and proteins 
relevant to the CDK4/6-related pathway. Further, access to tissue at the time of original 
diagnosis will allow a reference to a pre-chemotherapy status of the tumor.  
Based on the data from the metastatic HR+ breast cancer, almost uniform presence of intact 
Rb in HR+ breast cancer and  known CDK4/6 role in estrogen stimulated proliferation of 
breast cancer, it is hypothesized that all patients in PENELOPEB will derive benefit from 
addition of palbociclib. Hence the primary endpoint is iDFS in the intent-to-treat (ITT) 
population.  However, data set for assessment of markers of sensitivity is available in the 
metastatic breast cancer settings only. The data set is small to date and the preclinical 
studies evaluating the CDK4/6 related pathway are complex. Hence, a definitive prospective 
selection is not supported by available data and would be premature at this time. Therefore, 
certain specific secondary hypotheses, prospectively defined in statistical analysis plan, will 
be conducted to optimize understanding of possible patient subgroups benefit/risk effects 
based on measurable biological criteria.     
As the population eligible for PENELOPEB trial is heterogeneous with regard to molecular 
subtypes of HR+ cancer, these tests will further stratify patients with respect to both 
biomarkers related to RB pathway alteration and a pre-planned subgroup analysis of luminal 
B patients (based on a at the time of analysis (which will be around the final efficacy analysis) 
commercially available CE-marked tests (e.g. PAM50, EndoPredict® or any other newly 
available test) will be conducted.  


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The prospective hypotheses will be described in detail in the study statistical analysis plan.  
This approach is expected to lead to determination of specific subpopulation(s) in which 
palbociclib would demonstrate enhanced efficacy (eg, luminal B as assessed by PAM50), or a 
specific prognostic group or specific molecular alterations (eg, cyclin D1 overexpression or 
amplification or others) for whom the benefit/risk of palbociclib would be even greater. It is 
expected that this enhanced benefit/risk profile in a subpopulation of early breast cancer 
HR+/HER2 normal patients would be reflected in the indication and/or conveyed in the 
product labeling. It is understood that during the study conduct, new information might 
emerge related to important markers in the RB pathway, and these markers will be 
incorporated prospectively into the statistical analysis plan before unblinding or analyzing 
this study. 
The prospectively defined hypotheses are important as the understanding of the CDK4/6 
driven pathway in breast cancer is currently incomplete.  Hence, palbociclib may lead to a 
significant improvement of iDFS with a moderate toxicity profile, but the treatment effect 
may be limited to, or predominantly seen in prospectively hypothesized subgroups, both at 
the time of diagnosis and at study entry.  This assumption could support a recommendation 
that 1-year treatment with palbociclib in combination with endocrine therapy is indicated for 
patients with HR-positive/HER2-normal disease in the prespecified biomarker subgroups at 
high relapse risk. 
Hypotheses to be tested in tumor samples from core biopsy at diagnosis and surgery: 
 It is hypothesized that tumors with alterations in RB/CDK4/6 pathway are more sensitive 
to the combination of anti-hormonal therapy and palbociclib.  The molecular 
alterations are characterized by presence of pRB1 (or total RB1) alone or in combination 
with one of the following: e.g. overexpression or amplification of cyclinD1 (CCND1), 
CDK4, CDK6; absence of p16 or loss of CDKN2A 
 It is also hypothesized that luminal B, higher risk population would achieve largest 
prolongation of iDFS; hence luminal B tumors or other high risk profile (defined by 
PAM50, Endopredict® or any other commercially available test at the time of analysis), at 
the time of diagnosis or after chemotherapy would be predictive of enhanced palbociclib 
benefit.  
The rationale for the second hypothesis is briefly summarized here: Genetic aberrations 
leading to hyperactivation of cyclin D1-CDK4/6 are particularly common in ER+ breast cancer, 
consistent with its critical role in the tumorigenesis of this cancer subtype.89,90  CCND1 
amplification and cyclin D1 overexpression correlates positively with ER+ status 91,92,93,94 and 
is an independent poor prognostic factor in women with ER+ disease who received adjuvant 
tamoxifen therapy.95 The recent report from The Cancer Genome Atlas (TCGA) project 
indicated that poorer prognosis ER+ disease (luminal B) is preferentially enriched with gene 
amplification of cyclin D1 (luminal A: 29%, luminal B: 58%), and CDK4 gain (luminal A 14%, 
luminal B 25%).96 Importantly RB1 (Rb), which is required for the activity of CDK4/6 


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inhibitors, is wild type in most luminal/ER+ breast cancers (unlike ER- disease), making 
CDK4/6 inhibitors particularly attractive agents for ER+ breast cancer. 
The TCGA breast cancer study also showed low levels of RB1 mutations in luminal-type breast 
cancer (∼1%) and frequent amplification of cyclin D1 (40%).97 
The cyclin D1/CDK4/6 complex phosphorylates the retinoblastoma (Rb) protein, which leads 
to cell-cycle activation.98 Results from several studies indicate that CDK4 and CDK6 play an 
important role in estrogen-stimulated proliferation of breast cancer cells in early to mid G1 
phase. 99 100 101 102 103 Thus, CDK4 and CDK6 represent valuable therapeutic targets of ER+ 
advanced breast cancer104. Consistent with this conclusion, high levels of expression of the 
Rb-regulated E2F gene family is a frequent feature of endocrine-resistant luminal-type breast 
cancer. Unlike basal-like breast cancers, in which Rb loss is common105, inhibition of the 
critical cell-cycle inhibitory effect of Rb in luminal tumors is achieved primarily through 
overexpression or amplification of cyclin D1, overexpression or amplification of CDK4, and/or 
loss of the CDK inhibitors CDKN1B, CDKN2A, and 2B. 106,45 Luminal tumors are therefore 
likely to prove sensitive to CDK4/6 inhibitors as randomized Phase 2 trials are under way 
(NCT00721409), 107and a preliminary report of a randomized trial of letrozole versus letrozole 
plus palbociclib at the 2012 IMPAKT meeting in Brussels and San Antonio Breast Cancer 
meeting in December 2012 
108showed significant improvement in progression-free 
survival.109  Interestingly, mantle cell lymphoma, another chemotherapy-refractory cyclin D–
driven malignancy, is also sensitive to CDK4/6 inhibition. 110Basal-like tumors, and occasional 
luminal B tumors, harbor loss or mutation in Rb and are therefore highly unlikely to be 
responsive to these agents; thus, determination of the mode of Rb pathway inactivation will 
be critical to the success of CDK 4/6 inhibitors in breast cancer.111 
8.5 
Removal of Patients from Therapy or Assessment 
Patients with progressive disease, medical or subjective intolerability of toxicity, or lack of 
compliance will be removed from the treatment with palbociclib or placebo. However, the 
investigators are asked to continue medical treatment as closely as possible to the guidelines 
given by the protocol. These patients will be followed up for relapse and toxicity as long as 
the patient does not withdraw her consent. 
8.6 
Blinding 
The allocation of patients to either palbociclib or placebo will be blinded to patients and 
investigators. Neither the Investigator nor the Sponsor will have access to the individual data 
for the primary efficacy parameter obtained after the baseline visit in each patient. However, 
the Independent Data Monitoring Committee (IDMC) will review the blinded data for the 
safety and primary efficacy parameter in overall descriptive statistics during data review 
meetings. The descriptive statistics for use in any data review meeting will be generated by 
the GBG statistician/programmer. Only at the reasonable request of the IDMC, unblinded 
safety and/or efficacy results will be presented. The analysis will be conducted by an 


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independent GBG statistician, who is not involved in the study operation and execution. The 
DDI assessment will be conducted by Pfizer and supplied to the IDMC. The procedure for 
unblinding data to use for analysis of DDI assessment by the core laboratory will be described 
in the PK unblinding plan. 
8.7 
Rationale for the duration of treatment 
Duration of treatment was determined by the time considered acceptable for patients having 
received neoadjuvant chemotherapy based on the available safety profile and experience 
with palbociclib. As the annual risk of relapse appeared to be stable over at least 5 years, an 
optimal duration of treatment could not be identified based on the relapse profile and a year 
of treatment was chosen arbitrarily. 
8.8 
Treatment Compliance 
Compliance is monitored by a patients’ diary recording date and time of capsules intake as 
well by counting the number of capsules brought back by the patient before starting the next 
cycle. This information will be documented in a summarized form in the electronic data 
capturing system (e-CRF). 
No laboratory tests for compliance will be used. 
8.9 
Appropriateness of the Primary Efficacy Variable 
The primary endpoint of this protocol, iDFS, is defined according to a recent position / paper 
of Hudis C et al.112 In this paper it is stated that: “Overall survival has been recognized as the 
least ambiguous and most clinically relevant clinical end point in clinical trials of cancer 
therapy. However, in evaluating postoperative treatment for stage I, II, and IIIA breast cancer 
where all identifiable tumor has been resected, disease-free survival is frequently employed 
as a surrogate.“ 
Nevertheless, follow up of patients will continue for further 3 years after the required events 
for the final iDFS analysis has been observed as this will allow to adequately determining the 
effect of palbociclib on overall survival. As the final efficacy analysis will be conducted after 
the last patient stopped treatment with palbociclib, cross-over is not expected to occur. 
However, during the conduct of the study, palbociclib has received market approval for the 
treatment of metastatic breast cancer in some countries, therefore some patients in the 
control arm as well as in the palbociclib arm) might be (re-)treated with palbociclib after 
relapse.   
8.10 
Risk-benefit Analysis for the Participants 
All study participants must have received a standard taxane-containing neoadjuvant 
chemotherapy using regimes comparable to those currently used as adjuvant treatment, 
adequate surgery, as well as radiotherapy, if indicated. All patients will also receive adjuvant 


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endocrine treatment according to institutional standards. It is not expected that toxicity of 
palbociclib will reduce compliance with endocrine treatment. As currently no other kind of 
treatment is recommended for this subtype of breast cancer, under-treatment of study 
participants can be excluded.  
Data of a large randomized phase II metastatic breast cancer trial (A5481003) showed a 
prolongation of median progression-free survival by palbociclib of 10.0 months 
corresponding to a hazard risk ratio of 0.49. Median progression free survival increased from 
10.2 months for patient treated with letrozole alone to 20.2 months for patients treated with 
the combination of letrozole, The toxicity profile of palbociclib at the dose and schedule 
similar to the one that will be used in the PENELOPEB study, was moderate with neutropenia 
being the most frequent treatment related adverse event.  The clinical picture of neutropenia 
seen with the palbociclib/letrozole combination in A5481003 is notable for being quickly 
reversible, noncumulative and uncomplicated and managed without the use of growth 
stimulating factors. In fact, the majority of patients have discontinued from this randomized 
165 patient study due to disease progression rather than from adverse events.  While the 
neutropenia seen in the A5481003 advanced breast cancer setting has been managed using 
dose modifications, this has resulted in a high rate of dose interruptions (70%).  In the early 
breast cancer setting to help mitigate this on target toxicity, a more aggressive dose 
reduction algorithm will be employed. 
Data on cumulative toxicities seen with 1 year of palbociclib treatment as well as late 
toxicities after treatment discontinuation is available on >300 patients, and further data is 
being collected in a large clinical trial program in parallel to this study.  
As described before, there are no obvious differences in the clinical and laboratory safety 
profile between patients taking palbociclib for less than 12 months compared to those taking 
the compound for 12 months or longer based on data collected in clinical studies to date. It is 
concluded that the data available do not identify any safety concerns associated with long 
term administration of palbociclib. 
In addition, participating patients in the current trial will have marginal additional burden 
due to investigations required for study participation (e.g. additional visits at the site, 
additional blood tests, additional ECGs, and completion of questionnaires). However, the 
option to receive a treatment potentially significantly improving iDFS in this high-risk 
population is considered to balance uncertainties of the toxicity profile of palbociclib and the 
additional burden related to study investigations. 
8.11 
Interpretation of Potential Study Results 
Four scenarios of results can be envisaged which will lead to the following conclusions: 
 Palbociclib will lead to a significant improvement of iDFS with a moderate toxicity 
profile allowing the majority of patients to receive treatment at planned dose and 
schedule. This will support a recommendation that one year treatment with 


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palbociclib in combination with endocrine therapy is indicated for patients with HR-
positive/HER2-normal disease at high relapse risk. 
 Palbociclib will lead to a significant improvement of iDFS, but compliance with 
treatment 
is 
significantly 
impaired 
by 
toxicities. 
This 
might 
support 
a 
recommendation that one year treatment with palbociclib should be considered for 
selected group of patients with HR-positive/HER2-normal disease (e.g. at very high 
relapse risk, or based on predictive markers investigated in this study). Other doses 
and schedules will likely need to be explored. 
 Palbociclib will lead to an overall significant improvement of iDFS with a moderate 
toxicity profile, but the treatment effect is limited to or predominantly seen only in 
prospectively hypothesized subgroups in which palbociclib is at planned dose and 
schedule. This will support a recommendation that one year treatment with 
palbociclib in combination with endocrine therapy is indicated for patients with HR-
positive/HER2-normal disease in the relevant subgroups at high relapse risk. 
 Palbociclib does not significantly improve iDFS in the study population. No 
recommendation will then be made to use this compound in this setting outside of 
clinical trials.  
 
9. 
STUDY OBJECTIVES 
9.1 
Primary Objectives 
To compare invasive disease free survival (iDFS) for palbociclib vs. placebo in 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. 
9.2 
Secondary 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  


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 
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) 
 
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.  
 
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) 
 
10. 
STUDY DESIGN 
This is a prospective, international, multicenter, randomized, double-blinded, placebo-
controlled, parallel-group Phase III study comparing the 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: 


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 
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. 
 
11. 
STUDY POPULATION 
11.1 
Number of patients 
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. 
11.2 
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. 


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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. 
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 a taxane -containing neoadjuvant therapy (Exception: 
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 lymphnode dissection. Histologically complete resection (R0) of the 
invasive and ductal in situ tumor is required in case of breast conserving surgery as the 
final treatment. No evidence of gross residual disease (R2) is required after total 
mastectomy (R1 resection is acceptable). Axillary dissection is not required in patients 
with a negative sentinel-node biopsy before (pN0, pN+(mic)) or after (ypN0, ypN+(mic) 
neoadjuvant chemotherapy. 
9. Less than 16 weeks interval since the date of final surgery and date of randomization 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 ER 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 0). 
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). 


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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. 
11.3 
Exclusion Criteria 
1. Known severe hypersensitivity reactions to compounds similar to palbociclib or 
palbociclib/placebo excipients or to endocrine treatments. 
2. Inadequate organ function 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. 
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. 


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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 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. 
11.4 
Removal of Patients from Study 
11.4.1 
Drop-outs without treatment 
This study is conducted according to the principle of intent-to treat.  
Drop-outs without treatment are defined as those patients who have been randomized in the 
study but withdrew their consent or are withdrawn by the investigator from the study 
immediately thereafter but prior to first application of study medication. The reasons are 
collected and reported in the Consort Statement. Such patients are to be included in the 
intent-to-treat analysis and will not be replaced. 
11.4.2 
Premature Treatment Discontinuation 
Patients who have been randomized and have received study medication and, for whatever 
reason, did not participate throughout the entire study are classified as premature treatment 
discontinuation. 
Patients may discontinue study treatment at any time. Reasons for discontinuation must be 
documented in the case report form (eCRF) and in the patient’s medical records. 
Investigators must attempt to contact patients who fail to attend scheduled visits by 
telephone, letter, visit, etc., to exclude the possibility of an adverse event being the cause. 
Should this be the case, the adverse event must be documented, reported and followed-up 
as described in Section 17. A final examination should be performed if possible on each 
discontinuation. Patients should receive off study treatment as close as possible to the 
protocol. Treatment and outcome should be documented on the CRFs. In case a patient 
withdraws her consent for future data collection the CRFs have to be completed until the 
date of withdrawal. 
 
12. 
STUDY TREATMENT 
12.1 
Method of assigning patients to treatment group 
After a patient has completed the necessary screening visit procedures, the corresponding 
baseline CRFs have to be completed using the electronic data capturing MedCODES® 


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application. Central histologic assessment has to confirm an eligible tumor subtype 
(HR+/HER2-) as well to provide results of the biological stratification factors in a MEDCODES® 
interface. Eligibility of the patient will be checked and approved by GBG staff before 
randomization. 
Patients will be randomly assigned to one of the two arms (palbociclib or Placebo) in a 1:1 
ratio using a computerized system. Assignment will be stratified by the predetermined 
factors (see Section 10) using block randomization created by an independent GBG 
statistician not involved in the study conduct. Details of the computerized system procedure 
will be provided in the computerized system Site Manual. All data are collected and stored 
using the MedCODES® application.  
Randomization should occur no more than 6 business days before administration of the first 
dose of investigational product. The site will receive confirmation of randomization and drug 
supply is ordered automatically via IWRS system. 
 
12.2 
Breaking the Blind by Investigator 
12.2.1 
During treatment with IMP 
At the initiation of the trial, the trial site will be instructed on the method for breaking the 
blind.  The method will be an electronic process in MedCODES®.  Blinding codes should only 
be broken in emergency situations for reasons of patient’s safety.. When the blinding code is 
broken, the date and reason for unblinding must be fully documented in source documents 
and entered on the case report form. However, every effort should be made by the site staff 
to ensure that the treatment arm in which the unblinded patient is assigned is not 
communicated to any sponsor personnel or designee involved in the conduct of the trial.  
 
12.2.2 
 After IMP treatment discontinuation 
Blinding codes may also be broken after a patient discontinues treatment due to disease 
relapse, as determined by the treating investigator using RECIST v.1.1 criteria or diagnosis of 
a second primary malignancy, but only if deemed essential to allow the investigator to select 
the patient's next treatment regimen and after discussion and agreement with GBG staff. 
Code should not be broken in the absence of  relapse of disease as per RECIST v.1.1 (e.g., in 
case of clinical deterioration, increase in tumor markers or any other evidence suggestive a 
relapse but in the absence of RECIST-defined new evidence of disease).  In case of unblinding 
after treatment discontinuation, the  “end of treatment” and “relapse form” have to be 
submitted via  MedCODES® . The investigator can then send an unblinding request to the 
GBG unblinded statistician specifying the reason for unblinding. The unblinded information 
will then be shared as password protected file via email. Every effort should be made by the 


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site staff to ensure that the treatment arm in which the unblinded patient is assigned is not 
communicated to any sponsor personnel or designee involved in the conduct of the trial. 
 
12.3 
Investigational Product 
12.3.1 
Formulation and Packaging 
 Palbociclib  
Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of 
palbociclib free base. Capsules will be supplied in HDPE bottles containing 23 capsules. The 
capsules can be differentiated by their size and color (see below). 
 
Table 1 Palbociclib/Placebo Capsule Characteristics 
Dosage 
Capsule color 
Capsule size 
75 mg 
Sunset Yellow/Sunset Yellow 
2 
100 mg  
Caramel/Sunset Yellow 
1 
125 mg 
Caramel/Caramel 
0 
 
 
 Placebo of palbociclib  
Placebo will be indistinguishable from the palbociclib capsules and will be supplied as 
capsules matching in size and color the various palbociclib formulations (see Table 1). 
Placebo capsules will be supplied in HDPE bottles containing 23 capsules.   
12.3.2 
Preparation and Dispensing 
Palbociclib/Placebo will be provided in non-patient-specific bottles. The patient number 
should be recorded on the bottle label in the spaces provided by site personnel at the time of 
assignment to patient. Site personnel must ensure that patients clearly understand the 
directions for self-medication. Patients should be given a sufficient supply to last until their 
next study visit. Unused drug and/or empty bottles should be returned to the site at the next 
study visit. Returned unused medication MUST NOT be re-dispensed to a patient.  
Palbociclib/placebo is an agent that must be handled and administered with care. Patients 
should be instructed to keep their medication in the bottles provided and not transfer it to 
any other container. Due to possible unknown hazards associated with topical and 
environmental exposure to experimental agents, capsules must not be opened and/or 
emptied into any vehicle for oral ingestion; capsules must be swallowed intact. 


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Only one capsule strength will be dispensed to the patient at each dispensing visit.  In the 
event of dose modification, request should be made of the patient to return all previously 
dispensed medication to the clinic and new capsules will be dispensed. 
12.3.3 
Administration 
Palbociclib/placebo at a dose of 125 mg will be administered orally once a day at the same 
day time for 21 days followed by 7 days off treatment of every 28-day cycle, a delay of up to 
3 days due to administrative reason is acceptable. A total of thirteen 28-day cycles should be 
administered palbociclib/placebo capsules will be administered together with endocrine 
treatment.). Patients should take Palbociclib /placebo with food. 
Patients should be instructed to swallow palbociclib/Placebo capsules whole and not to chew 
them prior to swallowing. No capsule should be ingested if it is broken, cracked, or otherwise 
not intact. Patients should be encouraged to take their dose at approximately the same time 
each day. Patients should be instructed to record daily administration of the study drugs in a 
patient diary. 
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section. 12.3.5. 
General Rules: 
 Patients who miss a day’s dose entirely (latest intake 18:00 of a day) must be 
instructed NOT to “make it up” the next day. 
 Patients who vomit any time after taking a dose must be instructed NOT to “make it 
up,” and to resume treatment the next day as prescribed.  
 Patients who inadvertently take 1 extra dose during a day must be instructed to skip 
the next day’s dose.  Also refer to Section 12.3.10 for further details on medication 
errors and overdose. 
12.3.4 
Premedication and supportive treatment 
No premedication or prophylactic supportive treatment is recommended. 
 
12.3.5 
Recommended Dose Modification 
Every effort should be made to administer study treatment on the planned dose and 
schedule. However, in the event of significant treatment-related toxicity, administration of 
investigational product palbociclib/placebo may need to be adjusted as described in the 
following sections. Depending on the nature of the toxicity observed, dosing adjustment may 
be required for just one or both study drugs in the combination.  


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In the event of significant treatment-related toxicity, palbociclib/placebo dosing may be 
interrupted or delayed and/or reduced as described below. In the event of multiple toxicities, 
dose modification should be based on the worst toxicity observed.  Patients are to be 
instructed to notify Investigators at the first occurrence of any adverse sign or symptom. 
Dose modifications may occur in three ways: 
 Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 
 Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start; 
 In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
12.3.6 
Dosing Interruptions 
Patients experiencing the following adverse events should have their treatment with 
palbociclib or palbociclib/placebo interrupted/delayed until criteria for retreatments are met 
(see 12.3.7):  
 Uncomplicated Grade 3 or 4 neutropenia (ANC<1000/mm3); 
 Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection 
or febrile neutropenia (fever 38.5C with or without infection); 
 Grade 3 or Grade 4 thrombocytopenia (Platelet count <50,000/mm3); 
 Non-hematologic toxicity persisting despite optimal medical treatment if either 
Grade 2 lasting more than 3 weeks or Grade 3 (excluding side effects likely related to 
endocrine treatment (e.g. joint pain of Grade 3) or alopecia ; 
 Grade 3 QTc prolongation (QTc ≥501 msec on at least two separate ECGs). 
 if a  patient experiences concurrent > 3xULN ALT and 2xULN  bilirubin the dose needs 
to be held while the cause is investigated.   
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. Criteria required before treatment can resume are described in 
Section 12.3.7. 
Doses may be held as needed until toxicity resolution. Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle.  
If the adverse event that led to the treatment interruption recovers within the same cycle, 
then re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the 
same cycle. The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in Section 12.3.8 unless expressly agreed otherwise following 
discussion between the investigator and GBG staff.  If a dose reduction is applied in the same 
cycle, the patient will need to return to the clinic to receive new drug supply. 


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In the event of a treatment interruption for reasons other than treatment related toxicity 
(eg, non-cancer related surgery) lasting ≥3 weeks, treatment resumption will be decided in 
consultation with GBG medical staff. 
 
12.3.7 
Retreatment 
Retreatment following treatment interruption for treatment related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met: 
 Platelet count  50,000/mm3;  
 ANC  1000/mm3 and no fever; G-CSF is not generally recommended as secondary 
prophylaxis 
 Grade 3 or higher treatment-related non-hematologic AEs considered related to 
palbociclib (including, nausea, vomiting, diarrhea, and hypertension only if persisting 
despite optimal medical treatment; not including alopecia) have recovered to Grade ≤ 
1 or baseline (or, at the investigator’s discretion, Grade ≤ 2 if not considered a safety 
risk for the patient). 
 QTc ≤500msec and potential reversible causes (eg, electrolyte imbalance, 
concomitant medications known to prolong QTc) corrected. If QTc remains above 480 
msec, a cardiologist should be consulted and ECG should be monitored more 
frequently until QTc ≤480 msec. 
If a treatment delay results from decline in hematologic parameters, the frequency of blood 
count assessments should be adjusted as clinically indicated. 
If the retreatment parameters are met within 3 weeks of treatment interruption or cycle 
delay, palbociclib/Placebo may be resumed. Please refer to Table 3 and 4 for adverse events 
requiring dose reduction at the time of treatment resumption.  
If these parameters have not been met after 3 weeks of dose interruption (including the 
scheduled 1 week off treatment) or 3 weeks of cycle delay, permanent discontinuation of 
palbociclib/Placebo treatment should be considered. Treatment resumption for patients 
recovering from treatment-related toxicity after >3 weeks of treatment interruption or cycle 
delay but deemed to be suitable to continue with a lower dose per the investigator’s best 
medical judgment is recommended but left at the investigator’s discretion. 
 
12.3.8 
Dose Reductions 
Following dose interruption or cycle delay for palbociclib/placebo toxicity, a 2 step dose 
reduction schedule is recommended, when treatment is resumed.  


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No specific dose adjustments are recommended for Grade 1 or short lasting Grade 2 
treatment related toxicity. However, investigators should always manage their patients 
according to their medical judgment based on the particular clinical circumstances. 
In case of a history of a grade 2 toxicity lasting for >3 weeks or grade 3 toxicity (both assessed 
in the presence of maximum supportive care, and as judged by investigator to be associated 
with palbociclib/placebo and to achieve easily manageable safety profile) a dose reduction is 
recommended in subsequent cycle (except for neutropenia, alopecia). For details please refer 
to Table 3 and 4. Dose reduction of palbociclib/placebo by 1 and, if needed, by 2 dose levels 
(Table 2) is recommended depending on the type and severity of toxicity encountered. In 
addition a break on day 10-12 or a prolonged holiday of up to 2 weeks after 2 weeks of 
treatment are further options to modify dose according to tolerability (if in investigator 
judgment such schedule is manageable and preferred). Taking palbociclib according to 
recommendation (with food) needs to be reinforced and checked. Alternatively patient will 
be discontinued from the study and entered into the follow-up phase of the study. All dose 
modifications/adjustments must be clearly documented in the patient's source notes and 
Investigational product administration CRF.  
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that same reduced dose level, unless further dose reduction is required.  
Dose re-escalation is not allowed. 
Table 2 Available Dose Levels 
 
Dose Level  
palbociclib/placebo for 3 out of 4 
weeks (3/1 schedule) 
Starting dose 
125 mg/d 
-1 
100 mg/d 
-2 
75 mg/d* 
Discontinue Study Treatment or consider 75mg/d 2/2 
schedule 
 
* Palbociclib/placebo dose de-escalation below 75 mg/d is not allowed the schedule may move to 75mg/day 
two weeks on followed by two weeks 
 
 
 
 
 
 


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Table 3:  
Palbociclib/placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal Medical Treatment. 
Toxicity 
1st episode 
2nd episode 
Subsequent 
episodes 
Uncomplicated Grade 3 neutropenia 
(ANC 500 to <1000/mm3) with recovery 
to ≤ Grade 2 until planned D1 of next 
cycle 
Same dose 
level (DL) 
Same DL 
Same DL 
Uncomplicated Grade 3 or 4 
neutropenia  without recovery  to          
≤ Grade 2 at planned D1 of next cycle 
Uncomplicated grade 4 neutropenia 
(ANC  <500/mm3) with recovery to  
≤ Grade 2 until planned D1 of next cycle 
Reduce to 
Dose Level-1 
(DL-1) 
DL-1 and 
break from 
day 10-12  
DL-2 and break 
from day 10-12 
Next episode 
stop or continue 
with 2 weeks 
treatment and 2 
weeks holiday 
Neutropenia grade 3 or 4 associated 
with a documented infection ; 
Febrile neutropenia 
Thrombocytopenia grade 3 or 4 
DL -1 and 
either break 
from day 10-12 
or 2 week drug 
holiday 
DL -2 and 
either break 
from day 10-
12 or 2 week 
drug holiday 
Stop 
Any grade 2 toxicities for more than 3 
weeks (except for neutropenia or 
alopecia) 
DL-1 
DL-2 
Stop 


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Non-hematologic toxicity grade 3 or 4 
(including, nausea, vomiting, diarrhea, 
and hypertension only if persisting 
despite optimal medical treatment; non-
including alopecia) 
DL-1    
Consider break 
from day 10-12  
Consider DL-2 
for 2 weeks or 
2 weeks 
holiday if 
recovery is 
delayed 
DL-2 
Consider 
break from 
day 10-12 
Consider DL-2 
for 2 weeks 
or 2 weeks 
holiday if 
recovery is 
delayed 
Stop 
QT interval changes see table 4 
 
 
 
 
12.3.9 
QTc prolongation management 
In the event of QTc prolongation of >480-500 msec, possible alternative reversible causes 
such as serum electrolytes abnormalities, or usage of concomitant medications with the 
potential to prolong the QTc interval should be evaluated.  
If such reversible causes are identified, then they should be corrected accordingly (ie, 
correction of electrolyte abnormalities with supplements to within normal limits and/or 
discontinuation (if possible) of concomitant medications known to prolong the QT interval).  
Recommended dose modifications in the event of QTc prolongation are provided in  Table 4.  


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Table 4 Palbociclib/placebo Dose Modifications in the Event of QTc Prolongation 
 
 
Toxicity (NCI CTC Grade, Version 4.0) 
 
Grade 2 QTc 
prolongation 
QTc 481 - 500 ms  
Grade 3 QTc 
prolongation 
(>=501 msec) 
Grade 4 QTc 
prolongation 
(>=501 msec or >60 ms 
change from baseline 
and life-threatening 
signs incl. Torsade de 
points) 
Reversible 
cause 
identified  
Treat reversible cause  
Initiate more frequent 
ECG monitoring according 
to investigator’s best 
medical judgment until 
QTc≤480 msec  
Continue at the same 
dose level (1) 
Treat reversible cause  
Withhold treatment until 
QTc<500 msec  
Resume treatment at the 
same dose level. 
Monitor ECG more 
frequently as per 
investigator’s best 
medical judgment until 
QTc≤480 msec.   
Permanently 
discontinue 
No 
reversible 
cause 
identified 
Consult cardiologist and 
initiate more frequent 
ECG monitoring until 
QTc≤480 msec  
Continue at the same 
dose level (1) 
Consult cardiologist. 
Withhold treatment until 
QTc<500 msec  
Resume treatment at the 
next lower dose level (2) 
Monitor ECG more 
frequently as until 
QTc≤480 msec. 
Permanently 
discontinue 
(1) If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the 
absence of other alternative causes or despite correction of alternative causes, dose adjustment 
and/or discontinuation should be considered in consultation with a cardiologist and the study 
medical monitor, taking into account the emerging safety data from palbociclib trials and the 
investigator’s best medical judgment. 
(2) If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment 
and/or discontinuation should be discussed with study medical monitor in consultation with a 
cardiologist, taking into consideration the emerging safety data from palbociclib trials and the 
investigator’s best medical judgment. 
 


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12.3.10 
Medication Errors and Overdose 
Medication errors may result in this study from the administration or consumption of the 
wrong drug, by the wrong patient, or at the wrong dosage. Such medication errors are to be 
captured irrespective of the presence of an associated toxic event like an SAE on the SAE 
form.  In the event of medication dosing error, GBG should be notified immediately. 
 
12.3.11 
Compliance 
Patients will be required to return all bottles of palbociclib/placebo as well as the completed 
patient diary at the beginning of each cycle for drug accountability. Drug accountability will 
be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.  The 
number of remaining capsules will be documented and recorded.  
To be considered compliant, each study patient must have received at least 80% of the 
prescribed number of doses of palbociclib/placebo based on the number of days of actual 
dose administration. Dose adjustments must follow instructions provided in Section 12.3.4 - 
12.3.8.  
12.4 
Drug Storage and Drug Accountability 
Palbociclib/placebo capsules should be stored at controlled room temperature (15-30C, 
59-86F) in their original container. 
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements. Returned medication should be stored separately from 
medication that needs to be dispensed. 
To ensure adequate records, palbociclib/placebo capsules will be accounted for as instructed 
by GBG.  Patients are requested to return previously dispensed containers as well as their 
completed patient diary to the clinic at each visit for accountability purposes even if they will 
not be issued with new medication at that visit.  
Storage conditions stated in this protocol or in the Investigator’s Brochure (IB), United States 
Package Insert (USPI), Summary of Product Characteristics (SPC), or Local Product Document 
(LPD) may be superseded by the label storage. 
Investigators and site staff are reminded to continuously monitor room storage temperatures 
and ensure that thermometers are working correctly as required for proper storage of 
investigational products. These include thermometers for the room storage. Any 
temperature excursions must be reported immediately to GBG and documented. Once a 
deviation is identified, palbociclib/placebo MUST be quarantined and not used until GBG 
provides documentation of permission to use the investigational product.  


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At the end of the trial, GBG will provide instructions as to disposition of any unused 
investigational product. If GBG authorizes destruction at the trial site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by GBG.  Destruction 
must be adequately documented. 
12.5 
Concomitant Medications 
Patients must be instructed not to take any additional medications (including 
over-the-counter (OTC) or other products) during the study without prior consultation with 
the investigator as some herbal supplements or OTC can impact pharmacokinetics of 
palbociclib/placebo and are in the list on prohibited medications.  Any medications including 
herbal supplements, vitamins, or treatment taken by the patient from 28 days prior to the 
start of study treatment and up to 28 days following the last dose of investigational product 
and the reason for their administration must be recorded on the CRF.  
Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded.  Anesthetics used for 
any surgical procedures performed during the patient’s participation in the study can be 
recorded as “unspecified anesthesia” on the concomitant treatment records; it is not 
necessary to list the specific anesthetics.  Supportive care for cancer-related symptoms 
should be offered to all patients in this study. 
 
12.5.1 
Prohibited Medications 
The following treatments are prohibited throughout the duration of the active treatment 
phase:  
 Anticancer agents: No additional investigational or commercial anticancer agents 
such as chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy (other than tamoxifen, LHRH analogues or aromatase 
inhibitors) will be permitted during the active treatment phase. In general, any drugs 
containing “for the treatment of breast cancer” on the product insert are not 
permitted on study. 
 Strong CYP3A inhibitors/inducers: palbociclib is metabolized to multiple metabolites 
in a qualitatively similar manner in rat, dog and human liver microsomes. In vitro, 
palbociclib is primarily metabolized by CYP3A4 enzymes.  Co-administration with 
drugs that are CYP3A inhibitors and inducers may change the plasma concentrations 
of palbociclib in humans (see Section 6.3.3 for details). The concurrent use of CYP3A 
inhibitors, including amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, 
delavirdine, 
diltiazem, 
erythromycin, 
fosamprenavir, 
indinavir, 
itraconazole, 
ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and 


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grapefruit, grapefruit juice or any product containing grapefruit, are not allowed in 
the study.  The concurrent use of CYP3A inducers, including carbamazepine, 
felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, 
rifapentin, and St. John’s wort, are not allowed in the study (see also Appendix 21.3) 
 Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (eg, 
raloxifene) are prohibited during the active treatment phase. 
 
12.5.2 
Medications Not Recommended  
The following treatments are not recommended throughout the duration of the active 
treatment phase.  Alternative therapies should be considered whenever possible.  If usage of 
the following treatments is deemed necessary, consultation and agreement with GBG is 
required prior to treatment initiation.  
 Moderate CYP3A Inducers: The concurrent use of moderate CYP3A inducers such as 
dexamethasone or modafinil is not recommended.  
 Sensitive CYP3A Substrates:, As described in Section 6.3.3, palbociclib is a weak time-
dependent inhibitor of CYP3A and caution should be exercised in patients receiving 
palbociclib in combination with drugs that are predominantly metabolized by CYP3A 
and have a narrow therapeutic window. In particular, co-administration of palbociclib 
with CYP3A4 sensitive substrates with narrow therapeutic index including, but not 
limited to alfentanil, aripiprazole, cyclosporine, ergotamine, fentanyl, halofantrine, 
pimozide, quinidine, sirolimus, tacrolimus, triazolam, astemizole*, cisapride*, and 
terfenadine* (*withdrawn from U.S. market) are not recommended during the active 
treatment phase of the trial.  Alternative therapies should be used when available, 
but if use cannot be avoided the treating physician should be aware that dose 
reductions of the coadministered drug may be required.  
 Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids.  Steroids given for physiological replacement, as anti-emetics or 
inhaled as well as short course of oral/topical steroids given for allergic reactions or 
asthma flares are allowed. 
 Erythropoietin for the supportive treatment of anemia.  
 The use of herbal medicine is not recommended during the active treatment phase.  
12.5.3 
Permitted Medications 
The following treatments are permitted throughout the duration of the active treatment 
phase:  
 Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications.  Any medication intended solely for supportive care (eg, analgesics, 


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antidiarrheals, antidepressants) may also be used at the investigator’s discretion.  All 
medications should be recorded.  
 Bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) 
inhibitors  
Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on 
this study if necessary for treatment or prevention of osteopenia or osteoporosis. 
The need to initiate or increase the dose of these therapies during the study will not 
be considered as indicative of disease progression leading to the discontinuation of 
patient from the active treatment phase unless disease progression can be confirmed 
by adequate imaging methods. 
 Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic 
use of granulocyte-colony stimulating factors is not permitted but they may be used 
to treat treatment-emergent neutropenia as indicated by the current American 
Society of Clinical Oncology (ASCO) guideline.113  If neutropenic complications are 
observed in a cycle in which primary prophylaxis with CSFs was not received, 
secondary prophylaxis may be given at the discretion of the investigator, but only if 
dose reduction or delay are not considered a reasonable alternative. 
12.6 
Concomitant Radiotherapy or Surgery 
Any concurrent radiotherapy is prohibited throughout the duration of the active treatment 
phase of the study.  Adjuvant radiotherapy should be completed before entering the study. 
Patients requiring radiotherapy during the active treatment phase will be discontinued from 
the active treatment phase and will enter the follow-up phase. 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and palbociclib required to minimize the risk of 
impaired wound healing and bleeding, if any, has not been determined.  Based on the 
available pharmacokinetic data, stopping palbociclib/placebo is recommended at least 7 days 
prior to elective surgery. Postoperatively, the decision to reinitiate palbociclib/placebo 
treatment should be based on a clinical assessment of satisfactory wound healing and 
recovery from surgery. 
12.7 
Pregnancy and Lactation 
Palbociclib/placebo as well as endocrine treatment must not be administered to pregnant 
women, or to women who are breastfeeding. Treatment has to be immediately been 
stopped as soon as a pregnancy is diagnosed. 
A negative pregnancy test is required prior to study entry. Highly effective non-hormonal 
contraceptive methods that result in a low failure rate should be applied, i.e. some IUDs , 
sexual abstinence or vasectomised partner (CPMP/ICH/286/95). The use of hormonal 
contraceptives is not allowed during the entire duration of the study. Patients should be 


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advised not to get pregnant or breast feed during the first 3 months after the end of 
endocrine therapy. 
In case a patient becomes pregnant during study treatment, endocrine therapy or 3 months 
thereafter, this has to be documented within one working day using the SAE reporting form 
and outcome of the pregnancy has to be reported on a separate form provided by GBG. 
12.8 
Non-investigational Products 
12.8.1 
Description, Formulation, and Handling of the non-investigational products 
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. 
 
Treatment should be performed according to institutional guidelines. Patients discontinuing 
endocrine treatment due to treatment-related toxicity should first be switched to another 
type of endocrine therapy. If again this treatment is not tolerated, the patient will be 
discontinued from the active treatment phase of the study and enter the follow-up phase.  
Patients discontinuing palbociclib/placebo treatment due to treatment-related toxicity 
preferably continue endocrine treatment as per the investigator’s discretion.  
For all other information refer to the package insert (PI) and/or the summary of product 
characteristics (SmPC). 
12.9 
Post-study Treatment 
After completion of palbociclib/placebo patients will continue with endocrine treatment for a 
total of 5 to 10 years. No other kind of treatment is recommended. 
 
13. 
STUDY PROCEDURE - ASSESSMENTS AND SCHEDULE 
 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 


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perform the test. In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The monitor should be informed of these incidents in a timely fashion. 
Safety assessment will consist of monitoring of all adverse events (AEs), including serious 
adverse events (SAEs), regular monitoring of hematology, serum chemistry, and routine 
monitoring of ECGs, physical examinations, vital signs, and ECOG performance status. 
Adverse event assessment will include type, incidence, severity (graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 4.0, 
see Severity Assessment section), timing, seriousness, and relatedness. 
 
 


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Investigations prior to study entry to any protocol 
investigations or procedures - Prescreening 
Timing 
(within days prior to 
randomization) 
Imaging tests 
** 
•  Breast ultrasound (<13 months) and either 
Bilateral mammography (< 13 months) OR bilateral 
breast MRI (<13 months).  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 < 13 month  
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. 
Data including imaging from intial results for 
calculation of clinical score of CPS-EG needs to be 
available as source data. 
•Imaging tests for 
staging < 13 Months 
 
Surgery 
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 
 
Radiotherapy  
Completed adiotherapy after surgery according 
to 
guidelines 
if 
indicated 
(IORT 
allowed). 
Radiotherapy reports including information of time 
period of radiotherapy, irradiated region and dose per 
region, dose per day have to be provided 
less than 10 weeks 
prior to 
randomization 


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13.1 
Study Procedures at Screening 
 
Investigations with Screening 
Timing (within days 
prior 
to 
randomization) 
Patient 
informed 
consent 
 Obtained  
Prior to any protocol 
investigations 
or 
procedures 
History and 
physical 
exam 
History - including: diagnosis of breast cancer, 
menopausal status, general medical history including 
cardiac history and allergy, concurrent illnesss, 
response to neoadjuvant chemotherapy (assessed 
according to Appendix1 21.1) 
 Concomitant medications, and their indication, 
used within one month prior to study entry 
 Physical exam - including: height and weight, 
ECOG for performance status according to 
Appendix 2, 21.2) / vital signs, heart rate (pulse), 
blood pressure 
 Palpation 
of 
breasts, 
axillae, 
supra- 
and 
infraclavicular region 
 Preexisting signs and symptoms 
 Check FSH and E2 in patients aged <55 and  
history of hysterectomy. 
 < 30 days 
Hematology *  Hemoglobin 
 White blood cells (WBC) and absolute neutrophil 
count (ANC) 
 Platelet count 
 < 8 days 
Pregnancy 
Test 
 Serum (if applicable) 
 
 Highly 
effective 
non-hormonal 
contraceptive 
methods, (barrier methods, intrauterine contraceptive 
devices, 
sterilization) 
; 
sexual 
abstinence 
or 
vasectomized partne 
< 
14 
days 
(if 
applicable) 


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Investigations with Screening 
Timing (within days 
prior 
to 
randomization) 
Biochemistry 
* 
 Sodium, Potassium , total calcium, magnesium 
 Albumin 
 Alkaline phosphatase  
 ASAT (SGOT), ALAT (SGPT) 
 Total bilirubin 
 Serum creatinine  
 < 8 days 
 
Biochemistry 
* 
 HbA1C 
< 30 days 
Cardiac 
Monitoring 
 12-lead ECG including automated calculation of 
PR interval, QT interval, RR interval, and QRS 
complex 
 < 30 days 
Biomaterials 
 Formalin-fixed paraffin-embedded (FFPE) tumor 
tissue block from post-neoadjuvant surgically 
removed tissue or if not available, involved lymph 
nodes (mandatory). 
Formalin-fixed paraffin-embedded (FFPE) tumor 
tissue block from pre-neoadjuvant core biopsies 
for further exploratory analysis or to confirm 
luminal status (mandatory) 
After ICF signature 
 10 mL full blood for serum (mandatory) needs to 
be provided before 1st dosing with IP 
 10 ml full blood for plasma (mandatory) needs to 
be provided before 1st dosing with IP 
 < 30 days but  
 latest 
before 
1st 
dosing with IP 
 10 mL full blood for SNP analysis (mandatory) (can 
also be taken any time after randomization) 
< 30 days but 
 latest before EoT 
 20 ml full blood for detection of ctDNA (optional) 
< 30 days 
 latest before 1st 
dosing with IP 


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Investigations with Screening 
Timing (within days 
prior 
to 
randomization) 
Patient 
reported 
outcome / 
Health 
economics 
 EORTC QLQ C30,  
 EORTC QLQ BR-23,  
 EORTC QLQ FA-13 Fatigue, 
 GAD7 patient self-rating mood scale 
 EQ-5D. 
See Appendix 5-8 (21.5 – 21.8) 
 Use of medical resources related to breast cancer 
and that may differ between trial arms**** 
< 14 days  
Other 
Investigations  as clinically indicated 
< 30 days 
* Laboratory assessments will be performed whenever possible by the same laboratory 
throughout the study.  
**Every effort will be made to use the same instrumental examination from baseline 
through follow-up. 
**** Medical resource use at the treating center should be recorded by study staff without 
involving the patient. Assessment of medical resource use by other health care providers 
and of lost resources (days of work etc.) should be based on patient interview 
 
13.2 
Evaluation during active treatment with palbociclib/placebo 
 
Investigations during Treatment 
Timing 
History 
and 
physical 
exam** 
since 
previous visit 
 Clinical 
history 
and 
concomitant 
medication 
 Physical exam – including: weight, 
ECOG performance status (Appendix 
2, 21.2), heart rate , blood pressure 
 Adverse events* 
 Information on external hematology 
lab results or from site lab taken on 
day 1 of cycles 6,8,10,12 only  
Days 1 (+/-2) and 14 during 
cycles 1 and 2,  
Day 1 (+3) at cycle 3, 4, 5, 7, 9, 
11, 13 and at EOT.  
 
SAEs must be reported within 
24 hours. For all randomized 
patients 
SAEs 
must 
be 
reported until 30 days after 
last intake of IMP  once they 
received initial dose of study 
drug 


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Investigations during Treatment 
Timing 
Hematology** 
 Hemoglobin 
 White blood cells (WBC) and absolute 
neutrophil count (ANC) 
 Platelet count 
Days 1 (+/-2) and 14 (+/-2) 
during cycles 1 and 2, Day 1 
(+3) of 3, 4, 5, 6, 7,8, 9,10, 11, 
12, 13 and at EOT, and 
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). 
Biochemistry** 
 Sodium, Potassium , total calcium, 
 
magnesium 
 Albumin 
 Alkaline phosphatase  
 ASAT (SGOT), ALAT (SGPT) 
 Total bilirubin 
 Serum creatinine 
Day 1 (+/-2) Cycles 1, 2, Day 1  
(+3) of Cycle  3, 7, 11, and 
EOT, and as clinically 
indicated 
 
HbA1C  
Day 1 (+3) of Cycle 3, 7, 11, 
and EOT 
Drug 
compliance and 
dispensing 
 Palbociclib/placebo bottles including 
any unused medication will be 
returned to the clinic for drug 
accountability.  Drug accountability 
will be performed on Day 1 of each 
cycle prior to dispensing drug supply 
for the next cycle(s). 
Day 1 (+/-2) at cycle 1, 2, Day 
1 (+3) of Cycle  3, 4, 5, 7, 9, 11, 
13 


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Investigations during Treatment 
Timing 
Pharmaco-
kinetics 
 Plasma pk samples for drug-drug 
interaction(DDI)    
(sites not being prepared to collect pk 
samples will only be allowed to 
include 
patients 
planned 
for 
treatment with letrozole until these f 
24 patient of a respective cohort are 
being 
included) 
 
 
- 
sampling 
completed 
 
 plasma pk samples for drug exposure. 
(sampling ongoing since mandatory 
for all patients) 
 
Several samples in cycle 1 
and/or cycle 2 [only for the24 
patients 
each 
receiving 
tamoxifen, and goserelin plus 
tamoxifen, or anastrozole] 
 
 
 
 
 
pre-dose Day 14 of cycle 1 
and 2 [all patients] 
Clinical disease 
assessment 
Clinical disease assessment, relapse 
and survival status. 
Imaging 
(mammograph 
or 
MRI): 
Imaging should be performed at Cycle 
7 
and 
EOT.. 
In 
patients 
with 
mastectomy 
only 
contralateral 
mammography / MRI is required; 
patients with bilateral mastectomy 
should be assessed as per national 
guidelines 
recommended 
imaging 
examination.  
cycle 7 and at EOT 
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 
Cardiac 
monitoring** 
 12-lead 
ECG 
including 
automated 
calculation of PR interval, QT interval, 
RR interval, and QRS complex 
Day 14 Cycle 1 and as 
clinically indicated 


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Investigations during Treatment 
Timing 
Biomaterials 
 10 mL full blood for serum (mandatory) 
 10 
mL 
full 
blood 
for 
plasma 
(mandatory) 
 20 ml full blood for detection of ctDNA 
(optional) 
 Formalin-fixed 
paraffin-embedded 
(FFPE) tumor tissue from metastasis in 
case of recurrence – upon occurance 
 
Before cycle 7 and at EOT 
Patient 
reported 
outcome 
and health 
 
economics – 
 EORTC QLQ C30,  
 EORTC QLQ BR-23,  
 EORTC QLQ FA13 (Fatigue), 
 GAD7 patient self-rating mood scale 
 EQ-5D 
See Appendix 5-8 (21.5 – 21.8)  
Use of medical resources related to breast 
cancer and that may differ between trial 
arms**** 
Day 1 or (+/-2 days)  of Cycle 
1, 3, Day 1 or (+/ -7 days) of 
Cycle 5, 7, 9, 11, and EOT, and 
every 6 months until final 
primary endpoint analysis 
* Toxicities will be recorded according to NCI-CTCAE v4 criteria with the maximum grade per 
cycle.  
** Laboratory assessments will be performed whenever possible by the same laboratory 
throughout the study. Cycle 1/Day 1: Blood chemistry, hematology, 12-lead ECG and physical 
examination not required if acceptable screening assessment was  performed within 7 days 
prior to randomization 
***Every effort will be made to use the same instrumental examination from baseline until 
end of study treatment. 
**** Medical resource use at the treating center should be recorded by study staff without 
involving the patient. Assessment of medical resource use by other health care providers 
and of lost resources (days of work etc.) should be based on patient interview  
 
 


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13.3 
Pharmacokinetic measurements  
All groups 
Trough concentrations of palbociclib will be collected pre-dose on Day 14 of cycle 1 and 2 for 
all patients. These samples will be used for exposure/response analysis for safety and efficacy 
findings. 
If these PK samples are not collected during the planned nominal visit/time, “make-up” 
samples can be drawn within the same cycle on Days 15 to 21, or in a later cycle on Days 14 
to 21 providing that all planned doses of palbociclib in that cycle have been administered (ie 
no missed samples or dose interruptions) up until the PK collection day. The actual date and 
time of palbociclib administration for the most recent palbociclib dose before and the most 
recent dose after collection of the PK samples must be recorded in the study CRF. 
 
Note: PK-DDI sampling as descbribed below  is now complete, and communication that 
enrollment to PK-DDI cohorts was closed and further collections of PK-DDI samples should 
cease was communicated to sites via email and global newsletter. 
In subsets of at least 24 evaluable patients each starting with the combination of tamoxifen 
and palbociclib/placebo, anastrozole and palbociclib/placebo, goserelin and tamoxifen and 
palbociclib/placebo plasma PK samples will be collected to explore DDI between palbociclib 
and the combination drug. Patients enrolled as a part of the DDI assessment subset who 
dropout of the study prior to completion of all planned PK collections for their respective 
treatment combination DDI assessment, may be replaced at the discretion of the 
Sponsor/Investigator to ensure that evaluable PK data is available from 24 patients within 
each endocrine treatment group. The PK sample handling and processing instructions are at 
the end of this section and further details can be found in the biomaterial management 
manual. 
 
Tamoxifen together with palbociclib/placebo patients 
In 24 patients receiving tamoxifen together with palbociclib/placebo plasma PK samples will 
be drawn on Cycle 2 Day 14 pre-dose and 2, 4, 6, 8, and 24 hours post-dose for DDI 
assessment.  These samples will be analyzed for palbociclib, tamoxifen, 4-hydroxy-tamoxifen, 
N-desmethyltamoxifen, and endoxifen. The Cmax, Cmin, and AUC(0-24) of tamoxifen and its 
active metabolites will be compared between the palbociclip and placebo subgroups. The 
Cmax, Cmin, and AUC(0-24) of palbociclib will be compared with historical data.  These data will 
be used to explore the potential two-way DDI between tamoxifen and palbociclib and the 
result will be used to inform dose adjustment if necessary after IDMC review of the DDI 
analysis. 
 


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If the planned PK samples are not collected during the planned nominal visit on Cycle 2 Day 
14, then “make-up” samples can be drawn within the same cycle on Days 15 to 21, or in a 
later cycle on Days 14 to 21 providing that all planned doses of palbociclib and tamoxifen in 
that cycle have been administered (ie no missed samples or dose interruptions) up until the 
PK collection day. The actual date and time of administration for the most recent palbociclib 
and tamoxifen doses before and the most recent dose after collection of their respective PK 
samples must be recorded in the study CRF. Of note, the samples should be collected from 
the same dosing interval (ie if PK sampling starts with a pre-dose PK sample on Cycle 2 Day 
18, then the 24hr post-dose sample should be drawn on Cycle 2 Day 19 and all planned 
samples drawn in between), and the 24 hours post-dose samples should be drawn prior to 
administration of the next dose. 
 
Anastrozole together with palbociclib/placebo patients 
In 24 patients receiving anastrozole together with palbociclib/placebo plasma PK samples will 
be drawn on Cycle 1 Day 14 pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose for DDI 
assessment. These samples will be analyzed for palbociclib and anastrozole. The Cmax, Cmin, 
and AUC(0-24) of anastrozole will be compared between the palbociclib and placebo 
subgroups. The Cmax, Cmin, and AUC(0-24) of palbociclib will be compared with historical data. 
These data will be used to explore the potential two-way DDI between anastrozole and 
palbociclib and the result will be used to inform dose adjustment if necessary  after IDMC 
review of the DDI analysis. . 
If the planned PK samples are not collected during the planned nominal visit on Cycle 1 Day 
14, then “make-up” samples can be drawn within the same cycle on Days 15 to 21, or in a 
later cycle on Days 14 to 21 providing that all planned doses of palbociclib and anastrozole in 
that cycle have been administered (ie no missed samples or dose interruptions) up until the 
PK collection day. The actual date and time of administration for the most recent palbociclib 
and anastrozole doses before and the most recent dose after collection of their respective PK 
samples must be recorded in the study CRF. Of note, the samples should be collected from 
the same dosing interval (ie if PK sampling starts with a pre-dose PK sample on Cycle 1 Day 
18, then the 24hr post-dose sample should be drawn on Cycle 1 Day 19 and all planned 
samples drawn in between), and the 24 hours post-dose samples should be drawn prior to 
administration of the next dose. 
 
Goserelin and tamoxifen together with palbociclib/placebo 
In 24 patients receiving goserelin and tamoxifen together with palbociclib/placebo, plasma 
PK samples will be drawn on Cycle 2 and Cycle 3 Days 1 and Day 14 pre-dose for DDI 
assessment. These samples will be analyzed for palbociclib, goserelin and tamoxifen. 
Concentrations of Goserelin and tamoxifen will be compared between the palbociclib and 
placebo subgroups.  The concentrations of palbociclib will be compared with historical data. 


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These data will be used to explore the potential two-way DDI between goserelin and 
palbociclib and the result will be used to inform dose adjustment if necessary after IDMC 
review of the DDI analysis. 
 
If the planned PK samples are not collected during the planned nominal visit, then “make-up” 
samples can be drawn in a later cycle on the same planned cycle Day (ie a Cycle 3 Day 1 
sample can be made-up on Cycle 4 Day 1, and a Cycle 3 Day 14 sample can be made-up on 
Cycle 4 Day 14) providing that all planned doses of palbociclib, tamoxifen, and goserelin in 
that cycle (or the previous cycle in the case of Day 1 PK samples) have been administered (ie 
no missed samples or dose interruptions) up until the PK collection day. The actual date and 
time of administration for the most recent palbociclib, tamoxifen, and goserelin doses before 
and the most recent dose after collection of their respective PK samples must be recorded in 
the study CRF.  
 
PK sample handling and processing instruction (Refer to the biomaterial management for 
details) 
Collect 3 mL PK blood samples for each administered drug in the combination at each 
timepoint specified above and process each sample according to the procedure below: 
1. Upon collection of blood samples in 3mL Lavender Top K2EDTA Tube, keep the blood PK 
samples on wet ice at all times prior to centrifugation. 
2. Within 1 hour of collection, centrifuge the blood samples in the refrigerated centrifuges 
at approximately +4°C at about 1700xg for about 10 min. 
3. Using a separate pipette for each time point, transfer the plasma samples into pre-
labeled amber cryovials polypropylene tubes and stored at the following temperatures 
per analyte: the tamoxifen, anastrozole and palbociclib samples should be stored at -20°C 
and the goserelin samples at -80°C . 
4. As much as practical, keep the blood and the plasma samples away from direct sunlight 
and unfiltered lab light. 
5. Ship the samples on dry ice to the biobank as per study team request. 
 
Sites not being prepared to collect PK samples for DDI Assessment will only be allowed to 
include patients planned for treatment with letrozole until the 24 patients of a respective 
cohort are being accrued. Inclusion of patients into the study will not be put on hold to wait 
for the results of these Pk analyses. 
13.4 
Patient Reported Outcomes (PRO) and health economics 
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 


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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. Repeated-measures mixed-effects models will be 
used to explore the treatment effect changes over time and treatment-by-time interaction. 
Details on distribution, advising patients and analysis will be provided in the statistical 
analysis plan.  
13.4.1 
EORTC QLQ-C30, EORTC QLQ-FA13, QLQ-BR23 
The EORTC QLQ-C30 is a validated and reliable self-report measure 114 115 116) that consists of 
30 questions that assess five aspects of patient functioning (physical, emotional, role, 
cognitive, and social); three symptom scales (fatigue; nausea, vomiting, and pain; and the 
global health/quality of life) and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties). Scale scores can be obtained for the multi-
item scales. The fatigue module has been developed for use in all diagnoses, stages of the 
disease and treatment settings. It is measuring cancer related fatigue based on a 
multidimensional approach including physical, emotional and cognitive aspects of fatigue. 
One global item is assessing the interference of fatigue with activities of daily living. FA-13 
(reduced version with 13 items to be used in combination with EORTC QLQ-C30, Weis, J. 
2009;) The QLQ-BR23 breast cancer module is meant for use among patients varying in 
disease stage and treatment modality.117 The module comprises 23 questions assessing 
disease symptoms, side effects of treatment (surgery, chemotherapy, radiotherapy, and 
hormonal treatment), body image, sexual functioning, and future perspective. The breast 
cancer module incorporates five multiple-item scales to assess systemic therapy side effects, 
arm symptoms, breast symptoms, body image, and sexual functioning. In addition, single 
items assess sexual enjoyment, hair loss, and future perspective. The QLQ-C30  and QLQ-
BR23 take 10 to 15 minutes to complete.  
13.4.2 
EQ-5D 
The EQ-5D is a widely used, preference-based measure of health related quality of life 
(utility) that is frequently used as a basis for calculating quality-adjusted life years (QALY) and 
for conducting health economic evaluation studies118 119. The EQ-5D measures five 
dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), 
offering three answer categories for each120 121. Resulting health states are combined with 
country-specific value sets, derived from population-based studies, to calculate utility. In 
addition, a visual analogue scale (VAS) allows individuals to directly rate their self-perceived 
overall health state. It takes about 5 minutes to complete the EQ-5D. 
Health economics: medical resource use related to breast cancer and that may differ 
between trial arms will be collected as a basis for cost analysis and health economic 
evaluation. Medical resource use at the treating center will be recorded by study staff 


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without involving the patient. Assessment of medical resource use accrued with other health 
care providers and of lost resources (lost days of work etc.) will be based on patient 
interviews and/or patient diaries. It is estimated that during the treatment period, the 
additional time requirement will be 15 minutes of patient and staff time per clinical visit. 
During the follow-up period, the expected time requirement is an 20 minutes per assessment 
time point. 
Details of the cost analyses and health economic evaluation will be described in a Health 
Economic Analysis Plan. In brief, cost differences between treatment strategies will be 
assessed for the final iDFS (and interim OS) analysis time point (QIV 2018), for the final OS 
analysis time point (QIV 2021), and with a lifelong time horizon based on extrapolation. 
Incremental cost-effectiveness, expressed as cost per QALY gained, will be estimated based 
on the data available at the final iDFS and final OS analysis time points, using a lifelong time 
horizon. Supporting analyses may be added. 
Given the specifics of health economic analysis, some points must be noted: Approaches to 
analysis will follow the health economic state-of-the-art, which may evolve until the analyses 
are due. Assessments of cost and cost-effectiveness will make use of clinical, utility and 
medical resource use data collected within the PENELOPE tiral. Unit cost estimates and 
potentially a limited number of additional parameters will come from external sources. 
Health economic analysis is always country-specific; countries for which the analyses will be 
performed, and perspectives of cost assessment, remain to be specified. One option will be 
to select the largest recruiters into the trial. Consistency of medical resource use across 
centers and countries will be assessed.  If related issues are detected, the use of medical 
resource use data may need to be restricted to a subset of centers, with an implication of 
increased statistical uncertainty. If the recording of medical resource use data showed to be 
only partially feasible (e.g. due to issues with patient compliance), health economic 
methodology would allow to implement approximate solutions; related limitations of validity 
would be discussed. Depending on the clinical results of the trial (e.g. if no clinical advantage 
palbociclib is demonstrated), some of the planned analyses may become obsolete. 
13.4.3 
General Anxiety Disorder-7 (GAD-7) 
The General Anxiety Disorder-7 (GAD-7) will be collected with baseline and to aid in the 
identification and severity assessment of potential mood alterations. The GAD-7 are 
validated (Kroenke 2001, Spitzer 2006, Spitzer 1999), patient self-administered 
questionnaires developed for use in clinical practices. 
The GAD-7 is a one-dimensional questionnaire consisting of 7 questions. Patients are asked 
to indicate how often, over the past 2 weeks, they have been bothered by each of the seven 
core symptoms of generalized anxiety disorder as referenced in the DSM IV. Response 
options are ‘‘not at all,’’ ‘‘several days,’’ ‘‘more than half the days,’’ and ‘‘nearly every day,’’ 
scored as 0, 1, 2, and 3, respectively. The sum of all seven questions calculate the total GAD-7 
score. Therefore, GAD-7 scores range from 0 to 21.  


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Toxicity grading based on anxiety questionnaire scores 
 
 
Score Severity Grading 
 
 
* 
Note: 
The 
grading guidance 
above 
may 
be 
overruled at the 
discretion 
of 
a 
psychiatrist 
performing 
a 
consult. 
 
 
 
 
 
 
 


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13.5 
Collection of Biomaterials 
 
Collection of formalin-fixed paraffin-embedded (FFPE) tumor tissue block from 
diagnostic core before start of chemotherapy and at surgery is mandatory. For central 
review at least 3 cores should be sent to the central pathology laboratory.  
 
One serum sample (out of 10 mL full blood) should be collected before start study 
treatment, at day 1 of the 7th cycle and at EOT (mandatory). Serum preparation should 
be performed as follows: collect 10 ml of peripheral blood in an S-Monovette (Sarstedt; 
monovette contains granula-bound coagulation agent), invert the tube to mix blood 
with coagulation agent and leave the sample 20 to 30 min at room temperature. After 
20 to 30 min, the clotting of the blood is completed. Please centrifuge the sample for 
15 min at 1500g and transfer the clear or yellow supernatant (upper phase/layer = 
serum) into the 5 fresh tubes supplied. For tube labeling use adhesive labels provided 
with the lab kit. The serum samples must be frozen immediately at -20°C to -80°C. The 
samples frozen at -20°C to -80°C will be stored at the center. Samples will be picked up 
by a courier service.  
 
For plasma isolation 10ml of peripheral blood should be collected before start of study 
treatment, at day 1 of the 7th cycle and at EOT (mandatory). Peripheral blood will be 
sampled in an EDTA test tube and inverted for several times (5x). After centrifugation 
for 15 min at 1500g, the plasma can be collected from the supernatant and transferred 
into 5 fresh tubes. The samples must be frozen immediately at -20oC to -80oC and 
stored at the center until pick up by a courier service.  
 
One full blood sample (10 mL) of each patient will be collected preferably before start 
of study treatment (but can be also collected later) for SNP analysis (mandatory).  The 
samples must be stored frozen at -20°C to -80°C at the center.  
 
Additional optional full blood sample (20 mL) will be collected before study treatment, 
at day 1 of the 7th cycle, at EOT and within 4 weeks after confirmation of progressive 
disease for the analysis circulating DNA (ctDNA). 
All technical and transportation devices (material for blood and serum sampling and 
packaging) will be provided by the GBG. 
13.6 
Biomarker analysis 
Specific information and guideline on the detection of centrally assessed biomarkers before 
randomization or exploratory detected biomarkers after randomization are available upon 
request if required. 
13.7 
End of Treatment (EOT) 
The regular end of treatment for a patient is defined as 30 days after the end of the last 
capsule intake of palbociclib/placebo. 


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13.8 
Follow-up Period 
Post-Treatment Follow-Up will be assessed according to ASCO-guidelines 122. Patients who 
discontinue study treatment for any reason other than objective relapse of disease 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. 
Following the EoT visit, clinical disease assessment will be performed (in patients who have 
not experienced an iDFS event), and survival status will be collected in all patients (telephone 
contact or contact in writing with the patient or treating physician is acceptable) twice a year 
after the last dose of study treatment. Imaging tests have to be performed according to 
national guidelines for follow up and in case of symptoms suspicious for locoregional or 
distant relapse but at leaset once a year. Information will be collected on date and site of first 
non-invasive local recurrence, first invasive local recurrence, first contralateral breast 
recurrence, first regional recurrence, first distant recurrence, first palliative endocrine, first 
palliative cytotoxic (+/- targeted) treatment, date and cause of deaths as well as date and 
diagnosis of secondary malignancies, as well as every serious adverse reaction related to 
palbociclib/placebo. 
In case of disease progression it is recommended to confirm diagnosis by histological 
examination. A FFPE tumor tissue block from the metastatic lesion should be provided to 
GBG.  
Newly occurred serious adverse reactions (SARs) have to be documented on the SAE form 
and have to be sent to the Sponsor within 24 h after becoming aware of the event. 
Participating patients are recommended to be registered in the GBG self-reporting registry (if 
allowed by national regulations) that will allow further follow up and long-term efficacy 
evaluations beyond the end of the study.  
13.9 
Treatment Discontinuation of Individual Patient 
If a patient shows one of the following reasons palbociclib/placebo treatment has to be 
discontinued from study treatment: 
 Detection of local, regional or distant invasive recurrence breast cancer, 
 Unacceptable toxicity according to investigators decision 
 Detection of any secondary malignancy 
 Patients request or non-compliance. 
The reason and date of discontinuation for all patients will be documented on the Case 
Report Form (e.g. progressive disease, death, adverse event, withdrawal of consent, lost to 
follow-up, etc.). 


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The investigator will attempt to complete all discharge procedures at the time of 
discontinuation of palbociclib/placebo treatment. The procedures have to be documented in 
the CRF. 
13.10 
End of Study (EOS) 
13.10.1 
Regular End of Study 
No interventional procedures after final iDFS (and interim OS) analysis. All patients will be 
contacted by telephone before the database lock. The end of study is defined with evaluation 
of the primary objective. Planned end of study is QIII 2020. Survival and Relapse assessments 
will continue post study. 
13.10.2 
Premature Termination of Study 
The study may be terminated prematurely for safety reasons, slow accrual, or upcoming  
new data impairing the relevance of the study objective by the GBG Forschungs GmbH as the 
sponsor or the protocol board. The Independent Data Monitoring Committee will provide 
advice. The sponsor is allowed to close the trial for any reason at any time. A decision to 
prematurely terminate the study is binding to all investigators of all study sites. Responsible 
ethics 
committees 
and 
regulatory 
authorities 
will 
be 
informed 
about  
the reason(s) and time of termination according to the applicable laws and regulations. 
If the study is terminated prematurely, all investigators have to inform their patients and  
take care of appropriate follow-up and further treatment of the patients. 
 
13.10.3 
Premature Termination of Study at a Particular Study Site 
The GBG Forschungs GmbH as the sponsor reserves the right to discontinue the study  
at a particular study site at any time. The reasons will be discussed with the investigator. 
The GBG Forschungs GmbH may terminate this study in one particular study site for one  
of the following reasons: 
Non-compliance with GCP and/or regulatory requirements. 
Insufficient number of recruited patients. 
False documentation in the CRF due to carelessness or deliberately. 
Inadequate co-operation with GBG Forschungs GmbH or its representatives. 
The Investigator request to close of his/her study site. 
If the study is prematurely terminated in a study site, the responsible investigators have to 
inform their patients and take care of appropriate follow-up and further treatment of  


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the patients. The responsible ethics committee and regulatory authorities will be informed 
about the reason and time of termination according to the applicable laws and regulations. 
 
14. 
DATA QUALITY ASSURANCE 
14.1 
Data Management and Documentation 
Data management and monitoring will be carried out by the GBG Forschungs GmbH. Data 
management refers to eCRF design, database and application hosting and data validation. 
All CRF data will be entered into the trial database using the MedCODES® application, which 
will perform automated plausibility and value range checks before committing the data to 
the database. As soon as a Case Report Form is committed to the database it can no longer 
be edited or deleted by the investigator. Committed data, other than baseline, can be 
changed by the investigator as long as it is not monitored. Any changes made by the 
investigator are reviewed by data management. Once data is monitored, the investigator is 
not allowed to make any changes without a query. 
CRF data will be reviewed by a data entry clerk and queries created for every data field that 
do not match the trial guidelines. These queries will be forwarded to be resolved (within the 
MedCODES® application) to the center. Resolved queries will be checked by a data entry 
clerk and closed or if necessary requeried.  
The patient baseline and registration eCRFs will be checked for eligibility manually and using 
programmed checks. Visual and computerized methods of data validation are applied in 
order to ensure accurate, consistent and reliable data for the subsequent statistical analysis. 
These procedures detect out-of-range values, contradictory data, and abnormal changes over 
time, and possible protocol violations.  
As soon as all data is stored in the trial database and all queries are closed, patient data entry 
in MedCODES® is stopped, all patients (CRF) are set to “End Status”, any data changes in 
MedCODES® are stopped. The database is locked to any kind of manipulation and then 
handed over to the Statistics Department. Prior to statistical analysis, concomitant 
medications entered into the database will be coded using the WHO Drug Dictionary,. 
Medical history, adverse events, cause of death, antineoplastic surgeries, procedures or 
nondrug therapies will be coded using the Medical dictionary for regulatory activities 
(MedDRA) terminology.  
Pseudonymisation  
In order to keep patient data confidential and for safeguarding the privileged doctor patient 
relationship, each participating patient will be assigned a unique GBG reference number. This 
reference number consists of a trial specific prefix and a unique randomization number from 
a prepared block of numbers.  


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The pseudonym, instead of the true patient identity, is used in all communication between 
the trial site and the GBG Forschungs GmbH.  
User Access Control  
Every user is provided with a personal user name and password. Every user is assigned to a 
user group, which represents their role in the MedCODES® application.  
Access control is based on user name, group and place of work (e.g. center or the GBG 
Headquarters). Users can only access those datasets necessary for them to fulfill their role in 
the CRF workflow (“need to know basis”).  
14.2 
Monitoring and Source Data Verification 
All source data verification (SDV) is conducted according to GBG monitoring standard 
operations procedures (SOP). 
The investigator must permit the monitor, the sponsor’s internal auditors and 
representatives from the regulatory authorities to inspect all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs. 
After logging in to the MedCODES® application, the monitor chooses a trial center (their 
current location) and a trial. Source data verification is then performed by consulting the 
patient file. In case of discrepancies the monitor creates queries which must be solved by the 
center. 
14.3 
Computer Systems 
All data are collected and stored using the MedCODES® application. The MedCODES® 
application is based on an Apache 2.4 / PHP 5.5 application server and a MySQL 5.6 database 
backend. 
Due to the nature of the MedCODES® application, the trial centers must be equipped with 
computer terminals with online access and current versions of Microsoft Internet Explorer, 
Mozilla Firefox or Apple Safari. JavaScript execution must be enabled with the web browser. 
 
 


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15. 
STATISTICS 
 
The statistical analysis of the present study is performed in accordance with the principles 
stated in the Consensus Guideline E9 (Statistical Principles for Clinical Trials) of  
the International Conference on Harmonization (ICH). 
15.1 
Disposition of patient 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent. 
Randomized patients consist of all patients, who have been allocated to treatment with 
palbociclib or placebo of palbociclib based on the randomization process. It will consist of all 
patients with randomization number and recorded in the computerized system database and 
regardless of whether the treatment was used or not. 
Patients treated without being randomized will not be considered as randomized and will not 
be included in any population.   
For any patient randomized more than once, only the data associated with the first 
randomization will be used in any analysis population. The safety experience associated with 
any later randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, 
and these patients will not be in the All randomized and treated patients (SP) population. 
For patient study status, the total number of patients for each one of the following 
categories will be presented: 
Screened patients 
Randomized patients 
Randomized and treated patients 
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation. 
15.2 
Analysis populations 
Randomized patients consist of all patients who have given their written 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.  


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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. 
In addition:  
Not randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
Randomized patients for whom it is unclear whether they took the study medication will be 
included in the safety population as randomized. 
For patients receiving palbociclib and placebo during the trial, the treatment group allocation 
for as-treated analysis will be the palbociclib arm.  
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. 
Major protocol violations according to the sponsor guideline are applicable and made 
available to sites for referencing Major protocol violations leading to exclusions from the 
available subset will be defined in the statistical analysis plan. 
15.3 
Sample Size Determination 
Sample size was determined based on the analysis of the primary endpoint, 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.  


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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. 
Rationale of assumptions on sample size determination 
Estimation of 3-year iDFS rate was performed on the basis of a metadatabase containing 
2659 HR+/Her2- patients who received neoadjuvant therapy (about 18-24 weeks), surgery 
(average period of around 6 weeks after last cycle of chemotherapy) and radiation (about 6 
weeks). In the PENELOPEB study patients will be randomized after radiation or rehabilitation, 
if applicable, which is estimated to be approximately 9 months after start of neoadjuvant 
chemotherapy. Given these assumptions a 3-year iDFS rate of 0.77 was estimated for the 
control arm of patients with CPS-EG score >= 3 or CPS-EG score = 2 and ypN+. The 
assumption of exponential distribution on time-to-iDFS event for the control arm may affect 
the duration of study. This assumption cannot be assessed due to lack of patient-level data 
on surgery date. 
15.4 
Treatment Stratification 
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) 
 
Ki-67 measured (>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+) 
 
15.5 
Statistical Analyses 
15.5.1 
Analyses of primary and secondary endpoints 
Analysis of Primary Endpoint 
Primary efficacy endpoint is invasive disease-free survival (iDFS) which is defined according to 
Hudis as the time period between randomization and first event (ipsi- or contralateral 
invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, 
death from non-breast 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 


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status (CPS-EG 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. 
 
Analysis of Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
 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 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. 


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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 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. Repeated-measures 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 
15.5.2 
Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the All randomized and treated patients population. 
 
15.5.3 
Extent of investigational medicinal product exposure 
Duration of palbociclib/Placebo exposure is defined as:  last dose date – first dose date + 7 
days regardless of unplanned intermittent discontinuations. 
The overall extent of exposure will be assessed for each patient as: 
 Duration of exposure  
 Total number of cycles (K) 
Dose information: 
The actual dose received  


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Cumulative dose (mg) defined at cycle k as the sum of all doses from cycle 1 to and including 
cycle k, where k is based on Investigator’s report.  
The actual dose intensity (ADI) is defined as the cumulative dose divided by the number of 
weeks on treatment (mg/week) including delays. 
The relative dose intensity (RDI) is defined as the ratio of the actual dose intensity to the 
planned dose intensity. RDI, as an indicator of the feasibility of the chosen schedule of 
administration.  
Dose reduction and reason for dose reduction: Dose reduction will be derived using the 
definition provided in the protocol compared to the previous dose. For the second and 
subsequent cycles, a dose is deemed to have been reduced if the dose level a patient 
receives is lower than the previous actual dose level. 
Dose delays: A cycle is deemed to have been delayed if start date of the current cycle – start 
date of previous cycle > 3.  
 
15.5.4 
Analysis of Adverse Events 
The summary of safety results will be presented by treatment group. All safety analyses will 
be performed on the randomized and treated patient populations. 
The grade will be taken into account in the summaries. For patients with multiple 
occurrences of the same event, the maximum grade is used. 
Sorting within tables should ensure same presentation for the set of all AEs within the 
observation period. 
Adverse event incidence tables will be presented by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and 
preferred term (PT) sorted in alphabetical order for each treatment group, the number (n) 
and percentage (%) of patients experiencing an AE.  Multiple occurrences of the same event 
in the same patient will be counted only once in the tables within a treatment phase. The 
denominator for computation of percentages is the All randomized and treated patients 
population within each treatment group. 
 
15.5.5 
Analyses of laboratory variables 
The baseline value is defined as the last available value before randomization. 
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters. Each test result will be graded by NCI-common terminology criteria (version 4.0). 
The number of patients with abnormal laboratory tests at baseline (grade ≥1) will be 
presented by grade. The frequency of patients in each grade of laboratory test during 


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treatment will be summarized. For patients with multiple occurrences of the same laboratory 
variable during the treatment, the maximum grade (worst) per patient will be used. When 
appropriate, the summary table will present the frequency of patients with any grade of 
abnormal laboratory tests and with grade 3-4 of abnormal laboratory tests. 
For the non-NCI gradable parameters, out-of-normal laboratory range value analyses will be 
performed. 
15.5.6 
Translational research analyses 
The analyses will be defined in the separate Statistical Analysis Plan. 
 
15.5.7 
Interim Analysis for Safety 
Safety interim analysis (SIA) reviewed by the IDMC have a special focus on 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 SIA after approximately further 
50 patients each, then after further 50 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. 
Ad-hoc IDMC meetings may also be held if a significant safety issue or issue deemed 
important for discussion arise on this or any other palbociclib study. After each meeting, the 
IDMC will advise the  and the Sponsor’s representative on the further conduct of the trial. 
In subsets of 24 at least evaluable patients each starting with the combination of 
palbociclib/placebo and tamoxifen, palbociclib and anastrozole, and palbociclib/placebo 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. 
A PK unblinding plan will allow for review of the PK data prior to completion of the trial 
without unblinding the trial.  The PK unblinding will be applied once all planned PK samples 
from at least 24 evaluable patients of each assessed combination have been collected.  PK 
parameter analysis will proceed according to the PK analysis plan with results provided to the 
IDMC for review. The study will continue while PK analysis and data review are ongoing. 
Details of the analysis (along with other safety data included in the early safety review) will 
be provided in the IDMC charter. 
 


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15.5.8 
Interim Analysis for Efficacy 
Two efficacy interim analyses (EIA) will be performed in the study.  O’Brien – 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-I-error. 
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).  
The following table displays the decision rules regarding the objectives of the two EIA and the 
final analysis.  
Analysis 
Time / 
Information 
Fraction 
Number  
of events 
min/max 
Futility 
(HR) 
Sample size  
re-estimation 
Efficacy  
(-level) 
1st EIA 
April 2017 
67 
≥1.0 
Yes 
<0.0002 
2nd EIA 
2/3 
170/194 
≥0.90 
No 
<0.0120 
FA* 
3/3 
255/290 
N/A 
N/A 
<0.0463 
* Final Analysis 
 


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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  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 Pocock. 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.
 
 
15.5.9 
Further Analysis after the End of the Study 
Final survival will be analyzed 3 years after the final analysis on iDFS. Survival time in each 
treatment group will be estimated with the Kaplan-Meier product-limit method and will be 
reported together with the two-sided 95% confidence interval. The log-rank test will be 
performed to compare overall survival between the two treatment groups.  
The multivariate Cox proportional hazards model will be used for all efficacy endpoints in 
order to adjust for the major prognostic factors. 
 
16. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
16.1 
IDMC Members and Mission 
In addition to the Protocol Board, the Independent Data Monitoring Committee (IDMC) of 
the GBG reviews and monitors the conduct of the trial. The IDMC consists of five members, 
three medical oncologists, one biometrician and a patients advocate. An ad hoc member 
experienced in CDK inhibitors will join each meeting via telefon conference support the 
IDMC. The members are independent of the trial and familiar with the methodology of 
oncology trials. They are aware of the dangers of conclusions based on immature data and 
have agreed with the design and the goals of this protocol. IDMC meetings are held at least 
every six months or as stated in section 15.5.4. The mission of the IDMC is to ensure the 
ethical conduct of the trial and to protect patients' safety interests in this study. The work of 
the IDMC will further specified in a separate charter. 


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16.2 
Recommendations of the IDMC 
After each meeting, the IDMC will provide the Protocol Board with a written 
recommendation to either modify the trial (with reasons), or discontinue the trial  
(with reasons), or make the interim safety and efficacy results of the trial public (with 
reasons), or continue the trial unchanged. The final decision to amend the protocol or  
to discontinue the trial will be taken only by the International Steering Committee. 
16.3 
Early Termination of the Trial 
Early termination of the trial will be considered by the International Steering Committee 
based on suggestion of the IDMC if less than 50 patients are recruited within 12 months, 
unsatisfactory toxicity or compliance. 
 
17. 
ADVERSE EVENTS 
 
Patients will be instructed by the investigator to report the occurrence of any adverse event. 
17.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment.  
It also includes any undesirable clinical or laboratory changes which does not commonly  
occur in the patient.  
The study Investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0) 
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters. Each test result will be graded by NCI-common terminology criteria (version 4.0). 
(see section 15.5.5) .  
In case serum creatinine increase fulfills criteria to be reported as AE, the cause of the renal 
function impairment should be reported and the renal function impairment should be 
considered in the grade of the reported AE according to NCI-CTCAE version 4.0. If no cause 
can be identified and creatinine increase is considered serious or has an action taken on 
study treatment (dose reduction, dose delay, dose interruption or permanent 
discontinuation), the “creatinine increase” term should be preferred rather than the “renal 
failure” term.  
Any case of renal function impairment should be documented at least by a creatinine value 
and creatinine clearance. Tests will be repeated until recovery or stabilization and all results 
will be recorded in the e-CRF. Any complementary exams made to explore renal function or 


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the cause of renal failure should be reported in the e-CRF and product contrast 
administration for CT scan should be recorded in concomitant medication. 
17.2 
Adverse Reaction 
Adverse reactions are all untoward and unintended responses to a medicinal product  
related to any dose administered. 
All expected Adverse Reactions are listed in the Investigator's Brochure (IB). If the nature or 
the severity of an adverse reaction is not consistent with the applicable product information, 
the adverse reaction is defined as unexpected. The basis for the decision is the current 
version of the corresponding reference document that has been submitted and approved by  
the competent authority and the ethics committees. 
Pfizer has agreed to inform GBG in an expedited manner of any Suspected, Unexpected and 
Serious Adverse Reactions (SUSAR) for the product, observed at any time after a subject has 
received the study drug. 
The impact of any report on the benefit/risk profile of the Pfizer product is evaluated as part 
of Pfizer procedures for safety evaluation, including the review and analysis of aggregate 
data for adverse events. Any safety concern identified as part of this review (including, but 
not limited to, an increase in the frequency of expected serious adverse effects, events in 
connection with the study execution or the development of the study drug that can 
potentially affect the safety of the affected persons, significant safety findings from animal or 
in vitro studies), as well as any appropriate action in response, will be promptly notified to 
GBG. 
 
17.3 
Serious Adverse Event/Serious Adverse Reaction 
A serious adverse event (SAE) is any untoward medical occurrence or effect that at any  
dose results in death, is life-threatening, requires or prolongs hospitalization, results  
in persistent or significant disability or incapacity, a congenital anomaly or birth defect, or  
an important medical event from the time the patient signs the informed consent. Important 
medical events are those which may not be immediately life-threatening, but are clearly of 
major clinical significance. 
Pregnancy and AEs of special interest (see Section 17.5) must also be documented  
on the serious adverse event form. 
Exceptions: 
Progression of the malignancy during study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal and death occurred before EOT. 
Thereafter death due to disease progression has not to be reported as SAE. Hospitalization 
due to signs and symptoms of disease progression should not be reported as an SAE.   


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Hospitalization which is due solely to a planned study visit and without prolongation does not 
constitute a Serious Adverse Event. 
An overnight stay in the hospital that is only due to transportation, organization or 
accommodation problems and without medical background does not need to be 
handled/documented as a Serious Adverse Event.  
17.4 
Suspected Unexpected Serious Adverse Reactions 
All unexpected serious adverse events judged by either the investigator or the GBG 
Forschungs GmbH as the sponsor to have a reasonable suspected causal relationship  
to an investigational or an accompanying medicinal product qualify as suspected unexpected 
serious adverse reactions (SUSAR). Adverse event reporting, including suspected serious 
unexpected adverse reactions, will be carried out in accordance with applicable local 
regulations. 
All Suspected Serious Adverse Reactions (SAR) must be reported to the GBG Forschungs 
GmbH as the sponsor regardless of the time which has elapsed during the clinical trial 
(treatment and follow-up phase). 
17.5 
Adverse Events of Special Interest 
For AESIs the Sponsor will be informed immediately (ie, within 1 working day), as per the SAE 
notification instructions described in Section 17.7, even if not fulfilling a seriousness criterion, 
using the corresponding pages in the CRF (to be sent) or screens in the e-CRF. 
17.5.1 Pregnancy: 
Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be 
recorded as an AESI with immediate notification in all cases. It will be qualified as an SAE only 
if it fulfills the SAE criteria. 
In the event of pregnancy, IMP must be discontinued.  
Follow-up of the pregnancy is mandatory until the outcome has been determined. 
 
17.5.2 Relevant overdose with IMP: 
A relevant overdose (accidental or intentional) with the IMP is an event suspected  / 
identified by the Investigator or spontaneously notified by the patient and defined as the 
intake of more than 23 capsules during a cycle (28 days) or more than 2 capsules within 24h.  
It has to be reported within one working day as an AESI using the SAE reporting form. 
 


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17.5.3 Potential Cases of Drug-Induced Liver Injury  
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events.  
The threshold for laboratory abnormalities in the case of potential drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 
Patients with AST or ALT and total bilirubin baseline values within the normal range who 
subsequently present with AST or ALT 3 times the upper limit of normal (X ULN) concurrent 
with a total bilirubin 2 X ULN with no evidence of hemolysis and an alkaline phosphatase 
2 X ULN or not available. 
For patients with preexisting ALT OR  AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above: 
o For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller). 
Concurrent with 
o For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased twice the baseline value. 
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced subject, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may 
be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 


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investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs. 
 
17.6 
Death on Study 
Any death occurring during the active treatment part of the study and within 30 days 
following the last treatment must be reported to the GBG Forschungs GmbH as the sponsor 
within 24 hours, regardless of the relation to study drug(s), and has to be reported on the 
death report form section of the CRF. 
The cause of death should be documented (cancer-related, treatment-related, cancer- and 
treatment-unrelated). Autopsy reports should be collected whenever possible and sent  
to the GBG Forschungs GmbH. 
Deaths that occur due to tumor progression do not have to be reported as a SAE unless they 
occurred before EOT. 
Deaths after the end of study which are considered to be related to study treatment have to 
be reported as SARs.  
To the extent feasible sufficient information including  relevant  laboratory values, ECG, scan,  
biopsy or autopsy results must be provided by the investigator  in the SAE narrative  (even if 
investigator determines the  SAE is not related) so as to permit an independent causality 
assessment by a Health Authority.  
 
17.7 
SAE and AESI Reporting 
Refer to section 17.3 for the definition of a SAE and section 17.5 for definition of an AESI. All 
SAEs/AESI from the time the patient had the first dose of the investigational medicinal 
product (IMP) through 30 days following the last administration of IMP must be reported 
according to the procedure described below. All SAE regardless of timing must be reported, if 
considered related to study drug.   
Likewise, progression of a patient's underlying condition leading to one of the above should 
also not be reported as a serious adverse event, but documented as primary study endpoint. 
(See also Section 17.3). 
 
Address for reports on SAE/AESI (within 24 hours from documented awareness): 


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GBG Forschungs GmbH 
Martin-Behaim-Straße 12 
63263 Neu-Isenburg 
Germany 
Phone: +49 (0) 6102 / 7480-0 
Via MedCODES 
or alternatively via  
Fax: + 49 (0) 6102 / 7480-440 
The GBG will report all SAEs and AESIs immediately t to the pharmaceutical manufacturer. 
All SAEs and AESIs will be followed-up by the investigator until satisfactory resolution. 
Annually all SARs will be reported as the DSUR to the competent authorities and  
the leading ethics committee, including all SUSARs. 
Withdrawal from further treatment shall be at the discretion of the investigator. 
17.8 
SUSAR Reporting 
Expected serious adverse reactions are listed in the Investigator Brochure (IB). All serious 
unexpected adverse events judged by either the investigator or the GBG Forschungs GmbH 
as the sponsor will be reported in accordance with applicable local regulations.  
 
18. 
ADMINISTRATIVE EXECUTION 
18.1 
Monitoring 
On-site visits will be made before the study begins and at regular intervals during the study. 
Other forms of communication (e.g. by telephone, mail, fax etc.) may be used as needed to 
supplement visits. 
The monitor has the responsibility of reviewing the ongoing study with the investigator  
to verify adherence to the protocol and to deal with any problems if and when they arise.  
Special items monitored are: patient enrollment, completeness, exactness and plausibility of 
data entered on the CRFs, verification against source data and occurrence of Adverse Events. 
At all times, the confidentiality of study documents is maintained. Monitoring is performed 
by GBG Forschungs GmbH or designee. 
It is the responsibility of the investigator to ensure that, the dispensing and 
return/destruction of study medication on the drug accountability forms provided is 
documented correctly. The investigator should ensure that the investigational product use is 
documented in such a way as to ensure correct dosage. This documentation should confirm 
that each subject did receive the product dispensed for her and state the identity, including 
the dosage, of the product received. Drug reconciliation will be verified by a second 
responsible person at the close-out visit to the site by the study monitor. All discrepancies 
are accounted for and documented. 


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The investigator agrees to allow the monitor access to all study materials needed for  
the monitor to properly review the study progress. The investigator (or deputy) agrees to 
assist the monitor in resolving any problem that may be detected during the monitoring visit. 
 
 
18.2 
Sponsor’s Responsibilities 
The GBG Forschungs GmbH as the sponsor  
 agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the agreed protocol. 
 reserves the right to request the withdrawal of a patient due to protocol violations, 
administrative or other reasons. 
 reserves the right to terminate the study prematurely due to persistent protocol 
violations, administrative or other reasons. Should this be necessary, the procedures 
will be arranged after review and after consultation by both parties to ensure 
protection of the patients’ interests. 
18.3 
Investigator’s Responsibilities  
The investigator agrees to conduct the study in accordance with the procedures and 
requirements laid out in this protocol. In particular, the investigator agrees to conduct  
the study in accordance with strict ethical principles. Any modification to the agreed  
protocol must be approved in writing by both GBG Forschungs GmbH as the sponsor and,  
if appropriate, the ethics committee(s) approving the original protocol before any 
modifications are put into effect. 
On receipt of study medication, the investigator (or deputy) will conduct an inventory of  
the supplies and complete a supplies receipt. The investigator will retain a copy of  
this receipt at the site and return the original receipt to the study monitor. 
It is the responsibility of the investigator to ensure completeness of the CRFs for each patient 
in the study, and when a patient completes the study, the investigator must (electronically) 
sign  the complete CRFs for each patient. The investigator must comment on any missing, 
unused or spurious data on the appropriate CRF. 
In addition to the CRFs, the investigator will maintain adequate records that fully document 
the progress of the study. The investigator has to state that the patient has taken part in a 
study and record the study number in the patient’s medical records. The exact dates of the 
beginning and the end of treatment should be given as well. 
Copies of these study records (and all study-related documents) shall be kept by  
the investigator for will 10 years after commercialization and till 2 years if development is 


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halted. All documentation and materials provided by GBG Forschungs GmbH for  
this study are to be retained in a secure place and treated as confidential material. 
The investigator has the right to request termination of the study for administrative or other 
reasons. Should this be necessary and agreed upon, the procedures will be arranged after 
review and after consultation by both parties, to ensure protection of the patients’ interests. 
By signing this document the investigator indicates that he/she has read the protocol, fully 
understands the requirements and agrees to abide by all protocol requirements. 
Further obligations of the investigator are agreed on in the investigator’s contract with  
the GBG Forschungs GmbH as the sponsor. 
18.4 
Patient Informed Consent 
Prior to the beginning of specific protocol procedures, the patient is informed about  
the nature of the study drug and is given pertinent information as to the intended purpose, 
possible benefits, and possible adverse experiences. The procedures and possible hazards to 
which the patient will be exposed are explained. Patient insurance for the compensation of 
patients for possible study-related injury is provided by the GBG Forschungs GmbH as the 
sponsor according to local law. 
An approved informed consent statement will then be read and signed by the patient, and, if 
required, a witness, and the investigator. The patient will be provided with a copy of the 
signed informed consent statement. The patient may withdraw from the study at any time 
without prejudicing future medical treatment. Verification of a signed informed consent 
statement will be noted on the patient's study Case Report Form. 
Patients are informed that pseudonymised data from their case may be stored electronically 
and that such data will not be revealed to any unauthorised third party. Data will be 
reviewed by the monitor, an independent auditor and possibly by representatives of 
regulatory authorities and/or ethics committees. The terms of the local data protection 
legislation will be applied as appropriate. 
18.5 
Confidential Follow-up 
The investigator will be responsible for retaining sufficient information about each patient 
(e.g. informed consent form, name, address, phone number, and identity in the study)  
so that regulatory agencies or the GBG Forschungs GmbH as the sponsor may access  
this information should the need to do so arise. These records should be retained in  
a confidential manner for as long as legally mandated according to local requirements. 


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18.6 
Ethics and Regulatory Considerations 
The study described in this protocol is conducted in compliance with the ICH guideline for 
Good Clinical Practice and applicable regulations in all aspects of preparation, monitoring, 
reporting, auditing, and archiving. 
The final approved protocol and the informed consent statement is reviewed by a properly 
constituted Ethics Committee (EC) / Institutional Review Board (IRB). The EC/IRB decision 
concerning the conduct of the study is made in writing to the investigator. 
The investigator or designee agrees to make required progress reports to the EC/IRB, as well 
as report any serious adverse reaction (SAR) and suspected unexpected serious adverse 
reaction (SUSAR). The investigator or designee also informs the EC/IRB of reports of serious 
adverse reactions (provided to him/her by the GBG Forschungs GmbH) in other clinical 
studies conducted with the study drug if deemed necessary by the GBG Forschungs GmbH as 
the sponsor.  
The EC/IRB must be informed by the sponsor of the termination of the study. 
The sponsor is responsible for notifying the regulatory authorities of the study. 
18.7 
Declaration of Helsinki 
This study is to be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki  and are consistent with ICH/Good Clinical Practice (Sommerset 
West, 1996), (Appendix 10).  
Modification of the Protocol 
Any modifications to the protocol which may impact on the conduct of the study, on  
the potential benefit of the patient or may affect patient safety, including changes of study 
objectives, study design, patient population, sample sizes, study procedures, or significant 
administrative aspects, will require a formal amendment to the protocol. Such  
an amendment will be agreed upon by the Protocol Board, and approved by the EC/IRB prior 
to implementation, and reported to the health authorities in accordance with local 
regulations. 
Administrative changes of the protocol are minor corrections and/or clarifications that have 
no effect on the way the study is to be conducted. These administrative changes will be 
agreed upon by the Protocol Board and will be documented in a memorandum.  
The EC/IRB may be notified of administrative changes at the discretion of the investigator. 
18.8 
Study Documents 
All information concerning the study drug and trial conduction, such as scientific data and 
material not previously published are considered confidential and shall remain the sole 
property of GBG Forschungs GmbH. 


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The investigator agrees to use the information provided for the conduct of this study only 
and to use it for no other purposes unless she/he obtains the written consent of the GBG 
Forschungs GmbH as the sponsor. 
18.9 
Case Report Forms 
All key study information must be recorded in the patient’s hospital notes. Study procedures 
will be fully online documented on the electronic CRFs provided through the GBG own EDC-
System (electronic data capture) MedCODES. The investigator will be prompted with an 
interface to enter his/her login data to sign the document electronically according to the FDA 
regulatory known as “21 CFR Part 11”.  
The CRFs, as well as the protocol, are confidential. The CRFs remain the property of the GBG 
Forschungs GmbH at all times. On the CRFs, patients should be identified by their patient 
number. 
Patients’ data entries may only be made by the persons registered on the form “Delegation 
of responsibilities and signature list of investigators and medical staff”. 
For details concerning the CRF submission process, please refer to the application manual 
and electronic training material. 
18.10 
GCP Documents 
The following documents are collected from the investigator’s site: 
Signed Investigator’s Agreement, 
Curricula vitae of all investigators and medical staff, 
Name and address of the laboratories, 
List of laboratory reference ranges and a quality certificate, 
Form “Delegation of responsibilities and signature list of investigators and medical staff”, 
Any other relevant GCP documents. 
18.11 
Archiving 
After completing the study, the GBG Forschungs GmbH will retain all study documents for  
at least ten years after the completion of the study. 
The investigator shall arrange for the retention of the patient identification codes, patient 
files and other source data until at least ten years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least two years have elapsed since the formal 
discontinuation of the clinical development of the product. These documents need to  


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be retained for a longer period of time if required by the competent authorities or by 
agreement with the GBG Forschungs GmbH as the sponsor. 
Patient files and other source data shall be kept for the maximum period of time permitted 
by the hospital, institution or private practice. 
After completion of the study, all documents and data relating to the study will be kept in  
an orderly manner by the investigator in a secure study file. This file will be available  
for inspection by the sponsor or their representatives. Essential documents must be retained 
for 10 years after commercialization and till 2 years if development of palbociclib is halted.. 
The investigator will appoint individuals responsible for the storage of essential documents 
and access to the documents will be restricted to those people. Any alterations to essential 
documents must be traceable. The investigator must contact the sponsor before destroying 
any study-related documentation. 
18.12 
Use of Information and Publication 
To allow for the use of the information derived from this clinical study and to ensure 
compliance to current regulations, the investigator is obliged to provide the sponsor with 
complete test results and all data obtained in this study. This information is only  
made available to physicians and to the competent authorities, unless the sponsor is under 
legal obligation to pass it on a third party. The final statistical trial report will be prepared by 
the responsible biostatistician and the final medical report by the coordinating investigator 
and the sponsor. 
A publication policy will describe the process of preparation of any publication as well as the 
selection of authors. No publication is allowed by individual investigators without approval by 
the ICS. 
The data are owned by GBG. However, GBG are only allowed to use these for any purposes 
after approval by International Principal Investigator. 
18.13 
Finance and Insurance 
Details on finance and insurance will be outlined in a separate agreement between  
the investigator and the sponsor. 
19. 
SUBSTUDIES 
19.1 
TBD


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20. 
INVESTIGATOR'S AGREEMENT 
I have read the protocol  
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 
 
Protocol G (Version 11 - 9th April 2019) 
 
and agree to conduct the study in accordance with the current protocol. 
 
 
Principal Investigator’s Name  (CAPITAL LETTERS ) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
GBG Principal Investigators Site Number 
 
 
 
 
 


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21. 
APPENDICES 
21.1 
Appendix 1:  CPS-EG Score / AJCC Breast Cancer Staging 
  
 
 
 
 
 
* T1 includes T1mi.  
** T0 and T1 tumors with nodal 
micrometastases only are excluded from 
Stage IIA and are classified Stage IB. 


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21.2 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Description 
Grade 
Fully active, able to carry on all pre-disease performance 
without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature, ie, 
light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours. 
2 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
3 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
4 
21.3 
Appendix 3: List of foods and drugs known to be CYP3A4 inhibitors or inducers: 
The concurrent use of CYP3A inhibitors, including amprenavir, atazanavir, boceprevir, 
clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and 
grapefruit, grapefruit juice or any product containing grapefruit, are not allowed in the study.  
The concurrent use of CYP3A inducers, including carbamazepine, felbamate, nevirapine, 
phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s wort, are 
not allowed in the study.  
Please refer additionally to P450 Drug Interaction Table from Indiana University department 
of medicine: 
http://medicine.iupui.edu/clinpharm/ddis/main-table 
 
 


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21.4 
Appendix 4: List with examples of Drugs Known to Predispose to Torsade de 
Pointes  
No longer applicable. 


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21.5 
Appendix 5a and Appendix5b:EORTC OLQ-30 to be used in combination with 
Cancer Related Fatigue: EORTC QLQ-FA13  
http://groups.eortc.be/qol/eortc-qlq-c30 
 


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Cancer Related Fatigue: EORTC QLQ-FA13  will be used http://groups.eortc.be/qol/cancer-
related-fatigue-eortc-qlq-fa13  


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21.6 
Appendix 6 EORTC QLQ BR-23 
http://groups.eortc.be/qol/eortc-modules 
 


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21.7 
Appendix 7 GAD7 
http://www.phqscreeners.com/overview.aspx 
 
 
 


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21.8 
Appendix 8 EQ5D 
http://www.euroqol.org/  
 


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21.9 
Appendix 9: RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines  
Adapted from 123E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247  
Categorizing Lesions at Baseline 
Measurable Lesions   
Lesions that can be accurately measured in at least one dimension. 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5-8 mm). 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.   
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.  
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions.  
Non-measurable disease  
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
Bone disease: Bone disease is non-measurable with the exception of soft tissue components 
that can be evaluated by CT or MRI and meet the definition of measurability at baseline.  
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be 
recorded either as target or non-target disease.  Cystic lesions thought to represent cystic 
metastases can be measurable lesions, if they meet the specific definition above.  If 
non-cystic lesions are also present, these are preferred as target lesions. 
Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
Recording Tumor Assessments  


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All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required 
scans must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.  
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study.  
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used. 
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-target disease  
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, 
INCREASED.  Multiple non-target lesions in one organ may be recorded as a single item on 
the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
Objective response status at each evaluation 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.  
Target disease 
Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All target 
lesions must be assessed. 


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Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions.  The short diameter is used in the sum for target 
nodes, while the longest diameter is used in the sum for all other target lesions.  All target 
lesions must be assessed.  
Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  Stable 
can follow PR only in the rare case that the sum increases by less than 20% from the nadir, 
but enough that a previously documented 30% decrease no longer holds.  
Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is observed 
during therapy), with a minimum absolute increase of 5 mm.  
Indeterminate.  Progression has not been documented, and  
one or more target measurable lesions have not been assessed,  
or assessment methods used were inconsistent with those used at baseline, 
or one or more target lesions cannot be measured accurately (eg, poorly visible unless due to 
being too small to measure), 
or one or more target lesions were excised or irradiated and have not reappeared or 
increased.  
Non-target disease 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  All 
lymph nodes must be ‘normal’ in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the 
normal limits.  
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or PR in 
target disease, progression due to unequivocal increase in non-target disease should be rare.  
Indeterminate: Progression has not been determined and one or more non-target sites were 
not assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  If 
repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion. 
 
 


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Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status.  
Subjective progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.  
Table 1. Objective Response Status at each Evaluation  
   Target Lesions 
Non-target Disease 
New Lesions 
Objective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Indeterminate or Missing  
No 
PR 
PR 
Non-CR/Non-PD, 
Indeterminate, or Missing 
No 
PR 
SD 
Non-CR/Non-PD, 
Indeterminate, or Missing 
No 
Stable 
Indeterminate or Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used: 
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease Only 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Indeterminate 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 


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21.10 
Appendix 10: Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
http://www.wma.net/en/30publications/10policies/b3/index.html  
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002  
55th WMA General Assembly, Tokyo 2004 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient's best interest when providing 
medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving 
human subjects. 


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6.         The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for 
all human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to 
the environment. 
12.       Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and 
burdens. 


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           Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in the 
research in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
           When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, modify 
or immediately stop the study.            
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The protocol 
should include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for treating 
and/or compensating subjects who are harmed as a consequence of participation in the 
research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 


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Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final 
report to the committee containing a summary of the study’s findings and conclusions.  
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
 
           After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in writing, 
the non-written consent must be formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 


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27.       When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the physician must 
seek that assent in addition to the consent of the legally authorised representative. The 
potential subject’s dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the research  
group. In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot be 
delayed, the study may proceed without informed consent provided that the specific reasons 
for involving subjects with a condition that renders them unable to give informed consent 
have been stated in the research protocol and the study has been approved by a research 
ethics committee. Consent to remain in the research must be obtained as soon as possible 
from the subject or a legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek informed 
consent for its collection, storage and/or reuse. There may be exceptional situations where 
consent would be impossible or impracticable to obtain for such research. In such situations 
the research may be done only after consideration and approval of a research ethics 
committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 


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           Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results 
must be published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports of research 
not in accordance with the principles of this Declaration should not be accepted for 
publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 


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21.11 
Appendix 11: National Cancer Institute Common Terminology Criteria for Adverse 
Events  NCI CTCAE version 4.0 
 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, 
not an average. 
 
When 2 criteria are available for similar toxicities, the one resulting in the more severe 
grade should be used. 
 
The evaluator must attempt to discriminate between disease / treatment and related signs 
/ symptoms. 
 
An accurate baseline prior to therapy is essential. 
Please use the pdf from the following website: 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf  
21.12 
Appendix 12: Assessment of response to neoadjuvant chemotherapy 
Definition of response by physical examination and imaging tests 
Clinical (c) and imaging (i) response will be assessed by physical examination and imaging tests. 
Sonography or MRI are the preferred examination, however, if sonography appears not to provide 
valid results or is not performed; other imaging tests will be considered with the following priority: 
MRI, mammography, computed tomogram. The same imaging method should be considered for 
the measurement before and after treatment. 
• 
Clinical complete response (cCR) – (iCR) 
Complete disappearance of all tumor signs in the breast as assessed by imaging test. The response 
of the axillary nodes is not to be considered. 
• 
Clinical partial response (cPR) – (iPR) 
Reduction in the product of the two largest perpendicular diameters of the primary tumor size by 
50% or more assessed by palpation or imaging test. In patients with multifocal or multicentric 
disease, the lesion with the largest diameters should be chosen for follow-up. The response of the 
axillary nodes is not to be considered. 
• 
Clinical stable disease (cNC) – (iNC) 
No significant change in tumor size during treatment. This category includes no change, an 
estimated reduction of the tumor area by less than 50%, or an estimated increase in the size of the 
tumor area lesions of less than 25% measured by palpation or imaging test. 
• 
Clinical progressive disease (cPD) 
Development of new, previously undetected lesions, or an estimated increase in the size of pre-
existing lesions by 25% or more after at least two cycles of therapy. 
For all these defined categories of efficacy, the proportion of patients with success will be 
determined and appropriate confidence intervals will be calculated. 
 
Patients in whom success cannot be determined (e.g. patients in whom histology is not 
evaluable) will be included in the denominator, i.e. these patients will affect the success rate in the 
same way as treatment failures. The clinical tumor response by palpation prior to surgery will also 
be presented, if applicable 
 


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21.13 
Appendix 13 Administrative Letter 1 
 
 
 


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21.14 
Appendix 14 Administrative Letter 2 
 
 
 


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21.15 
Appendix 15 Administrative Letter 3 
 
 
 


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21.16 
Appendix 16 Administrative Letter 4 
 


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21.17 
 
Appendix 17 Administrative Letter 5 
 


 
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81 Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, 
preferentially inhibits proliferation of luminal estrogen receptor positive human breast 
cancer cell lines in vitro. Breast Cancer Research 2009; 11(5):R77. 
82 FINAL REPORT, Sponsor Reference No. 12LJ025, A 15-Week Toxicity Study of PD-0332991 
by Oral Gavage Administration in Rats with a 4-Week Recovery Period, SPONSOR: 
Pfizer Worldwide Research and Development Drug Safety Research & Development 
83  Miner PB Jr, Allgood LD, Grender JM.  Comparison of gastric pH with omeprazole 
magnesium 20.6 mg (Prilosec OTC) o.m. famotidine 10 mg (Pepcid AC) b.d. and 
famotidine 20 mg b.d. over 14 days of treatment.  Aliment Pharmacol Ther 2006; 
25:103-9. 
84 Weberg R, Berstad A, Osnes M.  Comparison of low-dose antacids, cimetidine, and placebo 
on 24-hour intragastric acidity in healthy volunteers.  Digestive Diseases and 
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85 D. J. Slamon, S. A. Hurvitz, S. Applebaum, J. A. Glaspy, M. K. Allison, B. A. DiCarlo, R. D. 
Courtney, S. T. Kim, S. Randolph, R. S. Finn. Phase I study of PD-0332991, cyclin D kinase 
(CDK) 4/6 inhibitor in combination with letrozole for first line treatment of patients with 
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86 F. Marmé, B. Lederer, J.U. Blohmer, S.D. Costa, C. Denkert, H. Eidtmann, B. Gerber, C. 
Hanusch, J. Hilfrich, J. Huober, C. Jackisch, S. Kümmel, S. Loibl, S. Paepke, M. Untch, G. von 
Minckwitz, A. Schneeweiss.Utility of the CPS+EG staging system in hormone receptor-
positive, human epidermal growth factor receptor 2-negative breast cancer treated with 
neoadjuvant chemotherapy. Eur J Cancer. 2015 Dec 13;53:65-74. 


 
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87 Chia S. Testing for Discordance at Metastatic Relapse: Does It Matter?  J Clin Oncol 
2012;30(6):575-6. 
88 Niikura N, et al.  Loss of human epidermal growth factor receptor 2 (HER2) expression in 
metastatic sites of HER2-overexpressing primary breast tumors.  J Clin Oncol 2012;30:593-
9. 
89 Miller TW, et al. ERalpha-dependent E2F transcription can mediate resistance to estrogen 
deprivation in human breast cancer. Cancer Discov 2011;1:338–51. 
90 Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour 
suppressor is a common event in basal-like and luminal B breast carcinomas. Breast 
Cancer Res 2008;10:R75. 
91 Hui R, Cornish AL, McClelland RA et al. Cyclin D1 and estrogen receptor messenger RNA 
levels are positively correlated in primary breast cancer. Clinical cancer research : an 
official journal of the American Association for Cancer Research 1996; 2: 923-928. 
92 Michalides R, Hageman P, van Tinteren H et al. A clinicopathological study on 
overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast 
cancer. British journal of cancer 1996; 73: 728-34. 
93 Nielsen NH, Emdin SO, Cajander J, Landberg G. Deregulation of cyclin E and D1 in breast 
cancer is associated with inactivation of the retinoblastoma protein. Oncogene 1997; 14: 
295-304. 
 
94 Zukerberg LR, Yang WI, Gadd M et al. Cyclin D1 (PRAD1) protein expression in breast 
cancer: approximately one-third of infiltrating mammary carcinomas show overexpression 
of the cyclin D1 oncogene. Modern pathology : an official journal of the United States and 
Canadian Academy of Pathology, Inc 1995; 8: 560-7. 
95 Jirström K, Stendahl M, Rydén L et al. Adverse Effect of Adjuvant Tamoxifen in 
Premenopausal Breast Cancer with Cyclin D1 Gene Amplification. Cancer research 2005; 
65: 8009-16. 
96 Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour 
suppressor is a common event in basal-like and luminal B breast carcinomas. Breast 
Cancer Res 2008;10:R75. 
97 Koboldt DC, et al.Comprehensive molecular portraits of human breast tumours. Nature 
2012;490:61–70. 
98 Harbour JW, et al.  Cdk phosphorylation triggers sequential intramolecular interactions 
that progressively block Rb functions as cells move through G1. Cell 1999;98:859–69 


 
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99 Leung BS, and Potter AH. Mode of estrogen action on cell proliferative kinetics in CAMA-1 
cells. I. Effect of serum and estrogen. Cancer Invest 1987;5:187–94. 
100 Sherr CJ. Cancer cell cycles. Science 1996;274:1672–7. 
101 Sherr CJ, and Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase 
progression. Genes Dev 1999;13:1501–12. 
102 van den Heuvel S, and Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle 
control. Science 1993;262:2050–4. 
103 Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995;81:323–30. 
104 Miller TW, et al.  ERalpha-dependent E2F transcription can mediate resistance to 
estrogen deprivation in human breast cancer.  Cancer Discov 2011;1:338–51. 
105 Herschkowitz JI,  et al.  The functional loss of the retinoblastoma tumour suppressor is a 
common event in basal-like and luminal B breast carcinomas.  Breast Cancer Res 
2008;10:R75. 
106 Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, et al.Whole-genome analysis informs 
breast cancer response to aromatase inhibition. Nature 2012;486:353–60. 
107 Study Of Letrozole With Or Without PD 0332991 For The First-Line Treatment Of 
Hormone-Receptor 
Positive 
Advanced 
Breast 
Cancer. 
http://clinicaltrials.gov/show/NCT00721409 
108 Finn R, et al.  Results of a randomized Phase 2 study of PD-0332991, a cyclin-dependent 
kinase (CDK) 4/6 Inhibitor, in combination with letrozole vs letrozole alone for first-line 
treatment of ER+/HER2- advanced breast cancer (BC).  San Antonio Breast Cancer 
Symposium 2012;S1-6:S1-6. 
109 Finn RS, et al.  Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent 
kinase (CDK) 4/6 inhibitor, in combination with letrozole versus letrozole alone for first-
line treatment of ER+/HER2- advanced breast cancer.  Annals of Oncology 2012;23:ii43-5. 
110 Leonard JP, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in 
patients with mantle cell lymphoma. Blood 2012;119:4597–607. 
111 Roberts PJ, et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer 
therapy. J Natl Cancer Inst 2012;104:476–87. 
112 Hudis CA, Barlow WE, Costantino JP et al., Proposal for standardized definitions for 
efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007 
May 20;25(15):2127-32.  
113 James L. Khatcheressian, Patricia Hurley, Elissa Bantug, Laura J. Esserman, Eva Grunfeld, 
Francine Halberg,Alexander Hantel, N. Lynn Henry, Hyman B. Muss, Thomas J. Smith, 
Victor G. Vogel, Antonio C. Wolff,Mark R. Somerfield, and Nancy E. DavidsonJCO 


 
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November 5, 2012 JCO.2012.45.9859 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.45.9859  
114 Aaronson NK, Ahmedzai S, Bergman B, et al., for the European Organization for Research 
and Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International 
Clinical Trials in Oncology. JNCI 85: 365-376, 1993 
115 Sprangers MAG, Groenvold M, Arraras JI, et al.. The European Organisation for Research 
and Treatment of Cancer: Breast Cancer Specific Quality of Life Questionnaire Module: 
First results from a three-country field study. J. Clin. Oncol. 14: 2756-2768, 1996. 
116 Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality of 
life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, 
the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur 
J Cancer. 1999;35:939–41. 
117 Sprangers MAG, Cull A, Groenvold M, et al. The European Organization for Research and 
Treatment of Cancer approach to developing questionnaire modules: An update and 
overview. EORTC Quality of Life Study Group. Qual. Life Res. 7: 291-300, 1998. 
118 Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med. 2001; 33: 337-43. 
119 Rasanen P, Roine E, Sintonen H, et al. Use of quality-adjusted life years for the estimation 
of effectiveness of health care: A systematic literature review. Int J Technol Assess Health 
Care. 2006; 22: 235-41. 
120 Bailey H, Kind P. Preliminary findings of an investigation into the relationship between 
national culture and EQ-5D value sets. Qual Life Res. 2010; 19: 1145-54. 
121 Norman R, Cronin P, Viney R, et al. International comparisons in valuing EQ-5D health 
states: a review and analysis. Value Health. 2009; 12: 1194-200. 
122 Khatcheressian JL, Hurley P, Bantug E, et al. Breast cancer follow-up and management 
after primary treatment: american society of clinical oncology clinical practice guideline 
update. J Clin Oncol. 2013 Mar 1;31(7):961-5 
123 E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
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 
Version: 
5.0 final 
Date: 
September, 21st 2020 
Biostatistician:  
 
 


 
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Protocol number: GBG-78 - BIG 1-13 - NSABP-B-54-I 
 
Protocol 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 
 
Version: 5.0 final 
Version Date: September, 21st 2020 
 
 
  
 
 
 
  
 
Date 
 
  
 
 
 
   
 
Date 
 
  
 
 
 
  
 
Date 
 
  
 
 
 


 
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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS .........................................................................................................3 
2. 
ABBREVIATIONS ..................................................................................................................6 
3. 
INTRODUCTION ....................................................................................................................8 
4. 
STUDY DESIGN ....................................................................................................................9 
4.1 
Overall design and treatment ..........................................................................................9 
4.2 
Randomization/stratification ..........................................................................................10 
4.3 
Sample size calculation.................................................................................................10 
5. 
STUDY OBJECTIVES, ENDPOINTS AND COVARIATES ...................................................13 
5.1 
Objectives and endpoints ..............................................................................................13 
5.1.1 
Primary efficacy ....................................................................................................13 
5.1.2 
Key Secondary ......................................................................................................14 
5.1.3 
Secondary efficacy ................................................................................................15 
5.1.3.1 
Overall survival (OS) .........................................................................................15 
5.1.3.2 
Locoregional recurrences-free interval ...............................................................15 
5.1.3.3 
Distant disease free survival ..............................................................................15 
5.1.3.4 
iDFS in patients with luminal-B tumors ...............................................................16 
5.1.4 
Safety ...................................................................................................................16 
5.1.5 
Compliance ...........................................................................................................17 
5.1.5.1 
Extent of exposure ............................................................................................18 
5.1.5.2 
Modification of treatment schedule ....................................................................19 
5.1.5.3 
Treatment discontinuation .................................................................................20 
5.1.5.4 
Changes in endocrine treatment ........................................................................20 
5.1.5.5 
Other .................................................................................................................21 
5.1.6 
Quality of life .........................................................................................................21 
5.2 
Baseline variables .........................................................................................................22 
5.2.1 
BMI .......................................................................................................................22 
5.2.2 
Ki-67 .....................................................................................................................23 
5.2.3 
HER2 status ..........................................................................................................23 
5.2.3.1 
Calculation prior to study protocol version C8 ....................................................23 
5.2.3.2 
Calculation with study protocol version C8 and later versions ............................23 
5.2.4 
Hormone-receptor status .......................................................................................23 
5.2.4.1 
Calculation prior to study protocol version ..........................................................23 
5.2.4.2 
Calculation with study protocol version        and later versions ...........................23 
5.2.5 
CPS-EG score ......................................................................................................25 


 
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5.2.5.1 
Calculation prior to study protocol version C8 ....................................................25 
5.2.5.2 
Calculation with study protocol version C8 .........................................................27 
5.2.5.3 
Calculation with study protocol version C8 V3 ....................................................29 
5.3 
Subgroups or covariates of interest ...............................................................................31 
5.3.1 
Subgroups ............................................................................................................31 
5.3.2 
Covariates.............................................................................................................31 
6. 
ANALYSIS SUBSETS..........................................................................................................33 
6.1 
Data subsets.................................................................................................................33 
6.1.1 
Intent-to-treat set ...................................................................................................33 
6.1.2 
Per protocol population for efficacy ........................................................................33 
6.1.3 
Safety analysis set ................................................................................................33 
6.1.4 
Evaluable subsets for QoL ....................................................................................34 
6.2 
Interim analyses sets ....................................................................................................34 
7. 
ADAPTIVE DESIGN.............................................................................................................35 
7.1 
First efficacy interim analysis ........................................................................................35 
7.1.1 
Re-estimation of sample size.................................................................................36 
7.1.2 
Early stopping of the trial due to futility...................................................................37 
7.2 
Second efficacy interim analysis ...................................................................................37 
7.2.1 
Early stopping of the trial .......................................................................................38 
7.3 
Final Analysis ...............................................................................................................38 
7.4 
Interim Overall Survival Analysis ...................................................................................38 
7.5 
Handling of blinding and unblinding ...............................................................................39 
8. 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .........................40 
9. 
DATA SCREENING AND ACCEPTANCE ............................................................................42 
9.1 
General principles .........................................................................................................42 
9.2 
Database lock ...............................................................................................................42 
9.3 
Data handling and electronic transfer of data ................................................................42 
9.4 
Handling of missing and incomplete data, drop-outs ......................................................42 
9.4.1 
Missing data in CPS-EG score ..............................................................................42 
9.4.2 
Missing dates ........................................................................................................42 
9.4.3 
Missing Data in Time-To-Event Endpoints .............................................................43 
9.4.4 
Date of Last Contact Derivation .............................................................................43 
9.4.5 
Death Date ............................................................................................................44 
9.4.6 
Missing data in safety analysis ..............................................................................44 


 
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9.5 
Evaluable subject subset(s) ..........................................................................................44 
9.6 
Outliers .........................................................................................................................44 
9.7 
Distributional characteristics..........................................................................................44 
9.8 
Testing/validation plan ..................................................................................................45 
10. 
STATISTICAL METHODS OF ANALYSIS .......................................................................46 
10.1 
General principles .........................................................................................................46 
10.1.1 
Analyses for Binary Data .......................................................................................46 
10.1.2 
Analyses for Categorical Data ...............................................................................46 
10.1.3 
Analyses for Continuous Data ...............................................................................46 
10.1.4 
Analyses for Time-to-Event Data ...........................................................................46 
10.1.5 
Standard Derivations and Reporting Conventions ..................................................47 
10.2 
Subject accountability ...................................................................................................47 
10.3 
Protocol deviations .......................................................................................................48 
10.4 
Demographic and baseline characteristics ....................................................................48 
10.5 
Safety analyses ............................................................................................................50 
10.6 
Compliance analyses ....................................................................................................52 
10.6.1 
Investigational product ..........................................................................................52 
10.6.2 
Non-investigational product ...................................................................................53 
10.7 
Primary efficacy analyses .............................................................................................54 
10.7.1 
Estimation of outcomes .........................................................................................54 
10.7.2 
Hypotheses to be tested ........................................................................................54 
10.7.3 
Subgroup analysis.................................................................................................55 
10.7.4 
Regression analysis ..............................................................................................55 
10.7.5 
Sensitivity/Supportive Analyses .............................................................................55 
10.8 
Secondary efficacy analyses .........................................................................................55 
10.8.1 
Estimation of outcomes .........................................................................................56 
10.8.2 
Hypotheses to be tested ........................................................................................56 
10.8.3 
Subgroup analysis.................................................................................................56 
10.8.4 
Regression analysis ..............................................................................................56 
10.9 
Quality-of-life analyses ..................................................................................................57 
10.10 
Follow-Up Therapy....................................................................................................57 
11. 
LITERATURE CITATIONS / REFERENCES ....................................................................58 
 


 
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2. 
ABBREVIATIONS 
ATDI 
Actual total dose intensity 
AE 
Adverse event 
AI 
aromatase inhibitor 
AESI 
Adverse Events of special interest 
ALAT 
Alanine aminotransferase 
ASAT 
Aspartate aminotransferase 
CHW 
Cui, Hung and Wang method  
CI 
Confidence interval 
CP 
Conditional power 
CPS-EG 
Clinical-pathological stage – estrogen/grade 
CRF 
Case report form 
CTC 
Common Terminology Criteria 
(NCI-)CTCAE 
(National Cancer Institute) Common Terminology Criteria for Adverse 
Events 
DMP 
Data management plan 
EIA 
Efficacy Interim Analysis 
EP 
Evaluable Patients 
EOT 
End of therapy 
EORTC 
European Organisation for Research and Treatment of Cancer 
ER 
Estrogen receptor status 
ET 
Endocrine treatment / therapy 
FDA 
Food and Drug Administration 
GBG 
German Breast Group 
HR 
Hazard ratio 
iDFS 
Invasive Disease Free Survival 
ITT 
Intent-to-treat 
LHRH 
Luteinizing Hormone Releasing Hormone 
LRRFI 
Loco-regional relapse-free interval 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
n.a. 
not applicable 
NACT 
neo-adjuvant chemotherapy  
NYHA 
New-York Heart Association 
QoL 
Quality of Life 
OS 
Overall Survival 
PP 
Per protocol 
RTD 
relative total dose 
RDTI 
relative total dose intensity 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Systems 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 


 
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SSR 
Sample Size Re-Estimation 
t.b.d. 
to be determined 
Table of abbreviation will be updated upon finalization of statistical report. 


 
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3. 
INTRODUCTION 
The PENELOPEB study is a prospective, international, multicenter, randomized, double-
blinded, placebo-controlled, parallel-group Phase III study comparing the efficacy and the 
safety of thirteen cycles adjuvant treatment with palbociclib versus placebo in high risk 
patients (CPS-EG score >= 3 or (CPS-EG score = 2 and ypN+)) without pathological 
complete response after neoadjuvant chemotherapy for hormone-receptor-positive / 
HER2-normal primary breast cancer. Patients will receive standard adjuvant endocrine 
treatment after completion of adequate local surgical and radio therapeutic treatment. 
There will be two interim analyses to monitor futility and to test for overwhelming efficacy 
and the study is designed for sample size adaptation. The final analysis will be performed 
to test for differences between the treatment arms in the primary endpoint invasive 
disease-free survival (iDFS). 
This SAP describes the statistical procedures required within the group-sequential, 
adaptive design for sample size adaptation. The planned safety and compliance analyses 
will be described. Templates for tables and figures will be given. 
Details on the cost analyses and health economic evaluation, on the analysis of 
biomarkers, and on the analysis of pharmacokinetics will be described in separate 
analyses plans. 


 
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4. 
STUDY DESIGN 
4.1 
Overall design and treatment 
The PENELOPEB study is a prospective, international, multicenter, randomized, double-
blinded, placebo-controlled, parallel-group Phase III study comparing the efficacy and the 
safety of thirteen cycles (1 year) adjuvant treatment with palbociclib versus placebo in 
high risk (either CPS-EG score >= 3 or CPS-EG score = 2 and ypN+) patients without 
pathological complete response after neoadjuvant chemotherapy for hormone-receptor-
positive / HER2-normal primary breast cancer. Patients will receive standard adjuvant 
endocrine treatment after completion of adequate local surgical and radio therapeutic 
treatment. 
The study has an adaptive design with two interim efficacy analyses to allow for sample 
size adaptation and to assess safety, including unexpected toxicity. The trial is designed 
to stop due to futility in each interim analysis and due to efficacy in the second interim 
analysis. The adaptive design procedure will be described in detail in section 7. 
Figure 1: PenelopeB Study Design 
 


 
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4.2 
Randomization/stratification 
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 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.) 
• 
Ki-67 value (>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. 
4.3 
Sample size calculation 
Sample size was calculated based on the analysis of the primary endpoint, iDFS.  
During the study the sample size estimation was amended twice. 
Original protocol version until and including protocol version C8 
For the placebo plus endocrine agent arm a 3-year iDFS rate of 0.72 was assumed based 
on an analysis of the GBG meta-database for patients with CPS-EG score ≥3. For the 
palbociclib plus endocrine agent arm a 3-year iDFS rate of 0.80 was assumed. This 
corresponds to a palbociclib/placebo HR=0.67. To detect a clinical relevant difference of 
0.08 with a power of 85% a minimal number of 233 events for iDFS endpoint are required 
using a two-sided stratified log-rank test at an overall two-sided significance level of 0.05.  
Additional to the above assumptions, an exponential distribution with a common hazard 
rate (0.04383 subjects per year) for both arms was assumed for time to drop-out. Applying 
a 1:1 randomization and a non-uniform enrollment rate of 25 subjects per month at the 
peak (the peak enrollment rate is estimated to be reached 1 year after enrollment start), 
800 patients will be enrolled within 36 months. The maximum study duration is estimated 
to be 5.9 years. A median follow up time at the final analysis on iDFS is estimated to be 
around 50 months. 
Power calculation is also done for the endpoint of iDFS excluding second primary of non-
breast cancer. Assuming that not more than 15% of iDFS event are second primary of 


 
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non-breast cancer, there is 79% power to detect statistical significance between the 2 
arms with a 2-sided significance level of 0.05. 
Protocol version D9 and E10 
For the arm placebo plus endocrine agent a 3-year iDFS rate of 0.77 was assumed based 
on an analysis of the GBG meta-database for patients with CPS-EG score ≥3 or Score 2 
and ypN+ disease. For the palbociclib plus endocrine agent arm a 3-year iDFS rate of 
0.836 was assumed. This corresponds to a palbociclib/placebo HR=0.685. To detect this 
HR with a power of 85% a minimal number of 255 events for iDFS endpoint are required 
using a two-sided stratified log-rank test at an overall two-sided significance level of 0.05.  
Additional to the above assumptions, an exponential distribution with a common hazard 
rate (0.04383 subjects per year) for both arms was assumed for time to drop-out. Applying 
a 1:1 randomization and a non-uniform enrollment rate of 40 subjects per month at the 
peak, it was originally estimated that 1100 subjects will need to be enrolled.  
Rationale of assumptions on sample size determination 
The clinical-pathologic stage – estrogen/grade (CPS-EG) (1,2) combining clinical 
stage before neoadjuvant treatment, pathological stage after neoadjuvant treatment, 
grading and estrogen-receptor status can be used to identify high-risk patients. The 
score was further validated on 2454 patients with HR-positive/HER2-normal tumors 
from the German neoadjuvant studies’ meta-database (3). 
Estimation of 3-year iDFS rate was performed on the basis of a meta-database containing 
2659 HR+/HER2- patients who received neoadjuvant therapy (about 18-24 weeks), 
surgery (average period of around 6 weeks after last cycle of chemotherapy) and radiation 
(about 6 weeks). In the PENELOPEB study patients will be randomized after radiation or 
rehabilitation, if applicable, which is estimated to be approximately 9 months after start of 
neoadjuvant chemotherapy. Given these assumptions a 3-year iDFS rate of 0.77 was 
estimated for the control arm of patients with CPS-EG score >= 3 or CPS-EG score = 2 
and ypN+. The assumption of exponential distribution on time-to-iDFS event for the 
control arm may affect the duration of study. This assumption cannot be assessed due to 
lack of patient-level data on surgery date.  
 


 
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Figure 2: Survival after completion of radiotherapy (iDFS adjusted) in 2659 patients with HR-
positive/HER2-normal tumors from the German neoadjuvant studies’ meta-database by 
CPS-EG score. The lower curve includes patients with 3 or more score points or score 2 and 
ypN+ status and the upper curve patients with less than 2 score points or score 2 and ypN. 
 
 
Protocol version G11 
The first efficacy interim analysis in April 2017 resulted in an increase of both sample size 
(n=1250) and number of events (290 events) based on calculated HR and a pre-defined 
threshold for conditional power. The sample size of 1250 patients is included in study 
protocol G11. The final analysis will take place when 290 iDFS events are observed which 
is estimated to occur about 6.5 years after first patient randomized (for details please refer 
to section 7.1). 
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. 


 
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5. 
STUDY OBJECTIVES, ENDPOINTS AND COVARIATES 
5.1 
Objectives and endpoints 
5.1.1 
Primary efficacy 
The primary objective of the study is to compare invasive disease-free survival (iDFS) for 
palbociclib vs. placebo in 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. 
The primary endpoint is invasive disease-free survival (iDFS) and is defined according to 
Hudis (4) as the time in months between randomization and first event. The following 
events will be considered as first events: ipsi- or contralateral invasive in-breast or loco-
regional recurrence, distant recurrence, death from breast cancer, death from non-breast 
cancer cause, death from unknown cause, invasive contralateral breast cancer, or second 
primary invasive cancer (non-breast). 
Events are documented on the relapse form (RF) or on the death report form (DRF). The 
following dates of events are available on RF and DRF: 
• 
date of loco-regional recurrence (for ipsi- or contralateral invasive in-breast or loco-
regional recurrence) 
• 
date of distant recurrence 
• 
date of second primary invasive cancer (non-breast) 
• 
date of death  
The iDFS time of patients with iDFS event is calculated as the interval between date of 
randomization and the first date of event.  
iDFS (in months) will be calculated as (first event date − randomization date +1)/30.4. 
The cut-off date for the analysis of iDFS is event-driven. After the first efficacy interim 
analysis the number of events was increased and now the final analysis will be performed 
after 290 events have been collected. 
The iDFS time of patients without iDFS event will be censored at the date of last disease 
assessment (where the patient was known to be alive and tumor-free/without new signs of 
disease). For patients who discontinued study treatment and have no follow-up visit, the 
maximum of the examination dates on 
       without significant findings and the 
examination dates on  
        will be used as date of last disease assessment. For 
patients with follow-up visit, the date of last disease assessment is documented on Follow 
up form FU01. 
• 
If the patient status was “alive and tumor-free/without new signs of disease” in the FU 
assessment, the date of follow-up assessment will be used as censoring date.  


 
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• 
If the patient status was “lost to follow-up” in the FU assessment, the date of follow-up 
assessment of a previous FU assessment will be used as censoring date where the 
patient was known to be alive and tumor-free/without new signs of disease.  
• 
If the patient status was “Withdrawal of informed consent” in the FU assessment, the 
date of follow-up assessment of a previous FU assessment will be used as censoring 
date where the patient was known to be alive and tumor-free/without new signs of 
disease.  
Patients who were randomized but had disease relapse prior to randomization will have 
their iDFS times censored at study Day 1 (i.e., randomization). Patients alive who do not 
have post baseline contact will have their iDFS times censored at Day 1 (i.e., 
randomization). The main iDFS analysis will be performed regardless of the initiation of 
new anticancer therapies, i.e., patients receiving further anticancer therapy before disease 
relapse or occurrence of second primary invasive non-breast cancers or death will be 
assigned as an iDFS events at the first date of relapse or occurrence of a second primary 
cancer (non-breast) or death. Sensitivity analyses will be performed as described in 
section 10.7.5. 
5.1.2 
Key Secondary  
The key secondary objective is to compare iDFS excluding second primary invasive non-
breast cancers for palbociclib vs. placebo in 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. 
The key secondary endpoint is iDFS excluding second primary invasive non-breast 
cancers and is defined as the time in months between randomization and first event. The 
following events will be considered as first events: ipsi- or contralateral invasive in-breast 
or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-
breast cancer cause, death from unknown cause, or invasive contralateral breast cancer. 
Patients who were randomized but had disease relapse prior to randomization will have 
their iDFS times censored at study Day 1 (i.e., randomization). Patients alive who do not 
have post baseline contact will have their iDFS times censored at Day 1 (i.e., 
randomization). The main analysis of iDFS excluding second primary invasive non-breast 
cancers will be performed regardless of the initiation of new anticancer therapies, i.e., 
patients receiving further anticancer therapy before disease relapse or occurrence of a 
second primary invasive non-breast cancers or death will be assigned as an iDFS events 
at the first date of relapse or death. Two sensitivity analyses will be performed (D and E 
as described in section 10.7.5). 


 
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5.1.3 
Secondary efficacy 
5.1.3.1 
Overall survival (OS) 
Overall survival (OS) is defined as the time period in months between randomization and 
death due to any cause. OS (in months) is calculated as (date of death − randomization 
date +1)/30.4. Patients alive will be censored at the date of the last contact. Patients 
lacking survival data beyond randomization will have their OS times censored at study 
Day 1 (i.e., randomization).  
An interim OS analysis will be conducted at the time of final iDFS analysis. Final survival 
will be analyzed 3 years after the final analysis of iDFS. 
5.1.3.2 
Locoregional recurrences-free interval 
This endpoint is described in the study protocol as locoregional recurrences-free survival 
(LRRFS) including death as event. However, locoregional recurrences, death and distant 
recurrences are events which prevent each other from happening, i.e. are competing. This 
competing risk situation will be handled appropriately by reformulating the endpoint 
LRRFS into locoregional recurrences-free interval (LRRFI) which is defined as the time 
period in months between randomization and diagnosis of any stand-alone loco-regional 
(ipsilateral breast (invasive or DCIS), local/regional lymph nodes) recurrence of disease, 
or any stand-alone invasive contralateral breast cancer, whichever occurs first. Distant 
recurrence, second primary invasive non-breast cancers and death are considered 
competing events. In case loco-regional recurrence of disease or invasive contralateral 
breast cancer are documented on the same date as a competing event, it will be 
considered the respective competing event in the analysis. If more than one competing 
event is documented on the same date as an event of interest, the following hierarchy 
applies: 1) distant recurrence, 2) second primary invasive non-breast cancers and 3) 
death.  
Locoregional events are documented on the relapse form (RF) with date of loco-regional 
recurrence (for ipsi- or contralateral invasive in-breast or loco-regional recurrence). LRRFI 
(in months) will be calculated as (first LRRFI event date − randomization date +1)/30.4. 
LRRFI time of patients without LRRFI event will be censored at the date of last disease 
assessment. Patients alive who do not have post baseline disease assessment will have 
their LRRFI times censored at Day 1 (i.e., randomization). The LRRFI analysis will be 
performed regardless of the initiation of new anticancer therapies.  
LRRFI will be analyzed at the time of final iDFS analysis. 
5.1.3.3 
Distant disease free survival 
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 


 
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(non-breast) or death due to any cause, whichever occurs first. Distant disease events are 
documented on the relapse form (RF) with date of distant recurrence. DDFS (in months) 
will be calculated as (first DDFS event date − randomization date +1)/30.4. Distant 
disease events will be considered in the analysis regardless of loco-regional recurrence 
being documented on the same date. 
The DDFS time of patients without DDFS event will be censored at the date of last 
disease assessment. Patients alive who do not have post baseline disease assessment 
will have their DDFS times censored at Day 1 (i.e., randomization). The DDFS analysis 
will be performed regardless of the initiation of new anticancer therapies.  
DDFS will be analyzed at the time of final iDFS analysis. 
5.1.3.4 
iDFS in patients with luminal-B tumors 
Analysis and censoring of iDFS in the subgroup of patients with luminal-B tumors will be 
performed similar to the analysis of the primary endpoint. However, no sensitivity analysis 
will be performed. This subgroup was initially planned to be determined by PAM50 (cut-
point t.b.d.) or any other commercially available test (t.b.d.) before unblinding data. In the 
translational research committee (TRC) meeting during SABCS 2018 it was decided to 
use HTG-Seq due to a broader panel with 2000 genes and less consumption of tissue. 
The assessment was performed in a laboratory which had no access to the treatment 
allocation of the patients and was provided to GBG in June 2020. Count data from the 
HTG measurements of tissue from post-neoadjuvant residual invasive disease of the 
breast were used to calculate the AIMS (Absolute Assignment of Breast Cancer Intrinsic 
Molecular Subtype) subtype. The AIMS variable is categorical with five categories: 
“Basal”, “Her2”, “LumA”, “LumB”, and “Normal”. The subtype of highest posterior 
probability was assigned. Patients with the AIMS variable “LumB” should constitute the 
subgroup of interest. It turned out that tissue from post-neoadjuvant residual invasive 
disease of the breast of 906 patients was available and that 64 (7%) of these patients 
were “LumB”. The pre-planned secondary endpoint iDFS in patients with luminal-B tumors 
can not be analyzed due to this small subgroup. Further exploratory analysis will be 
performed which will be described in a separate biomarker SAP.  
5.1.4 
Safety 
Safety will be assessed on the basis of any grade 1-4 adverse event (AE) including 
adverse events of special interest and serious adverse events (including AEs of grade 5). 
AEs are documented by type and severity as graded by National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0; seriousness, 
and relationship to study drug (palbociclib/placebo). 
An AE is defined as any untoward medical occurrence in a patient administered a 
medicinal product which does not necessarily have a causal relationship with this 


 
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treatment. It also includes any undesirable clinical or laboratory changes which do not 
commonly occur in the patient.  
Unexpected serious adverse reactions (SUSAR) will be reported as unexpected toxicities. 
Adverse Events of special interest (AESI) are defined as a) drug-induced liver injury, 
b) pregnancy, and c) overdose with IMP, defined as the intake of more than 23 capsules 
during a cycle (e.g. more than two capsules on more than two days of a cycle, more than 
two capsules during the week of break) and in addition more than 2 capsules on the same 
day. Non-relevant overdoses with IMP (defined as intake of 22 or 23 capsules in the same 
cycle) were considered as AESI until and including protocol version D9. Treatment 
modification due to an AESI will be documented (no action taken, dose delay, dose 
reduction, interruption, permanent discontinuation of treatment).  
Documentation of AEs by the investigator are scheduled for Day 1 and 14 of 
cycles 1 and 2, on Day 1 of each of the following cycles, and at EOT. Moreover, the 
investigator will document an AE whenever he/she finds out about an occurrence. 
Hematological parameters will be documented on Day 1 and 14 of cycles 1 and 2, on 
Day 1 of each of the following cycles, and at EOT, or if clinically indicated. Blood 
chemistry and liver function tests will be performed on Day 1 of cycles 1, 2, 3, 7, 11, and 
at EOT. Post-baseline blood chemistry values for ASAT, ALAT, bilirubin, alkaline 
phosphatases, serum creatinine, and serum albumin are not recorded on the CRF but 
corresponding CTCAE grades will be collected.  
HbA1c clinical abnormality (yes/no) will be collected and documented as glucose 
intolerance on the 
 
 in case of an abnormal finding. 
Predefined AEs will be documented on the following CRF  
 
 
 
 
      .         
   is not designed for documentation of multiple infections during 
one cycle. In such cases, the  
       will be used, on which in general AEs additional 
to the predefined AEs will be documented as free text AEs. 
Death will be reported on 
 
 with cause of death.  
5.1.5 
Compliance 
The date of first dose of study treatment is the earliest date of non-zero dosing of the 
study drug. The date of last dose of study treatment is the latest date of non-zero dosing 
of the study drug. 
In this study, study drug refers to palbociclib or placebo and study treatment refers to one 
of the following: 
- 
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 


 
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- 
Arm B: Placebo once daily Day 1 to Day 21 followed by 7 days off treatment in a 
28-day cycle for thirteen cycles 
 
5.1.5.1 
Extent of exposure 
The duration of palbociclib/placebo exposure is defined as: last dose date – first dose 
date + 7 days regardless of unplanned intermittent discontinuations. 
The total number of cycles includes all cycles including the last cycle in which doses 
were given even if the cycle was not completed. 
The cumulative dose (mg) is defined as the sum of all doses from cycle 1 to and 
including the last cycle, where the last cycle is based on the investigator’s report in the 
CRF. Overdoses are documented on the SAE form. The information concerning excessive 
doses will be included in the calculation of the cumulative dose. 
RTDI is the total dose intensity within the entire treatment achieved by a patient relative to 
intended dose intensity based on the planned schedule of the treatment. RTDI will be 
calculated according to the following step-by-step algorithm:  
Planned dose (PnD) is the amount of a drug planned to be given in a cycle. PnD is 
calculated separately for each component of a therapy. 
Planned total dose (PTD) is the planned cumulative dose over the entire treatment 
duration; i.e. if a patient was planned to receive n cycles of drug, then sum the total 
amount of drug planned during those n cycles. 
i.e. 
∑
=
=
n
i
i
PD
PTD
1
mg)
(
 
Planned total dose intensity (PTDI) is the planned average dose intensity over the 
entire treatment duration (described as planned dose intensity in the study protocol),  
i.e. 
)
(
mg/week)
(
weeks
therapy
of
duration
planned
PTD
PTDI
=
 
Actual dose (AD) is the total amount of drug that the patient has received over one cycle. 
Actual total dose (ATD) is the cumulative dose of the drug that has been given over the 
treatment duration of n cycles, 
i.e. 
∑
=
=
n
i
i
AD
ATD
1
)
mg
(
 


 
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ATD is similar to the cumulative dose. 
Actual total dose intensity (ATDI) is defined as the dose intensity of what has actually 
been administered over the n cycles (described as ADI in the study protocol). 
i.e. 
)
(
mg/week)
(
weeks
therapy
of
duration
ATD
ATDI
=
 
If a patient has not received some drug at all, ATDI for this drug is considered to be 0. 
 
Relative Total Dose (RTD) is the ratio of ATD and PTD, expressed as a percentage. 
i.e. 
( )
100
%
×
= PTD
ATD
RTD
 
Relative Total Dose Intensity (RTDI) is the ratio of ATDI and PTDI, expressed as a 
percentage (described as RDI in the study protocol). 
i.e. 
( )
100
%
×
= PTDI
ATDI
RTDI
 
Note that RTDI expresses the effect of reductions, interruptions and delays as well as 
premature discontinuation of a treatment. 
The algorithm will be modified for patients who die during study treatment or who 
discontinue study treatment due to disease relapse/second primary invasive non-breast 
cancers. In the calculation of the planned total dose and the planned total dose intensity 
for these patients, the planned number of weeks of the last cycle will be equal to the 
number of weeks actually completed.  
For all other patients who discontinued treatment prematurely, the actual dose of the 
remaining weeks will be considered zero doses without delay and the last planned dose 
will be used as planned dose in the remaining weeks. 
 
5.1.5.2 
Modification of treatment schedule  
According to the protocol dose modifications may occur as dosing interruption, dose 
reduction and dose delay.  
A dosing interruption is defined as the omission of capsules within a cycle.  
The recommended starting dose of palbociclib/placebo and the reduced dose levels are 
given in table 5-1.  


 
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Table 5-1: Available Dose Levels 
Dose Level 
Palbociclib/placebo for 3 out of 4 weeks (3/1 schedule) 
Starting Dose 
125 mg/d 
-1 
100 mg/d 
-2 
75 mg/d 
Discontinue Study Treatment or consider 75mg/d (2/2 schedule) 
* Palbociclib/placebo dose reduction below 75 mg/d is not allowed, the schedule may 
move to 75mg/day two weeks on followed by two weeks off. 
A special case of interruptions are omitted cycles where the interruption is extended to a 
complete cycle, but this omitted cycle is followed by at least one cycle, even if this next 
cycle was discontinued prematurely. Omitted cycles are not the last cycle of study 
treatment. Those are considered premature treatment discontinuations. 
A dose reduction is defined as a decrease of the actual dose level by at least one dose 
level. Once a dose has been reduced for a given patient, all subsequent doses should be 
administered at that dose level, unless further dose reduction is required. The reduced 
doses in those subsequent cycles are not defined as dose reductions. Dose re-escalation 
is not allowed. 
Relevant overdoses of study medication are defined as the intake of more than 23 
capsules instead of 21 capsules during a cycle, e.g. 
• 
More than two capsules on more than two days of a cycle 
• 
More than two capsules during the week of break 
• 
More than two capsules on the same day 
Dose delays: A cycle was deemed to have been delayed if (start date of the current cycle 
– start date of previous cycle – 28) > 3. Delays of ≤ 3 days should have been documented 
in the category "organizational reasons".  In case that those categorizations could not be 
followed, the actual dose delays will be displayed. i.e. all dose delays will be displayed 
within the group "Patients with any delay". 
5.1.5.3 
Treatment discontinuation 
Permanent discontinuation of treatment will be documented with reasons. 
5.1.5.4 
Changes in endocrine treatment 
Changes in the endocrine treatment and reasons for each treatment arm and overall will 
be summarized. 


 
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5.1.5.5 
Other 
Impact of drug exposure based on the PK analysis (described in a separate analysis plan) 
on efficacy and/or safety findings will be investigated. 
 
5.1.6 
Quality of life 
Quality of life (QoL) will be evaluated using a general QoL questionnaire (EORTC QLQ-
C30), a breast cancer questionnaire (QLQ-BR23) module, a fatigue questionnaire 
(EORTC QLQ FA13 Fatigue), a mood questionnaire (GAD7) and the EQ-5D instrument. 
The QoL questionnaires will be completed in cycle 1, 3, 5, 7, 9, 11, and End of Treatment 
and every six months until final primary endpoint analysis.  
The EORTC QLQ-C30 incorporates five functional scales (physical, role, cognitive, 
emotional, and social), three symptom scales (fatigue; nausea, vomiting and pain) a 
global health status / QoL scale, and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties). Scale scores can be obtained for the 
multi-item scales.  
The fatigue module is measuring cancer related fatigue based on a multidimensional 
approach including physical, emotional and cognitive aspects of fatigue. One global item 
is assessing the interference of fatigue with activities of daily living. The reduced fatigue 
module with 13 items (FA13) will be used in combination with the EORTC QLQ-C30 (5).  
The QLQ-BR23 breast cancer module comprises 23 questions assessing disease 
symptoms, side effects of treatment (surgery, chemotherapy, radiotherapy, and hormonal 
treatment), body image, sexual functioning, and future perspective. The breast cancer 
module incorporates five multiple-item scales to assess systemic therapy side effects, arm 
symptoms, breast symptoms, body image, and sexual functioning. In addition, single 
items assess sexual enjoyment, hair loss, and future perspective.  
The EQ-5D is a widely used, brief self-administered health status instrument consisting of 
two parts. In the first part patients are asked to describe their health state on five 
dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). 
The score on the five dimensions are summarized to create a single summary score. As 
the questions may be answered differently in different countries / regions due to different 
local customs and social perspectives, published weights from the Euroquol group are 
used in determining the country appropriate summary scores (EQ-5D User’s guide). The 
summary score is called the summary index or the health utility value. In the PENELOPE-
B study the UK summary score which ranges from -0.594 to 1 with lower scores 
corresponding to higher levels of dysfunction will be used. The second part is a visual 
analogue scale which allows individuals to directly rate their self-perceived overall health 
state using values from 0 (worst imaginable) to 100 (best imaginable). 


 
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The GAD-7 is a brief self-report scale to identify general anxiety disorders (GAD) 
consisting of 7 items. Response options are “not at all”, “several days”, “more than half the 
days” and “nearly every day” scored as 0, 1, 2, and 3, respectively. GAD-7 Anxiety 
Severity will be calculated as the total score of the 7 items.  
5.2 
Baseline variables 
Randomization is stratified by the following factors, as recorded in  
         where 
randomization was performed: 
• 
histological lymph node status at surgery (ypN 0-1 vs ypN2-3) 
• 
age at first diagnosis (<=50 vs >50 yrs.) 
• 
centrally measured Ki-67 value (>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+)  
Other baseline characteristics such as patient age at first diagnosis, race/ethnicity, height, 
weight, BMI, ECOG performance status, menopausal status, ER and HER2 status, Ki-67, 
primary diagnosis (histological confirmation of breast cancer in the core biopsy before 
start of neoadjuvant chemotherapy), cancer pretreatment, prior medication, medical 
history are collected. These baseline characteristics are not planned to be included as 
stratification variables or covariates in statistical models unless otherwise specified in 
subsections of 5.2.  
5.2.1 
BMI 
BMI will be calculated using the following formula: weight (kg)/(height (cm)*height (cm)), 
rounded to one decimal place. 
BMI classes will be calculated according to the WHO recommendation: 
BMI<18.5  
Underweight 
18.5<=BMI<25 
normal range 
25<=BMI<30 
preobese 
30<=BMI<35 
obese class 1 
35<=BMI<40 
obese class 2 
BMI>=40  
obese class 3 
 


 
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5.2.2 
Ki-67  
Ki-67 in Korea is given as a range of 10 points, e.g. 20-30. The mid-range is used to 
achieve comparable data to those from the other countries, in this example 25. 
5.2.3 
HER2 status 
5.2.3.1 
Calculation prior to study protocol version C8 
HER2 status will be determined using central classification on tissue from post-
neoadjuvant residual invasive disease of the breast or if not possible from residual nodal 
invasion as documented on  
5.2.3.2 
Calculation with study protocol version C8 and later versions 
HER2 status will be determined using central classification  
• 
preferably on tissue from post-neoadjuvant residual invasive disease of the 
breast or if not possible from residual nodal invasion as documented on 
 
 
 
 or 
• 
on tissue from core biopsy of the breast as documented on ( 
 
 
 
 
 
 
or 
If no surgical specimen and no residual nodal invasion is available, tissue from 
core biopsy of the breast will be used.  
 
5.2.4 
Hormone-receptor status 
5.2.4.1 
Calculation prior to study protocol version  
Hormone receptor status will be determined using central classification of ER and PgR 
(based on percentage of positive stained cells) on tissue from post-neoadjuvant residual 
invasive disease of the breast or if not possible from residual nodal invasion as 
documented on  
 
 
 
 
 
 
 
. Hormone 
receptor status is considered as negative if both ER and PgR were negative and as 
positive if at least one was positive.  
5.2.4.2 
Calculation with study protocol version        and later versions 
Hormone receptor status will be determined using central classification of ER and PgR 


 
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• 
preferably on tissue from post-neoadjuvant residual invasive disease of the 
breast or if not possible from residual nodal invasion as documented on  
 
 
 
 
 
 
 
 
  or 
• 
on tissue from core biopsy of the breast as documented on  
 
 
 
 
 
 
 
 
 
 
  or 
If no surgical specimen and no residual nodal invasion is available, tissue from 
core biopsy of the breast will be used. Hormone receptor status is considered as 
negative if both ER and PgR were negative and as positive if at least one was positive.  
Patients are eligible for the study with a positive HR status according to one of the 
assessments.  
 


 
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5.2.5 
CPS-EG score 
CPS-EG score will be calculated according to the point assignments given in the study 
protocol as follows:  
 
 
5.2.5.1 
Calculation prior to study protocol version C8 
Clinical stage  
Clinical tumor stage will be determined using the maximum diameters from palpation 
 
 
 
 
 
 
       , breast ultrasound  
 
 
 
 
 
 
 
 
 
, mammography 
 
 
 
 
 
 
 
 
     , and breast MRI   
 
 
 
 
 
 on baseline imaging   
     in hierarchical order: preferably 
MRI will be used followed by mammography, US, and palpation. Clinical tumor stage will 
be classified according to the TNM staging system. Clinical signs that result in tumor 
stage classification T4 are: 


 
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- 
extension to chest wall 
- 
skin involvement  
- 
inflammation 
Clinical lymph node status will be determined using the nodal status of palpation   
 
 
 
 
 and breast ultrasound 
 
 
 
        on 
baseline imaging  
 
in hierarchical order: preferably nodal status of US will be 
used followed by palpation.  
Clinical stage will be classified according to the right part of table 1 “ANATOMIC 
STAGE/PROGNOSTIC GROUPS”.  
Pathologic stage 
Pathologic tumor stage will be determined using the maximum diameter of the tumor  
 
 
 
 
 
 
 
as documented on surgery 
 
 
. If no tumor size is available the pathologic tumor stage will be determined on the 
basis of the TNM classification documented on the  
 
 
  .  
Pathologic lymph node status will be determined using the total number of positive lymph 
nodes   
 
 
 
         and classified according to TNM staging 
system. If the total number of positive lymph nodes is not available the pathologic lymph 
node status will be determined on the basis of the TNM classification documented on the 
 
 
 
    . If the lymph node status at surgery cannot be determined, it will 
be considered zero for the calculation of the CPS-EG score. 
Pathologic stage will be classified according to the right part of table 1 “ANATOMIC 
STAGE/PROGNOSTIC GROUPS”.  
ER status 
ER status will be determined using the percentage of positive stained cells as locally 
assessed on core biopsies taken before start of neoadjuvant treatment and documented 
on the  
 
 
 
 
 
   . If the percentage of positive 
stained cells is not available ER status will be determined using the estrogen receptor 
classification  
 
 
  . 
Tumor grading 
Tumor grading will be determined using grading 
 
 
 
        as locally 
assessed and documented on the 
 
 
       . 


 
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Points for the calculation of the CPS-EG score will be assigned according to the left part 
of table 1. Tumor grading will be used for calculation of CPS-EG score instead of nuclear 
grade. 
5.2.5.2 
Calculation with study protocol version C8 
Changes in the calculation of the CPS-EG score with study protocol version        will be 
highlighted in bold print. 
Clinical stage 
Clinical tumor stage will be determined using the maximum of all diameters from 
palpation ( 
 
 
 
 
 
 
), breast ultrasound   
  
( 
 
 
 
 
 
 
), mammography 
 
 
  
( 
 
 
 
 
 
      ), and breast MRI (  
 
 
 
 
 
) on baseline imaging CRF BL07. Clinical tumor stage will be 
classified according to the TNM staging system. Clinical signs that result in tumor stage 
classification cT4 are: 
- 
extension to chest wall (  
 
 
 
      ) 
- 
skin involvement (  
 
 
 
  ) 
- 
inflammation ( 
 
 
 
         ). 
Clinical lymph node status will be determined using the nodal status of palpation   
  
( 
 
 
 
) and breast ultrasound ( 
 
 
 
) on  
 
 
 
 
in hierarchical order: preferably nodal status of US will be 
used followed by palpation. Infraclavicular or supraclavicular affected lymph nodes    
( 
 
 
 
 
 
 
       ) result in lymph node 
classification cN3. 
Clinical stage will be classified according to the right part of table 1 “ANATOMIC 
STAGE/PROGNOSTIC GROUPS”.  
Pathologic stage 
Pathologic tumor stage will be determined using the maximum diameter of the tumor  
  
( 
 
 
 
 
 
           ) as documented on surgery CRF 
BL05b. If no tumor size is available the pathologic tumor stage will be determined on the 
basis of the TNM classification documented on the CRF (  
 
).  
Pathologic lymph node status will be determined using the total number of positive lymph 
nodes   
 
 
 
 
 and classified according to TNM staging 
system. If the total number of positive lymph nodes is not available the pathologic lymph 


 
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node status will be determined on the basis of the TNM classification documented on the 
 
 
 
   . If the lymph node status at surgery cannot be determined, it will 
be considered zero for the calculation of the CPS-EG score.  
Pathologic stage will be classified according to the right part of table 1 “ANATOMIC 
STAGE/PROGNOSTIC GROUPS”.  
 
ER status 
ER status will be locally assessed as the percentage of positive stained cells 
• 
on core biopsies taken before start of neoadjuvant treatment and documented 
on the  
• 
on surgical specimen after neoadjuvant treatment and documented on the  
 
 
 
If one of the percentages of positive stained cells is not available the estrogen 
receptor classification (negative/positive) will be used ( 
 
 
 
 
 
 
 
 
       ).  
A negative ER status according to one of the assessments will be considered in the 
calculation of the CPS-EG score.  
Tumor grading 
Tumor grading will be locally assessed on core biopsies taken before start of 
neoadjuvant treatment (documented on  
 
 
 
 
 
 
 
 
 
) and on surgical specimen after neoadjuvant treatment 
documented on 
 
 
 
 
 
 
      ). The highest 
grading according to one of the assessments will be considered in the calculation 
of the CPS-EG score. 
Points for the calculation of the CPS-EG score will be assigned according to the left part 
of table 1. 
Rationale for using ER status and grading alternatively from the core biopsy prior 
to neo-adjuvant chemotherapy (NACT) or from surgery material after NACT for the 
CPS-EG score. 
Agreement of ER and PgR expression between core needle biopsy performed prior to 
NACT and surgical sample after NACT have been analyzed extensively. In literature we 
can find at least six studies concluding that neoadjuvant chemotherapy does not affect the 


 
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ER status. In some studies no changes in ER receptor status were found (6, 7), whereas 
in others non-significant changes were reported. (8, 9, 10, 11, 12). 
Concordance between histologic grading tested on core needle biopsy or on excised 
breast specimen is approximately 83%. In the discordant cases, the grade at core needle 
biopsy tended to be lower than that at surgical excision. Previous studies noted that this 
tendency of the histological grade was mainly due to underestimation of the mitotic count 
at core needle biopsy (Usami S, Jpn J Clin Oncol 2007).  
As showing by those data CPS-EG score could be indifferently calculated using ER and 
grading assessment on both core needle biopsy or tumor sample.  
 
5.2.5.3 
Calculation with study protocol version C8 V3 
Changes in the calculation of the CPS-EG score since study protocol version C8 V3 will 
be highlighted in bold print. For details of CRF versions please refer to data management 
plan.  
Clinical stage 
Clinical tumor stage will be determined using the maximum of all diameters from palpation
 
 
 
 
 
 
 
, breast ultrasound  
 
 
 
 
 
 
 
 
 
, mammography 
 
 
 
 
 
 
 
 
    , and breast MRI   
 
 
 
 
 
on 
 
 
 
   . Clinical tumor stage will be 
classified according to the TNM staging system. Clinical signs that result in tumor stage 
classification cT4 are: 
- 
extension to chest wall 
- 
skin involvement 
- 
inflammation 
Clinical lymph node status will be determined using the maximum nodal status of 
palpation 
 
 
 
    , breast ultrasound  
 
 
 
 
 
 
 
     , and number of positive sentinel nodes  
 
 
 
 
 
 
 
 
         . Infraclavicular or 
supraclavicular affected lymph nodes  
 
 
 
 
 
 
 
 
 
         result in lymph node classification cN3. 
Clinical stage will be classified according to the right part of table 1 “ANATOMIC 
STAGE/PROGNOSTIC GROUPS”.  


 
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Pathologic stage 
Pathologic tumor stage will be determined using the maximum diameter of the tumor  
  
( 
 
 
 
 
 
           ) as documented on  
 
 
 
 . If no tumor size is available the pathologic tumor stage will be determined on the 
basis of the TNM classification documented on the CRF 
 
             .  
Pathologic lymph node status will be determined using the total number of positive lymph 
nodes ( 
 
 
 
         ) and classified according to TNM staging 
system. If the total number of positive lymph nodes is not available the pathologic lymph 
node status will be determined on the basis of the TNM classification documented on the 
CRF   
 
. If the lymph node status at surgery cannot be determined, it will be 
considered zero for the calculation of the CPS-EG score. 
Pathologic stage will be classified according to the right part of table 1 “ANATOMIC 
STAGE/PROGNOSTIC GROUPS”.  
 
ER status 
ER status will be locally assessed as the percentage of positive stained cells 
• 
on core biopsies taken before start of neoadjuvant treatment and documented on the 
 
 
 
 
• 
on surgical specimen after neoadjuvant treatment and documented on the  
 
 
 
 
If one of the percentages of positive stained cells is not available the estrogen receptor 
classification (negative/positive) will be used (from  
 
 
 
 
 
 
 
 
            ).  
A negative ER status according to one of the assessments will be considered in the 
calculation of the CPS-EG score.  
Tumor grading 
Tumor grading will be locally assessed on core biopsies taken before start of neoadjuvant 
treatment (documented on 
 
 
 
 
 
 
      ) and on 
surgical specimen after neoadjuvant treatment documented on 
 
 
 
 
 
 
 
. The highest grading according to one of the assessments 
will be considered in the calculation of the CPS-EG score. 
 


 
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Points for the calculation of the CPS-EG score will be assigned according to the left part 
of table 1. 
5.3 
Subgroups or covariates of interest 
5.3.1 
Subgroups 
Time-to-event data (iDFS, iDFS excluding second non-breast cancers, OS, LRRFI and 
DDFS) will be analyzed using univariate Cox-proportional hazards models to calculate 
hazard ratios for subgroups based on the stratification factors, which were recorded in 
XXXXXXXX  during randomization (predefined in the protocol): 
• 
age at first diagnosis (<=50 vs. >50 yrs.) 
• 
Ki-67 value (>15% vs <=15%) 
• 
histological lymph node status at surgery (ypN 0-1 vs ypN2-3) 
• 
risk status (CPS-EG Score >=3 vs CPS-EG Score=2 and ypN+) 
Additional exploratory subgroup analyses will be performed based on strata derived 
according to clean CRF data: 
• 
CPS-EG Score (score 1/2, score 3, score 4/5) 
• 
Patients with “worst” prognostic factors (age at first diagnosis <=40 years and CPS-EG 
Score >=3) 
• 
Age at first diagnosis (<=65, >65 years) 
• 
Ki-67 value (>25% vs <=25%) 
• 
Geographical region (North America, Europe, Asia (Pacific) ) 
• 
Baseline ECOG status (0, 1) 
• 
Baseline menopausal status (premenopausal, postmenopausal) 
• 
First endocrine therapy applied (tamoxifen, AI)  
• 
Duration of chemotherapy (shorter <= 20 wks. vs. longer > 20 wks.) 
• 
Type of surgery (mastectomy, breast conserving) 
• 
Overall response to neoadjuvant chemotherapy (response (CR, PR) vs non-response 
(SD, PD)) 
 
5.3.2 
Covariates 
Time-to-event data (iDFS, iDFS excluding second non-breast cancers, OS, LRRFI and 
DDFS) will be analyzed using multivariate Cox-proportional hazards models with the 
treatment group and 2 sets of covariates. Stratification factors (strat. factor) and variables 
to determine the relapse risk (relapse risk factors) of the patient are included in the first 
set of covariates.  


 
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Set 1: 
• 
age at first diagnosis (<=50 vs. >50 yrs.) 
strat. factor 
• 
Ki-67 value (>15% vs <=15%) 
strat. factor 
• 
global region of participating site (Asian vs non Asian) 
strat. factor 
• 
histological lymph node status at surgery  
(ypN 0-1 vs ypN2-3) 
strat. factor/ 
relapse risk 
• 
risk status (CPS-EG Score >=3 vs CPS-EG Score=2 and ypN+) 
strat. factor/ 
relapse risk 
• 
clinical tumor stage before neoadjuvant chemotherapy  
(cT1/2 vs cT3/4) 
relapse risk 
• 
pathological tumor stage after neoadjuvant chemotherapy  
(pTis/1/2 vs pT3/4) 
relapse risk 
• 
grade (grade 1, 2 vs. 3) before neoadjuvant chemotherapy 
relapse risk 
 
To investigate the impact of endocrine therapy on iDFS, a second set of covariates will be 
defined with endocrine therapy added to a reduced set of covariates.  
Endocrine therapy will be dummy-coded with tamoxifen as the reference category into 
four indicator categories: tamoxifen alone, tamoxifen + LHRH, aromatase inhibitors (AI) + 
LHRH, AI alone. 
 
Set 2: 
• 
age at first diagnosis (<=50 vs. >50 yrs.) 
strat. factor 
• 
Ki-67 value (>15% vs <=15%) 
strat. factor 
• 
global region of participating site (Asian vs non Asian) 
strat. factor 
• 
risk status (CPS-EG Score >=3 vs CPS-EG Score=2 and ypN+) 
strat. factor/ 
relapse risk 
• 
endocrine therapy (dummy coded) 
 
 


 
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6. 
ANALYSIS SUBSETS 
Randomized patients consist of all patients who have given their written informed consent 
and for whom there is confirmation of successful allocation of a randomization number 
through the web-based data collection interface. 
6.1 
Data subsets 
6.1.1 
Intent-to-treat set 
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, i.e. 
patients who took incorrect treatment will be reported under the study treatment assigned 
at randomization.  
6.1.2 
Per protocol population for efficacy 
The per protocol (PP) population for efficacy is a subset of the ITT and includes patients 
without major protocol violations. 
Prior to unblinding the patients' treatment allocation, the frequencies of the following 
deviations will be displayed: 
- 
eligibility criteria, 
- 
compliance with intake of study drugs, i.e. overdoses, never received study treatment, 
medication error (patient received medication she was not randomized to). 
On the basis of the protocol deviations’ frequencies a subgroup of the steering committee 
will define in a blinded review the major protocol violations which will lead to the exclusion 
of patients from the PP population for efficacy. The process of identification of major 
protocol violations will be documented. 
The PP population serves supportive efficacy analyses. If the patient receives the wrong 
study treatment for the complete duration of the trial, patients will be analyzed according 
to the treatment actually received. 
 
6.1.3 
Safety analysis set 
The safety analysis set includes all randomized patients who took at least once study 
medication. Patients will be analyzed according to the treatment actually received, i.e. a 
patient who was randomized to the palbociclib arm and received placebo for the entire 
treatment duration will be analyzed in the placebo arm and vice versa.  


 
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For patients in whom treatment was misallocated not for the entire treatment duration so 
that they received palbociclib and placebo during the trial, the treatment group allocation 
for safety analyses will be the palbociclib arm.  
This is the only population for all safety analyses. 
6.1.4 
Evaluable subsets for QoL  
QoL will be analyzed on the basis of the ITT population. Missing values will be reported 
descriptively.  
 
6.2 
Interim analyses sets 
Two event-driven efficacy interim analyses (EIA) were planned according to study 
protocol. The first EIA was performed after 67 events were documented (details are given 
in section 7.1). The second EIA was performed after 200 events were documented, 
(details are given in section 7.1).  


 
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7. 
ADAPTIVE DESIGN  
The study has an adaptive design with two interim efficacy analyses (EIA). The objectives 
of the first interim analysis were sample size re-estimation and the opportunity for early 
stopping of the trial due to futility.  
Sample size re-estimation was planned to be performed only in one of the two interim 
analyses. Therefore this objective was dropped in the second interim analysis and the 
remaining objectives were the opportunity for early stopping of the trial due to futility and 
overwhelming efficacy, respectively. 
The decision about early stopping of the trial due to futility or overwhelming efficacy was 
made on the basis of the primary efficacy parameter, iDFS.  
The decision rules for the efficacy interim analyses are summarized in table 7-1. 
Table 7-1: Decision rules for interim analyses 
Analysis 
Time/IF 
Futility (HR) 
Efficacy (p-value) 
SSR* 
1st EIA 
April 2017 / 67 
events 
≥1.0 
<0.0002 
Yes 
2nd EIA 
April 
2019 
/ 
200 events 
≥0.90 
<0.0120 
No 
Final 
290 events 
N/A 
<0.0463 
N/A 
* SSR – sample size re-estimation 
 
Safety including any unexpected toxicity was assessed in both EIAs, based on the 
description given in section 10.5. Unexpected toxicities were described regarding 
suspected unexpected serious adverse reactions (SUSAR) and coded according to the 
MedDRA preferred term (MedDRA version XXX was used). 
Details of the interim analyses' objectives are described in the following sections. 
 
7.1 
First efficacy interim analysis 
The first EIA was performed in April 2017 after 67 events were documented. The EIA was 
preponed to allow for sample size increase during the enrollment period of the study, 
which was estimated to be terminated in August 2017.  
The final first addendum to the general IDMC charter was signed on the 30th March 2017 
where study specific procedures were laid down, i.e. to define decision rules for sample 


 
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size re-estimation and for early stopping of the trial due to futility. The addendum to the 
IDMC charter also contained an overview of the required information and templates of the 
tables and figures that the IDMC received. The report of the 1st EIA was finalized on the 
21st April 2017 and sent to the IDMC on the 25th April 2017. In a telephone conference on 
3rd May 2017 the IDMC reviewed the unblinded results of the 1st EIA and recommended to 
increase the sample size to 1250 patients and the number of events to 290. The 
recommendation was approved in the SC meeting on 11th May 2017, and implemented in 
protocol version G11. 
 
7.1.1 
Re-estimation of sample size 
Sample size re-estimation was mainly based on the primary endpoint, iDFS. The 
secondary endpoint of iDFS excluding second primary of non-breast cancer was also be 
taken into consideration when performing sample size re-estimation. 
Sample size re-estimation (SSR) was performed according to Cui, Hung and Wang, CHW, 
(13) who proposed “a valid inferential procedure that allows flexibility for adjusting sample 
size based on the updated estimate of treatment effect during the course of the trial” (ibid., 
p. 853).  
The calculation of the total sample size N was described in the study protocol and was 
summarized in section 4.3 of this SAP. The decision whether to adapt the sample size or 
not was based on conditional power (CP) defined as "the probability that the final study 
result will be statistically significant, given the data observed thus far" (14).  
Sample size adaptation was performed according to Mehta and Pocock (15), depending 
on the zone in which the CP of the estimated 𝛿𝛿̂L at the Lth interim analysis (CP𝛿𝛿̂L) will fall. 
The zones were defined as follows: 
Unfavorable zone: CP𝛿𝛿̂L < CPmin 
Promising zone: CPmin < CP𝛿𝛿̂L < 1-β 
Favorable zone: 1-β < CP𝛿𝛿̂ 
If CP𝛿𝛿̂L falls into the promising zone, it is possible to increase the sample size to achieve a 
conditional power of an acceptable level. The threshold CPmin for determination of the 
promising zone was provided in the study specific addendum to the IDMC charter. This 
addendum was only reviewed by IDMC members and the unblinded statistician. 
Based on the initially planned number of 255 events, the upper limit of events was set to a 
maximum number of 290 events (approximately 14% increase). To increase the sample 
size in a comparable ratio as the number of events the maximum sample size was set to 
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Procedure for SSR in the first EIA (as described in the addendum to the IDMC 
charter): 
• 
The hazard ratio and its 95%CI was calculated for the primary endpoint iDFS, and for 
the secondary endpoint of iDFS excluding second primary, respectively. 
• 
The conditional power (CP) for both endpoints was computed based on their 
estimated treatment effects as though they were the true values of the treatment 
effect. Conditional power was derived from the power calculator within EAST 6.4.  
• 
For a CP in the promising zone the increase of CP was calculated using the maximum 
number of events. For a CP out of the promising zone, the trial was continued to the 
originally planned next interim analysis with the original number of events and sample 
size. 
• 
IDMC was asked to give their recommendation whether SSR might be contemplated 
and to what extent.  
• 
The final decision about the SSR was made by the sponsor after receiving advice from 
the Steering Committee. 
• 
In case of SSR the number of events was planned to be increased until target CP of 
85% is achieved or until maximum number of events (= 290 events) is achieved, 
whichever is achieved first. 
• 
If the estimated treatment effect from interim analysis was higher than the initially 
planned treatment effect, i.e. less events would be needed on the basis of the interim 
results, the original number of events were used. 
Type I error after sample size increase was preserved by re-weighting the Wald statistics 
for the following analyses, i.e. by down weighting the contribution of the subsequent stage 
relative to the precedent stage (13). 
7.1.2 
Early stopping of the trial due to futility 
O’Brien-Fleming type stopping boundaries based on the Lan-DeMets spending function 
were used. The main focus of the first EIA was to assess whether the treatment effect at 
this stage is futile. Futility criteria in terms of the HR and the Z-value are given in table 7-1. 
The nominal α level for the first efficacy interim analysis is provided, although there was 
no intention to stop the trial for efficacy at this time. 
 
7.2 
Second efficacy interim analysis 
A second addendum to the general IDMC charter was signed on the 2nd April 2019 where 
study specific procedures are laid down and detailed. The addendum to the IDMC charter 
also contains an overview of the required information and templates of the tables and 
figures that the IDMC received. 


 
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The report of the 2nd EIA was finalized on the 29th April 2019 and sent to the IDMC. In a 
telephone conference on 7th May 2019 the IDMC reviewed the unblinded results of the 
2nd EIA and recommended to continue the trial without any changes to the final analysis. 
7.2.1 
Early stopping of the trial 
The efficacy and futility boundaries were generated simultaneously keeping the former 
unaffected by the definition of the latter to receive non-binding futility boundaries. Futility 
and efficacy criteria are given in table 7-1. O’Brien-Fleming type stopping boundaries 
based on the Lan-DeMets spending function were used.  
Differences in the primary endpoint iDFS between treatment arms in the ITT population 
were tested with a 2-sided stratified log-rank test at the overall significance level 0.05. The 
factors used in the stratified log-rank test were histological lymph node status at surgery 
(ypN 0-1 vs ypN2-3), age at first diagnosis (<=50 vs >50 yrs.), Ki-67 (>15% vs <=15%), 
and risk status (CPS-EG Score >=3 vs CPS-EG Score=2 and ypN+) as recorded during 
randomization.  
Due to sample size increase the type I error in testing the primary endpoint was preserved 
using the CHW method. 
 
7.3 
Final Analysis 
In the final analysis the primary endpoint iDFS will be tested in the same way as in the 
second EIA (described in the previous section 7.2.1). According to the design parameters 
the nominal significance level for the final analysis on iDFS is 0.0463 (Z-statistic=-1.993) 
calculated using the Lan-DeMets (O’Brien-Fleming) α-spending function.  
To maintain the type I error after sample size increase, statistical significance will be 
determined using a weighted statistic based on the CHW method (13) which is 
implemented in the CHW interim monitoring in EAST version 6.5 (Cytel Inc.). The 
parameter from EAST will be derived, exported, and archived. 
 
7.4 
Interim Overall Survival Analysis 
At the time of the final iDFS analysis (with 290 documented iDFS events) an interim OS 
analysis will be conducted. OS was defined in section 4.1. 
 


 
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7.5 
Handling of blinding and unblinding 
Handling of blinding and unblinding was performed according to 
 
 
 
 
 
 
 
 
 
 
 
 
      . The study 
statistician prepared SAS programs to perform the analyses using a dummy variable 
representing the treatment code to remain blinded to the treatment allocation of the 
patients. The dummy treatment variable was created using the rantbl function in SAS to 
create a dichotomous variable; stratification was not incorporated in the dummy variable. 
Final SAS programs for the interim analyses were handed over to the unblinded 
statistician who replaced the dummy treatment code by the actual treatment allocation of 
the patients. The study statistician does not have access to the unblinded analyses or any 
unblinded results prior to database lock.  
 
The IDMC received reports in two parts: an "open" session, which presented data only in 
aggregate and focuses on trial conduct issues such as accrual and dropout rates, 
timeliness of data submission, eligibility rates and reasons for ineligibility; and a "closed" 
session, in which the comparative outcome data were presented." (FDA guideline (16). p. 
11). In the “closed” session of the IDMC meeting the unblinded statistician presented the 
study data to IDMC members while all people other than the unblinded statistician and 
IDMC members have to be absent. 
The IDMC gave advice concerning early stopping, modification on sample size, and 
continuing the study as planned after the meeting in writing (detailed procedures of the 
IDMC meetings are given in the general IDMC charter and in its study specific addendum 
for the PENELOPEB trial).  


 
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8. 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL 
Due to a very small subgroup of luminal B tumors in the patients’ cohort the respective 
secondary endpoint cannot be analyzed and further exploratory analysis will be performed 
which will be described in a separate biomarker SAP. 
The following Amendment(s) were implemented since the first study protocol A (Version 
6-23.09.2013) 
Country 
Amendment No. 
Date of 
Amendment 
Global 
Protocol G (Version 11 – 04th May 2017) 
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 adjustment of patient 
number based on outcome of 1st efficacy interim analysis. 
 
Administrative and corrective changes: 
1. Procedure for unblinding in case of progressive disease specified in 
section 12.2 
 
04th May 2017 
Global 
Protocol E (Version 10 – 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 
Exclusion Criterion #16: Study entry time was specified as date of 
randomization.  
Endocrine treatment options updated. (section 12.8.1) 
Safety Monitoring Frequency adjusted to IDMC recommendation in section 
15.5.7 
Specification of relevant overdose definition in section 17.5.2 and removal 
notification requirement for non-relevant overdose 
 
Administrative and corrective changes: 
Alignment of table “schedule of activities” and tables “assessments and 
schedules” with current protocol 
Addition of additional time points for PK-DDI samples in case a sample 
was missed for a patient. 
 
12 April 2016 
Global 
Protocol D (Version 9 - 09 February 2015)  
Summary of Changes: 
Substantial  
Inclusion criterion #5: Clarification for testing in case of bilateral breast 
09 Feb 2015 


 
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Country 
Amendment No. 
Date of 
Amendment 
cancer  
Inclusion criterion #6: Centrally testing possibility extended to core biopsy 
Inclusion criterion #12: allows now patients with a CPS-EG Score of 2 if 
ypN+ to participate 
Addition of new stratification criterion: CPS-EG score 3 vs 2&ypN+ 
Update of section 15.5 ff Statistical Analysis due to change of inclusion 
criterion #12 and increase of study population  
 
Administrative and corrective changes: 
Specification of PK sample set requirements in section 13.3 
Update of Section 7 rationale of the study 
 
Global 
Protocol C (Version 8-06.08.2014) 
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. 
 
06.Aug.2014 
 


 
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9. 
DATA SCREENING AND ACCEPTANCE 
9.1 
General principles 
The documentation and verification procedure will be performed according to 
 
 
 
. 
9.2 
Database lock 
The database lock for the final analysis is planned after 290 iDFS events are documented 
and confirmed  
 
 
 
 
 
 
    . Confirmation of 290 
events was documented on the 24th August 2020. DB lock will be performed on the 25th 
September 2020.  
9.3 
Data handling and electronic transfer of data 
Clinical trial data will be exported from  
 
 
 
 
 
 
 
into 
 
 
 
      . Additional / non-CRF data will be used for the final 
analysis, which are listed in  
 
 
 
 
 
 
  :  
All data will be imported in SAS®  (Statistical Analysis Software) Version 9.4 and SAS 
Enterprise Guide Version 7.1 on Microsoft Windows 10 Enterprise. 
 
 
9.4 
Handling of missing and incomplete data, drop-outs 
Missing statistics, e.g., when they cannot be calculated, should be presented as ‘n.a.”. For 
example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘n.a.’. 
9.4.1 
Missing data in CPS-EG score 
If no LN status could be determined for calculation of CPS-EG score, LN will be assumed 
to be 0. 
9.4.2 
Missing dates 
In general, missing or incomplete dates will be imputed as follows: if day is missing, the 
first day of the month will be assigned. If the day of the month and the month are missing 
for any date used in a calculation, January 1st will be used to replace the missing date. 
These rules are used unless the calculations result in negative time durations (e.g., date 


 
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of onset cannot be prior to day 1 date). In these cases, the dates resulting in 0 day 
duration will be used. 
9.4.3 
Missing Data in Time-To-Event Endpoints 
For all time to event endpoints if day of event is missing, the first day of the month will be 
assigned. However, if the month and the year of the event is similar to the month and year 
when the study drug was given, then the date of the application of study drug will be 
assigned.  
Drop-outs without treatment are defined as those patients who have been randomized in 
the study but withdrew their consent or are withdrawn by the investigator from the study 
immediately thereafter but prior to first application of study medication. The reasons are 
collected and reported in the Consort Statement. These patients will not be replaced but 
belong to the ITT efficacy population. 
In case of missing disease assessments before the last disease assessment, or before 
death iDFS will be calculated on the basis of the given disease assessments and not the 
scheduled disease assessments. Therefore, iDFS will be reported according to the actual 
reporting time and not the scheduled time. 
In case that the imputation of the start date of new anticancer treatment results in a start 
date which is before randomization the imputation will be corrected to the day after 
randomization (date of randomization + 1).  
All other missing values will be reported explicitly.  
9.4.4 
Date of Last Contact Derivation 
In the analysis of overall survival the date of last contact will be derived for patients not 
known to have died at the analysis cutoff using the latest complete date (after imputation) 
among but not limited to the following: 
• 
Date of follow up  
• 
Date of withdrawal  
• 
Date of last contact when patient status is “lost to follow up”  
• 
Date of relapse  
• 
Date of assessments (e.g., laboratory, physical examination, ECG, disease 
assessments, QoL questionnaires)  
• 
Date of first endocrine therapy 
 
    and end date of endocrine treatment and 
date of change on endocrine treatment   
• 
Date of first intake of study drug in given cycles 
• 
Date of last known treatment intake 
 
and date of last known endocrine 
treatment  


 
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• 
Start and end dates of follow-up anticancer therapies administered 
 
 
 
 
  
• 
Randomization date 
Only dates associated with actual examinations of the patient will be used in the 
derivation. Assessment dates after the cut-off date will not be applied to derive the last 
contact date. 
9.4.5 
Death Date 
Missing or partial death dates will be imputed based on the last contact date: 
• 
If the date is missing it will be imputed as the day after the date of last contact 
• 
If the day or both day and month is missing, death will be imputed to the maximum of 
the full day after the date of last contact and the following: 
o Missing day: 1st day of the month and year of death 
o Missing day and month: January 1st of the year of death 
9.4.6 
Missing data in safety analysis 
Missing CTC grades will be imputed by the worst (non-fatal) grade possible for the 
respective AE, i.e. CTC 2 for alopecia or CTC grade 3 for dysgeusia etc.  
AEs with missing relationship to study medication will be considered related.  
 
9.5 
Evaluable subject subset(s) 
Patients will be included in the Safety Population if they started treatment. Information 
about the start of the study treatment will be available for all patients. Therefore, 
imputation will not be performed. 
9.6 
Outliers 
Most variables in the analysis are time-to-event or categorical so the outlier problems do 
not apply to them. 
Before converting hematology and other lab values in CTC-grades, outliers will be 
examined and queries will be sent out by the 
 
        . 
9.7 
Distributional characteristics 
No tests for distribution will be performed, non-parametrical tests will be used for all 
continuous baseline variables. 


 
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9.8 
Testing/validation plan 
Analysis programs will be validated according to the  
 
     . 
All data, except for the HTG data, will be analyzed using SAS® (Statistical Analysis 
Software) Version 9.4 or higher with SAS Enterprise Guide Version 7.1 on Microsoft 
Windows 10 Enterprise. HTG data will be analyzed using an R-software package. Details 
are available in the biomarker SAP regarding the luminal B analyses. SAS programs will 
be clearly documented (using commenting facilities within programs) and stored. All SAS-
logs will be stored. 
Estimates based on the CHW method will be derived from the CHW interim monitoring 
implemented in EAST version 6.5 (Cytel Inc.). The EAST workbook will be stored. 
 


 
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10. 
STATISTICAL METHODS OF ANALYSIS 
10.1 
General principles 
The overall significance level for the primary endpoint is set to two-sided alpha = 0.05. 
There will be two interim efficacy analyses and a final analysis. Type I error inflation will 
be controlled by using the Lan-DeMets spending function which results in stopping 
boundaries comparable to O’Brien-Fleming stopping boundaries. 
For all other tests alpha is also set to 0.05 (two-sided). Adjustment for multiple testing in 
the other tests is not planned. These statistical tests are to be considered descriptive. 
All multivariate models will be fit as full models without variable selection. 
All percentage values will be valid percent, i.e. missing data will be excluded from the 
calculations. 
10.1.1 
Analyses for Binary Data 
In general, binary endpoints will be summarized as number in percentages in each group 
and overall. Fisher's exact test for binary variables will be used to assess the 
comparability of two treatment arms (usually used to assess baseline comparability).  
10.1.2 
Analyses for Categorical Data 
Categorical variables will be summarized by frequency counts and percentages. All 
percentage values will be valid percent. The Pearson Chi2-test for categorical parameters 
with more than 2 categories will be used to assess the comparability of two treatment 
arms. 
10.1.3 
Analyses for Continuous Data 
Continuous parameters will be summarized as mean, standard deviation, median, 
minimum and maximum. The Mann-Whitney test (for continuous parameters) will be used 
to assess the comparability of two randomized treatment arms. 
10.1.4 
Analyses for Time-to-Event Data  
The time-to-event data include iDFS, iDFS excluding second primary invasive non-breast 
cancers, LRRFI, OS, DDFS, and iDFS in patients with luminal-B tumors. 
Time-to-event variables (except LRRFI) will be presented using the Kaplan-Meier method 
and displayed graphically when appropriate. The survival probability at the specific time 
point will be estimated using the Kaplan-Meier method and a 2-sided 95% CI will be 
calculated using the log-log transformation with back transformation to a CI on the 
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LRRFI will be analyzed using the Fine-Gray model (21), as described in section 10.8.1. 
 
10.1.5 
Standard Derivations and Reporting Conventions 
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4 days, 1 year = 365.25 days. 
10.2 
Subject accountability 
The number of patients in each of the following categories will be reported:  
• 
Screened patients 
• 
Screening failures and reasons 
• 
Randomized patients 
• 
Randomized but not treated patients with reason for not starting treatment 
• 
Randomized and treated patients in the following subgroups: 
o histological lymph node status at surgery (ypN 0-1 vs ypN2-3) 
o age at first diagnosis (<=50 vs >50 yrs.) 
o Ki-67 value (>15% vs <=15%) 
o global region of participating site (Asian vs non Asian) 
o risk status (CPS-EG Score >=3 vs CPS-EG Score=2 and ypN+). 
• 
Patients who completed the study treatment period as per protocol 
• 
Patients who discontinued study treatment by main reason for permanent 
treatment discontinuation 
• 
Status at last study contact – will be reported with the time-to-event outcome 
analysis 
It will be checked for each patient enrolled whether she violates any of the inclusion or 
exclusion criteria. 
Median follow-up time will be estimated with the reverse Kaplan-Meier method and the 
completeness of the follow-up will be assessed according to Clark and colleagues (18). 


 
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10.3 
Protocol deviations 
Patients with deviation from the eligibility criteria will be listed with site ID, treatment arm, 
and protocol version under which the patient was randomized. 
Other important protocol deviations will be reported according to the following categories 
(subcategories) 
• 
Safety Reporting (SAE not reported within 24 hours to sponsor) 
• 
Concomitant treatment (Administration of prohibited concomitant medications 
during active treatment) 
• 
Informed Consent (Missing complete ICD or ICD not obtained, Missed date by 
patient, Missing patient’s signature, Randomization/specific protocol procedures 
initiated prior to signing/dating consent Investigational Product) 
• 
Administration/Study Drug (Study drug not dispensed by site via IWRS, Received 
study drug not as randomized, relevant overdose) 
• 
Randomization Errors (Patient randomized under incorrect stratification, Patient 
randomized twice) 
• 
Withdrawal Criteria (Patient experienced unacceptable toxicity requiring 
permanent treatment discontinuation but was not discontinued from active 
treatment) 
Frequency (number and percentage) of patients with concordant strata as documented 
during the randomization and based on clean data will be presented.  
Other than the above listed irregularities within the randomization process or any other 
occurrences related to the hand-over of randomization codes will be listed.  
10.4 
Demographic and baseline characteristics 
The demographic and baseline characteristics will be reported descriptively in each 
setting per treatment arm and overall.  
Categorical and ordinal data will be summarized using the number and percentage of 
patients in each treatment group. Continuous data will be summarized using the number 
of available data, mean, standard deviation (SD), median, minimum, and maximum for 
each treatment group. 
The Pearson Chi2-test (for categorical parameters with more than 2 categories), Fisher's 
exact test (for binary parameters), and the Mann-Whitney test (for continuous parameters) 
will be used to assess the comparability of two randomized treatment arms in each 
setting. These statistical tests are to be considered descriptive, no adjustment for multiple 
testing is planned.  


 
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The following demographic and baseline characteristics will be displayed: 
• 
Age at first diagnosis (prior to neo-adjuvant chemotherapy), race  
• 
Height, weight, BMI, BMI classes 
• 
ECOG performance status 
• 
Menopausal status 
• 
Tumor size, tumor focality 
• 
Tumor size assessed at surgery (after neo-adjuvant chemotherapy), histological tumor 
stage, lymph node status  
• 
CPS-EG score  
• 
Hormone receptor status assessed locally at the centers / at central pathology;  
• 
HER2 status assessed locally at the centers / at central pathology; 
• 
Tumor grading, local (calculated as the maximum of the assessment on core biopsy 
and on surgical tissue),  
• 
histological tumor type 
• 
Ki-67 assessed at central pathology;  
• 
Cardiac examination at baseline  
• 
General medical history 
• 
Concomitant medication 
• 
Cancer pretreatment 
• 
Previous neoadjuvant chemotherapy and duration 
• 
First Endocrine therapy applied 
• 
Radiotherapy 
• 
Overall clinical response after neoadjuvant chemotherapy  
• 
Time between date of histological confirmation of breast cancer and start of 
neoadjuvant chemotherapy  
• 
Time between end of neoadjuvant chemotherapy and first breast surgery 
• 
Time between last breast surgery / end of radiotherapy and start of study treatment 
• 
First endocrine therapy and concomitant start of endocrine therapy and 
Palbociclib/Placebo by treatment arm and by menopausal status 
 


 
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10.5 
Safety analyses 
All safety analyses will be performed using the evaluable subset for safety. 
The most current version of the MedDRA classification system available prior to database 
lock will be used for AE coding. 
Analysis will be performed using any AE that occurred after first dose of study medication 
ignoring baseline events.  
AE data will be aggregated based on the maximum grade that the patient experienced 
within each MedDRA preferred term (PT) during the reporting period. If a patient 
experiences more than one AE within a PT for the same summary period, only the AE 
with the worst NCI CTCAE v.4.0 severity grade will be included in the summaries of 
severity (‘patients-based’). Missing CTC grades will be imputed by the worst non-fatal 
grade possible for the respective AE, i.e. CTC 2 for alopecia or CTC grade 3 for 
dysgeusia etc. Safety analyses will be performed based on both all causality AEs 
(irrespective of relationship) and treatment-related AEs. If the relationship is missing the 
AE will be considered related.  
Predefined and free-text AEs are documented with CTC grades (NCI-CTCAE version 
4.0, NYHA for cardiac events) on the CRFs. The hematological parameters will be 
converted into CTC grades according to the  
 
 
 
 
        . 
Adverse Events of Special Interest (AESIs) are documented as being present or absent 
without CTC grades.  
If an AE is reported as free text but belongs to one of the predefined categories, it will be 
included in the corresponding predefined AE category (including multiple infections as 
described in section 5.1.4). 
Unless otherwise specified, AEs will be summarized by frequency and percentage of 
patients within the AE category of interest, by treatment arm, and overall, in the order 
given on  
         . 
SAEs and AEs will be completely reconciled. Therefore, all hematological and non-
hematological SAEs will be considered in the AE summary tables. In the AE summary 
tables the grade of the documented AE (only severity grade 1-4 available on  
 
will be given. This might result in discrepancies in case of fatal serious AEs, which 
will be displayed with CTC grade 5 in the ‘Listing of SAEs’ whereas the corresponding AE 
will be displayed with the CTC grade as documented on the CRF  
 
, 
respectively.  


 
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A summary table of the most common serious adverse events by preferred term will be 
displayed. “Most common” is defined as occurring in at least 2 patients in either treatment 
arm.  
Anemia, leucopenia, neutropenia, febrile neutropenia, and thrombocytopenia will be 
merged into ‘Patients with hematological AE’. All other AEs will be merged into ‘Patients 
with non-hematological AE. All AEs will be aggregated into ‘Patients with Adverse Event. 
AEs reported as free text (AE 02 - Adverse Events) will be summarized in ‘Patients with 
other AE’. SAEs will be aggregated as ‘Patients with Serious AE, ’ . ‘Patients with 
hematological SAE‘, and ‘Patients with non-hematological SAE’. This results in a 
“Summary of Adverse Events” table including the above mentioned categories.  
In addition, a summary table of the most common adverse events by preferred term will 
be given based on any grade AEs. “Most common” is defined as occurring in at least 10% 
of the patients in either treatment arm. 
Free text AEs occurred in at least 5% of patients will be reported according to MedDRA 
preferred terms, less frequent AEs will be included into “other AE SOC XX”. 
AESIs will be displayed according to the template table 14-21 with treatment modification 
(1 = no action taken / 2 = Dose delay / 3 = Dose reduction / 4 = Interruption / 5 = 
Permanent discontinuation of treatment). AESIs will not be included in the overall AE 
tables due to documentation without grades. 
The occurrence of AE categories will be displayed as  
• 
number and percentage of grades 1-4 (any grade) per treatment group and overall, 
• 
number and percentage of grades 3-4 (high grade) per treatment group and overall,  
• 
number and percentage of patients per grade (none, grade 1, grade 2, grade 3, grade 
4) per treatment group and overall.  
Fisher’s exact test will be performed to explore differences in the incidence of any grade 
and high grade AEs, respectively, between treatment groups. These p-values are 
descriptive in nature and no adjustment for alpha inflation will be performed. 
Any death of patients either under therapy (from start of treatment until and including 30 
days after last dose ) or in the follow-up period will be listed together with the treatment 
arm, cycle/follow-up number, and primary death cause. 


 
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Death occurring from start of treatment until and including 30 days after last dose will be 
displayed for each treatment arm and overall, grouped (according to DRF) as (single 
choice) 
o Tumor related 
o Therapy related 
o Not therapy and not tumor related 
o Unknown. 
10.6 
Compliance analyses 
The extent of study treatment exposure and compliance will be assessed and summarized 
by actual treatment received within the All randomized and treated patients population. 
10.6.1 
Investigational product 
The duration of palbociclib/placebo exposure and the total number of cycles per patient 
will be displayed for each treatment arm and overall.  
The cumulative dose, the ATDI, the RTDI, and the RTD will be given per patient for each 
treatment arm and overall. 
Incidence of dose delays, dose reductions and interruptions of palbociclib/placebo as well 
as duration of dose delays and interruptions will be reported per patient for each treatment 
arm and overall. 
Reasons for dose delays, dose reductions and interruptions (including omitted cycles) will 
be grouped according to CRF as (multiple choice): 
o Organizational  
o AE: 
o Hematological toxicity 
o (Other) non-hematological toxicity 
o AE not related to study medication 
o Other 
Based on blinded review of data the following additional reasons will be extracted for dose 
delays and interruptions from the category “other”:  
o Patient's non-compliance,  
o Surgical or Non-surgical medical procedure. 
o And Disease Progression only for interruption. 


 
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Treatment interruption and premature treatment discontinuation 
For patients who discontinue the study treatment prematurely within a cycle, all remaining 
days without drug intake are indicated by the center as “no intake” on the   
 
 
 
, which will be reported as treatment interruptions. To avoid that the 
documentation of a premature treatment discontinuation also has impact on other 
measure of the compliance analysis, the days without drug intake indicated by the center 
as “no intake” on Treat 01/P-P will not be taken into account. 
Frequency (number and percentage) of patients who completed 13 cycles of 
palbociclib/placebo and who completed at least 7 cycles of palbociclib/placebo, 
respectively, will be given for each treatment arm and overall. 
The incidence and reasons of premature end of treatment will be reported for each 
treatment arm and overall. 
Reasons for premature end of treatment will be grouped as (single choice) 
o Disease recurrence/Second primary invasive non-breast cancer  
o Death 
o Adverse event: 
o Hematological toxicity 
o (Other) non-hematological toxicity 
o AE not related to study medication 
o Patient decision 
o Investigator decision 
 
10.6.2 
Non-investigational product 
The incidence and reasons of changes in the endocrine treatment and the incidence and 
reasons of delays in the endocrine treatment will be reported for each treatment arm and 
overall.  
Reasons for changes and dose delays in the endocrine treatment will be grouped 
according to CRF as (multiple choice): 
o Organizational (only for delays and interruptions, up to 3 days) 
o AE: 
o Hematological toxicity 
o (Other) non-hematological toxicity 
o AE not related to study medication 
o Other 


 
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The incidence and reasons of premature end of endocrine treatment will be reported for 
each treatment arm and overall. 
by menopausal status 
10.7 
Primary efficacy analyses 
Final analysis of the primary endpoint will be conducted when 290 events in iDFS have 
been documented in the database and have been confirmed. 
The primary analysis will be the comparison of survivor functions between treatment arms 
in the primary efficacy endpoint iDFS in the ITT population.  
10.7.1 
Estimation of outcomes 
The Kaplan-Meier curves of iDFS, Kaplan-Meier estimates of 3-, and 5-year probability of 
iDFS and the corresponding 95% CI will be provided.  
Frequency (number and percentage) of patients with each type of iDFS event and 
censoring reasons will be presented by treatment arm. 
Duration of follow-up in the treatment arms will be summarized using the inverse Kaplan-
Meier method, reversing the OS censoring and event indicators. 
 
10.7.2 
Hypotheses to be tested 
Null hypothesis: survivor functions of the two treatment arms are equal; 
Alternative hypothesis: survivor functions of the two treatment arms are not equal. 
A two-sided stratified log-rank test at the overall significance level of 0.05 will be 
performed. The stratification factors are: histological lymph node status at surgery (ypN 0-
1 vs ypN2-3), age at first diagnosis (<=50 vs >50 yrs.), Ki-67 (>15% vs <=15%) and risk 
status (CPS-EG score >= 3 vs. CPS-EG score = 2 and ypN+). In the primary analysis the 
stratification factors will be used as randomized, i.e. with the values collected at the time 
of randomization. Based on the estimated treatment effect and its standard error the 
weighted statistic (CHW) and the repeated CI95% of the HR will be derived from the CHW 
Interim Monitoring dashboard in EAST taking into account the adaptive sample size re-
estimation and group-sequential nature of the design.  
This study will be considered a positive trial if the two-sided p-value from the weighted log-
rank test based on the CHW method is significant at the significance level of 0.0463 at the 
time of the final analysis. In addition, the unweighted stratified log-rank test will be 
presented to support the main analysis of the primary endpoint. The analysis of the key 
secondary endpoint will be performed to test the null hypothesis that the survivor functions 
of iDFS excluding second primary invasive non-breast cancers are the same for the two 


 
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treatment arms vs. the alternative hypothesis that the survivor functions are different for 
the two treatment arms.  
10.7.3 
Subgroup analysis 
The primary endpoint will be analyzed in the subgroups listed in 5.3.1. There will be no 
adjustment for multiple comparisons in the analyses in subgroups. The results will be 
presented in tables and graphically as a forest plot. 
10.7.4 
Regression analysis 
Univariate and multivariate Cox-proportional hazards model will be used for iDFS to report 
hazard ratios with 95% CI and to adjust for the covariates defined in 5.3.2. The results will 
be presented in tables and graphically as a forest plot. 
10.7.5 
Sensitivity/Supportive Analyses 
The following sensitivity analyses / supportive analyses will be performed to explore the 
robustness of the primary analysis’ results:  
A. Analysis based on the per protocol analysis set for efficacy, 
B. Unstratified analysis, 
C. Analysis using strata derived according to clean CRF data instead of those recorded in            
d                   during randomization, 
D. Analysis in which patients receiving new anticancer therapy prior to occurrence of an 
iDFS event will be censored at the date of last disease assessment where the patient 
was “alive and tumor-free/without new signs of disease” prior to new anticancer 
therapy. 
E. Analysis in which patients who start a new anticancer therapy prior to disease relapse 
or occurrence of a second primary invasive non-breast cancers or death will be 
considered to have had an event on the start date of new anticancer therapy. 
F. Analysis in which patients who are ER-positive at surgery based on centrally assessed 
tissue from post-neoadjuvant residual invasive disease. 
These analyses are regarded as purely exploratory. 
10.8 
Secondary efficacy analyses 
Final analysis on the secondary efficacy endpoints (except for OS) will be conducted 
when 290 events in iDFS have been observed and documented in the database. At the 
time of the final iDFS analysis an interim OS analysis will be conducted (see section 7.2). 
At the time of interim iDFS analyses iDFS excluding second primary invasive non-breast 
cancers was hierarchically tested for significance, provided the primary endpoint, iDFS, 


 
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was statistically significant. As iDFS was not significant, iDFS excluding second primary 
invasive non-breast cancers was not statistically evaluated. 
At the time of final iDFS analyses, the  hierarchical testing will be performed in the 
following sequence: primary endpoint iDFS, iDFS excluding second primary invasive non-
breast cancers and OS. The next level of testing will only be provided if the prior level is 
significant. If a test is not significant, the next test will not be statistically evaluated. 
10.8.1 
Estimation of outcomes 
The Kaplan-Meier curves of the time-to-event data, Kaplan-Meier estimates of 3-, and 5-
year probability of the time-to-event data and the corresponding 95% CI will be provided. 
The time-to-event data are: iDFS excluding second non-breast cancers, OS, DDFS, iDFS 
per treatment group in patients with luminal-B tumors.  
LRRFI including competing risks will be analyzed using the Fine-Gray model (21), both 
univariately (the cumulative incidence function will be presented graphically per treatment 
arm) and multivariately to report HR for treatment and to adjust for the stratification 
factors. 
10.8.2 
Hypotheses to be tested 
Null hypothesis: survivor functions of the two treatment arms are equal; 
Alternative hypothesis: survivor functions of the two treatment arms are not equal. 
A two-sided stratified log-rank test at the overall significance level 0.05 will be performed 
to compare time-to-event efficacy outcomes between treatment arms, the same 
stratification factors will be used as for the primary endpoint. 
10.8.3 
Subgroup analysis 
The secondary time-to event endpoints will be analyzed in the stratified subgroups. There 
will be no adjustment for multiple comparisons in the analyses in subgroups. The results 
will be presented in table and graphically as a forest plot. 
10.8.4 
Regression analysis 
Univariate and multivariate Cox-proportional hazards model will be used for time-to-event 
data to report hazard ratios with 95% CI and to adjust for the covariates defined in 5.3.2. 
The results will be presented in table and graphically as a forest plot. 
 


 
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10.9 
Quality-of-life analyses  
Quality of life analyses (QoL) will be performed using the evaluable subset for QoL.  
The scales (based on multiple items) of all QoL instruments will be computed according to 
the respective scoring manuals. Summary statistics (mean, standard deviation, median, 
and range) of observed values and calculated scores and their changes from baseline to 
each assessment time point  will be summarized for the two treatment arms measured as 
Cohens effect size. For the EORTC QLQ C30 questionnaire standard values are 
available, which will be displayed in the descriptive tables.  
Repeated-measures mixed-effects models will be used with main effect terms “treatment” 
and “time”, the interaction term “treatment-by-time”, and baseline values as covariate. 
Time is considered to be continuous. Treatment effect changes of the QoL scales over 
time and treatment-by-time interaction will be explored.  
Repeated-measures mixed-effects models will be fit for questionnaires / scales consisting 
of more than one item: 
• 
EORTC QLQ-C30: Global health status/QoL, Functional scales: Physical 
Functioning, Role functioning, Emotional functioning, Cognitive functioning, Social 
functioning; Symptom scales: Fatigue, Nausea and Vomiting, Pain. 
• 
EORTC QLQ-BR23: Functional scales: Body image; Symptom scales: Systemic 
therapy side effects, Breast symptoms, Arm symptoms; Sexual functioning and 
Sexual enjoyment are often missing and will also not be considered. 
• 
QLQ-FA13: Physical fatigue, Emotional fatigue, Cognitive fatigue. 
• 
EQ-5D-3L: Index score 
10.10 
Follow-Up Therapy 
Follow-up anti-cancer therapy will be summarized by treatment type (radiation, 
chemotherapy, hormone therapy, targeted therapy, surgery, and other) and treatment line 
as patients with number of regimens (0, 1, 2, ≥3). 
 


 
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11. 
LITERATURE CITATIONS / REFERENCES 
1. Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for 
disease-specific survival in patients with breast cancer treated with neoadjuvant 
chemotherapy. J Clin Oncol. 29(15):1956-62, 2011  
2. Jeruss JS, Mittendorf EA, Tucker SL, et al. Combined use of clinical and 
pathologic staging variables to define outcomes for breast cancer patients treated 
with neoadjuvant therapy. J Clin Oncol. 26(2):246-52, 2008   
3. Marmé F, Lederer B, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Gerber B, 
Hanusch C, Hilfrich J, Huober J, Jackisch C, Kümmel S, Loibl S, Paepke S, Untch M, 
von Minckwitz G, Schneeweiss A. Utility of the CPS+EG staging system in hormone 
receptor-positive, human epidermal growth factor receptor 2-negative breast cancer 
treated with neoadjuvant chemotherapy. Eur J Cancer. 2015 Dec 13;53:65-74.   
4. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA, Sparano 
JA, Hunsberger S, Enos RA, Gelber RD, Zujewski JA (2007). Proposal for 
standardized definitions for efficacy end points in adjuvant breast cancer trials: the 
STEEP system. J Clin Oncol. May 20;25(15):2127-32. 
5. Weis J, Arraras JI, Conroy T, Efficace F, Fleissner C, Görög A, Hammerlid E, Holzner 
B, Jones L, Lanceley A, Singer S, Wirtz M, Flechtner H, Bottomley A (2013). 
Development of an EORTC quality of life phase III module measuring cancer-related 
fatigue (EORTC QLQ-FA13). Psycho-Oncology, 22(5), 1002-1007 
6. Arens N, Bleyl U, Hildenbrand R (2005). HER2/neu, p53, Ki67, and hormone receptors 
do not change during neoadjuvant chemotherapy in breast cancer. Virchows Arch. 
2005 May;446(5):489-96. 
7. Miglietta L, Vanella P, Canobbio L, Parodi MA, Guglielmini P, Boccardo F (2009). 
Clinical and pathological response to primary chemotherapy in patients with locally 
advanced breast cancer grouped according to hormonal receptors, Her2 status, 
grading and Ki-67 proliferation index. Anticancer Res. May;29(5):1621-5. 
8. Lee SH, Chung MA, Quddus MR, Steinhoff MM, Cady B (2003). The effect of 
neoadjuvant chemotherapy on estrogen and progesterone receptor expression and 
hormone receptor status in breast cancer. Am J Surg. Oct;186(4):348-50. 
9. Faneyte IF, Schrama JG, Peterse JL, Remijnse PL, Rodenhuis S, van de Vijver MJ 
(2003). Breast cancer response to neoadjuvant chemotherapy: predictive markers and 
relation with outcome. Br J Cancer. Feb 10;88(3):406-12. 


 
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