POLARIS: PALBOCICLIB IN HORMONE RECEPTOR POSITIVE ADVANCED BREAST CANCER: A PROSPECTIVE MULTICENTER NON-INTERVENTIONAL STUDY
Conditions: Advanced Breast Cancer, Metastatic Breast Cancer
Sponsor: Pfizer

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 1 of 46 
 
NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
Study information 
Title 
POLARIS: Palbociclib in Hormone Receptor Positive Advanced 
Breast Cancer: A Prospective Multicenter Non-Interventional 
Study 
Protocol number 
A5481082 
Protocol version identifier 
FINAL AMENDMENT 1, 02AUG2017 
Date of last version of protocol 
31OCT2016 
Active substance 
Palbociclib/PD-332,991 
Medicinal product 
Palbociclib 
Research question and objectives 
This Non-Interventional Study will describe and analyze the 
clinical use of palbociclib in routine clinical practice in the 
treatment of advanced breast cancer.  
Main objectives: 
 
Palbociclib prescribing and treatment patterns in routine 
clinical practice in Advanced Breast Cancer (ABC) treatment 
 
Clinical outcomes 
 
Metastatic Breast Cancer (MBC) treatment sequence 
 
Patient quality of life  
 
Geriatric assessments 
 
 
 
Author 
, MD 
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
PPD
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 2 of 46 
TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS ................................................................................................4 
2. RESPONSIBLE PARTIES ....................................................................................................6 
3. ABSTRACT ...........................................................................................................................7 
4. AMENDMENTS AND UPDATES .......................................................................................8 
5. MILESTONES .......................................................................................................................9 
6. RATIONALE AND BACKGROUND ................................................................................10 
6.1. Breast Cancer ..........................................................................................................10 
6.2. Palbociclib ...............................................................................................................11 
6.3. EORTC QLQ-C30 ...................................................................................................12 
6.4. Geriatric Assessments .............................................................................................12 
6.5. Summary .................................................................................................................14 
7. RESEARCH QUESTIONS AND OBJECTIVES ...............................................................14 
8. RESEARCH METHODS ....................................................................................................15 
8.1. Study Design ...........................................................................................................15 
8.2. Setting ......................................................................................................................15 
8.2.1. Inclusion Criteria ........................................................................................15 
8.2.2. Exclusion Criteria .......................................................................................16 
8.3. Variables ..................................................................................................................16 
8.4. Data Sources ............................................................................................................19 
8.4.1. Patient Medical Charts ................................................................................19 
8.4.2. Patient Questionnaires and Quality of Life ................................................19 
8.4.3. Site Questionnaires .....................................................................................19 
 
8.5. Study Size ................................................................................................................20 
8.6. Data Management ...................................................................................................22 
8.7. Data Analysis ..........................................................................................................23 
8.7.1. EORTC QLQ-C30 ......................................................................................23 
8.7.2. G8 Screening Tool ......................................................................................23 
8.7.3. ADL ............................................................................................................23 
8.8. Quality Control ........................................................................................................24 
8.9. Limitations of the Research Methods ......................................................................24 
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 3 of 46 
8.10. Other Aspects ........................................................................................................25 
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................25 
9.1. Patient Information and Consent .............................................................................25 
9.2. Patient Withdrawal ..................................................................................................25 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............25 
9.4. Ethical Conduct of the Study ..................................................................................26 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS ......................................................................................26 
10.1. Single Reference Safety Document .......................................................................34 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........34 
12. REFERENCES ..................................................................................................................35 
13. LIST OF TABLES .............................................................................................................39 
14. LIST OF FIGURES ...........................................................................................................39 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................39 
EORTC QLQ-C30 ..........................................................................................................40 
G-8 Screening Tool ........................................................................................................43 
ADL Activities of Daily Living .....................................................................................45 
 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 4 of 46 
1. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABC  
Advanced breast cancer  
AE 
Adverse event 
AEM 
Adverse event monitoring 
ADL 
Activities of Daily Living 
CAN 
Canada 
CBC 
Complete blood count 
CDK 
Cyclin Dependent Kinase 
cfDNA 
Circulating cell free deoxyribonucleic acid 
CGA 
Comprehensive Geriatric Assessment 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
eCRF  
Electronic case report form  
DNA 
Deoxyribonucleic acid 
ECOG  
Eastern Cooperative Oncology Group  
EDC 
Electronic data capture  
EDP 
Exposure during pregnancy 
EMA 
European Medicines Agency 
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
EORTC QLQ-C30 
European Organisation for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 
ER 
Estrogen receptor 
ER+  
Estrogen receptor positive  
ESMO 
European Society for Medical Oncology 
FDA 
Food and Drug Administration 
GA 
Geriatric Assessment 
GEP 
Good Epidemiological Practice 
GPP 
Good Pharmacoepidemiology Practices  
HER2-  
Human epidermal growth factor receptor 2 negative  
HR 
Hazard ratio 
HR+ 
Hormone receptor positive  
IEA 
International Epidemiological Association 
IEC  
Independent ethics committee   
IRB 
Institutional review board   
ISMF 
Investigator Site Master File 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR 
International Society for Pharmacoeconomics and Outcomes 
Research 
MBC 
Metastatic breast cancer 
NCCN 
National Comprehensive Cancer Network 
NIS  
Non-interventional study   
PFS 
Progression free survival  
PR+  
Progesterone receptor positive  

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 5 of 46 
PRO  
Patient reported outcomes   
PV 
Pharmacovigilance 
QOL  
Quality of life  
RB 
Retinoblastoma 
RNA 
Ribonucleic acid 
SAE  
Serious adverse event  
SAP  
Statistical analysis plan   
SAS 
Statistical analysis system 
SIOG 
Society of Geriatric Oncology 
SOC 
Standard of care 
SOP 
Standard operating procedure 
US 
United States 
 
 
 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 6 of 46 
2. RESPONSIBLE PARTIES 
Pfizer Inc. 
235 East 42nd Street 
New York, NY 10017 
212-573-1000 
 
Lead Principal Investigator(s) of the Protocol 
Name, degree(s) 
Title 
Affiliation 
Address 
, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
, MD 
  Pfizer Inc.  
235 East 42nd Street 
New York, NY 10017  
 
 
PPD
PPD
PPD
PPD
PPD
PPD

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 7 of 46 
3. ABSTRACT 
POLARIS: Palbociclib in Hormone Receptor Positive Advanced Breast Cancer: A 
Prospective Multicenter Non-Interventional Study (NIS) 
 
BACKGROUND: Palbociclib is a novel cyclin dependent kinase (CDK)4/6 inhibitor 
approved in the United States (US) and Canada (CAN) in combination with certain 
endocrine therapies for hormone receptor positive (HR+)/human epidermal growth 
factor receptor 2 negative (HER2-) advanced breast cancer (ABC). With the 
introduction of this first in class therapy, it is important to understand palbociclib 
treatment patterns in routine clinical practice in the US and CAN; and as a result, the 
evolving treatment landscape of ABC. This study will provide prospective, 
observational data in the real world setting to contribute to the knowledge of 
palbociclib in ABC disease management and the new ABC treatment paradigm. 
OBJECTIVES: The objectives of this prospective NIS of palbociclib in ABC 
treatment are to describe and analyze palbociclib prescribing and treatment patterns in 
routine clinical practice, clinical outcomes, metastatic breast cancer (MBC) treatment 
sequencing prior to, during, and after palbociclib, patient quality of life, geriatric 
specific assessment; and 
 
    
STUDY DESIGN: A prospective, observational, NIS.  
POPULATION: HR+/HER2- ABC patients whose treatment decision with 
palbociclib has been made by their treating physician and who meet the eligibility 
criteria will be invited to participate in the study. 
DATA SOURCES: This prospective, observational study will be conducted 
according to each site’s routine clinical practice. Data will be captured using a web- 
based collection tool.  
STUDY SIZE: Approximately 1500 patients from approximately 100 US sites 
and 10 CAN sites (community and academic) will be enrolled. Study duration 
will consist of observation of patients on palbociclib treatment and 
approximately 3 years of follow-up post each patient’s end of treatment with 
palbociclib, or until patient withdrawal from the study or death.  
DATA ANALYSIS: Descriptive statistics will be used to summarize all endpoints.  
 
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 8 of 46 
4. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed  
Summary of amendment(s) 
Reason 
1 
02AUG 
2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial 
Study 
Information 
Section 1. List of 
Abbreviations 
Section 3.  
Abstract 
Section 6. 
Background and 
Rationale 
Section 7. 
Research 
Objectives and 
Questions 
Section 8. 
Research 
Methods 
Section 12. 
References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Information: Research 
objectives and questions updated to 
include clinical outcomes as a main 
objective.   
Section 1. List of Abbreviations: 
Canada added to the table.  
Section 3. Abstract: Updated to 
include approximately 10 Canadian 
sites, and added clinical outcomes as 
a main objective.  
Section 6. Background and 
Rationale: Updated to include 
Canada and provide background 
information on Canadian Breast 
Cancer Statistics.  
Section 7. Research Objective and 
Question: Main research objectives 
updated to include clinical outcomes.  
Section 8. Research Methods: 
Updated to include approximately 10 
sites in Canada.   
Section 8. Table 1: Data Entry 
Schedule: Footnotes updated to 
clarify physician MBC treatment 
selection survey, 
 
 clarify CBC data 
collection, and clarify reporting of 
adverse event data.   
  
 
 
 
 
 
 
   
 
Section 12. References: References 
updated.   
Study amended to include Canada for 
participation, specify clinical outcomes 
as a research main objective, and 
update the data entry table to clarify 
safety reporting time period, 
 
 potential 
analysis and clarify CBC data entry and 
references were updated.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 9 of 46 
5. MILESTONES 
Milestone 
Planned date 
Start of data collection  
16Dec2016 
End of data collection  
16Dec2021 
Final study report 
15NOV2022 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 10 of 46 
6. RATIONALE AND BACKGROUND 
6.1. Breast Cancer 
Breast cancer remains the most common cancer in women worldwide, with 1.6 million new 
cases diagnosed and a half a million deaths reported annually. In the US, an estimated 
246,660 new cases of invasive breast cancer, and an additional 61,000 new cases of in situ 
breast cancer, are expected to be diagnosed in 2016 (American Cancer Society, 2016).  
Breast cancer is ranked the second highest cause of cancer death in American women 
(American Cancer Society, 2016) and is the third highest cause of cancer death overall, 
behind lung cancer and colon/rectum cancer, with 40,450 estimated deaths in the US in 2016 
(Howlader et al 2016). Breast cancer represents about 29% of all new cancer cases and 14% 
of all cancer deaths in women in the US (American Cancer Society, 2016). From 2003 to 
2012, breast cancer incidence rates in the US were stable in white women and increased 
slightly, at rate of 0.3% per year, in black women. While death rates declined over the same 
time period (by 1.9% in white women and 1.4% in black women), due to early detection and 
treatment (American Cancer Society, 2016), breast cancer still remains a major heath issue in 
the US. Statistics for breast cancer in males are also notable: 2,600 new cases are expected to 
be diagnosed in the US in 2016, with 440 estimated deaths (American Cancer Society, 2016).  
According to latest figures from the Canadian Cancer Society (Canadian Cancer Society’s 
Advisory Committee on Cancer Statistics, 2016), 1 in 9 Canadian women are expected to 
develop breast cancer in their lifetime, with 25,700 expected new cases in 2016. Breast 
cancer is the second most common cause of cancer death in Canadian women, accounting for 
13% of all cancer deaths in women, and is the third most common cancer in Canada (CAN), 
accounting for 13% of all cancers and 26% of cancers among women. Consistent with data 
from the US, breast cancer incidence rate in CAN stabilized from 2004 through 2010 and the 
death rate due to breast cancer has fallen from a peak of 41.7 deaths per 100,000 in 1987 to a 
projected rate of 23.4 deaths per 100,000 in 2016 (Canadian Cancer Society’s Advisory 
Committee on Cancer Statistics, 2016).  
Approximately 80% of breast cancers expressed estrogen receptor (ER), progesterone 
receptor (PR), or both. Endocrine therapy is the mainstream treatment for the HR+ cancers. 
Currently, first-line treatment in the ER+/HER2-ABC postmenopausal population typically 
includes endocrine therapies, such as letrozole, anastrozole, exemestane, fulvestrant, and 
tamoxifen with time to progression and prolongation of progression free survival (PFS) 
ranging from 5 to 15 months (Cardoso, 2012; Bergh, 2012; Mehta, 2012). These treatment 
options are supported by clinical practice guidelines published by the European Society for 
Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) as 
preferred first-line options in patients who are antiestrogen naïve or who are more than 
2 years from previous antiestrogen therapy and do not have extensive visceral involvement 
(Cardoso, 2012; NCCN, 2016). Single-agent treatment with an aromatase inhibitor or 
tamoxifen has shown limited clinical benefit (Baselga et al 2012; Klijn et al 2000). The 
selective ER degrader fulvestrant has modest activity in this population of patients (Di Leo et 
al 2010, 2014) and the development of effective therapies that can address resistance to 
endocrine therapy is of clinical importance.  

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 11 of 46 
6.2. Palbociclib 
In vitro evidence suggests that breast cancer that has developed resistance to prior endocrine 
therapy remains dependent on cyclin D1–CDK4/6 to promote proliferation (Miller et al, 
2011; Thangavel et al, 2011). Palbociclib is an orally bioavailable small-molecule inhibitor 
of CDK4 and CDK6, with a high level of selectivity for CDK4 and CDK6 over other cyclin-
dependent kinases (Toogood et al, 2005). Palbociclib inhibits CDK4 and CDK6 in vitro, 
resulting in loss of retinoblastoma (RB)1 phosphorylation. It has high activity in hormone-
receptor–positive breast-cancer cell lines and is synergistic in combination with endocrine 
therapies (Finn et al, 2009). 
In a phase 1/2 study, PALOMA-1 (Finn et al, 2015), patients were randomized to a 1:1 ratio 
to receive palbociclib + letrozole or letrozole alone. The median PFS was 20.2 months with 
palbociclib + letrozole and 10.2 months with letrozole alone (Hazard ratio [HR]=0.488; 
P=0.0004). In terms of the safety profile, Grade 3/4 neutropenia was significantly higher in 
patients receiving palbociclib + letrozole compared with letrozole alone (54% vs 1%). 
Additionally, the rate of Grade 3/4 leucopenia (19% vs 0%) and fatigue (4% vs 1%) were 
also higher with palbociclib + letrozole. No cases of febrile neutropenia or neutropenia-
related infections were reported in the study (Finn et al, 2015).   
A phase 3 study, PALOMA-2 (Finn et al, 2016), was conducted with 666 post-menopausal 
women without prior systemic therapy for ER+/HER2– ABC. Patients were randomized to a 
2:1 ratio to receive palbociclib + letrozole or placebo + letrozole. The median PFS was 24.8 
months with palbociclib + letrozole and 14.5 months with placebo + letrozole (HR=0.58; 
95% confidence interval [CI] 0.46, 0.72, P<0.000001). Common adverse events (AEs; all 
grades) with palbociclib + letrozole vs placebo + letrozole were neutropenia (75% vs 5%), 
fatigue (41% vs 23%), nausea (25% vs 13%), arthralgia (33.3% vs 33.8%), and alopecia 
(32.9% vs 15.8%). Grade 3/4 neutropenia occurred in54% of patients; other AEs were of 
Grade 1 severity. Febrile neutropenia was seen only with palbociclib + letrozole (2.5%). 
Permanent discontinuation due to AEs occurred in 9.7% of patients receiving palbociclib + 
letrozole vs 5.9% receiving placebo + letrozole. PALOMA-2 confirmed the significant 
clinical benefit and safety of palbociclib + letrozole in ER+/HER2– ABC patients who had 
not received prior systemic therapy for their advanced disease (Finn et al, 2016). 
Another phase 3 study, PALOMA-3, was conducted with 521 patients with advanced 
HR+/HER2– patients that had relapsed or progressed during prior endocrine therapy (Turner 
et al, 2015). Patients were randomized to a 2:1 ratio to receive palbociclib + fulvestrant or 
placebo + fulvestrant. The median PFS was 9.2 months (95% CI, 7.5, upper limit not 
estimable) with palbociclib + fulvestrant and 3.8 months (95% CI 3.5, 5.5) with placebo + 
fulvestrant (HR for disease progression or death, 0.42; 95% CI 0.32, 0.56; P<0.001). The 
most common grade 3 or 4 AEs in the palbociclib+fulvestrant group were neutropenia 
(62.0%, vs. 0.6% in the placebo + fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia 
(2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile 
neutropenia was reported in 0.6% of patients in each treatment group. The rate of 
discontinuation due to AEs was 2.6% vs. 1.7% (Turner et al, 2015).  

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 12 of 46 
Estrogen receptor-positive breast cancer is biologically heterogeneous. Although palbociclib 
clinical trial results are very promising, it is also recognized that not all patients may respond 
to palbociclib treatment, and palbociclib treatment does come with mechanism based 
toxicities. 
 
 
  
6.3. EORTC QLQ-C30 
In recent years, progress has been made in using patient-reported outcome (PRO) measures 
to determine how patients experience their disease over the course of treatment, receive 
aftercare, and live with cancer as a chronic condition. There is a growing demand for routine 
monitoring of PROs to complement clinical data with the patient’s perspective (Wintner et al, 
2016) and to evaluate cancer treatment-related symptoms, which are common and often 
underreported (American Cancer Society 2016).  
The European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) (Luckett et al 2011; Velikova et al, 2012; 
Wintner et al, 2016) is widely used to assess changes in quality of life for patients 
undergoing treatment for cancer. The EORTC QLQ-C30 is a 30-item questionnaire 
composed of five multi-item functional subscales (physical, role, cognitive emotional, and 
social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a 
global health/quality of life (QOL) subscale, and six single items assessing other cancer-
related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation, and the 
financial impact of cancer), with responses based on recall during the past week (see Annex 
1: Stand Alone Documents: EORTC QLQ-C30). The EORTC QLQ-C30 has been translated 
and linguistically validated into more than 60 languages (Velikova et al, 2012). 
6.4. Geriatric Assessments 
The median age at diagnosis of breast cancer in the US is 62 years, and the majority of 
women who die of breast cancer in the US are age 65 years and older (median: 68 years) 
(Howlader et al 2016). In CAN, the majority (51%) of breast cancers occur in women 50 to 
69 years of age, and approximately 32% of breast cancers are diagnosed in females aged 70 
and over (Canadian Cancer Society, 2016). The US population that is 80 years and older is 
rapidly expanding—from 9 million members in 2001 to an anticipated 30 million members 
by 2050 (United Nations, 2001; Shachar et al, 2016a,b). As a group, older adults are more 
vulnerable to the adverse effects of cancer when compared with younger patients, in large 
part because of their higher incidence of comorbidities, their frequent use of many 
concomitant medications, and age-associated physiologic changes that may affect organ 
function (Schachar et al 2016b). To understand the population better in order to provide more 
appropriate treatment options, in 2005 the International Society of Geriatric Oncology 
(SIOG) recommended the use of geriatric assessment in cancer patients aged 70 years or 
older (Decoster et al, 2015). It is believed that the plausible data from the geriatric 
assessment can help devise treatment strategy and maximize the benefit of treatment 
outcome. Based on the lack of information in this population (Schachar et al 2016a,b), it is 
intended that the geriatric assessment effectively addresses these and many other areas of 
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 13 of 46 
geriatric care that are crucial to the successful treatment and prevention of disease and 
disability in older people, especially in cancer patients.   
The comprehensive geriatric assessment (CGA) is a multidimensional, multidisciplinary 
assessment designed to evaluate an older person's functional ability, physical health, 
cognition and mental health, and socioenvironmental circumstances (Elsawy and Higgins, 
2011). CGA has been found to improve treatment outcomes in older patients in the areas of 
prediction of treatment related toxicities, treatment adherence, quality of life, treatment 
decision making, and overall survival (Owusu and Berger 2014). A lack of consensus 
remains as to which domains to be included in a CGA, and what subsequent assessment and 
interventions to be used. CGA is time consuming and makes implementation in busy clinical 
practice challenging (Hurria et al, 2005).  
Several screening tools have been developed as brief assessment in older patients, to identify 
vulnerable patients in need of full CGA. These tools may also have prognostic or predictive 
value in the outcome measures of treatment related toxicity, functional decline and survival 
(Decoster et al, 2015). One of the most studied screening tools for elderly cancer patients is 
G8 Screening Tool, which will be completed in the current protocol only for patients equal to 
or greater than 70 years of age at the time of study enrollment. The G8 was introduced by 
Bellera et al. in 2012 as a physician-assessed tool to identify geriatric cancer patients for 
whom the administration of a time consuming comprehensive geriatric assessment would be 
beneficial. Patients can fill in this instrument with the assistance of a healthcare professional 
(Soubeyran et al, 2014). The G8 has shown high sensitivity and specificity among different 
screening tools (Decoster et al, 2015; Hentschel et al, 2016; Martinez-Tapia et al, 2016). 
Eight items are included, based mainly on nutritional status, with responses based on recall 
for up to 3 months. The G8 has been found predictive for chemotherapy-related toxicity 
(Stokoe et al, 2012.) and prognostic for survival in mostly solid tumors (Liuu et al, 2012; 
Kenis et al 2014). A score of less than or equal to 14 indicates further full assessment may be 
needed (Bellera et al, 2012). 
An additional screening tool that will be completed only for patients equal to or greater than 
70 years of age at the time of study enrollment is activities of daily living (ADL). Although 
not specifically designed for geriatric patients, ADL assesses basic self-care skills to 
maintain independence in home (bathing, dressing toileting, feeding oneself, maintain 
continent, transferring from bed/chair). Studies have shown that functional status predicts 
survival, chemotherapy toxicity, postoperative morbidity, mortality (Eberhadt et al, 2006; 
Maione et al, 2005). Correlation of ADL dependence and outcome is less established in 
studies of older patients receiving outpatient oncology care, likely because there is a low 
proportion of patients requiring this degree of assistance (Extermann and Hurria, 2007. 
Elderly patients have not been significantly represented in clinical trials for targeted therapies 
for breast cancer, including those that led to registration of palbociclib (Shachar et al, 2016). 
Additional research on older patients being treated with palbociclib, such as in routine 
clinical practice setting, may generate data to bridge the gap in understanding the tolerability 
and outcomes in this venerable patient population, commonly with comorbidities and 
declining general health due to aging. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 14 of 46 
6.5. Summary 
Palbociclib is a novel CDK4/6 inhibitor approved in US and CAN in combination with 
certain endocrine therapies for HR+/HER2- ABC. With the introduction of this first in a new 
class of drugs, it is important to understand palbociclib treatment patterns in routine clinical 
practice in the US and CAN and, as a result, the evolving treatment landscape of ABC. It is 
important to understand real-world practice patterns and patient reported outcomes as clinical 
trial populations may not be representative of the target populations of patients given the 
enrollment criteria in clinical trials coupled with the focus on a single line of therapy. This 
study will provide prospective, observational data in the real world setting to contribute to 
the knowledge of palbociclib in ABC disease management and the new ABC treatment 
paradigm, and
 
 It is also of value to understand patient quality of life and the utility of geriatric 
assessment (GA) screening tools in treatment outcome measures of older breast cancer 
patients to further inform treatment decisions. 
7. RESEARCH QUESTIONS AND OBJECTIVES 
The objectives of this prospective NIS of palbociclib in ABC treatment are to describe and 
analyze palbociclib prescribing and treatment patterns in routine clinical practice, clinical 
outcomes, MBC treatment sequencing prior to, during, and after palbociclib, patient quality 
of life, geriatric specific assessment; and 
 
   
The main research questions to be addressed may include the following: 
 
 Palbociclib prescribing and treatment patterns in routine clinical practice in ABC 
treatment 
 Clinical outcomes 
 MBC treatment sequence 
 Patient quality of life, as measured by EORTC QLQ-C30 
 Geriatric Assessments in patients equal to or greater than 70 years of age at enrollment 
 
 
 
 
 
  
CCI
CCI
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 15 of 46 
8. RESEARCH METHODS  
8.1. Study Design  
This is a prospective, non-interventional (NI), multicenter study being conducted in the US 
and CAN. The primary goal is to understand palbociclib prescribing and treatment patterns 
for patients with ABC being treated in routine clinical practice in the US and CAN.  
Approximately 1,500 subjects will be enrolled across approximately 100 sites in the US and 
10 sites in CAN. Study duration will consist of observation of patients on palbociclib 
treatment and approximately 3 years of follow-up post each patient’s end of treatment with 
palbociclib, or until patient withdrawal from the study or death.  
Participation in this study is not intended to change the routine treatment patients receive, as 
determined by their prescribing physicians; all treatment decisions, type and timing of 
disease monitoring are at the discretion of treating physician and patient.   
Assessments include patient questionnaires and quality of life (EORTC QLQ-C30, G8 
Screening Tool, ADL), site questionnaires, physician MBC treatment selection survey, and 
, as detailed in Section 8.3 and Section 8.4.  
8.2. Setting 
Patients with HR+/HER2- ABC within the US and CAN will be enrolled from a 
geographically representative population as well as from diverse treatment settings (e.g., 
academic and community sites). ABC patients whose treatment decision with palbociclib has 
been made by their treating physician and meet the eligibility criteria will be invited to 
participate in the study. Eligibility will be assessed at the date of the enrollment visit (i.e. 
Baseline/Visit 1). 
8.2.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:  
1. Age ≥18 years or older.  
2. Diagnosis of adenocarcinoma of the breast with evidence of metastatic disease or 
advanced disease not amenable to treatment with curative intent.   
3. Documented HR+ (ER+ and/or PR+) tumor based on local standards.   
4. Documented HER2- tumor based on local standards.    
5. Physician has determined that treatment with palbociclib is indicated. 
6. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study.  
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 16 of 46 
7. Patients who in the opinion of the investigator are willing and able to comply with 
regular clinic visits as per standard of care practice at the site. 
8.2.2. Exclusion Criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. Patients with a life expectancy of less than 3 months at the time of ABC diagnosis, per 
the investigator’s judgment.  
2. Patients participating in any interventional clinical trial that includes investigational or 
marketed products at the time of enrollment. (Patients participating in other investigator 
initiated research or NIS can be included as long as their standard of care is not altered by 
the study).  
3. Patients on active treatment for malignancies other than ABC at the time of enrollment.  
4. Patients who are unable to understand the nature of the study and are unwilling to sign an 
informed consent. 
Patient eligibility should be reviewed, documented, and confirmed by an appropriately 
qualified member of the investigator’s study team before patients are enrolled in the study. 
8.3. Variables 
Patient demographics, study site characteristics, medical history, baseline concomitant 
medications, breast cancer diagnosis and recurrence history, metastatic disease status, MBC 
treatment, disease status and characteristics, performance status (ECOG), palbociclib dosing 
and treatment management, routine clinical efficacy assessment, physician MBC treatment 
selection survey, quality of life, geriatric screening tool and questionnaire, and 
 
will be assessed. Detailed definitions of variables that will be collected or derived for 
statistical analyses and summaries will be included in the Statistical Analysis Plan (SAP).  
Data collected will be from the treating physicians’ routine clinical assessments as per their 
local standard of care. Patients will be asked to complete the EORTC QLQ-C30; the G8 
Geriatric Screening Tool and ADL will be completed for patients greater than or equal to 
70 years of age at the time of study enrollment. The G8 Screening Tool will be completed by 
the treating physician or appropriately delegated site staff and the ADL will be completed by 
the patient or in conjunction with the appropriately delegated site staff. 
 
 
 
   
The Data Entry Schedule is provided in Table 1 and the EORTC QLQ-C30 and Geriatric 
Assessments in Table 2. 
CCI
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 17 of 46 
Table 1: Data Entry Schedule 
Data Collection and Entry1                                                       ► 
 Baseline 
During Treatment with Palbociclib 
Post Treatment with Palbociclib 
  
SOC Visit 1 
SOC Visit 2 through 
 End of Treatment with Palbociclib 
 
Follow-up through 
End of Study2 
Informed Consent & Inclusion/Exclusion Criteria  
x 
 
 
Patient Demographics, Study Site Characteristics, Medical 
History, Baseline Concomitant Medications, Baseline 
Metastatic Disease Status 
x 
 
 
Breast Cancer Diagnosis and Recurrence History  
x 
 
 
Breast Cancer Treatment3 
 x3 
x3 
x3 
Physician MBC Treatment Selection Survey4  
 x4 
x4 
x4 
Performance Status (ECOG) 
x 
x 
 
Clinical Assessments5 
 x5 
x5 
x5 
 
 
 
 
 
 
Laboratory: CBC7 
x7 
x7 
 
Adverse Events and Serious Adverse Events8 
x8 
x8 
 
SOC = Standard of care; ABC = advanced breast cancer; CBC = complete blood count; ECOG = Eastern Cooperative Oncology Group; MBC = metastatic breast cancer; SAE = 
serious adverse event  
1. Data is collected in accordance with normal standard of care visits, enter all data available per Data Entry Schedule into the electronic data capture system. 
2. Follow up through End of Study: Enter data at SOC visits where each subsequent (post palbociclib treatment) MBC treatment regimen is prescribed and at end of study.    
3. Breast cancer treatment: including surgery, radiation, systemic chemotherapy, hormone therapy, and/or targeted therapy, in both neoadjuvant/adjuvant and metastatic disease 
settings, prior to, during, and post palbociclib treatment; supportive care is also collected in the metastatic setting while on this study. 
4. Physician MBC Treatment Selection Survey: Treating physicians will complete a treating physician MBC treatment selection survey that will capture the reason(s) for treatment 
choice at start of palbociclib therapy and at start of subsequent therapies.    
5. Clinical assessments: overall clinical response as judged by treating physician, at intervals per standard of care schedule: imaging assessment, clinical progression, and clinical 
biomarkers. 
 
 
 
 
7. CBC: Baseline and during palbociclib treatment, enter any CBC during the 1st 3 cycles, then enter Day 1 (or prior to start of a new cycle) CBC for the subsequent cycles as per 
standard of care.  
8. AE/SAE reporting begins at the time of the patient’s first dose of palbociclib or the time of the patient’s informed consent if s/he is already exposed to palbociclib and up to 28 
calendar days following the last administration of palbociclib.  
CCI
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 18 of 46 
Table 2: EORTC QLQ-C30 and Geriatric Assessments 
Data Collection and Entry 
Baseline 
 ► 
SOC Visit 1 
Through End of Treatment with Palbociclib 
EORTC QLQ-C301 
x1 
x1 
G8 Screening Tool2 
x2 
x2 
ADL: Activities of Daily Living2 
x2 
x2 
ADL = Activities of Daily Living; EORTC QLQ-C30 = European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 
1. EORTC QLQ-C30 will be collected at baseline (before starting palbociclib) then monthly for the first 3 months of treatment with palbociclib, then every three 
months until the end of treatment with palbociclib.   
2. G8 Screening Tool and Activities of Daily Living to be completed only for patients equal to or greater than 70 years of age at the time of study enrollment. G8 
and ADL will be collected at baseline (before starting palbociclib) then monthly for the first 3 months of treatment with palbociclib, then every three months 
until the end of treatment with palbociclib.  ADL to be completed by the patient or in conjunction with the appropriately delegated site staff, G8 to be completed 
by the treating physician or the appropriately delegated site staff.

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 19 of 46 
8.4. Data Sources  
All data collected in this study are intended to capture the real world treatment patterns and 
outcomes of patients with HR+, HER2- ABC. An electronic case report form (eCRF) will be 
used for data collection. The eCRF must be signed by the investigator. The signature serves 
to attest that the information contained on the eCRF is true. At all times, the investigator has 
the final responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered into the eCRFs.  
Data for this study will be obtained via the sources outlined below.  
8.4.1. Patient Medical Charts  
The investigator or authorized medical staff will record clinical and treatment data from 
patients’ existing medical records into an eCRF following each patient’s standard of care 
clinic visit.   
8.4.2. Patient Questionnaires and Quality of Life   
All patients enrolled in the study will be asked to participate in completing the Quality of 
Life instrument and Questionnaires: 
 EORTC QLQ-C30 (see Annex 1 Stand Alone Documents: EORTC QLQ-C30): Collected 
at baseline (before starting palbociclib) then monthly for the first 3 months of treatment 
with palbociclib, then every three months until the end of treatment with palbociclib.   
 G8 Screening Tool (see Annex 1 Stand Alone Documents: G8 Geriatric Screening Tool) 
and ADL (see Annex 1 Stand Alone Documents: ADL Activities of Daily Living): 
Collected at baseline (before starting palbociclib) then monthly for the first 3 months of 
treatment with palbociclib, then every three months until the end of treatment with 
palbociclib.  ADL to be completed by the patient or in conjunction with the appropriately 
delegated site staff, G8 to be completed by the treating physician or the appropriately 
delegated site staff. 
Patients can complete these assessments either on a paper form or via an electronic direct 
patient data capture software system.     
8.4.3. Site Questionnaires 
The following site questionnaires will be completed: 
 Study Site Characteristics: A study site information form will be used to collect 
information at baseline pertaining to the practice, patient population, specialty and 
treatment pathways.   
 Physician MBC Treatment Selection Survey: Treating physicians will also be asked to 
complete a treating physician MBC treatment selection survey that will capture the 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 20 of 46 
reason(s) for treatment choice at start of palbociclib therapy and at start of subsequent 
therapies.   
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
   
 
 
 
 
 
   
 
 
 
 
  
8.5. Study Size 
This is an observational study of drug usage without any pre-defined hypothesis to be tested; 
rather, it addresses descriptive objectives. The estimated sample size is applied to ensure 
adequate exploration of the objectives and sufficient generalizability.   
Power Analysis and Sample Size (PASS 13) Software (NCSS Statistical Software, 2014) was 
used to calculate sample size. Sample sizes are based on a range of conservative estimates for 
univariate statistics (hypothesis test and confidence intervals) for both dichotomous and 
continuous outcomes. 
Dichotomous Outcomes 
Hypothesis testing: A sample size of 1287 achieves 90% power to detect a difference (P1-P0) 
of 0.04 using a two-sided Z test. The target significance level is 0.05. These results assume 
that the population proportion under the null hypothesis is 0.243 (Zar 1984; Lachin 2000; 
Fleiss et al, 2003; Chow 2011; Machin et al, 2011; DeSantis et al, 2014). If the null 
proportion is 0.163 (Tevaarwerk et al, 2013) this sample size has >90% power (Table 3). 
CCI

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 21 of 46 
Table 3: Sample Size for Proportion Hypothesis Test at α=0.05 
 
P1-P0 
P0 
Power 
N 
.04 
0.163 
0.80  
753 
.04 
0.163 
0.85 
856 
.04 
0.163 
0.90 
1004 
.05 
0.163 
0.80 
489 
.05 
0.163 
0.85 
567 
.05 
0.163 
0.90 
657 
.04 
0.243 
0.80  
955 
.04 
0.243 
0.85 
1009 
.04 
0.243 
0.90 
1287 
.05 
0.243 
0.80 
625 
.05 
0.243 
0.85 
714 
.05 
0.243 
0.90 
834 
P0 is the value of the population proportion under the null hypothesis. 
P1 is the value of the population proportion under the alternative hypothesis. 
 
Confidence Interval: When the sample size is 1134, a two-sided 95% CI for a single 
proportion using the large sample normal approximation will extend 0.025 (=0.05/2) from 
the observed proportion for an expected proportion of 0.243(Newcombe 1998; Fleiss et al, 
2003; DeSantis et al, 2014). Similarly, when the sample size is 1134, a two-sided 95% CI for 
a single proportion using the large sample normal approximation will extend 0.029 
(=0.058/2) from the observed proportion for an expected proportion of 0.50. This sample is 
adequate if the null proportion is 0.163 (Tevaarwerk et al, 2013) (Table 4).  
Table 4: Sample Size 95% Confidence Interval for a Proportion at α=0.05 
 
CI Width 
Proportion (p) 
Width if P=0.5 
N 
0.05 
0.163 
0.068 
839 
0.05 
0.200 
0.062 
984 
0.05 
0.243 
0.058 
1134 
0.05 
0.300 
0.055 
1291 
0.05 
0.400 
0.051 
1476 
0.06 
0.163 
0.081 
583 
0.06 
0.200 
0.075 
683 
0.06 
0.243 
0.070 
786 
0.06 
0.300 
0.065 
897 
0.06 
0.400 
0.061 
1025 
CI = confidence interval 
 
Continuous Outcomes 
Hypothesis testing: A sample size of 1052 achieves 90% power to detect a difference of -0.30 
between the null hypothesis mean of 0.00 and the alternative hypothesis mean of 0.30 with 
an estimated standard deviation of 3.00 and with a significance level (alpha) of 0.05 using a 
two-sided one-sample t-test (Zar 1984; Machin et al, 2011) (Table 5). 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 22 of 46 
Table 5: Sample Size for Mean Hypothesis Test at α=0.05 
 
Power 
Mean1-Mean0 
Standard Deviation 
Effect Size 
N 
0.80 
0.25 
2.0 
0.125 
505 
0.85 
0.25 
2.0 
0.125 
577 
0.90 
0.25 
2.0 
0.125 
673 
0.80 
0.25 
3.0 
0.083 
1131 
0.85 
0.25 
3.0 
0.083 
1294 
0.90 
0.25 
3.0 
0.083 
1514 
0.80 
0.30 
3.0 
0.100 
786 
0.85 
0.30 
3.0 
0.100 
899 
0.90 
0.30 
3.0 
0.100 
1052 
0.80 
0.30 
2.0 
0.150 
351 
0.85 
0.30 
2.0 
0.150 
401 
0.90 
0.30 
2.0 
0.150 
469 
0.80 
0.40 
2.0 
0.200 
199 
0.85 
0.40 
2.0 
0.200 
227 
0.90 
0.40 
2.0 
0.200 
265 
0.80 
0.40 
3.0 
0.133 
444 
0.85 
0.40 
3.0 
0.133 
507 
0.90 
0.40 
3.0 
0.133 
593 
 
Confidence Interval: A sample size of 1292 produces a two-sided 95% CI with a distance 
from the mean to the limits that is equal to 0.30 when the estimated standard deviation is 5.5 
(Hahn and Meeker 2011) (Table 6). 
Table 6: Sample Size 95% Confidence Interval for a Mean at α=0.05 
Distance from the Mean1 
Standard Deviation 
N 
0.1 
1.5 
865 
0.2 
3.5 
1177 
0.2 
5.5 
2906 
0.3 
3.5 
526 
0.3 
5.5 
1292 
1. Distance from Mean to Limit is the distance from the confidence limit(s) to the mean. For two-sided 
intervals, it is also known as the precision, half-width, or margin of error. 
  
The plan to enroll 1500 participants includes the expectation of increasing attrition over time. 
Analyses will be conducted with the data available at that time point and adjusted for missing 
values. This sample size is adequate to detect small effect sizes even with large amounts of 
variability for univariate statistics (one sample hypothesis test and CI) for both proportions 
and means. The sample size tables for each test or interval demonstrate sustained power to 
detect small to moderate effect sizes even with large amounts of attrition and show potential 
power at longitudinal time points with fewer observations. 
8.6. Data Management  
The electronic data capture (EDC) system for this study is OmniComm Systems, Inc, a web-
based EDC system. It will be used to collect, monitor, and report clinical data as specified in 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 23 of 46 
the protocol. Investigators or authorized staff will enter the data via a web-portal. All data 
collected via the eCRF will be reviewed by remote data monitors for clarity and 
completeness. Missing or unclear data will be queried according to the data management 
plan. The database and data management plan will be generated according to approved 
specifications. All patient reported outcomes data and questionnaires will be captured in the 
EDC, either patients will directly enter their responses into a patient data capture software 
system which will transfer data into the EDC or the site staff will enter in data from paper 
versions.  
8.7. Data Analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in the SAP, which will be dated, filed and maintained by the sponsor.   
For the purposes of this study, analyses will be descriptive in nature and will be conducted 
using SAS (version 9.3 or higher). All variables will be summarized descriptively through 
the tabular and graphical display of mean values, medians, ranges and standard deviations of 
continuous variables of interest, and proportions and frequency distributions for categorical 
variables. A Kaplan-Meier analysis will be performed on time-to-event outcomes such as 
death. In addition, as data are longitudinal, a repeated measures model of outcomes over time 
assessments may be considered.  
No formal hypothesis testing is planned.  
The SAP may modify the plans outlined in the protocol; any major modifications of primary 
endpoint definitions or their analyses would be reflected in a protocol amendment. 
8.7.1. EORTC QLQ-C30 
The EORTC QLQ-C30 employs 28 4-point Likert scales with responses from “not at all” to 
“very much” and two 7-point Likert scales for global health and overall QOL. For functional 
and global QOL scales, higher scores represent a better level of functioning and are 
converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represents more 
severe symptoms.  
8.7.2. G8 Screening Tool  
The G8 consists of 7 items based on the Mini-Nutritional Assessment and a single item 
covering the patient’s age. Patients falling below the cut-off of 14 points are recommended to 
complete a GA. 
8.7.3. ADL 
The ADL is a subscale of the Medical Outcomes Study (MOS) Physical Health. The MOS 
Physical Health Scale measures a broad range of physical functioning, with questions 
ranging from “Can you bathe and dress yourself?” to “Can you perform vigorous activities, 
such as running or lifting heavy objects?” Items are rated on a 3-point Likert scale measuring 
independence in performing the activity. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 24 of 46 
8.8. Quality Control 
Investigators will be trained with an initial on-site visit to the clinic on the protocol, EDC 
system (i.e., eCRF), investigator site master file (ISMF), documentation, and any applicable 
study processes. Any new information relevant to the performance of this NIS will be 
forwarded to the medical staff during the study. Remote data monitoring will be conducted 
during the life of the study to ensure timely reporting of safety data, data integrity, and 
consistency. eCRFs for all included patients will be made available to the remote data 
monitor for review. A list of critical variables will be created as required elements for review 
during the remote data monitoring process.  The study sites will be queried and managed to 
request resolution to any issues that may arise during the course of the study.   
Monitoring visits may be made, if necessary, to monitor study process by Pfizer, Inc. or its 
delegate. In the event of a visit, direct access to original source data will be required for 
monitoring visits and/or inspections/audits, which will be carried out with due consideration 
for data protection and patient confidentiality.  
Items routinely checked during on-site visits include:  
 Documentation of the informed consent process  
 Compliance with patient eligibility criteria  
 Proper maintenance of records, such as study protocol  
 Completed eCRFs  
 Documentation of adverse events, and transmission of serious adverse events   
 Identification of patients lost to follow up  
 Study correspondence   
 Compliance with Institutional review board (IRB)/ Independent ethics committee (IEC) 
approval requirements   
 Review of the Investigator Site Master File  
Archiving of the study documents will be performed accordingly to Pfizer standard operating 
procedures (SOPs).  
8.9. Limitations of the Research Methods 
The source data described in this protocol contain the inherent limitation of any current NIS, 
real world study. These studies have the potential for missing, inaccurate, or incomplete data. 
The limitations of the observational nature can result in methodological challenges in 
attributing causality to outcomes. The patient selection and the diagnostic or monitoring 
procedures are those applied per the usual treatment paradigm of the treating physician and 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 25 of 46 
not dictated by the protocol. Heterogeneous patient populations could make the interpretation 
of the outcomes difficult. Hence, this study is intended for hypothesis generation, as opposed 
to hypothesis confirmation.   
8.10. Other Aspects 
Not applicable  
9. PROTECTION OF HUMAN SUBJECTS 
9.1. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data. 
The informed consent form must be in compliance with local regulatory requirements and 
legal requirements. 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/ IEC and Pfizer before use. 
The investigator must ensure that each study patient, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  The investigator, or a person designated by the 
investigator, will obtain written informed consent from each patient or the patient’s legally 
acceptable representative before any study-specific activity is performed. The investigator 
will retain the original of each patient's signed consent form. 
9.2. Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. In any circumstance, every effort should be made to document 
subject outcome, if possible. The investigator should inquire about the reason for withdrawal 
and follow-up with the subject regarding any unresolved AEs.   
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC. All correspondence with 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 26 of 46 
the IRB/IEC should be retained in the Investigator Site Master File. Copies of IRB/IEC 
approvals should be forwarded to Pfizer.  
9.4. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR), International Ethical Guidelines for Epidemiological 
Research issued by the Council for International Organizations of Medical Sciences 
(CIOMS), European Medicines Agency (EMA) European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards in Pharmacoepidemiology, and FDA Guidance for Industry: Good 
Pharmacovigilance and Pharmacoepidemiologic Assessment, FDA Guidance for Industry 
and FDA Staff: Best Practices for Conducting and Reporting of Pharmacoepidemiologic 
Safety Studies Using Electronic Healthcare Data Sets, Guidance for Industry: Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
Claims and/or equivalent. 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS 
REQUIREMENTS 
The table below summarizes the requirements for recording safety events on the electronic 
case report form (eCRF) and for reporting safety events on the non-interventional study 
(NIS) adverse event monitoring (AEM) Report Form to Pfizer Safety.  These requirements 
are delineated for three types of events: (1) serious adverse events (SAEs); (2) non-serious 
AEs (as applicable); and (3) scenarios involving drug exposure, including exposure during 
pregnancy, exposure during breast feeding, medication error, overdose, misuse, 
extravasation, and occupational exposure.  These events are defined in the section 
“Definitions of safety events”.   
Table 7: Recording and Reporting of Safety Events 
Safety event 
Recorded on the eCRF 
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
SAE 
All 
All 
Non-serious AE 
All 
None 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 27 of 46 
Safety event 
Recorded on the eCRF 
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
Scenarios involving exposure 
to a drug under study, 
including exposure during 
pregnancy, exposure during 
breast feeding, medication 
error, overdose, misuse, 
extravasation; lack of efficacy; 
and occupational exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure  
All (regardless of whether 
associated with an AE) 
 
For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the adverse event and to assess whether it meets the criteria for classification 
as a SAE (see section "Serious Adverse Events” below)  
Safety events listed in the table above must be reported to Pfizer within 24 hours of 
awareness of the event by the investigator regardless of whether the event is determined 
by the investigator to be related to a drug under study. In particular, if the SAE is fatal or 
life-threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information. This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the events. 
For safety events that are considered serious or that are identified in the far right column of 
the table above that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with 
this 24-hour timeframe. In addition, an investigator may be requested by Pfizer to obtain 
specific follow-up information in an expedited fashion.  This information is more detailed 
than that recorded on the eCRF. In general, this will include a description of the adverse 
event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Any information relevant to the event, such 
as concomitant medications and illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.  
Reporting period  
For each patient, the safety event reporting period begins at the time of  the patient’s first 
dose of palbociclib or the time of the patient’s informed consent if s/he is already exposed to 
palbociclib,  and lasts through the end of the observation period of the study, which must 
include at least 28 calendar days following the last administration of a drug under study; a 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 28 of 46 
report must be submitted to Pfizer Safety (or its designated representative) for any of the 
types of safety events listed in the table above occurring during this period.   
If the investigator becomes aware of a SAE occurring at any time after completion of the 
study and s/he considers the SAE to be related to palbociclib, the SAE also must be reported 
to Pfizer Safety.  
Causality assessment 
The investigator is required to assess and record the causal relationship.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of 
each adverse event.  For AEs with a causal relationship to palbociclib, follow-up by the 
investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment.   
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that palbociclib caused or contributed to an adverse event. If the 
investigator’s final determination of causality is “unknown” and s/he cannot determine 
whether palbociclib caused the event, the safety event must be reported within 24 hours.   
If the investigator cannot determine the etiology of the event but s/he determines that 
palbociclib did not cause the event, this should be clearly documented on the eCRF and the 
NIS AEM Report Form.  
DEFINITIONS OF SAFETY EVENTS 
Adverse events 
An AE is any untoward medical occurrence in a patient administered a medicinal product.  
The event need not necessarily have a causal relationship with the product treatment or 
usage.  Examples of adverse events include but are not limited to:   
 Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an adverse event); 
 Clinically significant symptoms and signs; 
 Changes in physical examination findings; 
 Hypersensitivity; 
 Lack of efficacy;  
 Drug abuse;  
 Drug dependency. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 29 of 46 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
 Drug overdose; 
 Drug withdrawal; 
 Drug misuse;  
 Off-label use;  
 Drug interactions; 
 Extravasation; 
 Exposure during pregnancy; 
 Exposure during breast feeding; 
 Medication error; 
 Occupational exposure. 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows:  
 Test result is associated with accompanying symptoms, and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
 Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 
Serious adverse events 
A serious adverse event is any untoward medical occurrence in a patient administered a 
medicinal or nutritional product (including pediatric formulas) at any dose that: 
 Results in death; 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 30 of 46 
 Is life-threatening; 
 Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute adverse events); 
 Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
 Results in congenital anomaly/birth defect. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal within the safety 
reporting period.  Hospitalization due to signs and symptoms of disease progression should 
not be reported as a serious adverse event.  If the malignancy has a fatal outcome during the 
study or within the safety reporting period, then the event leading to death must be recorded 
as an adverse event and as a serious adverse event with severity Grade 5. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are considered 
synonymous.  These cases are considered unexpected and handled as serious expedited cases 
by PV personnel.  Such cases are also considered for reporting as product defects, if 
appropriate. 
Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance.  

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 31 of 46 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. 
For example, the following reports of hospitalization without a medical AE are not to be 
reported.  
 Social admission (e.g., patient has no place to sleep) 
 Administrative admission (e.g., for yearly exam) 
 Optional admission not associated with a precipitating medical AE (e.g., for elective 
cosmetic surgery) 
 Hospitalization for observation without a medical AE 
 Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (e.g., for work-up of 
persistent pre-treatment lab abnormality) 
 Protocol-specified admission during clinical study (e.g., for a procedure required by the 
study protocol) 
Scenarios necessitating reporting to Pfizer Safety within 24 hours  
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below. 
Exposure during pregnancy 
An exposure during pregnancy (EDP) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (e.g., environmental) palbociclib, or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to palbociclib (maternal exposure). 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (e.g., a nurse reports that she is pregnant and 
has been exposed to chemotherapeutic products). 
2. A male has been exposed, either due to treatment or environmental exposure to 
palbociclib prior to or around the time of conception and/or is exposed during the 
partner pregnancy (paternal exposure). 
As a general rule, prospective and retrospective exposure during pregnancy reports from any 
source are reportable irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 32 of 46 
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with palbociclib, this information must be submitted 
to Pfizer, irrespective of whether an adverse event has occurred using the NIS AEM Report 
Form and the EDP Supplemental Form.  
In addition, the information regarding environmental exposure to palbociclib in a pregnant 
woman (e.g., a subject reports that she is pregnant and has been exposed to a cytotoxic 
product by inhalation or spillage) must be submitted using the NIS AEM Report Form and 
the EDP supplemental form. This must be done irrespective of whether an AE has occurred.   
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-
up is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy termination 
(e.g., induced abortion) and Pfizer is notified of the outcome.  This information is provided 
as a follow up to the initial EDP report.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
 Spontaneous abortion includes miscarriage and missed abortion; 
 Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product 
Additional information regarding the exposure during pregnancy may be requested.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on 
preterm infants to identify developmental delays).   
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that the 
study participant was given this letter to provide to his partner. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 33 of 46 
Exposure during breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (e.g., vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an AE associated with such a 
drug’s administration, the AE is reported together with the exposure during breastfeeding. 
Medication error 
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer.  Such events may 
be related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.   
Medication errors include: 
 Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or 
prescription on the part of the healthcare provider or the patient/consumer); 
 Confusion with regard to invented name (e.g., trade name, brand name). 
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE: 
 Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE. 
 Medication errors that do not involve a patient directly (e.g., potential medication 
errors or near misses).  When a medication error does not involve patient exposure to 
the product the following minimum criteria constitute a medication error report: 
 An identifiable reporter; 
 A suspect product; 
 The event medication error. 
 
Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE.  

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 34 of 46 
Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product. 
Occupational Exposure 
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the 
investigator, irrespective of the presence of an associated AE/SAE. 
10.1. Single Reference Safety Document 
The product label will serve as the single reference safety document during the course of the 
study, which will be used by Pfizer safety to assess any safety events reported to Pfizer 
Safety by the investigator during the course of this study.  
The product label should be used by the investigator for prescribing purposes and guidance. 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The results of this study are not part of any planned submission. The results of this study will 
be submitted for abstracts and publications. The final output will be filed in Pfizer’s Global 
Document Management System upon final study completion.  
COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NIS protocol that the investigator becomes aware of.

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 35 of 46 
12. REFERENCES 
American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Atlanta: American 
Cancer Society, Inc. 2015. 
American Cancer Society. Cancer Facts & Figures 2016. Atlanta: American Cancer Society; 
2016. 
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor–
positive advanced breast cancer. N Engl J Med. 2012;366:520-9. 
Bellera CA, Rainfray M, Mathoulin-Pélissier S, et al. Screening older cancer patients: first 
evaluation of the G-8 geriatric screening tool. Ann Oncol. 2012; 23: 2166–2172. 
Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of 
fulvestrant and anastrozole in combination compared with anastrozole alone as first-line 
therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 
2012;30(16):1919-25.  
Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer 
Statistics 2016. Toronto, ON: Canadian Cancer Society; 2016.  
Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 
2012;23 (Suppl 7):vii11–vii19. 
Carey LA, Perou CM. Palbociclib — taking breast-cancer cells out of gear. N Engl J Med. 
2015;373(3):273-274. 
Chow S-C. Sample size calculations for clinical trials. Wiley Interdiscip Rev Comput Stat. 
2011;3(5):414-427. Doi:10.1002/wics.155. 
Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health 
problems warranting a geriatric assessment in older cancer patients: an update on SIOG 
recommendations. Ann Oncol. 2015;26:288–300. 
DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. 
CA Cancer J Clin. 2014;64(4):252-271. doi:10.3322/caac.21235. 
Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial 
comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with 
estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28:4594-600. 
Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 
250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106: djt337. 
Eberhardt B, Dilger S, Musial F, et al. Medium term effects of chemotherapy in older cancer 
patients. Support Care Cancer. 2006;14:216-222. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 36 of 46 
Elsawy B, Higgins KE. The Geriatric Assessment. Am Fam Physician. 2011;83(1):48-56.  
Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. 
J Clin Oncol. 2007 25(14):1824-1831. 
Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen 
receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a 
randomised phase 2 study. Lancet Oncol. 2015;16:25-35. 
Finn RS, Dering J, Conklin D, et al. PD0332991, 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 Res. 2009;11:R77. 
Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of 
palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women 
with ER+/HER2– advanced breast cancer (ABC). J Clin Oncol. 2016;34 (suppl; abstr 507). 
Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. Hoboken, NJ, 
USA: John Wiley & Sons, Inc.; 2003. doi:10.1002/0471445428.  
Hahn GJ, Meeker WQ. Statistical Intervals: A Guide for Practitioners. Vol 328. John Wiley 
& Sons; 2011. 
Hentschel L, Rentsch A, Lenz F, et al. a questionnaire study to assess the value of the 
vulnerable elders survey, G8, and predictors of toxicity as screening tools for frailty and 
toxicity in geriatric cancer patients. Oncol Res Treat. 2016;39:210–216. 
Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-
2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based 
on November 2015 SEER data submission, posted to the SEER web site, April 2016. 
Accessed 27 September 2016. 
Hurria A, Gupta S, Zauderer M. Developing a cancer-specific geriatric assessment a 
feasibility study. Cancer. 2005;104:1998–2005. 
Kenis C, Decoster L, Van Puyvelde K et al. Performance of two geriatric screening tools in 
older cancer patients. J Clin Oncol. 2014;32(1):19–26. 
Klijn JG, Beex LV, Mauriac L, et al. Combined treatment with buserelin and tamoxifen in 
premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst. 
2000;92:903-11. 
Lachin JM. Biostatistical Methods The Assesment of Relative Risks. New York: John Wiley 
& Sons, Inc; 2000. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 37 of 46 
Liuu E, Canoui-Poitrine F, Tournigand C et al. External validation of the G8 geriatric 
screening tool to identify vulnerable elderly cancer patients: the ELCAPA-02 study. J Geriatr 
Oncol. 2012;3:S45 (abstr P23). 
Luckett T, King MT, Butow PN, et al. Choosing between the EORTC QLQ-C30 and FACT-
G for measuring health-related quality of life in cancer clinical research: issues, evidence and 
recommendations. Ann Oncol. 2011;22: 2179–2190. 
Machin D, Campbell MJ, Tan SB, Tan SH. Sample Size Tables for Clinical Studies. Wiley-
Blackwell; 2011. 
Maione P, Perrone F, Gallo C, et al. Pretreatment quality of life and functional status 
assessment significantly predict survival of elderly patients with advanced non-small-cell 
lung cancer receiving chemotherapy: A prognostic analysis of the multicenter Italian Lung 
Cancer in the Elderly study. J Clin Oncol. 2005;23:6865-6872. 
Martinez-Tapia G, Canoui-Poitrine F, Bastuji-Garin S, et al. Optimizing the G8 screening 
tool for older patients with cancer: diagnostic performance and validation of a six-item 
version. The Oncologist. 2016;21:188–195. 
Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in 
metastatic breast cancer. N Engl J Med. 2012;367(5):435-44. 
Miller TW, Balko JM, Fox EM, et al. ERα-dependent E2F transcription can mediate 
resistance to estrogen deprivation in human breast cancer. Cancer Discov. 2011;1:338-51. 
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, 
breast cancer: version 2.2016. Fort Washington, PA: National Comprehensive Cancer 
Network; 2016. 
NCSS LLC. PASS 13 Power Analysis and Sample Size Software. 2014. 
ncss.com/software/pass. 
Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of 
seven methods. Stat Med. 1998;17(8):857-872. 
http://www.ncbi.nlm.nih.gov/pubmed/9595616. Accessed September 26, 2016. 
Norton SE, Lechner JM, Williams T, Fernando MR. A stabilizing reagent prevents cell-free 
DNA contamination by cellular DNA in plasma during blood sample storage and shipping as 
determined by digital PCR. Clin Biochem. 2013;46:1561–1565. 
Owusu C, Berger NA. Comprehensive geriatric assessment in the older cancer patient: 
coming of age in clinical cancer care. Clin Pract. 2014;11(6):749-762. 
Shachar SS, Hurria A, Muss HB. Targeted therapies in older adults with breast cancer: what 
do we know? J Clin Oncol. 2016a;Jul 18:pii. JCO688242. [Epub ahead of print] 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 38 of 46 
Shachar SS, Hurria A, Muss HB. Breast cancer in women older than 80 years. J Oncol Pract. 
2016b;12(2):123-133. 
Soubeyran P, Bellera C, Goyard J, et al.: Screening for vulnerability in older cancer patients: 
the ONCODAGE Prospective Multicenter Cohort Study. PLoS ONE. 2014;9:e115060. 
Stokoe JM, Pearce J, Sinha R, Ring A. G8 and VES-13 scores predict chemotherapy toxicity 
in older patients with cancer. J Geriatr Oncol. 2012;3:S81 (abstr P95). 
Tevaarwerk AJ, Gray RJ, Schneider BP, et al. Survival in Metastatic Recurrent Breast 
Cancer after Adjuvant Chemotherapy: Little Evidence for Improvement Over the Past Three 
Decades. Cancer. 2013;119(6):1-19. doi:10.1115/1.3071969.  
Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle 
control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18:333-45. 
Toogood PL, Harvey PJ, Repine JT, et al. Discovery of a potent and selective inhibitor of 
cyclin-dependent kinase 4/6. J Med Chem. 2005;48:2388-406. 
Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast 
cancer. N Engl J Med. 2015;373:209-19.  
United Nations. World Population Ageing: 1950-2050. Department of Economic and Social 
Affairs Population Division, United Nations New York, 2001. Sales No. E.02.XIII.3. 
Available from http://www.un.org/esa/population/publications/worldageing19502050/ 
(Accessed 27 September 2016). 
Velikovaa G, Coens C, Efficace F, et al. Health-related quality of life in EORTC clinical 
trials − 30 years of progress from methodological developments to making a real impact on 
oncology practice. Eur J Cancer Suppl. 2012;10(1):141-149. 
Wintner LM, Sztankay M, Aaronson N, et al. The use of EORTC measures in daily clinical 
practice: A synopsis of a newly developed manual. Eur J Cancer. 2016;68:73-81. 
Zar JH. Biostatistical Analysis. 2nd. Edn; 1984. 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 39 of 46 
13. LIST OF TABLES  
Table 1: Data Entry Schedule 
Table 2: EORTC QLQ-C30 and Geriatric Assessments 
Table 3: Sample Size for Proportion Hypothesis Test at =0.05 
Table 4: Sample Size 95% Confidence Interval for a Proportion at =0.05 
Table 5: Sample Size for Mean Hypothesis Test at =0.05 
Table 6: Sample Size 95% Confidence Interval for a Mean at =0.05 
Table 7: Recording and Reporting of Safety Events 
14. LIST OF FIGURES 
None  
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
 EORTC QLQ-C30 (version 3) 
 G8 (Geriatric Screening Tool): POLARIS STUDY VERSION 1 26OCT2016 
 ADL Activities of Daily Living: POLARIS STUDY VERSION 1 26OCT2016 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 40 of 46 
EORTC QLQ-C30 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 41 of 46 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 42 of 46 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 43 of 46 
 
G-8 Screening Tool 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 44 of 46 
 
G8 Screening Tool 
 
Items 
Possible responses (score) 
A 
Has food intake declined over the past 3 months 
due to loss of appetite, digestive problems, 
chewing, or swallowing difficulties? 
0 = severe decrease in food intake 
1 = moderate decrease in food intake 
2 = no decrease in food intake 
B 
Weight loss during the last 3 months? 
0 = weight loss >3 kg 
1 = does not know 
2 = weight loss between 1 and 3 kg 
3 = no weight loss 
C 
Mobility? 
0 = bed or chair bound 
1 = able to get out of bed/chair but 
does not go out 
2 = goes out 
E 
Neuropsychological problems? 
0 = severe dementia or depression 
1 = mild dementia 
2 = no psychological problems 
F 
BMI? (weight in kg)/(height in m2)  
0 = BMI <19 
1 = BMI 19 to <21 
2 = BMI 21 to <23 
3 = BMI ≥23 
H 
Takes more than three prescription drugs per 
day? 
0 = yes 
1 = no 
P 
In comparison with other people of the same 
age, how does the patient consider his/her 
health status? 
0.0 = not as good 
0.5 = does not know 
1.0 = as good 
2.0 = better 
Age 
 
0: >85 
1: 80–85 
2: <80 
Total score 
0–17 
 
POLARIS STUDY VERSION 1 26OCT2016 
 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 45 of 46 
ADL Activities of Daily Living 

Palbociclib 
A5481082 NON-INTERVENTIONAL STUDY PROTOCOL 
FINAL AMENDMENT 1, 02AUG2017 
 
 
 
Pfizer Confidential 
Page 46 of 46 
 
 
 
POLARIS STUDY VERSION 1 26OCT2016