Clinical trial NCT02679755
Conditions: Breast Cancer
Keywords: Hormone receptor positive advanced breast cancer
Sponsor: Pfizer
Start date: 2016-03-09; Completion date: 2019-07-25
Enrollment: 252 participants; Allocation: NON_RANDOMIZED; Intervention model: 

Brief summary:
A study of palbociclib in combination with letrozole as treatment of post-menopausal women with hormone receptor-positive, her2-negative advanced breast cancer for whom letrozole therapy is deemed appropriate.

Detailed description:
To provide access to palbociclib to post-menopausal patients with hormone receptor-positive \[HR(+)\], HER2-negative \[HER2(-)\] ABC who are deemed appropriate for letrozole therapy.

Arms: arm 1: Palbociclib plus Letrozole
Interventions: intervention 1: Palbociclib intervention 2: Letrozole
Intervention descriptions: intervention 1: 125 mg/d capsules orally for 3 out of 4 weeks in repeated cycles intervention 2: 2.5 mg/d tablets orally on a continuous regimen

Protocol documents:
Prot_000.pdf: 
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A STUDY OF PALBOCICLIB IN COMBINATION WITH LETROZOLE AS 
TREATMENT OF POST-MENOPAUSAL 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:
69,324
European Clinical Trial Database 
(EudraCT) Number:
N/A
Protocol Number:
A5481037
Phase:
Phase 3b/4


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Document History
Document
Version Date
Summary of Changes
Amendment 3
31 May 2016
•
Based on internal review of available current 
clinical and non-clinical data,
 
 
routine monitoring of HbA1c will no longer 
be conducted in the study.
•
 
 the primary objective of the study 
has been revised to include safety.
•
The following study endpoint has been 
removed as it is redundant from the endpoint 
characterizing adverse events: death from any 
cause while on treatment and within 28 days 
of palbociclib discontinuation.
•
The number of patients to be enrolled in the 
study has been increased to approximately 
300 patients.
•
To ensure appropriate patients are enrolled in 
the study in the first-line setting, a 
clarification has been added for the inclusion 
criterion #5: in the first-line 
advanced/metastatic disease setting.
•
A clarification has been added that exclusion 
criterion #6 (QTc >480 msec) will be based 
on the mean value from triplicate ECGs.
•
An additional condition, symptomatic 
pulmonary embolism, has been added to the 
exclusion criterion #7.
•
For the Schedule of Activities, the End of 
Treatment Visit has been combined with the
End of Study Visit as there are no long 
term/survival follow-ups in this protocol, and 
the visit window for study procedures has 
been clarified with -2 days to ensure 
hematology laboratory test is performed prior 
to start of each cycle.
•
Permitted Medications and Concomitant 
Radiotherapy or Surgery sections have been 
added to provide further guidance.
•
The definition of end of trial has been updated 
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to provide further clarification. 

The following sections have been updated in 
accordance with the Pfizer protocol template:
Section 4.  Patient Selection, Section 5. Study 
Treatments, Section 7. Assessments, Section 
8. Adverse Event Reporting, Section 10. 
Quality Control and Quality Assurance, 
Section 11. Data Handling and Record 
Keeping, Section 12. Ethics, Section 14. 
Sponsor Discontinuation Criteria, and Section 
15. Publication of Study Results.

Minor clarifications and typographical errors 
have been corrected throughout the protocol.
Amendment 2
14 August 2015
Laboratory tests were updated in Section 7.1.3, 
including WBC, Sodium, Potassium, Total 
Calcium, Total Bilirubin, BUN, Serum 
Creatinine, and HbA1c.
In Section 13, the language defining end of this 
study was updated.
The first part of the study title was changed to ‘‘A 
study of palbociclib in combination with 
letrozole.”
The time window for safety checks was reduced 
from 7 days to 3 days in Cycles 3 and increased
from 2 days to 3 days in Cycles 1 and 2.
The items which are related to QTc prolongation 
and concomitant medication were deleted in 
exclusion criteria and Appendix 2 because there 
has not been a QTc signal in the clinic to date, 
and they are not currently in the IBRANCE USPI.
Amendment 1
13 April 2015
Korea was removed from this study, and India 
and Australia were added to this study.
Study sample size was changed from 
approximately 200 patients to approximately 150 
patients.
In Section 10, monitoring frequency was
increased to at least 3 months for sites who enroll 
≥8 patients.
Original protocol
24 September 2014
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
APPENDICES ...........................................................................................................................7
1. INTRODUCTION ...............................................................................................................11
1.1. Indication.................................................................................................................11
1.2. Background .............................................................................................................11
1.3. Palbociclib...............................................................................................................12
1.3.1. Preclinical Data...........................................................................................12
.............................................................13
.........................13
1.3.2. Palbociclib Clinical Activity.......................................................................14
1.4. Study Rationale .......................................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................15
2.1. Objectives................................................................................................................15
2.2. Endpoints.................................................................................................................15
3. STUDY DESIGN.................................................................................................................16
4. PATIENT SELECTION......................................................................................................16
4.1. Inclusion Criteria.....................................................................................................16
4.2. Exclusion Criteria....................................................................................................18
4.3. Sponsor’s Qualified Medical Personnel..................................................................19
5. STUDY TREATMENTS.....................................................................................................19
5.1. Allocation to Treatment ..........................................................................................19
5.2. Patient Compliance .................................................................................................19
5.3. Investigational Product Supplies.............................................................................20
5.3.1. Dosage Form(s) and Packaging..................................................................20
5.3.1.1. Palbociclib.................................................................................20
5.3.1.2. Letrozole....................................................................................20
5.3.2. Preparation and Dispensing - Palbociclib...................................................20
5.4. Administration.........................................................................................................21
5.4.1. Palbociclib ..................................................................................................21
5.4.2. Letrozole.....................................................................................................21
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5.4.3. Recommended Dose Modification .............................................................21
5.4.3.1. Dosing Interruptions/Delays – Recommendations for 
Palbociclib.........................................................................................22
5.4.3.2. Retreatment Criteria - Palbociclib.............................................22
5.4.3.3. Dose Reductions - Palbociclib ..................................................23
5.5. Investigational Product Storage ..............................................................................25
5.6. Investigational Product Accountability...................................................................25
5.6.1. Destruction of Investigational Product Supplies ........................................26
5.7. Concomitant Treatments .........................................................................................26
5.7.1. Prohibited Medications...............................................................................26
5.7.2. Medications Not Recommended.................................................................27
5.7.3. Permitted Medications................................................................................27
5.8. Concomitant Radiotherapy or Surgery....................................................................27
6. STUDY PROCEDURES .....................................................................................................28
6.1. Screening.................................................................................................................28
6.2. Study Period ............................................................................................................28
6.3. Patient Withdrawal..................................................................................................28
7. ASSESSMENTS..................................................................................................................29
7.1. Safety Assessments .................................................................................................29
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
7.3. Patient Reported Outcomes (Australia only)...........................................................31
7.3.1. EuroQol Health Utilities Index EQ-5D ......................................................31
8. ADVERSE EVENT REPORTING......................................................................................31
8.1. Adverse Events........................................................................................................31
8.2. Reporting Period .....................................................................................................32
8.3. Definition of an Adverse Event...............................................................................32
8.4. Medication Errors....................................................................................................33
8.5. Abnormal Test Findings..........................................................................................34
8.6. Serious Adverse Events...........................................................................................34


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8.6.1. Protocol-Specified Serious Adverse Events...............................................35
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................35
8.7. Hospitalization ........................................................................................................36
8.8. Severity Assessment................................................................................................37
8.9. Causality Assessment..............................................................................................38
8.10. Exposure During Pregnancy..................................................................................38
8.11. Occupational Exposure .........................................................................................39
8.12. Withdrawal Due to Adverse Events (See Also Section on Patient 
Withdrawal)...............................................................................................................39
8.13. Eliciting Adverse Event Information ....................................................................40
8.14. Reporting Requirements........................................................................................40
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 ................41
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
9.3.4. Patient Reported Outcomes ........................................................................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


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12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................44
12.2. Ethical Conduct of the Study ................................................................................44
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
14. SPONSOR DISCONTINUATION CRITERIA ................................................................46
15. PUBLICATION OF STUDY RESULTS..........................................................................46
15.1. Communication of Results by Pfizer ....................................................................46
15.2. Publications by Investigators ................................................................................47
16. REFERENCES ..................................................................................................................49
LIST OF TABLES
Table 1.
Palbociclib Capsule Characteristics......................................................................20
Table 2.
Available Dose Levels..........................................................................................23
Table 3.
Recommended Palbociclib Dose Modifications for Treatment-Related 
Toxicities ..............................................................................................................24
APPENDICES
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status .................51
Appendix 2. Calculation of QTc as per Fridericia’s Formula .................................................52
Appendix 3. EuroQol-5D (EQ-5D) (for Australian patients only)..........................................53
Appendix 4. List of Abbreviations...........................................................................................56


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the Study Procedures and Assessments 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 subject.
Schedule of Activities
Study Procedure/ Assessment
Screening 
[1]
Treatment
Cycle duration=28 days [2]
End of 
Study [3]
Cycles 1 & 2
Cycles ≥3 
Day 1 
Day 14
Day 1
Procedures at Screening
Informed Consent [4]
X
Eligibility Criteria Evaluation [5]
X
Registration [6]
X
Medical/Oncological History [7]
X
Procedures at Screening and on study
Physical Examination [8]
X
Per routine clinical practice
ECOG Performance Status [9]
X
Per routine clinical practice
X
12-Lead ECG [10]
X
As clinically indicated
Treatments
Palbociclib [11]
Orally once daily from D1 to 
D21 of each cycle
(Schedule 3/1)
Letrozole [12]
Orally once daily
(Schedule: continuous 
dosing)
Clinical Assessments
Tumor Assessments  (CT or MRI 
Scans) [13]
X
Per routine clinical practice
Adverse Events [14]
X
Monitoring as per routine clinical practice
Concomitant Medications/Treatments 
[15]
X
Monitoring as per routine clinical practice
Hematology [16]
X
X
X
X
X
Blood Chemistry [17]
X
Per routine clinical practice
EuroQol-5D (EQ-5D) (for Australian 
patients only) [18]
X
Every clinical visit 
X
Footnotes to the Schedule of Activities
1.
Screening: All assessments should be performed within 30 days (45 days for tumor 
assessments) prior to the start of study treatment.
2.
Clinical Visits: Clinical visits will be conducted as per local practice and as clinically 
indicated considering that the duration of a cycle of treatment is 28 days based on 


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palbociclib schedule of treatment: 3 weeks on therapy/1 week off therapy.  All 
assessments should be performed prior to dosing on the visit day with an allowed visit
window for study procedures of -2 days.  This window DOES NOT apply to the 
treatment administration schedule but only for the study procedures.  On Cycle 1/Day 1, 
blood chemistry and hematology are not required if acceptable screening assessment is 
performed within 7 days prior to the start of study treatment.
3. End of Study: When palbociclib is permanently discontinued for any reason, the 
patients will undergo assessments of Eastern Cooperative Oncology Group Performance 
Status (ECOG PS), hematology, and EQ-5D (for Australia only).  The indicated 
assessments are to be obtained if not completed in the last week of therapy.  Adverse 
events should be followed up until 28 days after the last treatment administration.  Refer 
to Adverse Event Reporting section.
4. Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
5. Eligibility Criteria Evaluation:  Patients must meet all of the eligibility criteria 
described in protocol Section 4.
6. Registration: Patient identification number will be attributed to each patient.
7. 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 anti-tumor treatments and radiotherapy, and oncologic 
surgeries.
8. Physical Examination: General clinical examination of major body systems.  To be 
performed at Screening and as per routine clinical practice during the treatment.
9. ECOG Performance Status: To be performed at Screening, as per routine clinical practice
during the treatment, and at the end of study.  ECOG performance scale is available in 
Protocol Appendix 1.
10. 12-Lead ECG:  Three consecutive 12-lead ECGs will be performed approximately 
2 minutes apart at Screening to verify eligibility.  ECGs will 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 the ECGs at Screening will be recorded on the CRF.
11. Palbociclib Administration: Palbociclib 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 clinical visit.
12. 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.  The patient will receive letrozole at the clinical site that will be 
sufficient to last until their next clinical visit.
13. Tumor Assessments: Tumor assessments are to be performed at Screening and as per 
local practice and according to the patient’s clinical status thereafter.  Tumor assessment 
evaluation will be conducted as per local guidelines.  Investigators’ assessments will be 
recorded on the CRF as well as the date of tumor progression.
14. Adverse Events: Refer to Adverse Event Reporting section.
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16. Hematology: To be performed to check patient’s eligibility at Screening, Days 1 and 
14 of the first 2 cycles, then on Day 1 of each subsequent cycle of treatment and at the 
end of study.  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 1,000 cells/mm3.  Retreatment criteria are based on time to recovery of 
neutrophil count.  
17. 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.
18. EuroQol-5D (EQ-5D) (Australia only):  The questionnaires are to be administered to 
patients at pre-dose at Cycle 1/Day 1, at every clinical visit thereafter and at the end of 
study.  All self-assessment questionnaires must be completed by the patients while in the 
clinic and cannot be taken home.  EQ-5D questionnaire is available in Appendix 3.


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1. INTRODUCTION
1.1. Indication
Palbociclib is being developed for the treatment of hormone receptor-positive [HR(+)], 
HER2-negative [HER2(-)] Breast Cancer (BC).
1.2. Background 
HR(+)/HER2(-) 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(+)/HER2(-) 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 post-menopausal women 
with HR(+) advanced breast cancer (ABC), particularly for those with slowly progressive 
disease and limited tumor-related symptoms (3).  Studies of estrogen receptor-positive 
[ER(+)] BC cell lines indicate that estrogens (4) and antiestrogens (5) 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 post-menopausal women.  Letrozole is an oral nonsteroidal aromatase 
inhibitor that is approved worldwide for the first line treatment of post-menopausal women 
with HR(+) 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(+) 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(+) luminal breast cancer cell lines. 
Furthermore, pre-clinical exploration using a BC cell line panel demonstrated the presence of 
retinoblastoma (Rb) protein and upregulation of cyclin D1 (CCND1) 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. 
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, 


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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(+)/HER2(-) ABC patients.  An interim 
analysis performed after 50% of anticipated Progression Free Survival (PFS) events had 
occurred showed a consistent trend of clinically meaningful improvements in PFS (primary 
endpoint).
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(+) subtype (7).  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(+) human BC cell lines indicating a
synergistic interaction (7) 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 direct effect on growth 
arrest as well as potential secondary cytotoxic activity.


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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 
non-cumulative.  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/d.  This schedule and associated dose was further explored in 
combination with letrozole in the Phase 1/2 study in patients with ABC (Study A5481003).  
Results from the Phase 1 portion (12) indicated no PK interaction between palbociclib and
letrozole. The recommended dose of palbociclib in combination with letrozole 2.5 mg QD 
continuously was confirmed to be 125 mg QD on Schedule 3/1.
The detailed clinical pharmacology background for palbociclib, including pharmacokinetics 
and drug-drug interaction potential, can be found in the palbociclib Investigator’s Brochure 
(IB).
Results of the final analysis of the Phase 2 portion (13) indicated that the addition of 
palbociclib to letrozole resulted in statistically significant and clinically meaningful 
improvement in PFS as compared with letrozole alone in the treatment of postmenopausal 
women with ER(+), HER2(-) advanced breast cancer (20.2 months vs 10.2 months, 
HR=0.488; 95% CI: 0.319-0.748; 1-sided p=0.0004).  The palbociclib plus letrozole 
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combination resulted in improved rates of objective response (OR; 42.9% vs 33.3%) and 
clinical benefit response (CBR; 81.0% vs 58.0%) compared with letrozole alone, as assessed 
by investigators. 
The safety profile of the palbociclib plus letrozole combination was tolerable and 
manageable with the most common adverse reactions of Neutropenia, Fatigue, Leukopenia, 
Nausea, and Diarrhoea in the palbociclib plus letrozole arm and Fatigue in the letrozole arm.  
These results indicate that the combination of palbociclib with letrozole demonstrated 
antitumor activity which was consistent with the sensitivity of ER(+) BC observed in the 
preclinical models.  Additionally, the combination appears to have a manageable side effect
profile. 
1.4. Study Rationale
The purpose of this study is to provide access to palbociclib before it becomes commercially 
available to patients with HR(+)/HER2(-) 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 Investigator's Brochure. 
The US Food and Drug Administration (FDA) approved label for letrozole is the Single 
Reference Safety Document for letrozole.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective
To gain additional safety data while providing access to palbociclib to post-menopausal 
patients with hormone receptor-positive [HR(+)], HER2-negative [HER2(-)] ABC who are 
deemed appropriate for letrozole therapy.
Secondary Objectives
To gain additional anti-tumor activity data for the combination of palbociclib with letrozole 
in the post-menopausal HR(+)/HER2(-) ABC population.
To gain additional Patient Reported Outcomes (PRO) data for the combination of palbociclib 
with letrozole in the post-menopausal HR(+)/HER2(-) ABC population (Australian patients 
only).
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] v.4.03), and 
seriousness.
Tumor response (based on investigator assessment reported on Case Report Form [CRF]).


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EuroQol (EQ-5D) Score (Australian patients only).
3. STUDY DESIGN
This is an open-label, single arm, multinational, multicenter clinical trial. 
Eligible patients will be post-menopausal women with HR(+) and HER2(-) ABC.  Patients 
will have histologically or cytologically proven diagnosis of adenocarcinoma of the breast 
(locoregionally recurrent or metastatic disease) and will be candidates to receive letrozole as
their best therapeutic option.
Approximately 300 patients will be enrolled in this study.  Patients will continue to receive 
treatment with palbociclib and letrozole until disease progression, symptomatic deterioration, 
unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.  Patients who 
permanently discontinue palbociclib or letrozole for any reason will be off study.
Upon marketing approval of palbociclib by the local health authorities in the participating 
countries, patients enrolled in Study A5481037 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 undergo study-related assessments as outlined 
in the Schedule of Activities table.  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 last dose of 
study treatment will be recorded.
Hematology will be performed on Days 1 and 14 during the first 2 cycles and Day 1 of each 
cycle thereafter. 
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.
Patient reported outcomes will be assessed in Australia only (Australian Sub-study) in each 
patient using the EuroQol Group’s EQ-5D Self-Report Questionnaire (EQ-5D).  The 
questionnaire will be administered to each patient before starting the study treatment, at 
every clinical visit during study treatment, and at the end of study.
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 non-medical 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.


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Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Women of 18 years of age with proven diagnosis of advanced adenocarcinoma of the 
breast (locoregionally recurrent or metastatic disease). 
2. Post-menopausal status defined as per local practice. 
3. ER(+) and/or PgR(+) tumor based on local laboratory results (test as per local practice).
4. HER2(-) breast cancer based on local laboratory results (test as per local practice or local 
guidelines).
5. Patients must be appropriate candidates for letrozole therapy (in the first-line
advanced/metastatic disease setting).
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix 1).
7. Adequate bone marrow function: 

Absolute Neutrophil Count (ANC) ≥1,500/mm3 (1.5 x 109/L); 

Platelets ≥100,000/mm3 (100 x 109/L); 

Hemoglobin ≥9 g/dL (90 g/L).
8. Adequate liver function:

Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) ≤3 x 
Upper Limit of Normal (ULN) (≤5.0 x ULN if liver metastases present);

Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present);

Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease).
9. Adequate renal function:

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.


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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.
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 Section 5.7.1).
3. Prior treatment with any CDK inhibitor.
4. Previous participation in a palbociclib trial.
5. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
2 weeks before the current study begins and/or during study participation.
6. QTc >480 msec (based on the mean value from triplicate electrocardiograms [ECGs]; see
Appendix 2 for suggested QTc calculation); 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 myocardial infarction, 
severe/unstable angina, severe cardiac dysrhythmias, and symptomatic pulmonary 
embolism in the past 6 months of enrollment.
8. Diagnosis of any second malignancy within the last 3 years prior to enrollment, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.
9. Active uncontrolled or symptomatic brain metastases. Previously treated and clinically 
stable, as per Investigator’s judgment, brain metastases are permitted.
10. Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.


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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.
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 located in the study portal. 
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 number, 
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 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 Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient (palbociclib) or placebo 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 and 
recorded on all Case Report Form (CRF) pages.
5.2. Patient Compliance
Patients will be required to return all bottles of palbociclib at the beginning of each clinical 
visit 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.


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5.3. Investigational Product Supplies
The investigational drug used in the course of this trial is palbociclib (PD-0332991). 
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 (see below).
Table 1.
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 used.  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 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 clinical visit.  
Unused returned medication MUST NOT be re-dispensed to patients.
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.
In the event of dose modification, request should be made of the patient to return all 
previously dispensed medication to the clinic and new capsules will be dispensed.


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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 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 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 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 
one or both study drugs in the combination.  In the event treatment interruption is deemed 
necessary for just one 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 
pre-planned schedule.


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In case of palbociclib permanent discontinuation, the patient will undergo End of Study visit
as described in Schedule of Activities.  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 retreatment are met (Section 5.4.3.2).
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-hematological side effects 
potentially or likely related to 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 Retreatment 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 
1,000 cells/mm3. Retreatment criteria are based on time to recovery of neutrophil count.
If a dose reduction is applied in the same cycle, the patient will need to return to the clinic to 
receive new drug supply.
5.4.3.2. Retreatment Criteria - Palbociclib
Retreatment with palbociclib following treatment interruption for treatment-related toxicity 
may not occur until all of the following parameters have been met.


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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 the 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 should be 
evaluated and corrected accordingly to best clinical practice.
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 retreatment parameters are met within 3 weeks of dose interruption, palbociclib may 
be resumed as per recommended dose modification guidelines.
If the retreatment parameters have not been met after 3 weeks of dose interruption, the 
patient should be permanently discontinued from the study.  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 2.
Table 2.
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. 


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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 recommended dose modifications for treatment-related toxicities requiring 
treatment interruption/delay or persisting despite optimal medical treatment are described in
Table 3.
Table 3.
Recommended Palbociclib Dose Modifications for Treatment-Related 
Toxicities
Worst toxicity during previous administration
Subsequent administration of palbociclib
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 palbociclib and initiation of next cycle 
until recovery to Grade 2, then resume at next 
lower dose level.
Grade 3 neutropenia (ANC<1000/mm3) 
associated with a documented infection or 
fever 38.5C
Withhold palbociclib and initiation of next cycle 
until recovery to Grade 2, then resume at next 
lower dose level.
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 palbociclib and initiation of next cycle 
until recovery to Grade 2, then resume at next 
lower dose level.
Grade 3 non-hematologic toxicity (including, 
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.


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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 Single Reference Safety Document (SRSD) for palbociclib
(ie, Investigator’s Brochure (IB), will 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 
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 clinical 
visit for drug accountability (see also Section 5.2 Patient Compliance). 


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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).  If the 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.
5.7. Concomitant Treatments
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 Sections 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 indicated by the 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 well as other agents used to 
treat/manage neutropenia 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. 
Strong/Moderate CYP3A inhibitors/inducers: palbociclib is metabolized to multiple 
metabolites in a qualitatively similar manner in rat, dog and human liver microsomes.  In 
vitro, palbociclib is primarily metabolized by CYP3A4 enzymes.  Co-administration with 
drugs that are strong CYP3A inhibitors and inducers may change the plasma concentrations 
of palbociclib in humans.  The concurrent use of the following drugs 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.


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
moderate CYP3A inhibitors: amprenavir, atazanavir, diltiazem, erythromycin, 
fosamprenavir, and verapamil.

strong CYP3A inducers, including carbamazepine, phenytoin, primidone, rifampin, 
rifapentin, and St. John’s wort.

moderate CYP3A inducers: felbamate, nevirapine, phenobarbital, and rifabutin.
Hormone replacement therapy: estrogens (including any topical and intra-vaginal 
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 physiological replacement, as anti-emetics or inhaled as well as short 
course of oral/topical steroids given for allergic reactions or asthma flares are allowed.
The concurrent use of moderate CYP3A inducers such as dexamethasone or modafinil is not 
recommended.
The concurrent use of herbal medicines is not recommended.
5.7.3. Permitted Medications
Standard therapies for pre-existing medical conditions: medical and/or surgical 
complications, and palliation.  Any medication intended solely for supportive care (eg, 
analgesics, antidiarrheals, antidepressants) may be also used at the investigator’s discretion.
Bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors
for the treatment of osteoporosis or management of existing bone metastases may be 
continued for patients who are already receiving them at the time of study entry.  However, 
the need to initiate these therapies while on study may be considered indicative of disease 
progression.
5.8. Concomitant Radiotherapy or Surgery
Palliative radiotherapy is permitted for the treatment of painful bony lesions.  In view of the 
current lack of data about the interaction of palbociclib with radiotherapy, palbociclib 
treatment should be interrupted during palliative radiotherapy, stopping 1 day before and 
resuming treatment 1 week after.  
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and palbociclib required to minimize the risk of
impaired wound healing and bleeding has not been determined.  Based on the available 
pharmacokinetic data, stopping palbociclib is recommended at least 7 days prior to surgery.  


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Postoperatively, the decision to reinitiate palbociclib treatment should be based on a clinical 
assessment of satisfactory wound healing and recovery from surgery.
6. STUDY PROCEDURES
6.1. Screening
For screening procedures, see Schedule of Activities.
6.2. Study Period
For procedures during study period, see Schedule of Activities.
6.3. 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.
Reasons why patients may discontinue or be withdrawn from the protocol may be due to the 
following:

Adverse events;

Intercurrent illness;

Disease progression;

Patient is noncompliant;

Patient is lost to follow-up;

Withdrawal of consent.
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 the patient to 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 adverse events (AEs).
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.


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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 of 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 mostly of monitoring of all adverse events (AEs), including 
serious adverse events (SAEs) at every clinical visit and hematology.
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 Section 8 for Adverse Event Reporting). 
Information generated from these assessments may also be used to determine if an adverse 
event occurred as defined in Section 8.
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 the end of study.  Data 
collected at Screening and at the end of study will be recorded on the CRF.  Other ECOG PS 
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 Protocol Appendix 1.
7.1.2. 12-Lead ECG
Three consecutive 12-lead ECGs will be performed approximately 2 minutes apart at 
Screening.  ECGs will 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 


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person at the institution for confirmation.  Only the ECGs 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.
7.1.3. Laboratory Safety Assessments
Blood tests will include the following:
Hematology Panel
Blood Chemistry Panel
1
Neutrophils
1
Alanine aminotransferase (ALT)
2
Platelets
2
Aspartate aminotransferase (AST)
3
Hemoglobin
3
Alkaline phosphatase
4
White blood cell (WBC)
4
Sodium
5
Potassium
6
Total calcium
7
Total bilirubin
8
Blood urea nitrogen (BUN) or 
Blood urea
9
Serum creatinine
Blood tests will be drawn at the time points described in Schedule of Activities, and analyzed 
at local laboratories. 
Hematology will be performed to verify patient’s eligibility at Screening, on Days 1 and 
14 of the first 2 cycles, then on Day 1 of each subsequent cycle of treatment and at the end of 
study.  Laboratory 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 
1,000 cells/mm3.  Retreatment criteria are based on time to recovery of neutrophil count. 
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. In the case a 
laboratory abnormality meets the definition of AE, as determined by the investigator and 
according to Adverse Event Reporting Section 8, this must be captured on the AE CRF page.


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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 (see also Schedule of Activities). 
Tumor assessment evaluation will be conducted as per local practice at each institution. 
Investigators’ assessments will be recorded on the CRF as well as the date of tumor 
progression.
7.3. Patient Reported Outcomes (Australia only)
Patient reported outcomes of health-related quality of life and health status will be assessed 
using the EQ-5D instrument in the Australian sub-study.  Patients will complete the 
questionnaire at pre-dose at Cycle 1/Day 1, at every clinical visit thereafter and at the end of 
study.  Completed questionnaires are always considered source document and must be filed 
accordingly.  Data will be reported in the CRF.
Patients must complete these instruments in clinic (cannot be taken home) and prior to 
having any tests and to any discussion of their progress with healthcare personnel at the site.  
Interviewer administration in clinic may be used under special circumstances (eg, patient 
forgot their glasses or feels too ill).  The instruments will be given to the patient in the 
appropriate language for the site. 
7.3.1. EuroQol Health Utilities Index EQ-5D 
The EuroQol-5D (EQ-5D) (version 3L) (see Appendix 3) consists of 2 parts.  The first part is 
a 5 item questionnaire designed to assess health status in terms of a single index value or 
utility score.  It consists of 5 descriptors of current health state (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression); a patient is asked to rate each state on a 
three level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher 
levels indicating greater severity/impairment.  The second part consists of a visual analogue 
scale: the EQ VAS.  The EQ VAS records the patient’s self-rated health on a scale from 
0 (worst imaginable health state) to 100 (best imaginable health state).  For the EQ-5D index, 
published weights are available that allow for the creation of a single summary score ranging 
from 0 to 1, with low scores representing a higher level of dysfunction and 1 as perfect 
health.
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 information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 


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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.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the patient has taken at least 1 dose of investigational product through and including 
28 calendar days after the last administration of the study treatment.
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;


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
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;

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.


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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 (outside of protocol-stipulated dose 
adjustments) 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.
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 Section 
on Severity Assessment).
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.


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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 Section on 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.
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 preexisting 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. 


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In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced 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 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.
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 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 preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment lab abnormality);

Social admission (eg, patient has no place to sleep);


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
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.
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 for Adverse Events (NCI CTCAE), (Version 4.03; Publish Date: June 
14, 2010).
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 patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); 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 Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product",
this should be clearly documented on study records. 
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; 
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). 
2. 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 Exposure During 
Pregnancy (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).


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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 pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (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.
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).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The Investigator must document in the source documents that 
the patient 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) gets in 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 Also Section on Patient Withdrawal)
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 
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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 patient/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.
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.


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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.
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.
9.1. Sample Size Determination
Considering the nature of the study, the number of patients to be enrolled is not determined 
for the hypothesis testing. It is expected that an estimated 300 patients will be enrolled in 
this study.
9.2. Efficacy Analysis
Because of the nature of the study, no inferential analyses are planned, and no hypotheses are 
to 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 in the CRF.
The ORR will be provided along with the corresponding exact 95% 2-sided confidence 
interval using standard methods based on the binomial distribution.
Duration of Clinical Benefit is defined as the time 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.
9.3.2. Baseline Characteristics
Demographic characteristics such as age, gender, race, and prior medication will be 
summarized.


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9.3.3. Treatment Administration
Study drug administration will be described in terms of total and median duration of 
treatment.
9.3.4. Patient Reported Outcomes
The EQ-5D index is derived by combining one level from each of the 5 dimensions and 
converting it to a single summary index or health utility value (14).
9.4. Safety Analysis
Safety data will be summarized for all patients who received at least one 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 v 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 system organ class
and preferred term.  Additional subcategories may be presented based on event severity, 
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 in the CRF at Screening and during the study while Blood 
Chemistry data will be collected in the CRF only at Screening.
Data listings will be prepared for each laboratory measurements 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.
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.


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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 on the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 


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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 source documents.  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 on 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, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls 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 to 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 (IRB)/Ethics Committee (EC)
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.
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). 


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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 laws. 
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 his/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, 
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 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.


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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 that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
The end of trial is defined as the time of regulatory approval and commercial availability of 
palbociclib (post regulatory approval) for the treatment of advanced breast cancer, after 
completion of enrollment targets in participating countries.  There will be some time lag 
between approval and commercial availability of palbociclib; therefore, there may be a 
≥4 months transition period after approval to allow patients to access commercial drug.  At
the end of trial, patients who are still active in the study will be moved to commercial supply.  
Pfizer will provide palbociclib to these patients after approval until palbociclib is 
commercially sourced.  Letrozole will not be provided after the ‘end of trial’. 
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.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by 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.


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Investigator will, on request, remove any previously undisclosed confidential information 
before disclosure, except for any study- or Pfizer product-related information necessary to 
the appropriate scientific presentation or understanding of the study results.
If the study is part of a multi-center 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 Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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.


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16. REFERENCES
1.
Jemal A, Siegel R, Xu J, Ward E. 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: 1687-1717.
3.
Wood WC, Muss HB, Solin LJ, Olopade OI. Malignant Tumors of the Breast. In: 
DeVita VT Jr, Hellmann S, Rosenberg SA, editors. Cancer, Principle and Practice of 
Oncology, 7th Edition, Lippincott Williams and Wilkins; 2005; 1415-1477.
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; 34:213-225.
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, Pérez-Carrión R, Boni C, Monnier A, 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. Journal of Clinical Oncology 2003; 2101-
2109.
7.
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.
8.
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.
9.
Bhat SP. The ocular lens epithelium. Bioscience Reports 2002;21(4):537-563.
10.
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: 4482–4489.
11.
Lee Y, Dominy JE, Choi YJ et al: Cyclin D1-Cdk4 controls glucose metabolism 
independently of cell cycle progression.  Nature 2014; 510:547-551
12.
Slamon DJ, Hurvitz SA, Applebaum S et al. Phase I study of PD-0332991, cyclin-D 
kinase (CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of 
patients with ER-positive, HER2-negative breast cancer. J Clin Oncol 28:15s, 2010 
(suppl; abstr 3060).


Palbociclib (PD-0332991)
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13.
Finn RS, Crown JP, Lang I et al.  Final results of a randomized Phase II study of PD 
0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole 
vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer 
(PALOMA-1; TRIO-18).  AACR 2014; Abstract CT101.
14.
Shaw JW, Johnson JA, Coons SJ.  US valuation of the EQ-5D health states: 
development and testing of the D1 valuation model.  Medical Care 2005; 43:203-220.


Palbociclib (PD-0332991)
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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


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Appendix 2. Calculation of QTc as per Fridericia’s Formula 
Fridericia’s formula is as follows:
Fridericia LS. “Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei 
Herzkranken.” Acta Med Scand 1920,53: 469-486
The paper title can be translated into English as "The duration of systole in the 
electrocardiogram of normal subjects and of patients with heart disease". 


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Appendix 3. EuroQol-5D (EQ-5D) (for Australian patients only)


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Appendix 4. List of Abbreviations
ABC
Advanced Breast Cancer
ASCO
American Society of Clinical Oncology
AE
Adverse Event
ALT
Alanine Aminotransferase 
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase 
BC
Breast Cancer
BUN
Blood Urea Nitrogen
CCND1
Cyclin D1
CDK
Cyclin-Dependent Kinase
CI
Confidence Interval
CRF
Case Report Form
CSA
Clinical Study Agreement
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P-450
DLT
Dose-Limiting Toxicity
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure During Pregnancy
ER
Estrogen Receptor
EQ-5D
Dimension Health State EuroQoL Score
EU
European Union
FDA
US Food and Drug Administration 
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
HDPE
High-Density Polyethylene
IB
Investigator’s Brochure
IC50
Concentration of 50% Inhibition 
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
LFT
Liver Function Test
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
PD
Progressive Disease
PK
Pharmacokinetic 
PgR
Progesterone Receptor
PS
Performance Status
QD
Quaque Die (once daily)


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RB/Rb
Retinoblastoma
SAE
Serious Adverse Event
SD
Stable Disease or Standard Deviation (depending on context)
TEAE
Treatment-Emergent AE
ULN
Upper Limit of Normal
US IND
United States Investigational New Drug
WBC
White Blood Cells

SAP_001.pdf: 
Protocol A5481037  
Statistical Analysis Plan 
 
 
Page 1 
 
 
 
Protocol A5481037 
 
A 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: 
2.0 
Author:  
 
Date:  
June 29, 2016  
 
 
 
PPD


Protocol A5481037  
Statistical Analysis Plan 
 
 
Page 2 
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................3 
2. INTRODUCTION .......................................................................................................................3 
2.1. Study Design ...................................................................................................................3 
2.2. Study Objectives .............................................................................................................4 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................4 
4. HYPOTHESES AND DECISION RULES .................................................................................5 
4.1. Statistical Hypotheses .....................................................................................................5 
4.2. Sample Size Determination and Statistical Decision Rules ............................................5 
5. ANALYSIS SETS .......................................................................................................................5 
6. ENDPOINTS AND COVARIATES ...........................................................................................5 
6.1. Efficacy Endpoints ..........................................................................................................5 
6.2. Safety Data ......................................................................................................................6 
6.2.1. Treatment Emergent Adverse Event ...................................................................6 
6.2.2. Treatment Related Adverse Event ......................................................................7 
6.2.3. Laboratory Safety Assessments ..........................................................................7 
6.2.4. Electrocardiogram (ECG) ...................................................................................7 
6.3. Other Endpoints ...............................................................................................................7 
6.4. Covariates and Stratification Factors ..............................................................................8 
7. HANDLING OF MISSING VALUES ........................................................................................8 
7.1. Missing Dates ..................................................................................................................8 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..................................8 
8.1. Statistical Methods ..........................................................................................................8 
8.2. Statistical Analyses .........................................................................................................9 
8.2.1. Primary Efficacy Analysis ..................................................................................9 
8.2.2. Standard Analyses ..............................................................................................9 
8.2.3. Safety Analyses ..................................................................................................9 
8.2.3.1. Adverse Events ..................................................................................9 
8.2.3.2. Laboratory abnormalities ................................................................10 
Patient Reported Outcomes Analyses ..................................................................................11 
9. REFERENCES ..........................................................................................................................11 
10. APPENDICES .........................................................................................................................12 
 
 


Protocol A5481037  
Statistical Analysis Plan 
 
 
Page 3 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
The SAP is being amended to reflect the changes in Protocol Amendments 1 (April 13, 
2015), 2 (August 14, 2015), 3 (May 31, 2016). Following changes were made in this 
amendment: 
• Per the request from the Regulatory Agency in India, the primary objective of the study 
has been revised to include safety. 
• Removed country limitation to make the study open to other countries. 
• The number of patients to be enrolled in the study has been increased to approximately 
300 patients. 
• Removed Schedule of Activity from Appendices since it is in study protocol and could be 
amended over time.  
• Other editorial modification of the analysis plan. 
 
2. INTRODUCTION 
This document describes the planned statistical analyses for Protocol A5481037 (dated 
September 24, 2014), Protocol Amendment 1 (April 13, 2015), Protocol Amendment 2 
(August 14, 2015), and Protocol Amendment 3 (May 31, 2016). This analysis plan is meant 
to supplement the study protocol.  Any deviations from this analysis plan will be described in 
the Clinical Study Report.  
 
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. 
 
Both pre-clinical and clinical study results indicate that the combination of palbociclib with 
letrozole demonstrated antitumor activity among patients with ER(+), HER2(-) advanced 
breast cancer. Additionally, the combination appears to have a manageable side effect 
profile. 
 
The purpose of this study is to collect safety data while providing access to palbociclib 
before it becomes commercially available to post-menopausal patients with hormone 
receptor-positive [HR(+)], HER2-negative [HER2(-)] ABC who are deemed appropriate for 
letrozole therapy. 
 
 
2.1. Study Design 
This is an open-label, single arm, multi-center clinical trial. Patients will be enrolled and will 
continue to receive treatment with the combination therapy until disease progression, 
 


Protocol A5481037  
Statistical Analysis Plan 
 
 
Page 4 
symptomatic deterioration, unacceptable toxicity, death, withdrawal of consent, or at the time 
of commercial availability of palbociclib.  
 
Upon marketing approval of palbociclib by the local health authorities in the participating 
countries, patients enrolled in Study A5481037 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 study-related assessments as outlined in the Schedule of Activities 
table.  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 last dose of study treatment will be 
recorded. 
 
Tumor response will be assessed by investigator as per local practice. The overall tumor 
assessment will be collected on CRF. The date of tumor progression will be recorded. No 
statistical tests will be performed.  
 
Patients enrolled in Australia will be subjected to additional assessments (Australian Sub-
study).  Patient reported health utility and general health status will be assessed in each 
patient using the EuroQol Group’s EQ-5D Self-Report Questionnaire (EQ-5D).  The 
questionnaire will be administered to each patient before starting the study treatment 
(baseline), at every clinical visit during study treatment and at the end of treatment. 
 
2.2. Study Objectives 
Primary Objective: 
• To collect safety data while providing access to palbociclib to post-menopausal 
patients with hormone receptor-positive [HR(+)], HER2-negative [HER2(-)] ABC 
who are deemed appropriate for letrozole therapy. 
 
Secondary Objectives: 
• To gain additional anti-tumor activity data of the combination therapy of palbociclib 
with letrozole in postmenopausal HR(+)/HER2(-) population. 
• To gain additional Patient Reported health utility and general health status (Australian 
patients only). 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
The study is designed as an open-label study to collect additional safety data while providing 
access to palbociclib to post-menopausal patients with hormone receptor-positive [HR(+)], 
HER2-negative [HER2(-)] ABC who are deemed appropriate for letrozole therapy. No 
 


Protocol A5481037  
Statistical Analysis Plan 
 
 
Page 5 
interim analyses are planned. 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 
The purpose of this study is to collect safety data while providing access to palbociclib to 
post-menopausal patients with hormone receptor-positive [HR(+)], HER2-negative 
[HER2(-)] ABC who are deemed appropriate for letrozole therapy before it becomes 
commercially available to patients. There is no statistical hypothesis test for the study. 
 
4.2. Sample Size Determination and Statistical Decision Rules 
Due to the nature of the study, no sample size determination is made by statistical procedure 
and there are no statistical decision rules.    
 
Approximately 300 patients will be enrolled in this study.  Patients will continue to receive 
treatment with palbociclib and letrozole until disease progression, symptomatic deterioration, 
unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.  Patients who 
permanently discontinue palbociclib for any reason will be off study. 
Upon marketing approval of palbociclib by the local health authorities in the participating 
countries, patients enrolled in Study A5481037 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.  When patients exit the study, all study related 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. The PRO-evaluable population 
will be defined as patients from the as-treated (AT) population who completed the EQ-5D at 
baseline and at least 1 visit post baseline. The PRO-evaluable population will be the primary 
population for analysis of change from baseline scores. 
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoints 
Because of the nature of the study, no inferential analyses are planned, and no hypotheses are 
to be tested. However, some exploratory analyses may be conducted if data are available. 
Specifically, analyses on objective response (OR, 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 
 


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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 their assessments will be collected in the CRF. 
 
The OR rate will be provided 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 are 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. 
6.2. Safety Data 
Overall safety profile as characterized by type, frequency, severity of adverse events as 
graded by NCI Common Toxicity Criteria for Adverse Events version 4.03 (NCI CTCAE 
v.4.03), timing and relationship to treatment on each arm, and laboratory abnormalities 
observed. 
Adverse events (AEs), hematology, blood chemistry will be assessed as described in the 
Schedule of Activities of the protocol. 
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 frequency of patients with values below, within, and above the normal range for 
the local lab may be summarized. 
Patients who start treatment are assessed for toxicities up to 28 days after the final dose of 
treatment. Toxicities observed up to 28 days after the last dose of treatment will be included 
in safety summaries.   
6.2.1. 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. 
 


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6.2.2. Treatment Related Adverse Event 
Adverse events defined as treatment emergent adverse events with cause possibly, probably 
or definitely related to treatment as judged by the investigator are defined as treatment related 
adverse events. Events that are continuation of baseline abnormalities are not considered 
treatment related unless there is an increase in grade, or if there is an increase following a 
decrease, and the increase is judged by the investigator to be caused by the treatment. 
6.2.3. Laboratory Safety Assessments 
Laboratory assessment will be assigned to cycles based on the collection date of the sample 
relative to the start dates of cycles from the study drug administration. 
Baseline evaluations for laboratory are those collected 
• Within 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. 
 
6.2.4. Electrocardiogram (ECG) 
Three consecutive 12-lead ECGs will be performed approximately 2 minutes apart at 
Screening. ECG could 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, it is captured on an AE CRF page. 
 
 
 
6.3. Other Endpoints 
6.3.1 Patient Reported Outcomes Endpoints 
The patient reported outcomes endpoints will include health utility and general health status 
measured using the EQ-5D questionnaire . 
The EQ-5D questionnaire consists of the EQ-5D descriptive system and a visual analogue scale (the 
EQ VAS).  The EQ-5D descriptive system measures a patient’s health state on 5 dimensions which 
include: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  The 
respondent’s self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 
(best imaginable health state) by the EQ-VAS.  
 
 
 


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6.4. Covariates and Stratification Factors 
N/A 
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 unless the 
calculation results in a negative time duration (e.g., date of onset cannot be prior to day one 
date).  In this case, the date resulting in 1 day duration will be used. If the day of the month 
and the month is missing for any date used in a calculation, January 1 will be used to replace 
the missing 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, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date. 
 
For the EQ-5D, in cases where two answers are given to one item, the item will be 
considered missing. For the EQ-5D, questions not answered will be considered missing items 
and will not be utilized. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
Descriptive statistics for continuous variables will include the mean, standard deviation, 
median, minimum, and maximum values.  
 
For categorical variables, summary measures will include the number and percentage of 
patients in each category.  
 
Missing data will not be imputed or carried forward. Individual patient data will be presented 
in data listings. 
 
 
 
 


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8.2. Statistical Analyses  
8.2.1. Primary Efficacy Analysis 
No formal efficacy analysis will be conducted. Summary of OR, assessed by investigator, 
and duration of clinical benefit may be performed if appropriate. 
 
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 - an accounting of the study patients will be 
tabulated including number of patients enrolled, treated, accrual by study center, assessed 
for AEs, laboratory data, etc.  Patients not meeting the eligibility criteria will be 
identified.  Patients not completing the study will be listed along with the reason for their 
premature discontinuation.  Reasons for premature discontinuation will be summarized.   
• 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 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, dose intensity, dose 
modifications, dose interruptions, and reasons for dose interruptions. 
• Concomitant medications and Non-drug treatments 
 
Concomitant and non-drug treatments are not collected on the CRFs but will be available 
in patients’ medical record files, except for Granulocyte Colony Stimulating Factor (G-
CSF) treatment for neutropenia. G-CSF use will be documented in CRF and summarized 
in study report.   
 
 
8.2.3. Safety Analyses 
Listings of AE, SAE, death, lab data, and physical examinations (if available in database) 
will be provided according to reporting standard. 
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.  
 


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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 trial treatment, 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. 
8.2.3.2. Laboratory abnormalities 
The hematologic laboratory results will be graded according to the NCI CTCAE v.4.03 
severity grade. For parameters for which an NCI CTCAE v.4.0 scale does not exist, the 
frequency of patients with values below, within, and above the normal range for the local lab 
 


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may be summarized. Each patient will be summarized by the worst severity grade observed 
for a particular laboratory parameter.  
Hematologic laboratory data will be summarized by maximum change from baseline. 
Chemistry data will be reported in data listing.  
Patient Reported Outcomes Analyses 
The PRO-Evaluable population will be the primary population for the analysis change from 
baseline. Visit windows will be applied for the analysis of the PRO endpoints. 
 
The EQ-5D will be scored according to its scoring manual1.  Each dimension of the health 
state profiles (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) 
will include the proportion of patients reporting “no health problems,” “moderate health 
problems” and “extreme health problems”.  A health utility index score will be calculated 
using the standard algorithm for Australia provided in the manual. 
 
Instrument Compliance Rates 
At each time point, the number and percentage of patients who complete the EQ-5D will be 
summarized in a table, as will the reasons for non-completion.   The questionnaire is 
considered complete if at least one item was answered by the patient. 
 
Descriptive statistics by treatment arm will be reported for the actual score and change from 
baseline for health utility index and EQ-5D VAS scores.  It will include the mean (and 95% 
CI), median (and range), and number of patients completing the scale for each arm at each 
time assessment after baseline A chart depicting the mean of actual score sand change from 
baseline scores along with the SE error bars at each time assessment will be provided. 
To calculate overall actual scores and change from baseline scores repeated measures mixed-
effects modelling will be carried for the EQ-5D health utility index and the general health 
status scores.  Repeated measures over time will be accounted by unstructured covariance 
structure (using the REPEATED statement in PROC MIXED).   
9. REFERENCES  
1. 
The EuroQol Group. EQ-5D: A measure of health-related quality of life developed by the EuroQol 
Group: User Guide. V 5.0., Oct 2013.  
2. 
Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing 
of the D1 valuation model. Medical Care 2005; 43:203-220 
 
 
 
 
 


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10. APPENDICES  
 
Euro Qol-5D (EQ-5D) (for Australian patients only) 
 


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