Clinical trial NCT02600923
Conditions: Advanced Breast Cancer Female
Keywords: palbociclib, ibrance, breast cancer
Sponsor: Pfizer
Start date: 2016-04-15; Completion date: 2019-05-28
Enrollment: 131 participants; Allocation: NA; Intervention model: 

Brief summary:
The purpose of this study is to provide access to palbociclib in Mexico and in selected Latin American countries before it becomes commercially available to patients with HR positive/HER2-negative ABC who are appropriate candidates for letrozole therapy.

Detailed description:

Arms: arm 1: palbociclib and letrozole combination
Interventions: intervention 1: Palbociclib intervention 2: Letrozole
Intervention descriptions: intervention 1: Palbociclib will be administered orally once a day at 125 mg/day for 21 days followed by 7 days off treatment for each 28-day cycle (Schedule 3/1). intervention 2: Letrozole will be administered orally at 2.5 mg once daily as continuous daily dosing schedule according to product labeling and in compliance with its local prescribing information.

Protocol documents:
Prot_000.pdf: 
Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 1
STUDY OF PALBOCICLIB IN COMBINATION WITH LETROZOLE AS 
TREATMENT OF POSTMENOPAUSAL WOMEN WITH HORMONE 
RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER FOR 
WHOM LETROZOLE THERAPY IS DEEMED APPROPRIATE
Compound:
PD-0332991
Compound Name:
Palbociclib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
A5481053
Phase:
Phase 3
CCI


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 2
Document History
Document
Version Date
Summary of Changes
Original protocol
23 July 2015
Not applicable (N/A)


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................6
SCHEDULE OF ACTIVITIES..................................................................................................7
1. INTRODUCTION ...............................................................................................................10
1.1. Mechanism of Action/Indication.............................................................................10
1.2. Background and Rationale ......................................................................................10
1.3. Palbociclib...............................................................................................................11
1.3.1. Preclinical Data...........................................................................................11
1.3.1.1. Ocular Preclinical Data .............................................................11
1.3.1.2. Cataracts and Other Eye Disorders; Relationship of 
Cataracts to Hyperglycemia-Related Events.....................................12
1.3.2. Palbociclib Clinical Activity.......................................................................13
1.4. Study Rationale .......................................................................................................13
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................14
2.1. Objectives................................................................................................................14
2.2. Endpoints.................................................................................................................14
3. STUDY DESIGN.................................................................................................................14
4. PATIENT SELECTION......................................................................................................15
4.1. Inclusion Criteria.....................................................................................................15
4.2. Exclusion Criteria....................................................................................................17
4.3. Sponsor’s Qualified Medical Personnel..................................................................18
5. STUDY TREATMENTS.....................................................................................................18
5.1. Allocation to Treatment ..........................................................................................18
5.2. Patient Compliance .................................................................................................18
5.3. Investigational Product Supplies.............................................................................18
5.3.1. Dosage Form(s) and Packaging..................................................................19
5.3.1.1. Palbociclib.................................................................................19
5.3.1.2. Letrozole....................................................................................19
5.3.2. Preparation and Dispensing - Palbociclib...................................................19
5.4. Administration.........................................................................................................20
5.4.1. Palbociclib ..................................................................................................20


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 4
5.4.2. Letrozole.....................................................................................................20
5.4.3. Recommended Dose Modification .............................................................20
5.4.3.1. Dosing Interruptions/Delays - Recommendations for 
Palbociclib.........................................................................................21
5.4.3.2. Re-Treatment Criteria - Palbociclib ..........................................22
5.4.3.3. Dose Reductions - Palbociclib ..................................................22
5.5. Investigational Product Storage ..............................................................................24
5.6. Investigational Product Accountability...................................................................25
5.6.1. Destruction of Investigational Product Supplies ........................................25
5.7. Concomitant Treatment(s).......................................................................................26
5.7.1. Prohibited Medications...............................................................................26
5.7.2. Medications Not Recommended.................................................................27
6. STUDY PROCEDURES .....................................................................................................27
6.1. Patient Withdrawal..................................................................................................27
7. ASSESSMENTS..................................................................................................................28
7.1. Safety Assessments .................................................................................................28
7.1.1. Physical Examination .................................................................................29
7.1.2. 12-Lead ECG..............................................................................................29
7.1.3. Laboratory Safety Assessments..................................................................30
7.2. Tumor Assessments.................................................................................................31
8. ADVERSE EVENT REPORTING......................................................................................31
8.1. Adverse Events........................................................................................................31
8.2. Reporting Period .....................................................................................................31
8.3. Definition of an Adverse Event...............................................................................32
8.4. Medication Errors....................................................................................................33
8.5. Abnormal Test Findings..........................................................................................33
8.6. Serious Adverse Events...........................................................................................34
8.6.1. Protocol-Specified Serious Adverse Events...............................................34
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................34
8.7. Hospitalization ........................................................................................................36
8.8. Severity Assessment................................................................................................37
8.9. Causality Assessment..............................................................................................37


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 5
8.10. Exposure During Pregnancy..................................................................................38
8.11. Occupational Exposure .........................................................................................39
8.12. Withdrawal Due to Adverse Events (See Patient Withdrawal, Section 6.1).........39
8.13. Eliciting Adverse Event Information ....................................................................39
8.14. Reporting Requirements........................................................................................39
8.14.1. Serious Adverse Event Reporting Requirements .....................................40
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................40
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................40
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................41
9.1. Sample Size Determination.....................................................................................41
9.2. Efficacy Analysis ....................................................................................................41
9.3. Analysis of Other Endpoints ...................................................................................41
9.3.1. Patient Disposition......................................................................................41
9.3.2. Baseline Characteristics..............................................................................41
9.3.3. Treatment Administration...........................................................................42
9.4. Safety Analysis........................................................................................................42
9.4.1. Analysis of Adverse Events (AEs) .............................................................42
9.4.2. Analysis of Clinical Laboratory Data.........................................................42
9.5. Interim Analysis ......................................................................................................42
9.6. Data Monitoring Committee ...................................................................................42
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................43
11. DATA HANDLING AND RECORD KEEPING .............................................................43
11.1. Case Report Forms/Electronic Data Record .........................................................43
11.2. Record Retention...................................................................................................44
12. ETHICS..............................................................................................................................44
12.1. Institutional Review Board/Ethics Committee......................................................44
12.2. Ethical Conduct of the Study ................................................................................45
12.3. Patient Information and Consent...........................................................................45
12.4. Patient Recruitment...............................................................................................46
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................46
13. DEFINITION OF END OF TRIAL...................................................................................46


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 6
14. SPONSOR DISCONTINUATION CRITERIA ................................................................46
15. PUBLICATION OF STUDY RESULTS..........................................................................47
15.1. Publications by Investigators ................................................................................47
16. REFERENCES ..................................................................................................................48
LIST OF TABLES
Table 1.
Schedule of Activities.............................................................................................8
Table 2.
Palbociclib Capsule Characteristics......................................................................19
Table 3.
Adverse Events Leading to Dose Interruption/Delay...........................................21
Table 4.
Palbociclib Re-Treatment Criteria........................................................................22
Table 5.
Available Dose Levels..........................................................................................23
Table 6.
Palbociclib Dose Modifications for Treatment Related Toxicities ......................24
APPENDICES
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status .................49
Appendix 2. List of Drugs Known to Predispose to Torsade de Pointes.................................50
Appendix 3. Abbreviations......................................................................................................52


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 7
SCHEDULE OF ACTIVITIES
The schedule of activities table (Table 1) provides an overview of the protocol visits and 
procedures.  Refer to STUDY PROCEDURES (Section 6) and ASSESSMENTS (Section 7) 
sections of the protocol 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 
well-being of the patient.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 8
Table 1.
Schedule of Activities
Visit Identifier
Screeninga
Treatment: One cycle = 28 daysb
End of 
Treatmentd
End of 
Studyd
Cycles 1 and 2
Cycles 3
Study day
Within 28-30 
days prior to 
randomization 
unless specified 
otherwise
Day 1c
Day 14
Day 1
Time window
2 days
2 days
2 days
Procedures at Screening
Informed consente
X
Eligibility criteria 
evaluationf
X
Registrationg
X
Medical/Oncological 
historyh
X
Procedures at Screening and on study
Physical examinationi
X
Per routine clinical practice
ECOG performance 
statusj
X
Per routine clinical practice
X
12-Lead ECGk
X
As clinically indicated
Treatments
Palbociclib 
(PD-0332991l)
Orally once daily from Day 1 to 
Day 21 of each cycle
(Schedule 3/1)
Letrozolem
Orally once daily
(Schedule: continuous dosing)
Clinical Assessments
Tumor assessment 
(CT or MRI scans) n
X
Per routine clinical practice
Adverse eventso
X
X
X
Hematology (platelet
count, ANC, WBC
count, hemoglobin) p
X
X
X
X
X
HbA1cq
X
Every 3 months
X
Blood chemistryr
X
Per routine clinical practice
Abbreviations: ECOG=Eastern Cooperative Oncology Group; ECG=electrocardiogram; CT=CAT scan; MRI=magnetic 
resonance imaging; ANC=absolute neutrophil count; WBC=white blood cell; HbA1c=Glycated hemoglobin.
a.
Screening: All assessments should be performed within 28-30 days prior to study randomization.
b.
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.  Clinical visits will be conducted as per local practice and as clinically indicated.  Each subsequent cycle will 
begin 7 days after the last dose of study drug in the prior cycle to allow patients a 7-day washout period for each cycle.
c.
Cycle 1/Day 1: Blood chemistry and hematology not required if acceptable screening assessment is performed 
within 7 days prior to randomization.
d.
End of Treatment/End of Study: The End of Treatment (EOT) visit will be conducted when palbociclib is 
permanently discontinued for any reason.  The indicated assessments are to be obtained if not completed in the last week 
of therapy.  Patients who permanently discontinue palbociclib for any reason will also complete an End of Study (EOS)
visit that will occur 28 days after last dose of palbociclib.  An EOS visit will be completed if a patient will continue on 
commercial palbociclib.  Adverse events should be followed up until all serious or study drug-related toxicities have 
resolved or are determined to be “chronic” or “stable”.
e.
Informed Consent: Must be obtained prior to undergoing any study specific procedures.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 9
Table 1.
Schedule of Activities
Visit Identifier
Screeninga
Treatment: One cycle = 28 daysb
End of 
Treatmentd
End of 
Studyd
Cycles 1 and 2
Cycles 3
Study day
Within 28-30 
days prior to 
randomization 
unless specified 
otherwise
Day 1c
Day 14
Day 1
Time window
2 days
2 days
2 days
f.
Eligibility Criteria Evaluation: Patients must meet all of the eligibility criteria in the protocol.
g.
Registration: Patient identification number will be attributed to each patient. Patients will be assigned a single 
subject identification number (SSID) which will be obtained at the time of screening using the automated registration 
system and retained throughout the study.  A separate randomization number will be assigned by the automated 
registration system at Cycle 1 Day 1 and will be recorded on the CRF.
h.
Medical/Oncologic History: Medical history includes history of disease process other than oncology (active or 
resolved).  Oncological history includes date of primary diagnosis, information on prior antitumor treatments and 
radiotherapy, and oncologic surgeries.
i.
Physical Examination: General clinical examination of major body systems.  To be performed at Screening, and as 
per routine clinical practice during the treatment.
j.
ECOG Performance Status: To be performed at Screening, as per routine clinical practice during the treatment, 
and at EOT.  ECOG performance status scale is available in Appendix 1.
k.
12-Lead ECG: Three consecutive 12-lead ECGs will be performed approximately 2 minutes apart at Screening to 
verify eligibility.  ECG to be repeated during the treatment, as clinically indicated.  If the mean QTc is prolonged (value 
of >500 msec), then the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Only ECG 
at Screening will be recorded on the CRF (Case Report Form).
l.
Palbociclib Administration: PD-0332991 will be administered orally once daily at the starting dose of 125 mg on 
Day 1 to Day 21, followed by 7 days off treatment (Schedule 3/1).  The patient will receive drug supply at the clinical site 
that will be sufficient to last until their next cycle visit.
m.
Letrozole Administration: Letrozole will be administered orally once daily at the dose of 2.5 mg (continuous daily 
dosing schedule).  Locally obtained commercial supplies of letrozole will be used
n.
Tumor Assessments: Tumor assessments are to be performed at Screening as per local practice and according to 
the patient’s clinical status thereafter.  Tumor assessment evaluation will be conducted as per local guidelines.  Only 
investigator’s assessments will be recorded on the CRF.
o.
Adverse Events: Patients must be followed for adverse events (AEs) from the time they signed the informed 
consent until 28 days after the last treatment administration or until all palbociclib-related toxicities have resolved, 
whichever is later.  AEs (serious and nonserious) should be recorded on the CRF from the time the patient has taken at 
least 1 dose of investigational product through the patient’s last visit.  AEs should be documented and recorded at each 
clinical visit using NCI CTC-AE version 4.03.  For serious adverse events (SAEs), the active reporting period to Pfizer or 
its designated representative begins from the time that the patient provides informed consent through and including 
28 calendar days after the last administration of the investigational product.  SAEs experienced by a patient after the 
active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a 
minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor.
p.
Hematology: To include platelet count, absolute neutrophil count (ANC), white blood cell (WBC) count, and
hemoglobin.  To be performed to check patient’s eligibility at Screening, every 2 weeks (Days 1 and 14) of the first 
2 cycles, then monthly on Day 1 of each subsequent cycle of treatment with palbociclib and at EOT.  In the case of Grade 3
neutropenia consider repeating complete blood count monitoring 1 week later in accordance with best local practice and 
report on the CRF in order to document the ANC value at the time of severe neutropenia as well as the time to recovery 
of neutrophils to 1000 cells/mm3.  Re-treatment criteria are based on time to recovery of neutrophil count.  For patients 
who develop Grade 3 or 4 neutropenia, refer to the dose modifications described in Table 6.  If granulocyte-colony
stimulating factors (G-CSF) and/or antibiotics are administered, their use will be documented on the CRF.
q.
Glycated Hemoglobin (HbA1c): To be assessed at Screening, every 3 months, and EOT, and will be documented 
on the CRF.
r.
Blood Chemistry: To be performed to check patient’s eligibility at Screening and as per routine clinical practice 
thereafter.  Only laboratory data at Screening will be recorded on the CRF.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 10
1. INTRODUCTION
1.1. Mechanism of Action/Indication
Palbociclib is being developed for the treatment of hormone receptor-positive (HR-positive), 
HER2-negative (human epidermal growth factor receptor 2 negative) breast cancer (BC).
1.2. Background and Rationale
HR-positive/HER2-negative BC is the most common subset of breast cancer.1  Most patients 
are diagnosed at an early stage and remain relapse-free if treated with a prolonged course of 
endocrine therapy.  However, about one third of patients with HR-positive/HER2-negative
tumors, diagnosed initially with early stage disease, experience disease recurrence.2  The 
fundamental problem is that endocrine agents are only partially effective, typically causing 
cell cycle arrest and tumor dormancy rather than true cure.
The role of estrogens in BC etiology and progression is well established.  Modification of 
estrogen activity or synthesis represents the treatment of choice for postmenopausal women 
with HR-positive advanced breast cancer (ABC), particularly for those with slowly 
progressive disease and limited tumor-related symptoms.3 Studies of estrogen receptor
(ER)-positive BC cell lines indicate that estrogens4 and antiestrogens5 act on sensitive 
populations of cells in early to mid-G1 phase.  G1/S transition is under the control of 
cyclin-dependent kinases (CDKs) activated by specific complex formation with regulatory 
cyclins.  
Conversion of androgens to estrogens via aromatase enzyme action represents the main 
source of estrogens in postmenopausal women.  Letrozole is an oral nonsteroidal aromatase 
inhibitor that is approved worldwide for the first line treatment of postmenopausal women 
with HR-positive ABC.  Letrozole is administered orally in a continuous regimen at a 2.5-mg 
daily dose.  In a multicenter Phase 3 study in patients with HR-positive or HR-unknown 
ABC, letrozole was superior to tamoxifen for time to progression, time to treatment failure, 
overall objective response rate, and overall clinical benefit response.6  Multiple clinical 
studies have shown that letrozole is well tolerated.
Palbociclib is an oral, selective, CDK 4/6 inhibitor that has been under investigation in 
clinical trials in multiple indications. Palbociclib inhibits cell proliferation by preventing cell 
cycle progression from G1 to S phase and has demonstrated antitumor activity in multiple 
preclinical models, including ER-positive luminal breast cancer cell lines. 
Furthermore, preclinical exploration using a BC cell line panel demonstrated the presence of 
retinoblastoma (Rb) protein and upregulation of cyclin D1 as well as decreased CDKN2A 
(p16) being associated with sensitivity to palbociclib as well as with its effects upon cell 
cycle and growth inhibition.  These gene expression findings were also associated with the 
luminal subtype versus basal-like subtype of BC.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 11
These results, together with published data on the known interaction of estrogens and CDKs 
and the important role of cell cycle-related proteins in the genesis and maintenance of BC, 
led to the initiation of a randomized Phase 2 clinical trial (A5481003 study; PALOMA-1) 
investigating the antitumor activity of palbociclib in combination with letrozole and
single-agent letrozole in the first-line treatment of ER-positive/HER2-negative ABC patients.  
The final analysis of this study demonstrated a consistent trend of clinically meaningful 
improvements in progression-free survival (PFS, the primary endpoint) and response based 
secondary endpoints,7 and the study results led to the approval of palbociclib for advanced 
BC by the US Food and Drug Administration (FDA) on 03 February 2015.
1.3. Palbociclib
Oral palbociclib is a novel, first-in-class highly selective reversible inhibitor of 
cyclin-dependent kinases (CDK) 4 and 6 that is being studied for use in the treatment of 
cancer. The compound inhibits cell proliferation by preventing progression of the cell cycle 
from G1 into the S phase.
1.3.1. Preclinical Data
Palbociclib inhibits purified CDK4-catalyzed phosphorylation of retinoblastoma protein with 
an IC50 of less than 20 nm, and also tumor growth of several types of human xenograft 
tumors (SF-295, MDA-MB-435, Colo-205, and others) grown in mice. 
Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied 
by the inhibition of specific retinoblastoma (Rb) phosphorylation by CDK4 or CDK6 on 
residues serine -780 and -795 of Rb.  Consequently, the phosphorylation status of these sites 
serves as specific biomarkers of CDK4/6 inhibition by palbociclib.  Estimated steady-state 
plasma concentrations of 1000 ng/mL resulted in 80% to 90% inhibition of phospho-Rb 
formation and 50% reduction of tumor growth. Reduction in phospho-Rb was rapidly 
reversible as plasma palbociclib concentrations declined.  
Palbociclib was tested in vitro on molecularly characterized human BC 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-positive subtype.8 The combination of palbociclib and aromatase inhibitors 
has not been tested in preclinical models. However, the combination of palbociclib with 
tamoxifen has recently been tested in vitro in ER-positive human BC cell lines indicating a 
synergistic interaction7 and provides a biologic rationale for evaluating the combination of 
palbociclib with antihormonal therapy in the clinic.
Palbociclib preclinical data indicate that it may be expected to have a direct effect on growth 
arrest as well as potential secondary cytotoxic activity.
1.3.1.1. Ocular Preclinical Data
Preliminary results from an ongoing 27-week repeat-dose oral toxicity study with palbociclib 
in rats identified a potential nonclinical safety finding related to the eye. Animals were 
evaluated by indirect ophthalmoscopy and by slit lamp biomicroscopy predose and prior to


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 12
termination.  The available data suggests that the cataracts observed in both male and female 
rats are palbociclib-related. Exposures in this nonclinical study are comparable to clinical 
exposures at the recommended human dose of 125 mg once daily (QD).
The mechanism for cataract formation in palbociclib-treated rats is unknown; however, its 
pathogenesis may be related to primary pharmacology. CDK4 expression (mRNA and 
protein) has been identified in the lens epithelial layer and in lens fibers of rats, suggesting its 
importance to lens fiber differentiation.9 Altered cell growth of the lens epithelium is also 
recognized as a potential mechanism for cataract formation.10  As CDK 4 and 6 expressions 
have also been identified in the human lens epithelial cell,11 a potential risk for cataract 
formation in patients who received palbociclib cannot be completely excluded. 
A review of the Pfizer safety database for cases received through 14 January 2014 identified 
no serious cases from clinical studies or other solicited sources.  The adverse event (AE) 
cataract has been reported in 2 patients (1 Grade 2 and 1 Grade 3) out of approximately 400 
patients who received palbociclib in Pfizer-sponsored studies. Neither event was considered 
serious, nor related to palbociclib; both patients had other identifiable risk factors for 
cataracts, such as age and long-term corticosteroid use. Both patients continued on treatment 
for 16-18 months beyond the diagnosis of cataract.
Based on the limited preclinical and clinical data currently available, it is not known whether 
true clinical risk exists for palbociclib-associated cataracts.  In order to assess this potential 
risk in detail, the Phase 3 Studies A5481008 and A5481023 were amended to implement 
prospective ophthalmic assessments in all newly enrolled patients. In addition, ophthalmic
assessments will be collected in all patients who will be enrolled in the Phase 3 
Study A5481027.  The results of the ophthalmic assessments will provide a better 
understanding of the risk of ocular adverse events and will provide information to determine 
whether further actions are warranted.
1.3.1.2. Cataracts and Other Eye Disorders; Relationship of Cataracts to 
Hyperglycemia-Related Events
Cataracts/lens degeneration was identified in nonclinical studies in rats in association with 
altered glucose metabolism (glycosuria and/or hyperglycemia) following 27 weeks of 
intermittent dosing (a scheduled dosing regimen of 3 weeks of consecutive daily dosing 
followed by a 1-week nondosing period).  A further association was found between glucose 
metabolism and pancreatic islet vacuolation.  Investigatory analysis of the data from the 
27-week rat study indicated that the islet cell vacuolation involved beta cells including beta 
cell depletion, with corresponding decreases in serum insulin and C-peptide.  Reversibility 
was not established for the changes in glucose homeostasis or the effects on the pancreas and 
eye following a 3-month recovery period.  Alterations of glucose metabolism, pancreatic 
histopathology, or cataracts/lens degeneration were not identified in dogs in studies up to 
39 weeks in duration.  


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 13
Review of all available laboratory data from the first-in-patient Study A5481001 has not 
suggested any apparent effect of duration of palbociclib exposure or palbociclib dose on 
glucose levels and consequently development of cataracts.
Cataract was experienced by 2 patients with advanced breast cancer receiving palbociclib 
plus letrozole in Study A5481003 as of 02 January 2015. These events were considered to be 
unrelated to study treatment.  In addition, these events were experienced by patients who had 
not experienced hyperglycemia-related events. 
In summary, based on a careful review of the available clinical data, there is currently 
insufficient evidence that palbociclib is causally related to the development of hyperglycemia 
and cataracts in humans.
1.3.2. Palbociclib Clinical Activity
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 dose-limiting toxicities (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 
noncumulative.  A greater proportion of patients on the 2/1 schedule had treatment-related 
adverse events during and after Cycle 1 than patients on the 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.  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 recommended dose for this schedule was 
determined to be 125 mg once daily.  This schedule and associated dose was further explored 
in combination with letrozole in the Phase 1/2 study in patients with ABC described below.
1.4. Study Rationale
The purpose of this study is to provide access to palbociclib in Mexico and in selected Latin 
American countries before it becomes commercially available to patients with 
HR-positive/HER2-negative ABC who are appropriate candidates for letrozole therapy. 
Complete information for palbociclib may be found in the Single Reference Safety 
Document (SRSD), which for this study is the palbociclib Investigator’s Brochure (IB).
The FDA approved label for letrozole12 is the SRSD for letrozole.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 14
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

To provide access to palbociclib in Mexico and in selected Latin American countries
to postmenopausal patients with hormone receptor-positive (HR-positive), 
HER2-negative ABC who are deemed appropriate for letrozole therapy.
Secondary Objectives

To gain additional safety data of the combination of palbociclib with letrozole in the 
postmenopausal HR-positive/HER2-negative population.

To gain additional antitumor activity data of the combination of palbociclib with 
letrozole in the postmenopausal HR-positive/HER2-negative population.
2.2. Endpoints
Adverse events as characterized by type, frequency, severity (as graded by National Cancer 
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4.03), 
and seriousness.
Death from any cause while on treatment and within 28 days of palbociclib discontinuation.
Tumor response (based on investigator assessment reported on Case Report Form [CRF]).
3. STUDY DESIGN
A multicenter, single-arm, open-label clinical trial will be conducted in Mexico and in 
selected Latin American countries.
Eligible patients will be postmenopausal women with HR-positive and HER2-negative ABC.  
Patients will have a histologically or cytologically proven diagnosis of adenocarcinoma of 
the breast (locoregionally recurrent or metastatic disease) and will be candidates to receive 
letrozole for their advanced disease as first- or later lines of treatment. 
Approximately 130 patients will be enrolled. This total number of patients will allow for 
enrollment of an adequate number of patients from each participating country. Patients will 
continue to receive treatment with palbociclib until disease progression, symptomatic 
deterioration, unacceptable toxicity, death, withdrawal of consent, or time of commercial 
availability of palbociclib, whichever occurs first.
Upon marketing approval of palbociclib by the local health authorities in the participating 
countries, patients enrolled in Study A5481053 will end participation in this study and be 
moved to commercially available palbociclib (if considered to be appropriate by the 
investigator), as soon as feasible.  


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 15
Patients will undergo AE monitoring as per local practice and per protocol.  All grade, all-
causality AEs and all serious adverse events (SAEs) will be recorded on the CRF.  All deaths 
occurring up to 28 days after palbociclib is discontinued will be recorded. 
Hematology laboratory data will be recorded every 2 weeks for the first 2 cycles of therapy, 
then monthly at the start of each cycle thereafter.  In the case of Grade 3 neutropenia, 
consider repeating complete blood count monitoring 1 week later in accordance with best 
local practice and report on the CRF in order to document the level of neutropenia and the 
time to recovery of neutrophils to 1000 cells/mm3.  Re-treatment criteria are based on time 
to recovery of neutrophil count. For patients who develop Grade 3 or 4 neutropenia, refer to 
the dose modifications described in Table 6. The clinical actions taken as a result of 
Grade 3 neutropenia, including the use of granulocyte colony stimulating factor (G-CSF), if 
any, should be recorded.
Tumor response will be assessed as per local practice and only investigator tumor 
assessments will be collected.  The date of tumor progression will be recorded.
When patients are moved to commercial supply of palbociclib, their participation in the study 
and clinical study data collection will be discontinued.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Women 18 years of age with proven diagnosis of advanced adenocarcinoma of the 
breast (locoregional recurrent or metastatic disease). 
2. Women who are not of childbearing potential (ie, meet at least 1 of the following 
criteria):
a.
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed ovarian failure; or 
c.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathologic or physiologic 
cause; and have a serum follicle-stimulating hormone (FSH) level confirming the 
postmenopausal state.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 16
3. ER-positive and/or Progesterone receptor (PgR)-positive tumor based on local 
laboratory results (test as per local practice).
4. HER2-negative breast cancer based on local laboratory results (test as per local 
practice or local guidelines).
5. Patients must be appropriate candidates for letrozole therapy.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see 
Appendix 1).
7. Adequate bone marrow function: 
a.
Absolute Neutrophil Count (ANC) ≥1500/mm3 (1.5 x 109/L); 
b. Platelets ≥100,000/mm3 (100 x 109/L); 
c.
Hemoglobin ≥9 g/dL (90 g/L).
8. Adequate liver function:
a.
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤3 x 
Upper Limit of Normal (ULN) (≤5.0 x ULN if liver metastases present);
b. Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases 
present);
c.
Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease).
9. Adequate renal function:
a.
Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min.
10. Resolution of all acute toxic effects of prior therapy, including radiotherapy to 
Grade 1 (except toxicities not considered a safety risk for the patient) and recovery 
from surgical procedures.
11. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study. 
12. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 17
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Known hypersensitivity to letrozole, or any of its excipients, or to any palbociclib 
excipients.
2. Current use of food or drugs known to be potent inhibitors or inducers of CYP3A4
isoenzymes within 7 days prior to study entry (see Prohibited Medications, Section 
5.7.1).
3. Prior treatment with any CDK inhibitor.
4. Previous participation in a palbociclib clinical study.
5. Participation in other studies involving investigational drug(s) within 2 weeks prior to 
study entry and/or during study participation.
6. QTc >480 msec; history of QT syndrome, Brugada syndrome or known history of 
QTc prolongation, or Torsade de Pointes.
7. High cardiovascular risk, including, but not limited to recent myocardial infarction, 
severe/unstable angina and severe cardiac dysrhythmias in the past 6 months prior to 
enrollment.
8. Diagnosis of any second invasive malignancy within the last 3 years prior to 
enrollment.  Note: patients with adequately treated basal cell or squamous cell skin 
cancer, a history of intraepithelial neoplasia or in situ disease (eg, carcinoma in situ of 
the cervix or melanoma in situ) may enter.
9. Active uncontrolled or symptomatic brain metastases.  Previously treated and 
clinically stable, brain metastases are permitted.
10. Other severe acute or chronic medical or psychiatric conditions:
a.
Including recent (within the past year) or active suicidal ideation or behavior, or 
b. 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.
11. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 18
4.3. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list . 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient (palbociclib) being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Patients will be assigned a single subject identification number (SSID) which will be 
obtained at the time of screening using the automated registration system and retained 
throughout the study.  A separate randomization number will be assigned by the automated 
registration system at Cycle 1 Day 1 and will be recorded on the CRF.
5.2. Patient Compliance
Patients will be required to return all bottles of palbociclib at the beginning of each cycle for 
drug accountability.
Drug accountability will be performed at every clinical visit prior to dispensing drug supply 
for the next cycle.  The number of remaining capsules will be collected, documented, and 
recorded to assess compliance.
5.3. Investigational Product Supplies
The investigational product used in the course of this trial is palbociclib (PD-0332991).


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 19
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. Palbociclib
Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of 
palbociclib free base.  The oral drug formulation will be supplied in High Density 
Polyethylene (HDPE) bottles containing 75-mg, 100-mg, or 125-mg capsules.  The capsules 
can be differentiated by their size and color (Table 2).
Table 2.
Palbociclib Capsule Characteristics
Dosage
Capsule Color
75 mg
Sunset Yellow/Sunset Yellow
100 mg
Caramel/Sunset Yellow
125 mg
Caramel/Caramel
5.3.1.2. Letrozole
Commercially available letrozole will be provided.  Locally obtained commercial supplies of 
letrozole will be used in accordance with local regulations.
5.3.2. Preparation and Dispensing - Palbociclib
The patient number should be recorded on the bottle label in the spaces provided by qualified
site personnel at the time of assignment to the patient.  Qualified 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 cycle. Only a single 
capsule strength will be dispensed to the patient at each dispensing visit. 
Please note that bottles contain 23 capsules, but only up to 21 will be taken in a given 
cycle.  Patients should be advised of this to avoid confusion.
Unused drug and/or empty bottles should be returned to the site at the next cycle.  Unused 
returned medication MUST NOT be re-dispensed to patients.
In the event of dose modification, a request should be made of the patient to return all 
previously dispensed medication to the clinic and new capsules will be dispensed.
Palbociclib 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.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 20
5.4. Administration
5.4.1. Palbociclib
Palbociclib will be administered orally once a day at 125 mg/day for 21 days followed by 
7 days off treatment for each 28-day cycle (Schedule 3/1).
General rules for palbociclib administration:

Palbociclib should be taken with food.

Palbociclib capsules should be swallowed whole (do NOT manipulate or chew, crush,
or open 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 who miss a day’s dose entirely 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 the Medication Errors, Section 8.4 for further 
details on medication errors and overdose.
5.4.2. Letrozole
Letrozole will be administered orally at 2.5 mg once daily as a continuous daily dosing 
schedule, according to product labeling and in compliance with its local prescribing 
information.
5.4.3. Recommended Dose Modification
In the event of significant treatment-related toxicity, administration of palbociclib may need 
to be adjusted as described in the following sections.  As the letrozole dose cannot be 
reduced, letrozole treatment may be interrupted in the case of toxicity as described below.
Depending on the nature of the toxicity observed, treatment interruption may be required for 
1 or both study drugs in the combination.  In the event treatment interruption is deemed 
necessary for just 1 of the study drugs in the combination, treatment with the other drug may 
continue as planned if deemed clinically appropriate. 
In case of palbociclib dose delays, administration of letrozole may continue according to the 
preplanned schedule.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 21
In case of palbociclib permanent discontinuation, the patient will undergo end of treatment 
(EOT) and end of study (EOS) visits as described in Schedule of Activities (Table 1).  
Continuation of letrozole would be off study per treating physician discretion.
5.4.3.1. Dosing Interruptions/Delays - Recommendations for Palbociclib
Patients experiencing the following adverse events may have their treatment with palbociclib 
interrupted/delayed until criteria for re-treatment are met (Section 5.4.3.2).
Table 3.
Adverse Events Leading to Dose Interruption/Delay
Hematologic toxicity of Grade 3
Non-hematologic toxicity of Grade 3 (including nausea, vomiting, and diarrhea only if 
persisting despite optimal medical treatment).
Patients should not hold or discontinue palbociclib for non-hematologic side effects 
potentially or likely related to concomitant letrozole therapy (eg, Grade 3 or long lasting 
Grade 2 joint pain) as per the investigator’s judgment. 
Depending on when the adverse event resolves, a treatment interruption may lead to the 
patient missing all subsequent planned doses within that same cycle or even to delay in the 
initiation of the subsequent cycle. 
Doses omitted for toxicity are not replaced within the same cycle. 
Doses should be held until toxicity resolution as per Re-treatment Criteria (Section 5.4.3.2). 
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in the Dose Reductions (Section 5.4.3.3).
In the case of Grade 3 neutropenia, consider repeating complete blood count monitoring 
1 week later in accordance with best local practice and report on the CRF in order to 
document the level of neutropenia and the time to recovery of neutrophils to 
1000 cells/mm3. Re-treatment criteria are based on time to recovery of neutrophil count. 
For patients who develop Grade 3 or 4 neutropenia, refer to the dose modifications described 
in Table 6. The clinical actions taken as a result of Grade 3 neutropenia, including the use 
of G-CSF, if any, should be recorded. 
If a dose reduction is applied in the same cycle, the patient will need to return to the clinic to 
receive new drug supply.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 22
5.4.3.2. Re-Treatment Criteria - Palbociclib
Re-treatment with palbociclib, following treatment interruption for treatment-related toxicity,
may not occur until all of the following parameters have been met:
Table 4.
Palbociclib Re-Treatment Criteria
Platelet count 50,000/mm3
ANC 1000/mm3 and no fever
Grade 3 non-hematologic AEs (including nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment) 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 500 msec and potential reversible causes (eg, electrolyte imbalance, 
concomitant medications known to prolong QTc) corrected.*
If QTc remains >480 msec, treatment may re-start but the electrocardiogram (ECG)
should be monitored more frequently as per the investigator’s best medical judgment 
until QTc 480 msec.*
* In the event of QTc prolongation of >480 and 500 msec, possible reversible causes, such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong the QTc
interval (see Appendix 2) should be evaluated and corrected accordingly to best clinical practice.
Abbreviations: ANC=absolute neutrophil count; AE=adverse event, QTc=corrected QT interval, 
ECG=electrocardiogram.
If a treatment delay results from decline in hematologic parameters, the frequency of blood 
count assessments should be increased as per best clinical practice.
If the re-treatment parameters are met within 3 weeks of dose interruption, palbociclib may 
be resumed as per recommended dose modification guidelines.
If the re-treatment parameters have not been met after >3 weeks of dose interruption, the 
patient should permanently discontinue palbociclib treatment.  However, if a patient is
deemed to be suitable for a lower dose of palbociclib, treatment may be resumed at a lower 
dose at the investigator’s discretion.
5.4.3.3. Dose Reductions - Palbociclib
Following dose interruption or cycle delay, the palbociclib dose may need to be reduced 
when treatment is resumed.  Available dose levels in case of palbociclib dose reduction are 
reported in Table 5.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 23
Table 5.
Available Dose Levels
Dose Level
Palbociclib 
Letrozole
Starting dose
125 mg/day
2.5 mg/day
-1
100 mg/day
2.5 mg/day
-2
75 mg/day
2.5 mg/day
Palbociclib dose below 75 mg/day is not allowed. 
Once a dose has been reduced, all subsequent cycles should be administered at that dose 
level, unless further dose reduction is required.  Dose re-escalation is not allowed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
All dose modifications/adjustments must be clearly documented on the CRF along with 
reasons for dose modification/adjustment. 
Palbociclib dose modifications recommended for treatment-related toxicities requiring 
treatment, interruption/delay, or persisting despite optimal medical treatment, are described 
in Table 6.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 24
Table 6.
Palbociclib Dose Modifications for Treatment Related Toxicities
Worst toxicity
Palbociclib treatment
Grade 3 neutropenia (ANC<1000/mm3)
No dose adjustment is required.  Consider 
repeating complete blood count monitoring 1 week 
later.  Withhold initiation of next cycle until 
recovery to Grade 2, then resume at same dose 
level.
Grade 4 neutropenia (ANC<500/mm3)
Withhold initiation of next cycle until recovery to 
Grade 2, then resume at next lower dose.
Grade 3 neutropenia
(ANC<1000/mm3)
associated with a documented 
infection or fever 38.5C
Withhold initiation of next cycle until recovery to 
Grade 2, then resume at next lower dose.
Grade 3 thrombocytopenia (Platelet 
count<50,000/mm3)
No dose adjustment is required.  Consider 
repeating complete blood count monitoring 1 week 
later.  Withhold initiation of next cycle until 
recovery to Grade 2, then resume at same dose 
level.
Grade 4 thrombocytopenia (Platelet 
count<25,000/mm3)
Withhold initiation of next cycle until recovery to 
Grade 2, then resume at next lower dose.
Grade 3 non-hematologic toxicity 
(For nausea, vomiting, diarrhea, and 
hypertension only if persisting despite 
optimal medical treatment)
Withhold until symptoms resolve to:

Grade 1;

Grade 2 (if not considered a safety risk for 
the patient).
Resume at the next lower dose level.
Grade 3 QTc prolongation
Decrease 1 dose level *
Grade 4 QTc prolongation
Permanently discontinue
* Reduce the dose only if no reversible cause is identified, such as serum electrolytes abnormalities, or usage of 
concomitant medications with the potential to prolong the QTc interval (see Appendix 2).
Abbreviations: ANC=absolute neutrophil count; QTc=corrected QT interval.
5.5. Investigational Product Storage
The investigator, or an approved representative eg, pharmacist, will ensure that all 
investigational products including any marketed products are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.
Storage conditions stated in the SRSD (eg, IB) may be superseded by the storage conditions 
stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 25
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order.  
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
Sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the Sponsor approves the use of the investigational 
product after the temperature excursion. Use of the investigational product prior to Sponsor 
approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Site staff will instruct patients on the proper storage requirements for take-home 
investigational products. 
5.6. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
Patients will be required to return all bottles of palbociclib at the beginning of each cycle for 
drug accountability (see also Section 5.2, Patient Compliance).
Drug accountability will be performed at every clinical visit prior to dispensing drug supply 
for the next cycle.  The number of remaining capsules will be collected, documented, and 
recorded to assess compliance.
5.6.1. Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). The site will be responsible for drug destruction. If destruction is 
authorized to take place at the study site, the investigator must ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and 
any special instructions provided by Pfizer, and all destruction must be adequately 
documented.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 26
5.7. Concomitant Treatment(s)
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator.
All concomitant medications required to clinically manage patients while they are receiving 
palbociclib therapy are permitted unless specified below in Section 5.7.1 and 5.7.2.  
Documentation of these medications will not be collected on the CRF but will need to be 
available from the patient’s medical record upon request by the Sponsor.
An exception will be granulocyte colony stimulating factor (G-CSF).  G-CSF use is 
permitted to treat treatment-emergent neutropenia as per current American Society of 
Clinical Oncology (ASCO) guidelines.  Per these guidelines, if neutropenic complications are 
observed, secondary prophylaxis may be given at the discretion of the investigator.  G-CSF 
use will be documented on the CRF as will other agents used to treat/manage AEs while on 
therapy.
5.7.1. Prohibited Medications
Anticancer agents:  No additional investigational or commercial anticancer agents such as 
chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or endocrine 
therapy other than letrozole will be permitted during the study. 
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.  Coadministration with drugs that are CYP3A 
inhibitors and inducers may change the plasma concentrations of palbociclib in humans. The 
concurrent use of CYP3A inhibitors/inducers listed below is not allowed in the study:

Strong CYP3A inhibitors, including, boceprevir, clarithromycin, conivaptan, delavirdine, 
indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, suboxone, telaprevir, telithromycin, 
voriconazole, and grapefruit, grapefruit juice or any product containing grapefruit.

The following moderate CYP3A inhibitors: amprenavir, atazanavir, diltiazem, 
erythromycin, fosamprenavir, and verapamil.

Strong CYP3A inducers, including carbamazepine, phenytoin, primidone, rifampin, 
rifapentin, and St. John’s wort.

The following moderate CYP3A inducers: felbamate, nevirapine, phenobarbital, and 
rifabutin.
Drugs known to cause QT interval prolongation: Refer to Appendix 2 for a list of drugs 
known to predispose to Torsade de Pointes.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 27
Hormone replacement therapy: Topical estrogens (including any intravaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators (eg, raloxifene) are prohibited 
during the study.
5.7.2. Medications Not Recommended 
Alternative therapies should be considered whenever possible for the following treatments. 
Chronic immunosuppressive therapies should be avoided, including systemic corticosteroids.  
Steroids given for physiologic replacement, as anti-emetics or inhaled as well as short course 
of oral/topical steroids given for allergic reactions or asthma flares are allowed.
The concurrent use of moderate CYP3A inducers such as dexamethasone or modafinil is not 
recommended.
The use of herbal medicines is not recommended.
6. STUDY PROCEDURES 
The Schedule of Activities (Table 1) provides an overview of the protocol visits and 
procedures. 
6.1. 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 or behavioral 
reasons, or the inability of the patient to comply with the protocol-required schedule of study 
visits or procedures at a given study site. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs.
Withdrawal of consent: Patients who request to discontinue study treatment will remain in 
the study and must continue to be followed for protocol specified follow-up procedures. The 
only exception to this is when a patient specifically withdraws consent for any further contact 
with him or her, or persons previously authorized by the patient to provide this information. 
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 28
Lost to follow-up: All reasonable efforts must be made to locate patients to determine and 
report their ongoing status. This includes follow-up with persons authorized by the patient. 
Lost to follow-up is defined by the inability to reach the patient after a minimum of 2
documented phone calls, faxes, or e-mails as well as lack of response by the patient to 1 
registered mail letter. All attempts should be documented in the patient’s medical records. If 
it is determined that the patient has died, the site will use permissible local methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a Sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
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.
7. ASSESSMENTS
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 the control of the investigator that may make it unfeasible to 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 that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
There are minimal protocol-specified tests and procedures for this expanded access protocol.  
It is the responsibility of the investigator to perform medically appropriate tests and 
procedures as necessary to ensure the safety and well-being of the patient. 
7.1. Safety Assessments
Safety assessment will consist of monitoring of all AEs, including serious adverse events 
(SAEs) at every clinical visit and monitoring of hematology to be performed to check
patient’s eligibility at Screening, every 2 weeks (Days 1 and 14) of the first 2 cycles, then 
monthly on Day 1 of each subsequent cycle of treatment with palbociclib and at EOT.
In the
case of Grade 3 neutropenia, consider repeating complete blood count monitoring 1 week 
later in accordance with best local practice and report on the CRF in order to document the
ANC value at the time of severe neutropenia as well as the time-to-recovery of neutrophils to
1000 cells/mm3.
Re-treatment criteria are based on time-to-recovery of neutrophil count.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 29
For patients who develop Grade 3 or 4 neutropenia, refer to the dose modifications described 
in Table 6.  Glycated hemoglobin (HbA1c) will be assessed at Screening, every 3 months, at
EOT, and will be documented on the CRF.
Other procedures, as necessary according to standard of care and in accordance with each 
site’s institutional guidelines, will be assessed to monitor for adverse events related to the 
underlying disease, treatment with palbociclib, or treatment with letrozole or supportive 
therapies (see Adverse Event Reporting, Section 8). 
Information generated from these assessments may also be used to determine if an adverse 
event occurred, as defined in Section 8.3.
7.1.1. Physical Examination
A full physical examination of all major body systems will be required at Screening.  
Symptom-directed physical examinations will be performed as per routine clinical practice 
during the study.  Only physical examination at Screening will be recorded on the CRF.  
Physical examinations performed during treatment will need to be available from the 
patient’s medical record upon request by the Sponsor. 
The Eastern Cooperative Oncology Group (ECOG) performance status scale will be required 
at Screening, as per routine clinical practice during the study, and at EOT.  Data collected at 
Screening and at EOT will be recorded on the CRF.  Other ECOG performance status
assessments during study will need to be available from the patient’s medical record upon 
request by the Sponsor.  ECOG performance status scale is available in Appendix 1.
7.1.2. 12-Lead ECG
Three consecutive 12-lead ECGs will be performed approximately 2 minutes apart at 
Screening.  ECG is to be repeated during the treatment, as clinically indicated.  If the mean 
QTc is prolonged (value of >500 msec), then the ECGs should be re-evaluated by a qualified 
person at the institution for confirmation.  Only ECG at Screening will be recorded on the 
CRF.  ECGs performed during treatment will need to be available from the patient’s medical 
record upon request by the Sponsor.  In the case an ECG abnormality meets the definition of 
AE, as determined by the investigator and according to Adverse Event Reporting (Section 8),
this must be captured on an AE CRF page.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 30
7.1.3. Laboratory Safety Assessments
Blood tests will include the following:
Hematology Panel
Metabolic Panel
Blood Chemistry Panel
1
Absolute neutrophil
count (ANC)
1
Glycated hemoglobin 
(HbA1c)
1
Alanine 
aminotransferase 
(ALT)
2
Platelets
2
Aspartate
aminotransferase
(AST)
3
Hemoglobin
3
Alkaline phosphatase
4
White blood cell 
(WBC) count
4
Sodium
5
Potassium
6
Total calcium
7
Total bilirubin
8
Blood urea nitrogen 
(BUN)
9
Serum creatinine
10
Albumin
Blood tests will be drawn at the time points described in Table 1 (Schedule of Activities), 
and analyzed at local laboratories. 
Hematology will be performed to verify patient’s eligibility at Screening, every 2 weeks 
(Days 1 and 14) of the first 2 cycles of therapy, then monthly on Day 1 of each subsequent 
cycle of treatment with palbociclib and at EOT.  Hematology data will be recorded on the 
CRF.
In the case of Grade 3 neutropenia, consider repeating complete blood count monitoring 1
week later in accordance with best local practice and report on the CRF in order to document 
the level of neutropenia and the time-to-recovery of neutrophils to 1000 cells/mm3.
Re-treatment criteria are based on time-to-recovery of neutrophil count. For patients who 
develop Grade 3 or 4 neutropenia, refer to the dose modifications described in Table 6. The 
clinical actions taken as a result of Grade 3 neutropenia, including the use of G-CSF, if any,
should be recorded.
Glycated hemoglobin (HbA1c) will be assessed at Screening, every 3 months, at EOT, and 
will be documented on the CRF.
Blood chemistry will be performed to verify patient’s eligibility at Screening, and as per 
routine clinical practice thereafter.  Only laboratory data at Screening will be recorded on the 
CRF.  During the study, blood chemistry data will not be collected on the CRF but will need 
to be available from the patient’s medical record upon request by the Sponsor.  


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 31
Cycle 1/Day 1 visit: Blood chemistry and hematology are not required if acceptable 
screening assessment is performed within 7 days prior to randomization.
In the case any laboratory abnormality meets the definition of AE, as determined by the 
investigator and according to Section 8 (Adverse Event Reporting), this must be captured on 
an AE CRF page.
7.2. Tumor Assessments
Tumor assessments are to be performed at Screening and as per routine clinical practice and 
according to the patient’s clinical status thereafter (Schedule of Activities, Table 1). Only the 
investigators’ tumor assessments will be recorded on the CRF.
Tumor assessment evaluation will be conducted as per local practice at each institution. 
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to the investigational product(s), will be reported as described in the following
sections. 
For all AEs, the investigator must pursue and obtain adequate information, both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious advers event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
Sponsor.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 32
AEs (serious and nonserious) should be recorded on the case report form (CRF) from the 
time the patient has taken at least 1 dose of investigational product through the patient’s last 
visit.
If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends 
at the time the new treatment is started.  Death must be reported if it occurs during the SAE
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 33

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the Sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE 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 AE by the investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 34
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

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 an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. 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 AE and as an SAE with Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 5 (see Severity Assessment, Section 8.8).
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 AE outcomes, 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.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the Section 8.14.1, Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level 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.  


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 35
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients 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 values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For patients with pre-existing ALT or AST or total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches ≥3 × ULN (whichever is smaller).
The patient 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.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, 
gamma-glutamyltransferase, prothrombin time (PT)/international normalized ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review 
of ethanol, acetaminophen (paracetamol), recreational drug, supplement consumption, family 
history, occupational exposure, sexual history, travel history, history of contact with a 
jaundiced person, 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, 
acetaminophen (paracetamol) blood levels, 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 liver function test (LFT) abnormalities identified at the time,
should be considered potential Hy’s Law cases irrespective of availability of all the results of 
the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 36
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes a transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

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 (eg, for 
workup of persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 37
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria (NCI CTC), (version 4.03 Publish Date: June 14, 2010,
http://ctep.cancer.gov/reporting/ctc.html).
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally, the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see Reporting Requirements, Section 8.14).  If the 
investigator's causality assessment is “unknown but not related to investigational product,”
this should be clearly documented on study records.  


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 38
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes, or is found to be, pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The 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 and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  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 preprocedure 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 (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 39
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 the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). Only female patients will be enrolled in 
this study. In the case of paternal exposure, the investigator will provide the study subject 
with the Pregnant Partner Release of Information Form to deliver to his partner.  The 
investigator must document in the source documents that the subject was given the Pregnant 
Partner Release of Information Form to provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) has unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Patient Withdrawal, Section 6.1)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient or legally acceptable representative.  In addition, each study patient/legally 
acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
CCI


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 40
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or 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. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 41
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
Sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
Due to the nature of this study, the number of patients to be enrolled is not determined for the 
hypothesis testing. Based on the prevalence of the disease and eligible study population over 
the timelines of this study, it is estimated that the study will enroll 130 patients.  
9.2. Efficacy Analysis
Because of the nature of the study, no inferential analyses are planned, and no hypotheses 
will be tested. However, some exploratory analyses may be conducted if data are available.
Specifically, analyses on objective response rate (ORR, assessed by investigator), and 
duration of clinical benefit may be conducted if appropriate.
Tumor assessments are to be performed at Screening and as per local practice and the 
patient’s clinical status thereafter.  No uniformed assessment schedule is planned for patients 
across the sites.  Tumor assessments will be evaluated as per local guidelines by investigators
and only their assessments will be collected on the CRF.
The ORR will be reported along with the corresponding exact 95% 2-sided confidence 
interval using standard methods based on the binomial distribution.
Duration of Clinical Benefit: For patients who were taking palbociclib combination treatment 
in the study, duration of clinical benefit is defined as the length of time patients remain on 
palbociclib treatment from the first day of treatment until the last day of treatment in this 
study.
9.3. Analysis of Other Endpoints
9.3.1. Patient Disposition
The number of patients treated and the number of patients who withdrew from the study, as 
well as reasons for discontinuation, will be summarized in data table format.
9.3.2. Baseline Characteristics
Demographic characteristics such as age, gender, race, prior medication, and physical 
examination results will be tabulated.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 42
9.3.3. Treatment Administration
Study drug administration will be described in terms of total and median number of weeks 
administered, dose, and reasons for deviation from planned therapy.
9.4. Safety Analysis
Safety data will be summarized for all patients who received at least 1 dose of study 
medication.
9.4.1. Analysis of Adverse Events (AEs)
All AEs reported after initiation of study drug treatment will be considered as 
treatment-emergent AEs (TEAE).  All AEs will be coded by system organ class and 
preferred term using Medical Dictionary for Regulatory Activities (MedDRA) coding.  AE 
severity will be graded according to CTCAE version 4.03.
Summary tables will present the number of patients observed with TEAEs and corresponding 
percentages.  Within each table, the AEs will be categorized by MedDRA body system and 
preferred term.  Additional subcategories may be presented based on event severity, and/or 
relationship to study drug.
Individual patient listings will be prepared for all AE data.
9.4.2. Analysis of Clinical Laboratory Data
Hematology data will be recorded on the CRF at Screening and during the study as outlined 
in Schedule of Activities (Table 1), while blood chemistry data will be collected on the CRF 
only at Screening.
Data Listings will be prepared for each laboratory measurement and will be structured to 
permit review of the data per patient over time.
Summary tables will be prepared to display the distribution of laboratory measures over time.
Nadir ANC values and time-to-lowest ANC count, as well as time-to-recovery of ANC to 
1000 cells/mm3, will be reported on the CRF and summarized as appropriate.
9.5. Interim Analysis
No interim analysis is planned for this study. However, summaries of accumulating safety 
and efficacy data from the study may be presented at academic meetings during the course of 
the study, as appropriate.
9.6. Data Monitoring Committee 
This study will not use a Data Monitoring Committee (DMC).


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 43
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the Institutional Review Board (IRB)/Ethics Committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 44
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as a source document.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, detailed 
records of treatment disposition, and adequate documentation of relevant correspondence 
(eg, letters, meeting minutes, and telephone call reports).  The records should be retained by 
the investigator according to the ICH guidelines, according to local regulations, or as 
specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 45
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The study site 
will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the Sponsor, approved by the IRB/EC before use, and available 
for inspection.
The investigator must ensure that each study patient or her legally acceptable representative
is fully informed about the nature and objectives of the study and possible risks associated 
with participation.  
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents
must record why the patient did not provide consent (eg, minor, decisionally-impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 46
spouse), and that the patient’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative, when applicable,
before any study-specific activity is performed, unless a waiver of informed consent has been 
granted by an IRB/EC. The investigator will retain the original of each patient's signed 
consent document.
12.4. Patient Recruitment
Patient recruitment efforts are not required for this study due to its nature of expanded access 
protocol.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
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 protocol or of ICH GCP of which the investigator becomes 
aware of.
13. DEFINITION OF END OF TRIAL
The end of the trial is defined by the time of regulatory approval and commercial availability 
of palbociclib for the treatment of advanced breast cancer.  At that time, patients enrolled in 
the study will be moved to commercial supply.  A separate patient assistance program is 
designed to cover all patients (ie, “no patient left behind”).  There will be some time lag
between approval and commercial availability of palbociclib; therefore, there will be a 4 
month or more transition period after approval to allow patients to access locally available 
commercial drug.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of
palbociclib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a week of notification. As directed by Pfizer, all 
study materials must be collected and all CRFs completed to the greatest extent possible.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 47
15. PUBLICATION OF STUDY RESULTS
15.1. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the
principal investigator of the results of the study based on information collected or generated 
by the principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study-related or Pfizer product-related 
information necessary to the appropriate scientific presentation or understanding of the study 
results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 48
16. REFERENCES
1.
Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 
2010;60:277-300.
2.
EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on 
recurrence and 15-year survival: an overview of the randomised trials. Lancet 
2005;365:1687-717.
3.
Wood WC, Muss HB, Solin LJ, et al. Malignant tumors of the breast. In: DeVita VT Jr, 
Hellmann S, Rosenberg SA, eds. Cancer, Principle and Practice of Oncology. 7th ed.
Philadelphia, Pa: Lippincott Williams and Wilkins; 2005:1415-77.
4.
Leung, BS, Potter AH. Mode of estrogen action on cell proliferation in CAMA-1 cells. 
II. Sensitivity of G1 phase population. J Cell Biochem. 1987;34:213-25.
5.
Sutherland RL, Hall RE, Taylor IW. Cell proliferation kinetics of MCF-7 human 
mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing 
and plateau-phase cells. Cancer Res. 1983;43:3998-4006.
6.
Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus 
tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: 
analysis of survival and update of efficacy from the international Letrozole Breast 
Cancer Group. J Clin Oncol 2003;2101-9.
7.
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 
randomized phase 2 study. Lancet Oncol 2015;16(1):25-35.
8.
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.
9.
Gao CY, Rampalli AM, Cai H-C, et al. Changes in cyclin dependent kinase expression 
and activity accompanying lens fiber cell differentiation. Exp Eye Res 
1999;69:695-703.
10.
Bhat SP. The ocular lens epithelium. Bioscience Reports 2002;21(4):537-63.
11.
Awasthi N,, Wagner BJ. Suppression of human lens epithelial cell proliferation by 
proteasome inhibition, a potential defense against posterior capsular opacification. 
Invest Ophthalmol Vis Sci 2006;47:4482-9.
12.
Letrozole USPI, East Hanover, NJ: Novartis Pharma; 1997. Accessed on 10 July 2015.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 49
Appendix 1. 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
Dead
5


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 50
Appendix 2. List of Drugs Known to Predispose to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone, Pacerone
Anagrelide
Agrylin, Xagrid
Arsenic trioxide
Trisenox
Astemizole
Hismanal
Azithromycin
Zithromax
Bepridil
Vascor
Chloroquine
Aralen
Chlorpromazine
Thorazine
Cisapride
Propulsid
Citalopram
Celexa
Clarithromycin
Biaxin
Cocaine
Cocaine
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Dronedarone
Multaq
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S.
Escitalopram
Cipralex, Lexapro
Flecainide
Tambocor
Halofantrine
Halfan
Haloperidol
Haldol
Ibutilide
Corvert
Levofloxacin
Levaquin, Tavanic
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Moxifloxacin
Avelox
Ondansetron*
Zofran
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Cardioquin, Quinaglute
Servoflurane
Ulane, Sojourn
Sotalol
Betapace
Sparfloxacin
Zagam
Sulpiride 
Dogmatil, Eglonyl


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 51
Generic Name
Brand Name(s)
Terfenadine
Seldane
Thioridazine
Mellaril
Vandetanib
Caprelsa
*when administered intravenously at high dose (32 mg).
Adapted from the University of Arizona Cancer Center for Education and Research on Therapeutics: "Torsades 
List: Drugs with a Risk of Torsades de Pointes," drugs that are generally accepted by the QTdrugs.org Advisory 
Board to carry a risk of Torsades de Pointes on the University of Arizona CERT website: 
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm#.  This list is not meant to be considered all 
inclusive.  See website for current list.


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 52
Appendix 3. Abbreviations 
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BC
breast cancer
BUN
blood urea nitrogen
CDK
cyclin-dependent kinase
CDKN2A
cyclin-dependent kinase inhibitor 2A
CRF
Case Report Form
CSA
clinical study agreement
CT
CAT scan
CTCAE
Common Terminology Criteria for Adverse 
Events
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EOS
end of study
EOT
end of treatment
ER
estrogen receptor
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United 
States)
FSH
follicle-stimulating hormone
G1/S
cell cycle checkpoint/transition between G1
phase and S phase
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
HbA1c
glycated hemoglobin
HER2
human epidermal growth factor receptor 2
HR
hormone receptor
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation
IND
Investigational New Drug
INR
international normalized ratio
IRB
Institutional Review Board


Palbociclib (PD-0332991)
Advanced Breast Cancer
A5481053
Final Protocol, 23 July 2015
Page 53
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
mitochondrial ribonucleic acid
N/A
not applicable
NCI
National Cancer Institute
PFS
progression-free survival
PgR
progesterone receptor
PT
prothrombin time
QD
quaque die (once daily)
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
SRSD
Single Reference Safety Document
SSID
single subject identification number
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
WBC
white blood cell

SAP_001.pdf: 
Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 1 
 
 
 
Protocol A5481053 
 
STUDY OF PALBOCICLIB IN COMBINATION WITH LETROZOLE 
AS TREATMENT OF POSTMENOPAUSAL WOMEN WITH 
HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED 
BREAST CANCER FOR WHOM LETROZOLE THERAPY IS DEEMED 
APPROPRIATE 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
Version: 
1.0 
Author:  
 
Date:  
February 04, 2016 
 
 
PPD


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 2 
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................4 
2. INTRODUCTION .......................................................................................................................4 
2.1. Study Design ...................................................................................................................4 
2.2. Study Objectives .............................................................................................................5 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................5 
4. HYPOTHESES AND DECISION RULES .................................................................................5 
4.1. Statistical Hypotheses .....................................................................................................5 
4.2. Sample Size Determination and Statistical Decision Rules ............................................6 
5. ANALYSIS SETS .......................................................................................................................6 
6. ENDPOINTS AND COVARIATES ...........................................................................................6 
6.1. Efficacy Endpoints ..........................................................................................................6 
6.1.1. Objective Response (OR) ...................................................................................6 
6.1.2. Duration of Clinical Benefit ...............................................................................6 
6.2. Other Endpoints ...............................................................................................................6 
6.2.1. Patient Disposition ..............................................................................................6 
6.2.2. Baseline Characteristics ......................................................................................7 
6.2.3. Treatment Administration and Compliance........................................................7 
6.3. Safety Data ......................................................................................................................7 
6.3.1. Treatment Emergent Adverse Event ...................................................................7 
6.3.2. Treatment Related Adverse Event ......................................................................7 
6.3.3. Laboratory Safety Assessments ..........................................................................8 
6.3.4. ANC ....................................................................................................................8 
6.3.5. ECOG .................................................................................................................8 
6.3.6. Electrocardiogram (ECG) ...................................................................................8 
6.3.7. Death ...................................................................................................................8 
6.4. Covariates and Stratification Factors ..............................................................................8 
7. HANDLING OF MISSING VALUES ........................................................................................9 
7.1. Missing Dates ..................................................................................................................9 
7.2. Other Missing Data .........................................................................................................9 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..................................9 
8.1. Statistical Methods ..........................................................................................................9 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 3 
8.2. Statistical Analyses .......................................................................................................10 
8.2.1. Primary Efficacy Analysis ................................................................................10 
8.2.2. Standard Analyses ............................................................................................10 
8.2.3. Safety Analyses ................................................................................................10 
8.2.3.1. Adverse Events ................................................................................11 
8.2.3.2. ECG .................................................................................................12 
8.2.3.3. Death ...............................................................................................12 
8.2.3.4. Laboratory abnormalities ................................................................12 
8.2.3.5. ECOG performance status ...............................................................12 
9. REFERENCES ..........................................................................................................................12 
10. APPENDICES .........................................................................................................................12 
10.1. Schedule of Activities .................................................................................................12 
 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 4 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
Not Applicable 
2. INTRODUCTION 
This document describes the planned statistical analyses for Protocol A5481053 dated July 
23, 2015. This analysis plan is meant to supplement the study protocol.  Any deviations from 
this analysis plan will be described in the Clinical Study Report.  
 
Palbociclib is being developed for the treatment of hormone receptor-positive (HR-positive), 
HER2-negative (human epidermal growth factor receptor 2 negative) breast cancer (BC). 
 
The purpose of this study is to provide access to palbociclib in Mexico and in selected Latin 
American countries before it becomes commercially available to patients with HR-
positive/HER2-negative ABC who are appropriate candidates for letrozole therapy. 
 
2.1. Study Design 
A5481053 is a multicenter, single-arm, open-label clinical study which will be conducted in 
Mexico and in selected Latin American countries. 
 
Approximately 130 patients will be enrolled. This total number of patients will allow for 
enrollment of an adequate number of patients from each participating country. Patients will 
continue to receive treatment with palbociclib until disease progression, symptomatic 
deterioration, unacceptable toxicity, death, withdrawal of consent, or time of commercial 
availability of palbociclib, whichever occurs first. 
 
Upon marketing approval of palbociclib by the local health authorities in the participating 
countries, patients enrolled in Study A5481053 will end participation in this study and be 
moved to commercially available palbociclib (if considered to be appropriate by the 
investigator), as soon as feasible. 
 
Patients will receive palbociclib orally once a day at 125 mg/day for 21 days followed by 7 
days off treatment for each 28-day cycle, in combination with letrozole 2.5 mg orally once a 
day continuously. 
 
Patients will undergo AE monitoring as per local practice and per protocol. All grade, all 
causality AEs and all serious adverse events (SAEs) will be recorded on the CRF. All deaths 
occurring up to 28 days after palbociclib is discontinued will be recorded. 
 
Hematology laboratory data will be recorded every 2 weeks for the first 2 cycles of therapy, 
then monthly at the start of each cycle thereafter. In the case of Grade ≥3 neutropenia, 
consider repeating complete blood count monitoring 1 week later in accordance with best 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 5 
local practice and report on the CRF in order to document the level of neutropenia and the 
time to recovery of neutrophils to ≥1000 cells/mm3. Re-treatment criteria are based on time 
to recovery of neutrophil count. For patients who develop Grade 3 or 4 neutropenia, refer to 
the dose modifications. The clinical actions taken as a result of Grade ≥3 neutropenia, 
including the use of granulocyte colony stimulating factor (G-CSF), if any, should be 
recorded. 
 
Tumor response will be assessed as per local practice and only investigator tumor 
assessments will be collected. The date of tumor progression will be recorded. No statistical 
tests will be performed.  
 
The end of the trial is defined by the time of regulatory approval and commercial availability 
of palbociclib for the treatment of advanced breast cancer. At that time, patients enrolled in 
the study will be moved to commercial supply. A separate patient assistance program is 
designed to cover all patients (ie, “no patient left behind”). There will be some time lag 
between approval and commercial availability of palbociclib; therefore, there will be a 4 
month or more transition period after approval to allow patients to access locally available 
commercial drug.    
 
2.2. Study Objectives 
Primary Objective: 
• To provide access to palbociclib in Mexico and in selected Latin American countries 
to postmenopausal patients with hormone receptor-positive (HR-positive), HER2-
negative ABC who are deemed appropriate for letrozole therapy. 
Secondary Objectives: 
• To gain additional safety data of the combination of palbociclib with letrozole in the 
postmenopausal HR-positive/HER2-negative population. 
• To gain additional antitumor activity data of the combination of palbociclib with 
letrozole in postmenopausal HR-positive/HER2-negative population. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
This is an open-label study. No interim analysis is planned for this study. However, 
summaries of accumulating safety and efficacy data from the study may be presented at 
academic meetings during the course of the study, as appropriate. The final analyses will be 
performed at the time of study completion as determined by the Sponsor. 
 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
Because of the nature of the study, no inferential analyses are planned, and no hypotheses 
will be tested. 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 6 
4.2. Sample Size Determination and Statistical Decision Rules 
Due to the nature of this study, the number of patients to be enrolled is not determined for the 
hypothesis testing. Based on the prevalence of the disease and eligible study population over 
the timelines of this study, it is estimated that the study will enroll 130 patients. 
 
When patients are moved to commercial supply of palbociclib, their participation in the study 
and clinical study data collection will be discontinued.    
5. ANALYSIS SETS 
The as-treated (AT) population or safety analysis set will include all patients who receive at 
least 1 dose of palbociclib treatment.  The AT population will be the primary population for 
evaluating treatment administration/compliance and safety.  
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoints 
Tumor assessments are to be performed at Screening and as per local clinical practice and the 
patient’s clinical status thereafter. No uniformed assessment schedule is planned for tumor 
assessments across the sites. Tumor assessments will be evaluated as per local guidelines by 
investigators and the tumor responses which are based on their tumor assessments will be 
collected in the Investigator Overall Tumor assessment (IOTA) eCRF. 
 
6.1.1. Objective Response (OR) 
Objective response is defined as the overall complete response (CR) or partial response (PR). 
Objective Response Rate (ORR) is defined as the proportion of patients with CR or PR 
relative to all AT population. Patients who do not have on-study tumor re-evaluation, who 
receive anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 
who die, progress, or drop out for any reason prior to reaching a CR or PR will be counted as 
non-responders in the assessment of ORR. 
6.1.2.  Duration of Clinical Benefit  
Duration of clinical benefit is defined as the length of time patients remain on palbociclib 
treatment from the first day of treatment until the last day of treatment in this study. 
Duration of clinical benefit = (palbociclib last dose date – palbociclib 1st dose date 
+1)/7.02 
 
6.2. Other Endpoints 
6.2.1. Patient Disposition  
The number of patients treated with palbociclib and/or letrozole, treated with palbociclib, 
treated with letrozole, and the number of patients who withdrew from the study, as well as 
their reasons for discontinuation, will be summarized in data table format. 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 7 
 
6.2.2. Baseline Characteristics  
Demographic characteristics such as age, race, prior medication, and physical examination 
results will be tabulated. 
6.2.3. Treatment Administration and Compliance 
Study drug administration will be described in terms of: 
• Total and median number of weeks administered 
• Reasons for dose interruptions  
6.3. Safety Data 
Adverse events (AEs), hematology, blood chemistry will be assessed as described in the 
Schedule of Activities of the protocol. The records will be excluded from the analysis if AE 
onset date and laboratory data collecting date fall 28 days after the final dose of treatment or 
at/after a new non-study treatment’s starting date (whichever comes first). AE/SAE observed 
beyond 28 days and recorded in the database per Sponsor's agreement will be included and 
marked in the AE/SAE listings. 
Adverse events will be classified using the MedDRA classification system. The severity of 
the toxicities will be graded according to the NCI CTCAE version 4.03. The hematologic and 
chemistry laboratory results will be graded according to the NCI CTCAE v.4.03 severity 
grade. For parameters for which an NCI CTCAE v.4.03 scale does not exist, the categories of 
values below, within, and above the normal range for the local lab will be used. 
6.3.1. Treatment Emergent Adverse Event 
An adverse event is considered treatment emergent if: 
• The event occurs for the first time after the start of study treatment and before 28 days 
after final dose of study treatment and was not seen prior to the start of treatment, or 
• The event was seen prior to the start of treatment but increased in NCI CTCAE 
toxicity grade during study treatment. 
• Disease progression is not considered a treatment emergent adverse event unless the 
patient dies of disease prior to 28 days after discontinuation of treatment. 
6.3.2. Treatment Related Adverse Event 
Adverse events defined as treatment emergent adverse events with causality having 
‘YES/UNKNOWN related to study treatment’ as judged by the investigator are defined as 
treatment related adverse events.  


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 8 
6.3.3. Laboratory Safety Assessments 
Laboratory assessment will be assigned to cycle and week in the cycle based on the 
collection date of the sample relative to the study drug administration start date of each cycle. 
Baseline evaluations for laboratory are those collected 
• Within 28-30 days prior to or on first day of study drug and 
• If there is more than one baseline evaluation, closest to but any time prior to the 1st 
dosing on the first day of study treatment. 
 
Laboratory abnormalities 
• For parameters which have an NCI CTCAE v.4.03 scale: CTC grade is graded 
according to the NCI CTCAE v.4.03 severity grade 
• For parameters which do not have an NCI CTCAE v.4.03 scale: the categories of 
values below, within, and above the normal range for the local lab will be used 
 
6.3.4. ANC 
• Nadir ANC values during post-baseline  
• Time-to-lowest ANC count during post-baseline 
• Time-to-1st ANC count < 1000 cells/mm3  
• Time-to-recovery of ANC to ≥1000 cells/mm3  
6.3.5. ECOG  
All ECOG values  
 
6.3.6. Electrocardiogram (ECG)  
All ECG tests 
 
6.3.7. Death 
• Death from any cause while on treatment and within 28 days of palbociclib 
discontinuation 
• All reported deaths from any cause at any day (for death listing only) 
 
6.4. Covariates and Stratification Factors 
Not Applicable 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 9 
7. HANDLING OF MISSING VALUES 
7.1. Missing Dates 
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date.  If the month is 
missing for any date used in a calculation, January will be used to replace the missing month. 
For any imputed post-baseline date, if the calculation results in a negative duration, then the 
date resulting in 1 day duration will be used (e.g., date of onset cannot be prior to day one 
date).  
Missing dates for adverse events will be imputed based on the similar principle. 
• For the start date, if the day of the month is missing, the 1st day of the month will be 
used to replace the missing date. If both day and month are missing, January 1 of the 
non-missing year will be used to replace the missing date. If the first dose date is later 
than this imputed date, then impute the start date again to the first dose date. 
• For the stop date, if the day of the month is missing, the last day of the month will be 
used to replace the missing date. If both day and month are missing, December 31 of 
the non-missing year will be used to replace the missing date. 
 
If the start date is missing for an AE, then AE is considered to be treatment emergent unless 
the non-missing month and year indicate the AE onset prior to the treatment start date. 
 
7.2. Other Missing Data 
Other missing non-date data will not be imputed or carried forward. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
For the continuous variable, descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum values) will be summarized.  
 
For the categorical variables, the total patients count, number and percentage of patients in 
each category will be provided.  
 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence interval (log-
log transformation function is used (Kalbfleisch and Prentice 19801)) for each median will be 
provided.  
 
Individual patient data will be presented in data listings. 
 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 10 
8.2. Statistical Analyses  
8.2.1. Primary Efficacy Analysis 
No formal efficacy analysis will be conducted.  
 
• If applicable, ORR with will be summarized (N, n, %) in AT population along with 
the corresponding 2-sided 95% exact (Clopper-Pearson2) confidence intervals which 
are based on the binomial distribution. 
 
• If applicable, descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) for the duration of clinical benefit (in weeks) will be provided. 
 
8.2.2. Standard Analyses  
Descriptive statistics will be used to summarize study conduct and patient disposition, 
baseline characteristics, and treatment administration/compliance.   
 
• Study Conduct and Patient Disposition - the number and percentage of patients 
enrolled, accrual by study center, treated (treated-palbociclib or letrozole, treated-
palbociclib, and treated-letrozole), assessed for AEs, laboratory data, etc. The number 
and percentage of patients: 1) discontinued from the study and the reason for the 
discontinuation, 2) discontinued from treatment-palbociclib and reasons for the 
discontinuation, 3) discontinued from treatment- letrozole and reasons for the 
discontinuation. Listing on patients along with the reason for their premature 
discontinuation from the study will be provided.   
• Baseline Characteristics - patient characteristics such as patient age, height, weight, 
race, ethnicity, ECOG performance status, primary diagnosis, prior therapy (radiotherapy, 
surgery, systemic therapy), prior medication, medical history, and signs and symptoms at 
study entry (if applicable) will be summarized in frequency tables, and descriptive 
statistics will be provided for quantitative variables.  
• Treatment Administration and Compliance  
Study drug administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered, relative dose, relative dose 
intensity, dose modifications, dose interruptions, and reasons for dose interruptions. 
• Concomitant medications and Non-drug treatments 
Concomitant drug and non-drug treatments will be listed. Granulocyte Colony 
Stimulating Factor (G-CSF) treatment for neutropenia will be summarized.   
 
8.2.3. Safety Analyses 
Listings of AE, SAE, death, lab data, ECOG, and physical examinations (if available in 
database) will be provided according to reporting standard. 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 11 
8.2.3.1. Adverse Events 
All patients treated with at least one dose of study treatment (i.e. palbociclib / letrozole) will 
be included in all the safety analyses.  
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v.4.03 whenever possible (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
Adverse events will be summarized by the frequency of patients experiencing treatment 
emergent adverse events corresponding to body systems and MedDRA preferred term. 
 Adverse events will be graded by worst NCI CTCAE v.4.03 grade during the study.  
Adverse events leading to death or discontinuation of study, events classified as NCI CTCAE 
v.4.03 Grade 3 or higher, trial drug related events, and serious adverse events will be 
considered with special attention. 
The following summaries of treatment emergent adverse events will also be provided: 
• Discontinuations Due to Adverse Events including causality: all cause, treatment 
related, including relationship to specific study treatment of letrozole and /or 
palbociclib. 
• Temporary Discontinuations or Dose Reductions Due to Adverse Events including 
causality and relationship to specific study treatment of letrozole, and /or palbociclib. 
• Treatment-Emergent Adverse Events (All Causality, and Treatment Related) 
including the number of patients evaluable for adverse events, total number of 
adverse events (counting each unique preferred term across all patients), number of 
patients with serious adverse events, number of patients with Grades 3 and 4 adverse 
events, number of patients with Grade 5 adverse events, and number with dose 
reductions or temporary discontinuations due to adverse events 
• Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Maximum NCI CTCAE v.4.03 Grade (All Causality, and Treatment 
related) 
• Treatment-Emergent Adverse Events by MedDRA Preferred Term sorted by 
Descending Order of AE Frequency (All Causality, and Treatment related) 
• Treatment-Emergent Adverse Events by Preferred Term – Grade 3/4/5 events with 
number of patients experienced Grade 3-5 AEs and total number of Grade 3-5 AEs, 
sorted by Descending Order of AE Frequency (All Causality, and Treatment Related) 
A summary of Serious Adverse Events and listing of deaths reported as serious adverse 
events will be provided. 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 12 
8.2.3.2. ECG 
Only patient listing will be provided. Each patient’s individual ECG tests with mean of 3 
repeated ECG values of each test will be listed. 
8.2.3.3. Death 
All reported deaths are included. Total numbers of patients and percentage on cause of death 
and source of death will be summarized. Listing of all deaths will be provided. 
8.2.3.4. Laboratory abnormalities 
Laboratory data will be reported in data listing. 
The hematologic and metabolic laboratory results will be summarized in descriptive statistics 
on change from baseline and % change from baseline by cycle and by week in each cycle. 
The shift table from each patient’s baseline to her worst grade during post-baseline for each 
hematologic and metabolic laboratory parameter will be provided, respectively.  
Descriptive statistics on nadir ANC values during post-baseline and time-to-lowest ANC 
count during post-baseline in the AT population will be provided. Survival analyses using 
Kaplan-Meier method on time-to-1st ANC count < 1000 cells/mm3 (i.e. 1st Grade ≥3 
neutropenia) and time-to-recovery of ANC to ≥1000 cells/mm3 will be provided. The median 
event time and 2-sided 95% confidence interval for the median will be included, if 
applicable. Time-to-recovery of ANC to ≥1000 cells/mm3 is defined as the length of time (in 
week) from 1st ANC < 1000 cells/mm3 to 1st recovery of ANC to ≥1000 cells/mm3 in sub-AT 
population who ever have ANC < 1000 cells/mm3 during the post-baseline.  
8.2.3.5. ECOG performance status 
ECOG performance status shift table from each patient’s screening value to her end of study 
value will be provided. A listing of all ECOG data will be provided. 
9. REFERENCES  
1. J.D. Kalbfleisch and R.L. Prentice The statistical analysis of failure time data. John Wiley 
& Sons, Inc., New York, 1980 
2. Collett, D. (1991), Modelling Binary Data, London: Chapman & Hall 
10. APPENDICES  
10.1. Schedule of Activities 
 
Visit Identifier 
Screeninga 
Treatment: One cycle = 28 daysb 
End of 
Treatmentd 
End of 
Studyd 
Cycles 1 and 2 
Cycles ≥3 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 13 
Study day 
Within 28-30 
days prior to 
randomization 
unless specified 
otherwise 
Day 1c 
Day 14 
Day 1 
Time window 
±2 days 
±2 days 
±2 days 
Procedures at Screening 
Informed consente 
X 
Eligibility criteria 
evaluationf 
X 
Registrationg 
X 
Medical/Oncological 
historyh 
X 
Procedures at Screening and on study 
Physical examinationi 
X 
Per routine clinical practice 
ECOG performance 
statusj 
X 
Per routine clinical practice 
X 
12-Lead ECGk 
X 
As clinically indicated 
Treatments 
Palbociclib 
(PD-0332991l) 
Orally once daily from Day 1 to 
Day 21 of each cycle 
(Schedule 3/1) 
Letrozolem 
Orally once daily 
(Schedule: continuous dosing) 
Clinical Assessments 
Tumor assessment 
(CT or MRI scans) n 
X 
Per routine clinical practice 
Adverse eventso 
X 
X 
X 
Hematology (platelet 
count, ANC, WBC 
count, hemoglobin) p 
X 
X 
X 
X 
X 
HbA1cq 
X 
Every 3 months 
X 
 Blood chemistryr 
X 
Per routine clinical practice 
Abbreviations: ECOG=Eastern Cooperative Oncology Group; ECG=electrocardiogram; CT=CAT scan; MRI=magnetic 
resonance imaging; ANC=absolute neutrophil count; WBC=white blood cell; HbA1c=Glycated hemoglobin. 
a. Screening: All assessments should be performed within 28-30 days prior to study randomization. 
b. 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.  Clinical visits will be conducted as per local practice and as clinically indicated. Each 
subsequent cycle will begin 7 days after the last dose of study drug in the prior cycle to allow patients a 7-day 
washout period for each cycle. 
c. Cycle 1/Day 1: Blood chemistry and hematology not required if acceptable screening assessment is 
performed within 7 days prior to randomization. 
d. End of Treatment/End of Study: The End of Treatment (EOT) visit will be conducted when palbociclib is 
permanently discontinued for any reason. The indicated assessments are to be obtained if not completed in the 
last week of therapy. Patients who permanently discontinue palbociclib for any reason will also complete an 
End of Study (EOS) visit that will occur 28 days after last dose of palbociclib.  An EOS visit will be 
completed if a patient will continue on commercial palbociclib.  Adverse events should be followed up until 
all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable”. 
e. Informed Consent: Must be obtained prior to undergoing any study specific procedures 
f. Eligibility Criteria Evaluation: Patients must meet all of the eligibility criteria in the protocol. 


Palbociclib (PD-0332991) 
 
 
 
 
 
Advanced Breast Cancer 
A5481053 
Final Protocol, 23 July 2015  
 
 
 
 
Statistical Analysis Plan 
 
 
Page 14 
g. Registration: Patient identification number will be attributed to each patient. Patients will be assigned a single 
subject identification number (SSID) which will be obtained at the time of screening using the automated 
registration system and retained throughout the study.  A separate randomization number will be assigned by the 
automated registration system at Cycle 1 Day 1 and will be recorded on the CRF. 
h. Medical/Oncologic History: Medical history includes history of disease process other than oncology 
(active or resolved).  Oncological history includes date of primary diagnosis, information on prior 
antitumor treatments and radiotherapy, and oncologic surgeries. 
i. Physical Examination: General clinical examination of major body systems.  To be performed at Screening, 
and as per routine clinical practice during the treatment. 
j. ECOG Performance Status: To be performed at Screening, as per routine clinical practice during the 
treatment, and at EOT. ECOG performance status scale is available in Appendix 1 of the Protocol. 
k. 12-Lead ECG: Three consecutive 12-lead ECGs will be performed approximately 2 minutes apart at Screening 
to verify eligibility.  ECG to be repeated during the treatment, as clinically indicated.  If the mean QTc is 
prolonged (value of >500 msec), then the ECGs should be re-evaluated by a qualified person at the institution 
for confirmation. Only ECG at Screening will be recorded on the CRF (Case Report Form). 
l. Palbociclib Administration: PD-0332991 will be administered orally once daily at the starting dose of 125 mg 
on Day 1 to Day 21, followed by 7 days off treatment (Schedule 3/1). The patient will receive drug supply at 
the clinical site that will be sufficient to last until their next cycle visit. 
m. Letrozole Administration: Letrozole will be administered orally once daily at the dose of 2.5 mg (continuous 
daily dosing schedule).  Locally obtained commercial supplies of letrozole will be used 
n. Tumor Assessments: Tumor assessments are to be performed at Screening as per local practice and 
according to the patient’s clinical status thereafter.  Tumor assessment evaluation will be conducted as per 
local guidelines.  Only investigator’s assessments will be recorded on the CRF. 
o. Adverse Events: Patients must be followed for adverse events (AEs) from the time they signed the informed 
consent until 28 days after the last treatment administration or until all palbociclib-related toxicities have 
resolved, whichever is later.  AEs (serious and nonserious) should be recorded on the CRF from the time the 
patient has taken at least 1 dose of investigational product through the patient’s last visit.  AEs should be 
documented and recorded at each clinical visit using NCI CTC-AE version 4.03.  For serious adverse events 
(SAEs), the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent through and including 28 calendar days after the last administration of the 
investigational product. SAEs experienced by a patient after the active reporting period has ended should be 
reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor. 
p. 
Hematology: To include platelet count, absolute neutrophil count (ANC), white blood cell (WBC) count, and 
hemoglobin.   To be performed to check patient’s eligibility at Screening, every 2 weeks (Days 1 and 14) of the first 
2 cycles, then monthly on Day 1 of each subsequent cycle of treatment with palbociclib and at EOT. In the case of 
Grade ≥3 neutropenia consider repeating complete blood count monitoring 1 week later in accordance with best 
local practice and report on the CRF in order to document the ANC value at the time of severe neutropenia as 
well as the time to recovery of neutrophils to ≥1000 cells/mm3.  Re-treatment criteria are based on time to 
recovery of neutrophil count. For patients who develop Grade 3 or 4 neutropenia, refer to the dose modifications 
described in Table 6 of Protocol. If granulocyte-colony stimulating factors (G-CSF) and/or antibiotics are 
administered, their use will be documented on the CRF. 
q. Glycated Hemoglobin (HbA1c): To be assessed at Screening, every 3 months, and EOT, and will be 
documented on the CRF.  
r. 
Blood Chemistry: To be performed to check patient’s eligibility at Screening and as per routine clinical practice 
thereafter. Only laboratory data at Screening will be recorded on the CRF.