A MULTICENTER, RANDOMIZED, DOUBLE-BLIND PHASE 3 STUDY OF PALBOCICLIB (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS PLACEBO PLUS LETROZOLE FOR THE TREATMENT OF PREVIOUSLY UNTREATED ASIAN POSTMENOPAUSAL WOMEN WITH ER (+), HER2 (-) ADVANCED BREAST CANCER
Phase: PHASE3
Conditions: Breast Neoplasms
Sponsor: Pfizer

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A MULTICENTER, RANDOMIZED, DOUBLE-BLIND PHASE 3 STUDY OF 
PALBOCICLIB (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS 
PLACEBO PLUS LETROZOLE FOR THE TREATMENT OF PREVIOUSLY 
UNTREATED ASIAN POSTMENOPAUSAL WOMEN WITH ER (+), HER2 (-) 
ADVANCED BREAST CANCER
Compound:
PD-0332991
Compound Name:
Palbociclib
US IND Number:
Not Applicable (N/A)
European Clinical Trial Database 
(EudraCT) Number:
N/A
Protocol Number:
A5481027
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.

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Document History
Document
Version Date
Summary of Changes and Rationale (if 
applicable)
Amendment 1
21 July 2014
1. Study Title: Changed East Asian to Asian, and 
throughout as applicable.
2. Background and Rationale: Updated 
A5481003 study final results.
3. Secondary Objective: Included determination 
of trough Palbociclib plasma concentration in 
this patient population and exploration the 
correlations between exposure and response 
and/or safety findings;
4. Secondary Endpoints: Added Trough plasma 
concentration of Palbociclib;
5. Study design: Added region (China vs other)
as a randomization stratification.
6. Schedule of Activities / Section 6 Procedures: 
Added of ophthalmic procedures for all 
evaluable patients to assess the potential risk of 
palbociclib-associated crystalline lens changes.
7. Schedule of Activities: Added heamatology 
assessment on Day 21 of Cycle 1, changed
heamatology assessment on Day 14 of Cycle 2
to Day 21.
8. Schedule of Activities: Added of 12-lead ECG 
assessments on Day 14 of Cycle 1 and Cycle 2, 
and on Day 1 from Cycle 3.
9. Schedule of Activities / Section 6 Procedures: 
Added glucose levels and lipid levels to be
assessed in all patients at various intervals.
10. Schedule of Activities / Section 6 Procedures: 
Added of plasma PK samples collection for all 
patients.
11. Section 1.2.5.2. – Added preliminary results 
from two clinical pharmacology studies 

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supporting revisions of Sections 5.3.3, 5.5.1. 
and 5.5.2.
12. Section 1.2.5.4. Ocular Preclinical Data: 
Included preliminary results from a preclinical 
ocular study with palbociclib in rats.
13. Section 3 Study Design: Clarified that safety-
related assessments must continue if patients 
continue study treatment beyond RECIST-
defined disease progression.
14. Clarified inclusion criterion #10 to emphasize 
the importance of collecting 
recurrent/metastatic tissue whenever possible.
15. Clarified inclusion criterion #10 it is highly 
recommend to submit tissue block or 12 
unstained slides, but if there would be 
technical difficulties or other issues refraining 
from obtaining tissue block or 12 unstained 
slides, however, it is still mandatory to collect 
a minimum 7 unstained slides.
16. Modified inclusion criterion #4 to clarify that 
patients with FSH/estradiol blood levels within 
the post-menopausal range may be eligible. 
17. Clarified exclusion criterion #1 to highlight the 
need to confirm HER2 status on the most 
recent tumor sample whenever possible. 
18. Revised exclusion criterion #17 to only 
exclude patients participating in the active 
treatment phase of other interventional trials 
within the protocol-defined period.
19. Section 5.3.3 - Added recommendation to take 
palbociclib with a meal instead of under 
minimal fasting conditions.
20. Section 5.3.4 – Added Table 3.1 
Palbociclib/Placebo Dose Modifications for 
Hematologic Toxicities (by CTCAE Grade and 
on Day of Treatment).
21. Section 5.5.1 - Added prohibition to take 

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proton-pump inhibitors while receiving study 
drugs.
22. Section 5.5.2 - Added recommendation to use 
local antacids as well as H2-receptor antagonist 
as alternative treatment for patients requiring 
gastroprotective treatment.
23. Section 7.2.3. Ocular Safety Assessment: 
Section added to provide details on the 
ophthalmic procedures to be performed for all 
lens grading evaluable patients.
24. Section 7.2.4. Added glucose levels and lipid 
levels to be monitored in all patients at various 
intervals as outlined in the Schedule of 
Activities.
25. Section 7.3: Added pharmacokinetic
assessment.
26. Section 8 Adverse Event Reporting: Updated 
section to reflect current protocol template. 
27. Section 9.1 Sample Size Determination: 
Revised sample size to use the same 
assumption for the treatment effect as the 
corresponding global study (A5481008) 
originally proposed.  The required number of 
PFS events increased from 137 to 213.  This 
will allow the trial to have 90% power to 
detect statistically significant difference 
assuming a true hazard ratio of 0.64 in favor of 
palbociclib plus letrozole. Sample size 
justification for OS was also added. 
28. Section 9.1 Sample Size Determination / 
Section 9.6 Interim Analysis: Adjusted interim 
analysis to be performed after 65% target PFS 
events achieved (i.e., 139 PFS events).  The 
interim analysis for OS was also added.
29. Section 9.3.2 Analysis of Secondary 
Endpoints: Added pharmacokinetic analysis.
30. Section 15.1 Communication of Results by 
Pfizer: Updated section to match updated 

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Pfizer protocol template.
31. Appendix 6 FACT-B: updated
32. Appendix 8 Wisconsin Age-Related Eye 
Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure added.
33. Editorial changes made to adjust typos.
Original Protocol 
19 June 2013
N/A (Not Applicable)
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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PROTOCOL SUMMARY
Indication:
Estrogen receptor-positive (ER (+)), Human Epidermal Growth Factor Receptor 2-negative 
(HER2 (-)) Advanced Breast Cancer (ABC) in Asian patients who have not received any
prior systemic anti-cancer therapy for their advanced disease.
Background and Rationale:
Breast Cancer (BC) is the most common invasive cancer in women, with more than 
1.3 million cases and over 450,000 deaths occurring worldwide annually. In Asia, the 
incidence of breast cancer is 26 per 100,000 individuals, the mortality rate is 9.5 per 100,000 
individuals. In China, the incidence of breast cancer is 21.6 per 100,000 individuals, the 
mortality rate is 5.7 per 100,000 individuals. Although age-adjusted mortality from breast 
cancer has been decreasing since 1990, the median survival for patients with metastatic 
disease is still only approximately 18-24 months and the medical need for more active agents 
in this clinical setting remains very high. 
The role of estrogens in breast cancer etiology and progression is well established.  
Modification of estrogen activity or synthesis represents the treatment of choice for 
postmenopausal women with hormonal receptor positive advanced breast cancer, particularly 
for those with slowly progressive disease and limited tumor-related symptoms. Letrozole is 
an oral nonsteroidal aromatase inhibitor approved worldwide for the first-line treatment of 
postmenopausal women with hormone receptor-positive advanced breast cancer (ABC).
Palbociclib is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has been under 
investigation in Phase 1, 2 and 3 clinical trials in multiple indications. Palbociclib prevents 
cell cycle progression from G1 to S phase and has shown antitumor activity in multiple 
preclinical models, including in estrogen receptor-positive (ER+) luminal breast cancer cell 
lines. 
Furthermore, pre-clinical exploration using a breast cancer cell line panel has demonstrated 
presence of retinoblastoma (Rb) protein and upregulation of cyclin D1 as well as decreased 
CDKN2A (p16) that were 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 interaction of estrogens and CDKs and the 
important role of cell cycle-related proteins in the genesis and maintenance of breast cancer, 
led to the initiation of a randomized Phase 2 clinical trial (A5481003) investigating the 
antitumor activity of Palbociclib in combination with letrozole and single-agent letrozole in 
the first-line treatment of ER(+)/HER2(-) ABC patients.  The Phase 2 study was divided into
2 parts.  In Part 1, patient selection was based only on ER/HER2 status while in 
Part 2, patients were additionally prospectively selected taking into account tumor Cyclin D1
(CCND1) amplification and/or CDKN2A (p16) loss.

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Final results from Part 1 plus Part 2 of the Phase 2 portion included a total of 165
postmenopausal women with ER(+) / HER2(-) locally recurrent or metastatic breast cancer 
enrolled to either receive Palbociclib in combination with letrozole (n=84 patients) or 
letrozole monotherapy (n=81 patients). 
The combination therapy was generally well tolerated when compared to letrozole alone with 
adverse events (AEs) similar to those seen with Palbociclib and letrozole when administered 
alone, with the exception of hematologic toxicity.  Neutropenia(48%), leukopenia(19%) and 
anemia(5%)were the most frequent treatment-related Grade 3 adverse events in patients 
treated with the combination therapy.  Grade 4 treatment-related events included neutropenia 
and anemia, reported in 6% and 1% , respectively, of patients treated with 
Palbociclib plus letrozole. However, the neutropenia observed with the combination in this 
study was non-cumulative and clinically manageable. Neutropenia is an on-target, anti-
proliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone 
marrow.  
Efficacy analyses were performed on the basis of radiologic assessment of disease status by 
investigators to determine preliminary antitumor activity according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v.1.0.  Median Progression Free Survival (PFS) was 
prolonged in patients who received combination therapy compared to letrozole alone (20.2
months vs. 10.2 months). Objective response and clinical benefit rates (43% vs. 33% and 
81% vs. 58%, respectively)  were also superior with the combination therapy.
Based on the encouraging results from this Phase 2 study in ABC, a global randomized Phase 
3 study (A5481008) of Palbociclib in combination with letrozole is currently on-going in 
postmenopausal patients with ER(+), HER2(-) ABC.
A Phase 1 study (A5481010) is ongoing to evaluate Pharmacokinetic (PK), safety, 
tolerability and efficacy of Palbociclib in Japanese patients with advanced solid tumors and 
ER(+), HER2(-) ABC. To support the China Food and Drug Administration (CFDA) 
regulatory filing requirement of Palbociclib, a Phase 1 study (A5481019) has been designed 
to evaluate single-dose and multiple-dose PK, safety and efficacy of Palbociclib in 
combination with letrozole in postmenopausal Chinese women with ER(+), HER2(-) ABC.
This randomized Phase 3 Study (A5481027) provides the opportunity to confirm the clinical 
benefit of the combination of Palbociclib with letrozole observed in the randomized 
Phase 2 study in Asian patients. This study is designed to demonstrate that the combination 
of Palbociclib with letrozole provides superior clinical benefit compared to letrozole in 
combination with placebo in Asian postmenopausal women with ER(+)/HER2(-) ABC who 
have not received any prior systemic anti-cancer therapy for their advanced disease.

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Objectives:
Primary Objective:

To compare the combination of Palbociclib plus letrozole with placebo plus letrozole 
in term of progression-free survival (PFS) in Asian postmenopausal women with 
ER(+)/HER2(-) advanced breast cancer (ABC) who have not received any prior 
systemic anti-cancer therapy for advanced disease.
Secondary Objectives:

To compare Objective Response (OR), Duration of Response (DR), Disease Control
Rate (DCR), and Overall Survival (OS) between the treatment arms;

To evaluate the safeties and tolerability of the treatment arms;

To determine trough Palbociclib plasma concentration in this patient population and
explore the correlations between exposure and response and/or safety findings;

To compare health-related quality of life between the treatment arms;

To characterize alterations in genes, proteins, and ribonucleic acids (RNAs)
expression relevant to the cell cycle, drug targets, and tumor sensitivity and/or 
resistance in tumor tissues;

To explore the relationship between germline polymorphism in CDK6 gene and 
palbociclib treatment related neutropenia.
Study Design:
This is a multicenter, randomized (1:1), double-blind, placebo-controlled, parallel-group 
phase 3 trial comparing the efficacy and safety of Palbociclib in combination with letrozole 
versus placebo plus letrozole in Asian postmenopausal women with ER(+)/HER2 (-) ABC.
Eligible patients will have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease 
and will be candidates to receive letrozole as first-line treatment for their advanced disease.
In order to avoid inclusion of patients who are refractory or resistant to non-steroidal 
aromatase inhibitors, patients who received anastrozole or letrozole as a component of their 
(neo)adjuvant regimen may only enter the study if their disease did not progress while on or 
within 12 months from completion of their anastrozole/letrozole-containing (neo)adjuvant 
therapy. Patients will not have received any prior systemic anti-cancer therapy for their 
advanced disease and will not be candidates for curative therapies. Patients must have 
measurable disease as per RECIST v.1.1 or bone disease as their only site of disease.  Tumor 
tissue availability is required for patient participation.  At least approximately 330 patients 
will be randomized 1:1 between the investigational arm (Arm A: at least approximately 165
patients treated with Palbociclib plus letrozole) and the comparator arm (Arm B: at least 
approximately 165 patients treated with placebo plus letrozole). Among these approximately 
330 patients, at least 264 patients will be from China and the rest of the patients will be from
other Asia countries.

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Patients will be stratified at randomization by region (China vs other), by site of disease 
(visceral vs non-visceral), by disease-free interval since completion of prior (neo)adjuvant 
therapy (de novo metastatic; ≤12 months; >12 months) and by the nature of prior 
(neo)adjuvant anticancer treatment received (prior hormonal therapy; no prior hormonal 
therapy).
Patients randomized to Arm A (investigational arm) will receive: 

Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle
followed by 7 days off treatment;
in combination with

Letrozole, 2.5 mg, orally once daily (continuously). 
Patients randomized to Arm B (comparator arm) will receive: 

Placebo orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 
7 days off treatment;
in combination with

Letrozole, 2.5 mg, orally once daily (continuously). 
Patients will continue to receive their assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
would occur first.  However, patients may continue treatment as assigned at randomization 
beyond the time of RECIST-defined disease progression at the discretion of the investigator 
if that is considered to be in the best interest of the patient and as long as no new anticancer 
treatment is initiated. In this case, the patient would continue with scheduled safety 
assessments as per the schedule of activities for the active treatment period.
The importance of timely and complete disease assessments in this study cannot be 
overstated.  Disease assessments will be performed every 12 weeks (± 7 days) from the date 
of randomization.  Patients with bone lesions identified at baseline will also have repeat bone 
scans performed every 24 weeks (± 7 days) from the date of randomization.  Each assessment 
will be performed as scheduled according to the calendar regardless of any dosing delay to 
prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the 
required disease assessments will result in the inability to determine disease status for that 
time point.  Tumor assessments will be performed until radiographically and/or clinically 
(ie, for photographed or palpable lesions) documented Progressive Disease (PD) as per 
RECIST v.1.1, study treatment discontinuation (for patients continuing treatment beyond 
RECIST-defined disease progression), initiation of new anticancer therapy or discontinuation 
of patient from overall study participation (eg, death, patient's request, lost to follow-up), 
whichever would occur first.  A series of incomplete disease assessments will result in 
censoring of the primary endpoint of PFS back to the time of the last full assessment that did 
not show disease progression.  Off schedule or incomplete disease assessments have the 
potential to weaken the conclusion of this clinical trial and must be avoided wherever
possible.

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Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented PD as per 
RECISTv.1.1 will continue to have tumor assessment performed during the follow-up visits 
every 12 weeks (± 7 days) and bone scans (as applicable) every 24 weeks (±7 days) until 
RECIST-defined disease progression, initiation of new anticancer therapy or discontinuation 
of patient from overall study participation (eg, death, patient's request, lost to follow-up), 
whichever occurs first.
Patients discontinuing the active treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every 6 months from the 
last dose of investigational product. The follow-up period will conclude at the time of the 
final OS analysis.  Crossover will not be allowed in the trial.
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as the primary data source. However, a blinded independent third-party core 
imaging laboratory will complete a retrospective review of radiographic images and clinical 
information collected on-study to verify the protocol-defined endpoints of disease response 
and progression determinations as assessed by the investigator.
An independent third party External Data Monitoring Committee (E-DMC) will monitor the 
safety data on a periodic basis. The E-DMC will make recommendation as to whether the 
trial should continue based on ongoing reviews of safety data. The E-DMC will also evaluate 
efficacy at the interim analysis and make a recommendation regarding study continuation 
based on observed results of the study.  The E-DMC membership and governance is outlined 
in a separate charter.
Endpoints:
Primary Endpoint

Progression-Free Survival (PFS) based on investigator’s assessment.
Secondary Endpoint(s)

Progression-Free Survival (PFS) based on blinded independent central review
(BICR).

Objective Response (OR);

Duration of Response (DR);

Disease Control Rate (DCR);

Overall Survival (OS);

1-year, 2-year, and 3-year Survival Probabilities;

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
Trough plasma concentration of Palbociclib;

Quality of life assessments: EuroQol (EQ-5D) Score and Functional Assessment of 
Cancer Therapy - Breast (FACT-B); 

Type, incidence, severity (as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events, NCI CTCAE v4.0), seriousness and 
relationship to study medications of adverse events (AE) and any laboratory 
abnormalities;

Tumor tissue biomarkers, including genes, proteins, and RNA expression (eg, ER, 
Ki67).
Statistical Methods:
The primary purpose of this study is to compare the combination of Palbociclib with 
letrozole versus placebo plus letrozole in prolonging PFS in Asian postmenopausal women 
with ER (+), HER2 (-) ABC who have not received any prior systemic anticancer treatment 
for advanced stage disease. All primary and secondary endpoints based on radiological (and 
photographical where applicable) assessments of tumor burden (ie PFS, OR, DR, DCR) will 
be derived using the local radiologist’s/investigator’s assessment. Tumor assessments will 
also be performed by a blinded independent third-party core imaging laboratory and the data 
will be used for secondary supportive analyses.
The sample size for this study is determined based on the assumptions that the median PFS 
for ABC patients receiving placebo plus letrozole in the first-line treatment setting is 
9 months and it is desired to detect a risk reduction of 36% (hazard ratio 0.64), equivalent to 
an improvement in median PFS to 14 months in the Palbociclib plus letrozole treatment arm. 
A total of approximately 213 events are required in the 2 arms of the study based on a 
1:1 randomization to have 90% power to detect a difference assuming a true hazard ratio of 
0.64 in favor of the Palbociclib plus letrozole arm using a one-sided log-rank test at a 
significance level of 0.025.  Assuming a 10% drop-out rate on either treatment arm, an 
accrual accomplished over a 19-month period and follow-up that will continue for about 12
months after the last patient is enrolled, a total sample size of approximately 330 patients 
(approximately 165 patients per arm) is required. 
The sample size described above will also allow the assessment of differences in the 
secondary endpoint of OS.  The OS outcomes of a Phase 3 clinical trial in a similar patient 
population demonstrated a median OS of 34 months for the arm receiving letrozole.  Using 
this value as an assumption with a hypothesized 30% risk reduction (a hazard ratio of 0.7) or 
43% improvement in median OS (from 34 months to 48.6 months) in patients randomized to 
receive palbociclib plus letrozole and a follow-up period of approximately 61 months, 330
patients will provide approximately 247 events for 80% power to detect such a difference 
using a 1-sided, log-rank test at a significance level of 0.025. Descriptive statistics will be 
used to summarize all patient characteristics, treatment administration, investigational drug 
compliance, efficacy endpoints, safety parameters, and biomarkers.  Data will also be 
displayed graphically, where appropriate. 

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The primary efficacy analyses will be based on the intent-to-treat (ITT) population, defined 
as all patients randomized to the study. Some efficacy analyses will also be performed on the 
as-treated (AT) population, defined as patients who receive at least 1 dose of study treatment 
(ie, Palbociclib/placebo or letrozole), with treatment assignments designated according to 
actual study treatment received.
Time-to-event endpoints, including PFS, DR, and OS will be summarized using Kaplan 
Meier methods and displayed graphically.  The median event time and 2 sided 
95% confidence interval for the median will be provided for each endpoint.  Stratified log 
rank tests will be used to compare PFS and OS between the treatment arms.
The 1-year, 2-year, and 3-year survival probabilities will be estimated using the Kaplan 
Meier method and a 2 sided 95% confidence interval for the log [-log(1-year, 2-year or 
3-year survival probability)] will be calculated using a normal approximation and then back 
transformed to give a confidence interval for the 1-year, 2-year, and 3-year survival 
probability itself.
The objective response rate (ORR) will be summarized by treatment arm along with the 
corresponding exact 2 sided 95% confidence interval.  Response rate comparisons between
the 2 treatment arms as randomized will be assessed using Cochran-Mantel-Haenszel (CMH) 
test with the same stratification factors as for the PFS analysis.
The study is designed to have one interim analysis and the final analysis based on the 
primary endpoint of PFS.  A formal efficacy stopping boundary for rejecting the null 
hypothesis is constructed by using the spending function methodology of power family 
design withΔ = -0.5.  The purposes for the interim analysis are to allow early stopping of the 
study for efficacy and to assess safety of the combination regimen  The analysis will be 
performed after approximately 139 patients have documented progressive disease or die 
(approximately 65% of the total events expected).  If the results of the interim analysis
indicate serious safety concerns, the sponsor will communicate with the Health Authorities 
regarding stopping the clinical trial.
An interim analysis of efficacy is also planned for the secondary endpoint OS.  The analysis 
will be performed at the same time of the final analysis of PFS.  Even if the improvement in 
PFS is significant at its interim and the study is stopped due to the overwhelming resutls, the 
interim OS analysis will still be performed at the approximately planned PFS final analysis 
time.  The nominal significance levels for the interim analysis of OS will be determined by 
using the Lan-Demets procedure with an O’Brien-Flemming stopping rule.  The overall 
significance level for the efficacy analysis of OS will be preserved at 0.025 (one-sided test).
All patients treated with at least one dose of study treatment (ie, Palbociclib/placebo or 
letrozole) will be included in all safety analyses.  Summaries of AEs and other safety 
parameters will be provided as appropriate.  Frequencies of patients experiencing at least one 
AE will be displayed by body system and preferred term according to MedDRA terminology.  
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, severity, relationship to study drug, action taken, and clinical 

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outcome.  Severity of the AEs will be graded according to the NCI CTCAE version 4.0. 
Summary tables of clinical laboratory results will be prepared to examine the worst toxicity 
grade on study and distribution of laboratory measures over time.  Shift tables will be 
provided to examine the distribution of laboratory abnormalities.
Breast cancer-specific quality of life mean scores at each assessment time point and change 
from baseline scores will be compared between the treatment arms at various time points 
using a mixed model repeated measures (MMRM) approach adjusting for specified 
covariates.  In addition, analyses will be performed to determine if the change from baseline 
scores achieve the appropriate minimally important difference (MID) cut-off for the scale 
being examined. Patients from the ITT population who completed a baseline assessment and 
at least one post-baseline assessment will be considered evaluable for the patient-reported 
outcome (PRO) analysis.  

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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES
and ASSESSMENTS 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 wellbeing of the subject.
A5481027 Schedule of Activities
Protocol Activity
Screening
Active Treatment Phasea - One Cycle = 28 days
End of Treatment 
/ Withdrawalc
Post-Treatment 
Follow-Upd
Cycles 1 and 2
Cycle 1
Cycle 
Cycles ≥3
Study Day
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1b, v
Day 14
Day 21
Day 21
Day 1v
Time Window
±2d
±2d
±2d
±2d
±2d
±7d
Baseline Documentation
Informed Consent Processe
X
Medical / Oncological Historyf
X
Baseline Signs / Symptoms 
Xg
Banked Biospecimenh
X
Tumor Tissue for Biomarkeri
X
Xi
Physical Examination/Vital signsj
X
X b
X
X
Ophthalmic Examinationk
X
X
X
ECOG Performance Status
X
X
X
X
Laboratory Studies
Hematologyl
X
Xb
X (Only 
for Cycle 
1)
X
X
X
X
Blood Chemistryl
X
Xb
X
X
X

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A5481027 Schedule of Activities
Protocol Activity
Screening
Active Treatment Phasea - One Cycle = 28 days
End of Treatment 
/ Withdrawalc
Post-Treatment 
Follow-Upd
Cycles 1 and 2
Cycle 1
Cycle 
Cycles ≥3
Study Day
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1b, v
Day 14
Day 21
Day 21
Day 1v
Time Window
±2d
±2d
±2d
±2d
±2d
±7d
12-Lead ECGm
X
Xb
X
X
X
Fasting Glucosen
X (Cycle1Pre-dose)
X
X
Fasting Insulinn
X (Cycle1Pre-dose)
X
X
HgbA1Cn
X (Cycle1Pre-dose)
C4D1 and 
every 3
months 
thereafter
X
Fasting Lipid Panel (Total Cholesterol, 
HDL, LDL, triglycerides)n
X (Cycle1Pre-dose)
X
Disease Assessment 
CT/MRI Scans of Chest, Abdomen, Pelvis, 
any clinically indicated sites of disease, 
and of bone lesions; Clinical evaluation of 
superficial diseaseo
X
◄--►p o
Performed every 12 weeks (± 7 days) from the date of randomization
X
Xo
Radionuclide Bone Scan, Whole Bodyp
X
◄--►q o
Performed every 24 weeks (± 7 days) from the date of randomization
X
Xo
Other Clinical Assessments 
Drug Compliancer
◄--►
Averse Event Reportings
X
X
X
X
X
X
Review Concomitant 
Medications/Treatmentst
X
X
X
X
X
X
EuroQol; EQ-5Du
X
X
X
FACT - Breast Questionnaireu
Xu
X
X

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A5481027 Schedule of Activities
Protocol Activity
Screening
Active Treatment Phasea - One Cycle = 28 days
End of Treatment 
/ Withdrawalc
Post-Treatment 
Follow-Upd
Cycles 1 and 2
Cycle 1
Cycle 
Cycles ≥3
Study Day
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1b, v
Day 14
Day 21
Day 21
Day 1v
Time Window
±2d
±2d
±2d
±2d
±2d
±7d
Survival Follow-upw
X
Study Treatment
Randomization 
X
Letrozole (both treatment arms)
Once Daily ◄--►x
Palbociclib or Placebo
◄--►y
Once Daily on Day 1 to Day 21of each cycle followed by 7 days off
Special Laboratory Studies 
Pharmacokineticsz
X(Pre-dose)
a.
Active Treatment Phase: All assessments should be performed prior to dosing with study medications on the visit day unless otherwise indicated.  
Acceptable time windows for performing each assessment are described in the column headers.
b.
Cycle 1/Day 1: Blood chemistry, hematology, 12-lead ECG and physical examination not required if acceptable screening assessment is performed 
within 7 days prior to randomization.
c.
End of Treatment/Withdrawal: Obtain these assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks for 
disease assessments).
d.
Post Treatment Follow-up: After discontinuation of study treatment, post-treatment follow-up (including survival status and post-study anticancer 
therapy evaluation) will be collected every 6 months (±7 days) from the last dose of study treatment.  Telephone contact is acceptable.
e.
Informed Consent: Informed consent may be obtained greater than 28 days from randomization; however, must be obtained prior to any protocol 
required assessments being performed.
f.
Medical/Oncological History: To include information on prior anticancer treatments.
g.
Baseline Signs/Symptoms: Baseline tumor related signs and symptoms will be recorded at the Cycle 1 Day 1 visit prior to initiating treatment and 
then reported as adverse events during the trial if they worsen in severity or increase in frequency.
h.
Banked Biospecimen: A single 4 mL blood sample (Prep D1; K2 EDTA whole blood collection optimized for DNA analysis) will be collected 
pre-dose at the Cycle 1 Day 1 visit from all patients, unless prohibited by local regulations, to be retained for potential pharmacogenomic analyses
related to drug response or adverse drug reactions.  

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i.
Mandatory Tumor Tissue For Confirmatory Testing and for Biomarker Assessments: Tumor tissue is required for patient participation.  
Submission of formalin-fixed paraffin embedded (FFPE) tumor samples (blocks) of adequate size to allow for three 0.6 mm diameter x 5 mm deep 
cores that will be used to generate a tissue microarray are needed. If FFPE tissue block cannot be provided, then 12 glass slides each containing an 
unstained 5-micron FFPE tissue section, will be required for patient participation (highly recommend to submit tissue block or 12 unstained slides, but 
if there would be technical difficulties or other issues refraining from obtaining tissue block or 12 unstained slides, however, it is still mandatory to 
collect a minimum 7 unstained slides). Archived FFPE specimen from the original diagnostic tumor tissue will be collected and sent to the sponsor-
designated central laboratories for assessment of biomarkers associated with sensitivity and/or resistance to Palbociclib (eg, Ki67, ER). Tissue sample 
from a metastatic or recurrent tumor lesion, if available, will also be collected for restrospective confirmation of ER status by the central laboratory. If 
a tissue sample from a recurrent tumor or distant metastasis is unavailable, then a de novo fresh biopsy is recommended when, in the investigator’s 
judgment, such biopsy is feasible and can be safely performed. Original diagnostic tumor tissue will be used for confirmation of ER status in the event 
that a recurrent/metastatic tissue sample is not available and a fresh biopsy of the recurrent/metastatic lesion is not feasible. An optional fresh tumor 
biopsy will be collected at the end of treatment visit,only for patients who discontinue treatment due to disease progression. The tumor tissue will be 
used to determine possible mechanisms of resistance. Tissue samples from all patients will be used for additional biomarker analyses. Detailed 
information about biomarker sample collection, preparation, storage, labeling, and shipment is indicated in the Study Reference Manual. 
j.
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems, height (at screening only), 
weight, blood pressure and pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, will be 
required at screening and, Day 1 of Cycles 1 and 2.  Symptom-directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits.
k.
Ophthalmic Examinations: All enrolled patients will undergo an ophthalmic examination at screening, and on study treatment after 3 months (Cycle 
4 Day 1), 6 months (Cycle 7 Day 1), 12 months (Cycle 13 Day 1), every 12 months (Day 1 of Cycles 25, 37 etc.) thereafter, and at the End of 
Treatment visit. Additional ophthalmic examinations may be performed during the study as clinically indicated (including for patients randomized 
prior to Amendment 3 approval). The ophthalmic examinations will include: best corrected distant visual acuity (Snellen), refractive error associated 
with best corrected distant visual acuity, intraocular pressure (IOP – one reading), slit lamp biomicroscopy of the anterior segment including cell count 
and flare grading, crystalline lens grading using the Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens Opacity Grading 
procedure, and fundoscopy. All ophthalmic examinations will be performed by an ophthalmologist. Refer to Section 7.2.3. Ocular Safety 
Assessments for further details on these procedures.
l.
Hematology, and Blood Chemistry Panel: Hematology includes hemoglobin, WBC, absolute neutrophils, platelet count.  Blood chemistry includes 
AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, total calcium, total bilirubin, BUN (or urea), serum creatinine, and albumin.  
Additional hematology/chemistries panels may be performed as clinically indicated.
m. 12-Lead ECG: At each time-point, three consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine the mean QTc 
interval. If the mean QTc interval is prolonged (>500 msec), then the ECGs should be re-read by a cardiologist or other qualified person at the site for 
confirmation.  Additional triplicate ECGs may be performed as clinically indicated.  
n.
Fasting Glucose, Fasting Insulin, HgbA1c and Fasting Lipid Panel (Total Cholesterol, HDL, LDL, triglycerides): On Day 1, all the baseline
assessments should be performed prior to dosing(pre-dose). Fasting glucose and fasting insulin will be assessed on Cycle 1 Day 21 and at the End of 
Treatment visit; HgbA1C will be assessed on Cycle 4 Day1, every 3 months (Day 1 of Cycles 7, 10 etc.) thereafter, and at the End of Treatment visit; 
fasting lipid panel will be assessed at the End of Treatment visit.
o.
Disease Assessments: Please refer to the tumor assessment requirement flowchart for details and timing of procedures. A blinded independent 
third-party core imaging laboratory will complete a retrospective review of radiographic images and clinical information collected on-study to verify 
the protocol-defined endpoints of disease response and progression determinations as assessed by the investigator.

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p.
CT/MRI Scans of Chest, Abdomen, Pelvis, any clinically indicated sites of disease, and of bone lesions; clinical evaluation of superficial 
disease: Please refer to the tumor assessment requirement flowchart for details and timing of procedures.
q.
Radionuclide Bone Scan, Whole Body: Please refer to the tumor assessment requirement flowchart for details and timing of procedures.
r.
Drug Compliance: Palbociclib, placebo and letrozole bottles including any unused capsules/tablets will be returned to the clinic for drug 
accountability.  Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.
s.
Adverse Events: For SAEs, the active reporting period begins from the time that the patient provides informed consent through and including 28 
calendar days after the last administration of the investigational product.  AEs (serious and non serious) should be recorded on the CRF from the time 
the patient has taken at least one dose of study treatment through last patient visit.
t.
Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment 
and up to 28 days after the last dose of study treatment.
u.
EQ-5D, FACT-B Assessments: Patients will complete questionnaires prior to any study or medical procedure on Day 1 of Cycles 1, 2 and 3 and then 
Day 1 of every other cycle thereafter starting with Cycle 5 (ie, Cycle 5, 7, 9, etc), and at the end of treatment visit.  All self-assessment questionnaires 
must be completed by the patients while in the clinic and cannot be taken home.  Interviewer administration in clinic may be used under special 
circumstances.
v.
Cycle X, Day 1: In the event that the start of a new cycle is delayed due to treatment related toxicity, procedures required on Day 1 of the given cycle 
will be performed when Palbociclib/placebo is resumed.  New cycle Day 1 procedures (ie, physical examination, ECOG performance status, ECG, 
Quality of Life questionnaires, blood chemistry, hematology) that were performed prior to knowing the need to delay the start of the cycle do not need 
to be repeated (1) if not required to determine whether study drug may be resumed and (2) if performed within 7 days prior to study drug resumption.
w.
Survival Follow-Up: After discontinuation of study treatment, post-study survival status (including post-study anticancer therapies) will be collected 
every 6 months (±7 days) from the last dose of study treatment.  Telephone contact is acceptable.
x.
Letrozole (both treatment arms): To be taken orally once daily continuously.
y.
Palbociclib or Placebo: To be taken orally once daily from Day 1 to Day 21 (21 days) of every 28-day cycle followed by 7 days off treatment.
z.
Pharmacokinetics: For all patients, plasma PK samples for Palbociclib determination will be collected prior to dosing (pre-dose) on Day 14 of 
Cycle 1 and Cycle 2.
Additional blood samples may be requested from patients experiencing unexpected or serious adverse events, or adverse events that lead to 
discontinuation.

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TUMOR ASSESSMENT REQUIREMENTS FLOWCHART
Screeninga
Treatment Periodb
End of Treatment Visitc
CT d or MRI of chest, abdomen, and 
pelvis (CAP)
Requirede
Required
Required
CT d or MRI of any other site of 
disease, as clinically indicated
Required e,f
Required for sites of disease 
identified at screening
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere
Radionuclide bone scan (whole body)
and correlative bone imaging
Required g,h
Required for sites of disease 
identified at screening or if 
clinically indicated i
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere
Photographs of all superficial lesions 
as applicable j
Required
Required for sites of disease 
identified at screening
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere
a.
Screening scans must occur within 4 weeks (ie, 28 days) prior to randomization unless otherwise specified. 
b.
Tumor assessment must be done during the treatment period, every 12 weeks (±7 days) and bone scans (as applicable) every 24 weeks (±7 days) from 
randomization until radiographically and/or clinically (ie,for photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment 
discontinuation (for patients continuing treatment beyond RECIST-defined disease progression), initiation of new anticancer therapy or discontinuation 
of patient from overall study participation (eg, death, patient's request, lost to follow up), whichever occurs first.  The schedule of assessments should be 
fixed according to the calendar, regardless of treatment delays/interruptions.  Imaging assessments are to be scheduled using the randomization date as 
the reference date for all time-points and are NOT to be scheduled based on the date of the previous imaging time-point.  Imaging assessment delay to 
conform to treatment delay is not permitted.  The same tumor assessment technique MUST be used throughout the study for a given lesion/patient. 
c.
Patients who have already demonstrated objective disease progression as per RECIST v.1.1 do not need to have scans repeated at the end of treatment 
visit or during the post-treatment follow-up.  For patients who do not have documented objective disease progression at time of study treatment 
discontinuation, tumor assessment will continue to be performed every 12 weeks (± 7 days) and bone scans (as applicable) every 24 weeks (±7 days)
until radiographically and/or clinically confirmed objective disease progression, initiation of new anticancer therapy, or discontinuation of patient from 
overall study participation (eg, death, patient's request, lost to follow-up). 
d.
The CT scans, including brain CT scan if applicable, should be performed with contrast agents unless contraindicated for medical reasons. If IV 
contrast is medically contraindicated, the imaging modality to be used to follow the disease (either CT without contrast or MRI) should be the modality 
which best evaluates the disease, and the choice should be determined by the investigator in conjunction with the local radiologist.  MRI of the abdomen 

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and pelvis can be substituted for CT if MRI adequately depicts the disease.  However, MRI of the chest should not be substituted for CT of chest even if 
IV contrast is contraindicated.  In such case CT will be performed without contrast.  If MRI is used to follow-up bone lesion(s) it must be performed 
before any treatment that may affect bone-marrow cellularity (eg, G-CSF).
e.
Radiographic assessments obtained per the patient’s standard of care prior to randomization into the study do not need to be repeated and are acceptable 
to use as baseline evaluations, if (1) obtained within 28 days before randomization, (2) they were performed using the method requirements outlined in 
RECIST v.1.1 (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, and (4) appropriate 
documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. 
f.
Baseline brain scans are only required if signs and symptoms suggest presence of metastatic brain disease. Brain scans performed before the signing of 
informed consent as routine procedures (but within 6 weeks before randomization) do not need to be repeated and may be used as baseline assessments 
as long as (1) tests were performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality can be used to follow 
identified lesions throughout the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor assessments were 
performed as standard of care is available in the patient’s source notes.  Post-baseline repeat brain scans will only be required only if metastases are 
suspected. 
g.
Bone scans will be carried out at baseline for all patients within 12 weeks prior to randomization in order to detect bony sites of disease. Bone scans 
performed before the signing of informed consent as routine procedures (but within 12 weeks before randomization) do not need to be repeated and may 
be used as baseline assessments as long as (1) tests were performed using the method requirements outlined in RECIST v.1.1 (2) the same 
technique/modality can be used to follow identified lesions throughout the trial for a given patient (3) appropriate documentation indicating that these 
radiographic tumor assessments were performed as standard of care is available in the patient’s source notes.
h.
Any suspicious abnormalities (ie, hotspots) identified on the bone scans at baseline and on subsequent bone scans MUST be confirmed by X-ray, CT 
scan with bone windows or MRI.  The same modality must be used throughout the trial for confirmation for a given lesion/patient.  Bone lesions 
identified at baseline will be followed up according to the same assessment schedule (ie, every 12 weeks ±7 days from randomization) as for all other 
lesions.  Areas that have received palliative radiotherapy cannot be used to assess response to study treatment.
i.
If bone lesions were identified at baseline bone scans will be repeated during the active treatment phase every 24 week (±7 days) from the date of 
randomization and at the time of confirmation of CR.  If no bone lesions were identified at baseline, bone scans will only be repeated during the active 
treatment phase when clinically indicated (ie, patient describes new or worsening bone pain, or has increasing alkaline phosphatase level, or other signs 
and symptoms of new/progressing bone metastases) but are required at the time of confirmation of CR. New Abnormalities found on subsequent bone 
scans must also be confirmed by X-ray, CT scan with bone windows or MRI. 
j.
Clinical assessment of superficial disease must be carried out on the same date as the imaging studies and will include photographs of all superficial 
metastatic lesions. All lesion measurements must be recorded in the case report form (CRF).
Notes: 
- Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression at the discretion of the investigator.  If 
progressive disease is confirmed per RECIST v.1.1, patients are expected to discontinue study therapy and begin the follow-up phase of the trial. However, 
patients may continue treatment as assigned at randomization beyond the time of RECIST-defined PD at the discretion of the investigator if that is 
considered to be in the best interest of the patient and as long as no new anticancer treatment is initiated.  

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................26
APPENDICES .........................................................................................................................26
1. INTRODUCTION ...............................................................................................................28
1.1. Indication.................................................................................................................28
1.2. Background and Rationale ......................................................................................28
1.2.1. Role of Letrozole in the Treatment of Estrogen Receptor Positive 
Breast Cancer...................................................................................................28
1.2.2. Interaction of Estrogens and Cyclin-Dependent Kinases in Breast 
Cancer Cells.....................................................................................................29
1.2.3. Deregulation of Cell Cycle Related Genes and Proteins in Breast 
Cancer ..............................................................................................................30
1.2.4. ER and HER2 Status in Breast Cancer.......................................................31
1.2.5. Overview of Palbociclib .............................................................................31
1.2.5.1. Preclinical Data .........................................................................32
1.2.5.2. Human Pharmacokinetic (PK) Data..........................................32
1.2.5.3. QTc Evaluation Data.................................................................34
1.2.5.4. Preclinical Ocular Data .............................................................35
1.2.5.5. Palbociclib Dose Rationale .......................................................36
1.2.5.6. Phase I/II Data in Combination with Letrozole in 
Advanced Breast Cancer ...................................................................37
1.2.6. Study Rationale...........................................................................................39
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................40
2.1. Objectives................................................................................................................40
2.2. Endpoints.................................................................................................................40
3. STUDY DESIGN.................................................................................................................41
4. PATIENT SELECTION......................................................................................................44

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4.1. Inclusion Criteria.....................................................................................................44
4.2. Exclusion Criteria....................................................................................................46
4.3. Randomization Criteria ...........................................................................................48
4.4. Sponsor Qualified Medical Personnel.....................................................................49
5. STUDY TREATMENTS.....................................................................................................49
5.1. Allocation to Treatment ..........................................................................................49
5.2. Breaking the Blind ..................................................................................................50
5.3. Drug Supplies..........................................................................................................51
5.3.1. Formulation and Packaging........................................................................51
5.3.1.1. Palbociclib.................................................................................51
5.3.1.2. Placebo ......................................................................................51
5.3.1.3. Letrozole....................................................................................51
5.3.2. Preparation and Dispensing........................................................................51
5.3.2.1. Palbociclib/Placebo ...................................................................51
5.3.2.2. Letrozole....................................................................................52
5.3.3. Administration............................................................................................52
5.3.3.1. Palbociclib/Placebo ...................................................................52
5.3.3.2. Letrozole....................................................................................53
5.3.3.3. General Rules ............................................................................53
5.3.4. Dose Modification ......................................................................................53
5.3.4.1. Letrozole....................................................................................54
5.3.4.2. Palbociclib/Placebo ...................................................................54
5.3.5. Medication Errors and Overdose................................................................60
5.3.6. Compliance.................................................................................................60
5.4. Drug Storage and Drug Accountability...................................................................60
5.4.1. Palbociclib/Placebo.....................................................................................61

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5.4.2. Letrozole.....................................................................................................61
5.5. Concomitant Medications .......................................................................................62
5.5.1. Prohibited Medications...............................................................................62
5.5.2. Medications Not Recommended.................................................................63
5.5.3. Permitted Medications................................................................................65
5.6. Concomitant Radiotherapy or Surgery....................................................................65
6. STUDY PROCEDURES .....................................................................................................66
6.1. Screening.................................................................................................................66
6.1.1. Screen Failure .............................................................................................68
6.2. Active Treatment Phase ..........................................................................................68
6.3. End of Treatment Visit............................................................................................68
6.4. Follow-up Visit .......................................................................................................69
6.5. Patient Withdrawal..................................................................................................69
6.5.1. Active Treatment Phase Discontinuation ...................................................69
6.5.2. Study Discontinuation ................................................................................71
7. ASSESSMENTS..................................................................................................................71
7.1. Efficacy Assessments..............................................................................................72
7.1.1. Independent Review of Disease Assessments............................................72
7.1.2. Tumor Assessments....................................................................................73
7.1.3. Overall Survival..........................................................................................77
7.2. Safety assessments ..................................................................................................77
7.2.1. Laboratory Safety Assessments..................................................................77
7.2.2. Electrocardiogram (ECG)...........................................................................78
7.2.3. Ocular Safety Assessments.........................................................................78
7.2.3.1. Snellen Best Corrected Visual Acuity and Refraction..............78
7.2.3.2. Intraocular Pressure Measurement............................................79

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7.2.3.3. Slit-lamp Biomicroscopy...........................................................79
7.2.3.4. Lens Grading.............................................................................80
7.2.3.5. Funduscopy (Ophthalmoscopy) ................................................80
7.2.4. Other Safety Assessments...........................................................................81
7.3. Pharmacokinetic Assessments.................................................................................81
7.4. Patient Reported Outcomes.....................................................................................82
7.4.1. EuroQol Health Utilities Index EQ-5D (Appendix 5)................................82
7.4.2. Functional Assessment of Cancer Therapy-Breast (FACT-B) 
[Version 4] (Appendix 6).................................................................................83
7.5. Biomarker Assessment............................................................................................83
7.5.1. Optional Tumor Tissue Biopsy for Molecular Profiling ............................84
7.6. CDK6 Genotyping...................................................................................................84
7.7. Banked Biospecimen...............................................................................................85
7.7.1. Markers of Drug Response.........................................................................85
8. ADVERSE EVENT REPORTING......................................................................................86
8.1. Adverse Events........................................................................................................86
8.2. Reporting Period .....................................................................................................87
8.3. Definition of an Adverse Event...............................................................................88
8.4. Abnormal Test Findings..........................................................................................89
8.5. Serious Adverse Events...........................................................................................89
8.5.1. Protocol-Specified Serious Adverse Events...............................................90
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................90
8.6. Hospitalization ........................................................................................................91
8.7. Severity Assessment................................................................................................93
8.8. Causality Assessment..............................................................................................93
8.9. Exposure During Pregnancy....................................................................................94
CCI

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8.10. Occupational Exposure .........................................................................................95
8.11. Withdrawal Due to Adverse Events (See Also Section 6.5 Patient 
Withdrawal)...............................................................................................................96
8.12. Eliciting Adverse Event Information ....................................................................96
8.13. Reporting Requirements........................................................................................96
8.13.1. Serious Adverse Event Reporting Requirements .....................................96
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................97
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................97
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................97
9.1. Sample Size Determination.....................................................................................97
9.2. Analysis Population.................................................................................................98
9.2.1. Intent-to-Treat Population (ITT).................................................................98
9.2.2. As-Treated Population (AT).......................................................................98
9.3. Efficacy Analysis ....................................................................................................99
9.3.1. Analysis of Primary Endpoint ....................................................................99
9.3.2. Analysis of Secondary Endpoints.............................................................100
9.4. Analysis of Other Endpoints .................................................................................102
9.5. Safety Analysis......................................................................................................103
9.6. Interim Analysis ....................................................................................................104
9.7. Data Monitoring Committees................................................................................105
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................106
11. DATA HANDLING AND RECORD KEEPING ...........................................................106
11.1. Case Report Forms/Electronic Data Record .......................................................106
11.2. Record Retention.................................................................................................107
12. ETHICS............................................................................................................................107
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........107
12.2. Ethical Conduct of the Study ..............................................................................108

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12.3. Patient Information and Consent.........................................................................108
12.4. Patient Recruitment.............................................................................................109
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................109
13. DEFINITION OF END OF TRIAL.................................................................................109
13.1. End of Trial in a Member State...........................................................................109
13.2. End of Trial in all other Participating Countries.................................................109
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................109
15. PUBLICATION OF STUDY RESULTS........................................................................110
15.1. Communication of Results by Pfizer ..................................................................110
15.2. Publications by Investigators ..............................................................................111
16. REFERENCES ................................................................................................................113
LIST OF TABLES
Table 1.
Palbociclib/Placebo Capsule Characteristics........................................................51
Table 2.
Available Dose Levels..........................................................................................57
Table 3.
Palbociclib/Placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal 
Medical Treatment................................................................................................57
Table 4.
Palbociclib/Placebo Dose Modifications for Hematologic Toxicities (by
CTCAE Grade and on Day of Treatment)a...........................................................58
Table 5.
Palbociclib/Placebo Dose Modifications in the Event of QTc Prolongation .......59
APPENDICES
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............122
Appendix 2. Sponsor Approved HER2 Assays .....................................................................123
Appendix 3. List of Drugs Known to Predispose to Torsade de Pointes...............................124

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Appendix 4. Bone Marrow Reserve in Adult ........................................................................125
Appendix 5. EuroQol Health Utilities Index EQ-5D.............................................................127
Appendix 6. Functional Assessment of Cancer Therapy-Breast (FACT-B) [Version 4]......130
Appendix 7. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines...........................................................................................................133
Appendix 8. Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure ................................................................................139
Appendix 9. List of Abbreviation..........................................................................................141

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1. INTRODUCTION
Breast Cancer (BC) is the most common invasive cancer in women, with more than 
1.3 million cases and over 450,000 deaths occurring worldwide annually. In Asia, the 
incidence of breast cancer is 26 per 100,000 individuals, the mortality rate is 9.5 per 
100,000 individuals. In China, the incidence of breast cancer is 21.6 per 100,000 individuals, 
the mortality rate is 5.7 per 100,000 individuals.1 Although age-adjusted mortality from breast 
cancer has been decreasing since 1990, the median survival for patients with metastatic 
disease is still only approximately 18 to 24 months2 and the medical need for more active 
agents in this clinical setting remains very high.
The role of estrogens in breast cancer etiology and progression is well established.  
Modification of estrogen activity or synthesis represents the treatment of choice for 
postmenopausal women with hormonal receptor positive advanced breast cancer, particularly 
for those with slowly progressive disease and limited tumor-related symptoms. Letrozole is 
an oral nonsteroidal aromatase inhibitor and it is approved worldwide for the first-line 
treatment of postmenopausal women with hormone receptor-positive advanced breast cancer 
(ABC).
1.1. Indication
Estrogen receptor-positive (ER (+)), HER2-negative (HER2 (-)) Advanced Breast Cancer 
(ABC) in Asian patients who have not received any prior systemic anti-cancer therapy for 
advanced stage disease.
1.2. Background and Rationale
1.2.1. Role of Letrozole in the Treatment of Estrogen Receptor Positive Breast Cancer
Approximately two-thirds of breast cancers express estrogen receptor (ER)3 and a role for 
estrogens in breast cancer etiology and progression is well established. Modification of 
estrogen activity or synthesis represents the treatment of choice for postmenopausal women 
with hormone receptor-positive ABC, particularly for those with slowly progressive disease 
and limited tumor-related symptoms.2
Conversion of androgens to estrogens via aromatase enzyme action represents the main 
source of estrogens in postmenopausal women.  Letrozole is an oral nonsteroidal aromatase 
inhibitor that is approved worldwide for the first-line treatment of postmenopausal women 
with hormone receptor-positive ABC.  In a multicenter Phase 3 trial,4 916 patients with 

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hormone receptor-positive or hormone receptor-unknown ABC were randomized to receive 
either letrozole or tamoxifen until disease progression. Most of the patients (91%) had 
received no prior treatment for their advanced disease. Letrozole was superior to tamoxifen 
for time to tumor progression (median, 9.4 vs 6.0 months, P<0 .0001), time to treatment 
failure (median, 9 vs 5.7 months, P<0.0001), overall objective response rate (32% vs 21%, 
P= 0.0002), and overall clinical benefit (50% vs 38%, P=0 .0004). Median overall survival 
(OS) was slightly prolonged for the letrozole arm (34 vs 30 months); however, approximately 
50% of the patients in the tamoxifen arm crossed over to letrozole at disease progression.
Letrozole is administered orally on a continuous 2.5 mg daily dosing regimen. Multiple 
clinical studies have shown that letrozole is well tolerated. 
1.2.2. Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer Cells
Studies of ER-positive breast cancer cell lines indicate that estrogens5 and antiestrogens6 act 
on sensitive populations of cells in early to mid-G1 phase.  G1/S transition is under the 
control of CDKs activated by specific complex formation with regulatory cyclins.  
CDK4 and CDK6 are activated by binding to D-type cyclins and act early in G1 phase.7, 8, 9, 10
A primary target of CDK action in G1 phase is the retinoblastoma susceptibility gene product 
(pRb), which mediates G1 arrest through sequestration of transcriptional factors of the 
E2F-DP family. Phosphorylation of pRb and other members of the pocket protein family 
(p107 and p130) by active cyclin-CDK complexes leads to release of E2F and DP 
transcription factors and transcription of requisite genes for S-phase entry.10
D-type cyclins play an essential role in recognition of extracellular growth stimuli and 
initiation of G1 transit,11, 12 and several lines of evidence have linked estrogen regulation of 
cellular proliferation to cyclin D1 expression. Estrogen-induced proliferation of normal 
uterine and breast epithelium in vivo is associated with increased expression of 
cyclin D1 mRNA and protein.13, 14, 15, 16 Expression of cyclin D1 in breast tumor isolates 
correlates with ER-positive status.17, 18, 19 MCF-7 breast cancer cells treated with estrogen 
exhibit increased expression of cyclin D1 mRNA and protein, formation of active cyclin 
D1-CDK4 complexes, and phosphorylation of pRb leading to G1 /S transition.20, 21, 22, 23
Estrogen-induced S-phase entry in these cells is inhibited by microinjection of antibodies to 
cyclin D1.24 Antiestrogen-induced growth arrest of ER-positive breast cancer cells is 
associated with decreased cyclin D1 expression.25 Collectively, these studies are consistent 
with a model of estrogen action in which receptor activation induces increased 
cyclin D1 expression, CDK4 activation, and cell cycle progression. An upstream role for 

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cyclin D1 has been suggested by recent reports describing direct physical interactions 
between cyclin D1 and the ER, leading to recruitment of steroid receptor coactivators and 
activation of ER-dependent transcription.  This occurs in the absence of hormone and is 
independent of D-type cyclin association with CDK4.26, 27, 28, 29
Constraint upon CDK activity and G1 progression is provided by the universal CDK 
inhibitors of the Cip-Kip family, including gp21Cip1 and p27Kip1, and the specific 
CDK4 and CDK6 inhibitors of the INK4 family, typified by p16INK4a.12, 30, 31, 32, 33 The 
CDKN2A gene product inhibits formation of active D-type cyclin-CDK complexes through 
specific binding interactions with CDK4 or CDK6 that prevent D-type cyclin-CDK 
association.34, 35, 36 Over expression of p16INK4a in cells with functional pRb results in 
inhibition of both CDK4-and CDK6-associated kinase activity and pRb phosphorylation, 
with subsequent cell cycle arrest.34, 35 In addition, inhibition of D-type 
cyclin-CDK4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by 
these complexes in early G1, leading to suppression of cyclin E-CDK2 activity.37, 38, 39
Overexpression of p16INK4a through adenoviral transduction of CDKN2A into MCF-7 cells
leads to G1 arrest associated with inhibited CDK activity.40, 41 Cell cycle progression 
induced by estradiol requires action of the steroid through mid-G1, well beyond the point of 
cyclin D1-CDK4 activation.21 Functional association of cyclin D1-CDK4 is required for 
estrogen-induced CDK2 activation and G1/S transition and estrogen regulates expression of 
p21Cip1, p27Kip1, and Cdc25A independent of D-type cyclin-CDK4 function.42
1.2.3. Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer
Cell cycle related genes and proteins are frequently deregulated in breast cancer.  
Approximately 15%–20% of human breast cancers exhibit amplification of the 
cyclin D1 (CCND1) gene,43, 44, 45 while the majority of human mammary carcinomas over
express cyclin D1 protein.46, 47, 48 Over expression of cyclin D1 is seen early in breast cancer, 
and it is maintained at all stages of breast cancer progression, including metastatic 
lesions.46, 49 Amplification of the CDK4 gene, located at 12q13-q14, has been shown as an 
alternative genetic alteration to CDKN2A inactivation in various human tumor including 
breast cancer.50, 51 The continued presence of CDK4-associated kinase activity is actually 
required to maintain breast tumorigenesis.52 Direct analyses of primary tumors have revealed 
loss of pRb expression in 20–35% of tumors, and loss of heterozygosity or other alterations 
of the Rb locus in 7-37% of tumors.53, 54, 55, 56 In preclinical models, Rb depletion appears to 
be associated with resistance to antiestrogen therapy.57 Finally, virtually all ER-positive cell 

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lines harbor loss of p16INK4a 58, 59 expression, and low expression of CDK inhibitors p21 and 
p27 and high expression level of cyclin E and D1 have all been associated with resistance to 
anti-estrogen therapy.
1.2.4. ER and HER2 Status in Breast Cancer
The ER and HER2 status of breast metastatic disease are usually assumed to be the same as 
that of the primary tumor. However, mounting evidences from both prospective and 
retrospective studies have shown a discordant rate of approximately 25% in either ER or 
HER2 status between primary breast tumor and its metastatic lesions.60, 61 The change can be 
from ER- positive primary tumor to ER-negative metastatic disease or vice versa. The
analytical variables of immunohistochemistry (IHC) testing such as antigen retrieval and 
subjectivity in observer analysis also contribute to the observed discordance.62 Another 
dilemma in ER testing accuracy has been primary institutional site testing versus high 
volume central laboratory testing. It has been stated in the recently published American 
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines 
for ER testing that the concordance rate between local and central laboratory testing for ER is 
about 80 to 90%.63 This variation may be due to the lack of rigorous assay optimization 
and/or reproducibility of IHC testing procedures at some of local testing laboratories
including methods of antigen retrieval and subjectivity in observer analysis. This highlights
the importance of confirmative testing of ER status using Food and Drug Administration
(FDA)-cleared and/or approved kits and platform at a central Clinical Laboratory 
Improvement Amendments (CLIA)/CAP certified laboratory to minimize, if not eliminate, 
these differences/variables for patients participating in clinical trials.
1.2.5. Overview of Palbociclib
Palbociclib (Molecular Weight: 573.67) is an orally active potent and highly selective 
reversible inhibitor of CDK4 and CDK6 that has been under investigation in Phase 1, 2 and 3 
clinical trials in multiple indications.  The compound prevents cellular DNA synthesis by 
prohibiting progression of the cell cycle from G1 into the S phase and has shown antitumor 
activity in multiple preclinical models and phase I or phase II study, including in estrogen 
receptor-positive (ER+) luminal breast cancer cell lines.

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1.2.5.1. Preclinical Data
Treatment of cultured tumor cells with Palbociclib causes growth arrest that is accompanied 
by the inhibition of specific pRb phosphorylation by CDK4 or CDK6 on residues 
serine -780 and -795 of pRb.  The IC50 values for reduction of pRb phosphorylation at 
serine -780 and -795 in MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 µM, 
respectively.  The IC50 values for reduction of pRb phosphorylation are similar to the 
IC50 values of inhibition of thymidine incorporation across a range of cultured tumor and 
normal cells.
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines.  
Results from these experiments indicate that those cell lines that are more sensitive to 
Palbociclib (IC50 < 150 nM) have low levels of CDKN2A (p16) and high levels of 
Rb1, while resistant cell lines show the opposite characteristics. Sensitive cell lines in this 
panel represent mostly the luminal ER+ subtype.64 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 breast cancer cell 
lines indicating a synergistic interaction64 and provides a biologic rationale for evaluating the 
combination of Palbociclib with anti-hormonal therapy in the clinic.
1.2.5.2. Human Pharmacokinetic (PK) Data
To date, pharmacokinetic data have been collected in 4 clinical studies in cancer patients
(A5481001, A5481002, A5481003 and A5481004). Pharmacokinetic parameters are 
available from all 74 patients enrolled in Study A5481001 following a single dose (Day 1 of 
Cycle 1), and from 51 patients following multiple-dose administration (Day 8 of Cycle 1) at
daily doses ranging from 25 to 225 mg of Palbociclib.  In addition, PK parameters are also 
available for nine patients on Day 14 of Cycle 1 (from patients on Schedule 2/1, ie, 2 weeks
on treatment followed by 1 week off treatment) and 4 patients on Day 21 of Cycle 1 (from 
patients on Schedule 3/1, ie, 3 weeks on treatment followed by 1 week off treatment).  The 
exposure (AUC(0-10) and Cmax) increased in a dose proportional manner over the dose range 
of 25 to 225 mg once daily (QD) following Palbociclib administration on Days 1 and 8 of 
Cycle 1, although some variability (low to moderate) around these doses was observed 
particularly at the 150 mg QD dose level.  Following repeated daily dosing to Day 14 and 
Day 21 (assumed to be steady state), Palbociclib was absorbed with a median Tmax of 
~4 hours.  The mean Palbociclib Vz/F was 3103 L, which is significantly greater than total 
body water (42 L), indicating that Palbociclib extensively penetrates into peripheral tissues.  

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Palbociclib was eliminated slowly; the mean t½ was 26.5 hours (ranged 15.8 to 36.2 hours) 
and the mean CL/F was 86.1 L/hour.  Palbociclib accumulated following repeated dosing 
with a median Rac of 2.4, which is consistent with a half life of ~27 hours.
A pilot food effect assessment was built into Protocol A5481001 and conducted in 
12 patients following administration of either 125 mg or 200 mg doses (the Maximum 
Tolerated Dose/ Recommended Phase 2 Dose (MTD/RP2D) for the 3/1 and 2/1 schedules,
respectively).  In general, no change in the rate of absorption was observed between the fed 
and fasted state (median Tmax = 7 hours for both; range 3.5 23 hours).  However, higher 
exposures and peak concentrations were observed in the fed state compared to the fasted state 
(mean AUC(0 10): 370.5 vs 290.5 ng•hr/mL, respectively; mean Cmax: 59.7 vs 42.8 ng/mL, 
respectively).  Based on these data, it can be concluded that since administration of 
Palbociclib with a high fat meal may increase Palbociclib exposure, patients should be fasted 
from 1 hour before to 2 hours after dosing (water is allowed), unless otherwise indicated in 
clinical protocols.  The effect of a non-fat meal on the pharmacokinetics of Palbociclib has 
not been evaluated. 
Preliminary results from the recently performed food effect study, A5481021, a Phase 1, 
open-label 4 sequence 4 period crossover study of palbociclib (PD-0332991) in healthy 
volunteers to estimate the effect of food on the bioavailability of palbociclib, suggest that the 
administration of palbociclib with food results in more consistent drug absorption and 
exposure than administration of palbociclib in a fasted state. As a result of these findings, 
patients should be instructed to take palbociclib with food.  
Preliminary results from the recently performed antacid effect study, A5481018, a Phase 1, 
open-label fixed-sequence 2-period crossover study of palbociclib in healthy subjects to 
investigate the potential effect of antacid treatment on the pharmacokinetics of a single oral 
dose administered under fasted conditions, suggest that the administration of proton-pump 
inhibitors concomitantly with palbociclib treatment leads to a significant decrease in 
palbociclib exposure.  Since proton-pump inhibitors affect the pH of the upper GI tract for an 
extended period the concomitant use of proton-pump inhibitors with Palbociclib should be 
avoided. Further recommendations about the use of antacid are provided under Section 5.5.2.
Pharmacokinetic data from Study A5481002 indicate that Palbociclib exposure at steady 
state in mantle cell lymphoma patients, is similar to that observed in solid tumors 
(Protocol A5481001).

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Pharmacokinetic analysis of preliminary data from the Phase 1 portion of 
Study A5481003 (breast cancer, combination with letrozole) was conducted to evaluate the 
potential for drug-drug interaction between Palbociclib and letrozole.  The results indicate 
lack of a potential for drug-drug interaction between Palbociclib and letrozole when 
administered in combination.
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. 
 
 
 
 
 
 
  PF-05089326 was also observed in the circulation of rats 
following repeated daily oral administration of Palbociclib at the dose levels of 50 and 100 
mg/kg/day.  Plasma protein binding of Palbociclib and PF-05089326 is ~85% and 95%, 
respectively.
1.2.5.3. QTc Evaluation Data
In vitro (Human Ether-à-Go-Go, hERG) and in vivo (dog telemetry) studies revealed a 
potential for QT prolongation at unbound concentrations ≥14-fold the unbound steady-state 
Cmax associated with the clinical dose of 125 mg QD (refer to the Palbociclib investigator's 
brochure for additional details).
A preliminary pharmacokinetic/pharmacodynamic analysis has been conducted to explore 
the QT/QTc and plasma Palbociclib concentration relationship for Study A5481001 (First in 
Human, FIH study) by using graphical methods and mixed effects linear modeling 
(NONMEM).  Data from 73 patients were used for the analysis, and an analysis of the QTcF 
and QTcB data demonstrated that QTcF was the more appropriate correction method based 
on plots of the QTc versus RR interval. No patient had a maximum on treatment QTcF value 
of ≥ 500 msec.  The QTcF changes from the baseline at the mean Cmax calculated for 200 mg 
dose were simulated for 10000 patients.  The mean and upper 95% confidence interval of 
QTcF change from the baseline were 5.8 and 9.4 msec, respectively.
CCI

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1.2.5.4. Preclinical Ocular Data
Preliminary results from an ongoing 27-week repeat-dose oral toxicity study with Palbociclib
in Sprague-Dawley rats identified a potential nonclinical safety finding related to the eye. 
Palbociclib was administered by oral gavage at doses of 0, 10, 30, and 100 mg/kg/day in 
males and 0, 50, 100, and 300 mg/kg/day in females (20/sex/group; 15/sex/group in main and 
5/sex/group in recovery) on an intermittent dosing schedule (7 cycles of treatment where 
each cycle consisted of 3 weeks of continuous daily dosing followed by a 1-week non-dosing 
period) for 27 weeks. Animals were evaluated by indirect ophthalmoscopy and by slit lamp 
biomicroscopy predose and prior to termination (within 7 days prior to scheduled necropsy).
Indirect ophthalmoscopy results revealed a degraded view of the fundus and the presence of 
cataracts in males treated at high dose (100 mg/kg/day) that had normal fundus examinations 
prior to the start of the study. Cataracts (anterior cortical, incomplete, and complete) were 
identified by slit lamp biomicroscopy in male rats at ≥30 mg/kg/day with dose-related 
severity (Table 1), but not in females at any dose tested (up to 300 mg/kg/day).
Lens degeneration was observed microscopically with dose-related incidence and with 
minimal to moderate severity in males at  ≥30 mg/kg/day and minimal severity in males at 
10 mg/kg/day and females at ≤100 mg/kg/day (not identified in females at 300 mg/kg/day).  
Lens degeneration was identified in all animals that were noted with cataracts by slit lamp 
ophthalmoscopy.
The available data suggests that the cataracts (lens degeneration) observed at the lowest 
doses in both male and female rats are palbociclib-related. Exposures in this non clinical 
study are comparable to clinical exposures at the recommended human dose of 125 mg QD 
(unbound AUC 301 ng•h/mL).
The mechanism for cataract formation in palbociclib-treated rats is unknown; however, its 
pathogenesis may be related to primary pharmacology. CDK4 expression (mRNA and 
protein) has been identified in the lens epithelial layer and in lens fibers of rats, suggesting its 
importance to lens fiber differentiation.65 Altered cell growth of the lens epithelium is also 
recognized as a potential mechanism for cataract formation.66  As CDK 4 and 6 expressions 
have also been identified in the human lens epithelial cell67 a potential risk for cataract
formation in palbociclib-treated patients cannot be completely excluded. 

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To date, approximately 700 patients have enrolled in palbociclib trials. A review of the 
Pfizer safety database for cases received through 14 January 2014 identified no serious cases 
from clinical studies or other solicited sources including palbociclib or blinded therapy that 
included adverse events which code to the MedDRA  (Version 16.1) High Level Group Term 
“Anterior eye structural change, deposit and degeneration”. In addition, no cases coding to 
the aforementioned MedDRA term were reported to the safety database from any other 
sources during this period for patients who received palbociclib. Cataract has been reported 
as an adverse event in 2 patients (1 Grade 2 and 1 Grade 3) out of approximately 400 patients 
who have been treated with palbociclib in Pfizer-sponsored studies. Neither event was 
considered serious nor related to palbociclib and both patients had other identifiable risk 
factors for cataracts, such as age and long term corticosteroid use. Both patients continued 
on treatment for 16-18 months beyond the diagnosis of cataract. 
Literature report suggests that the incidence of cataract in women aged 35 and older with risk 
of breast cancer is approximately 2.3%.69 Cataract has also been  reported in patients treated 
with tamoxifen or letrozole.68,69
1.2.5.5. Palbociclib Dose Rationale
Palbociclib has been tested in a Phase 1 dose escalation Study (A5481001) in 74 patients 
with advanced cancer.  Two dosing schedules were evaluated: Schedule 3/1 (3 weeks on 
treatment/1 week off treatment) and Schedule 2/1 (2 weeks on treatment/1 week off 
treatment).
All Dose Limiting Toxicity (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.  The most 
common non-hematological adverse events included fatigue, diarrhea, constipation, vomiting 
and dyspnea, all with mild to moderate severity.  A greater proportion of patients on the 2/1
schedule had treatment-related Treatment Emergent Adverse Events (TEAEs) 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.  One partial response was reported in a patient with testicular cancer.  A 
total of 13/37 patients treated with Schedule 3/1 evaluable for efficacy experienced stable 
disease (SD), including 6 patients with SD lasting 40 weeks or longer.  One of these patients 
was a woman with ER+ breast cancer who had previously received 7 lines of treatment for 
her disease.  This patient remained on treatment for 80 weeks (7 cycles at 50 mg/d and 

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13 cycles at 75 mg/d) and eventually discontinued treatment due to disease progression.  
Based on the relatively improved safety profile of Schedule 3/1, and the efficacy results from 
this study, the Schedule 3/1 has been selected for further clinical development and the RP2D 
for this schedule was determined to be 125 mg/d.  This schedule and associated RP2D was 
further explored in combination with letrozole in the Phase I/II study in patients with ABC 
described below.
1.2.5.6. Phase I/II Data in Combination with Letrozole in Advanced Breast Cancer
Based on the preclinical evidence that Palbociclib is highly active in ER(+) cell lines and the 
encouraging safety and PK profiles observed in the initial clinical studies, a randomized, 
multicenter active-controlled Phase 1/2 Study (A5481003) was designed to assess the 
efficacy, safety and pharmacokinetics of letrozole 2.5 mg QD (continuously) in combination 
with Palbociclib 125 mg QD (schedule 3/1) versus single agent letrozole 2.5 mg QD 
(continuously) for the first-line treatment of ER(+), HER2 (-) ABC in postmenopausal 
women. Letrozole was selected as the active control based on its worldwide approval and 
use as standard of care for the first-line hormonal treatment of postmenopausal women with 
ER(+) ABC.
Study A5481003 was comprised of a limited Phase 1 portion, aimed at confirming the safety 
and tolerability of the combination and excluding a PK interaction with the combination, and 
a randomized Phase 2 portion aimed at evaluating the efficacy and safety of letrozole in 
combination with Palbociclib when compared to letrozole alone in the first-line treatment of 
postmenopausal patients with ER(+), HER2(-) ABC.  The Phase 2 portion consisted of 
2 parts. In Part 1, patient selection was based only on ER/HER2 status.  In Part 2, patients 
were prospectively selected also taking into account tumor CCND1 amplification and/or 
p16 loss. As of 18 May 2012, 177 patients have been enrolled in this study and enrollment is 
closed. Twelve (12) were enrolled in the Phase 1 portion and 165 (66 and 99 in Part 1 and 
2, respectively) were enrolled in the Phase 2 portion.
Results from the Phase 1 portion,70 indicated no PK interaction between Palbociclib and 
letrozole with mean AUC(0-24) of 2002 and 2043 ng•hr/mL (n=11) for Palbociclib in the 
absence and presence of letrozole, respectively, and 1990 and 1730 ng•hr/mL (n=10) for 
letrozole in the absence and presence of Palbociclib, respectively. The RP2D was 
determined to be 125 mg QD on Schedule 3/1 (3 weeks continuous treatment followed by 
1 week off treatment) in combination with letrozole 2.5 mg QD continuously.  Partial 
responses were reported for 3 (33%) out of 9 patients with measurable disease (3 had 

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bone-only disease). Another 5 patients (42%) had stable disease for ≥ 6 months and the 
clinical benefit rate (PR + SD ≥ 6 months) was 67%. Eight (8) patients discontinued from 
the study due to disease progression, including 2 patients with clinical progression, and 
4 patients are still ongoing. 
Final results from Part 1 plus Part 2 of the Phase 2 portion were presented at the 2014
American Association for Cancer Research (AACR) annual meeting71 and included a total 
of 165 postmenopausal women with ER(+) / HER2(-) locally recurrent or metastatic breast 
cancer enrolled to either receive Palbociclib in combination with letrozole (n=84 patients) or 
letrozole monotherapy (n=81 patients). 
The combination therapy was generally well tolerated when compared to letrozole alone with 
adverse events (AEs) similar to those seen with Palbociclib and letrozole when administered 
alone, with the exception of hematologic toxicity.  Neutropenia(48%), leukopenia(19%) and 
anemia(5%)were the most frequent treatment-related Grade 3 adverse events in patients 
treated with the combination therapy.  Grade 4 treatment-related events included neutropenia 
and anemia, reported in 6% and 1% , respectively, of patients treated with 
Palbociclib plus letrozole. However, the neutropenia observed with the combination in this 
study was non-cumulative and clinically manageable. Neutropenia is an on-target, anti-
proliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone 
marrow.  
Efficacy analyses were performed on the basis of radiologic assessment of disease status by 
investigators to determine preliminary antitumor activity according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v.1.0.  Median Progression Free Survival (PFS) was 
prolonged in patients who received combination therapy compared to letrozole alone (20.2
months vs. 10.2 months). Objective response and clinical benefit rates (43% vs. 33% and 
81% vs. 58%, respectively)  were also superior with the combination therapy.
These results indicate that the combination of Palbociclib with letrozole is well tolerated with 
AEs similar to those seen with either Palbociclib or letrozole when administered alone. 
Additionally, the combination demonstrated antitumor activity which was consistent with the 
sensitivity of ER(+) breast cancer observed in the preclinical models.

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1.2.6. Study Rationale 
In the first-line treatment setting, letrozole is among the preferred anti-hormonal therapies for 
postmenopausal women with ER(+)/HER2(-) ABC.72 It is approved and commercially 
available globally with a well known and manageable safety profile. However, median 
progression-free survival in this patient population remains less than 1 year and median 
overall survival is approximately 3 years.4  Furthermore, aromatase inhibitor failure has been 
linked to increased proliferative index and cell cycle dysregulation, providing a strong 
rationale for combining letrozole with Palbociclib. Preliminary data from 
Phase 1/2 Study A5481003 suggest that the combination of Palbociclib inhibition of
CDK 4/6 (blocking DNA synthesis by prohibiting progression of the cell cycle from G1 to 
S phase) with the antiproliferative effects of letrozole provides greater antitumor activity and 
prolongs PFS (ie median 26.1 months vs 7.5 months) when compared to single agent 
letrozole. Additionally, the study shows that the combination is generally well tolerated with 
uncomplicated neutropenia as the most frequent adverse event.71
This randomized Phase 3 Study (A5481027) provides the opportunity to confirm the clinical 
benefit of the combination of Palbociclib with letrozole observed in the randomized 
Phase 2 study in Asian patients. The study is designed to demonstrate that Palbociclib in 
combination with letrozole provides superior clinical benefit compared to letrozole in 
combination with placebo in Asian postmenopausal women with ER(+)/HER2(-) 
locoregionally recurrent or metastatic advanced breast cancer who have not received any 
prior systemic anti-cancer therapies for advanced stage disease.
Complete information for Palbociclib may be found in the Single Reference Safety 
Document for the compound, which for this study is the Investigator's Brochure. The Single 
Reference Safety Document for the active comparator agent, letrozole, is the local package 
insert.

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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives
Primary Objective:

To compare the combination of Palbociclib plus letrozole with placebo plus letrozole 
in term of progression-free survival (PFS) in Asian postmenopausal women with 
ER(+)/HER2(-) advanced breast cancer (ABC) who have not received any prior 
systemic anti-cancer therapy for advanced disease.
Secondary Objectives:

To compare Objective Response (OR), Duration of Response (DR), Disease Control
Rate (DCR), and Overall Survival (OS) between the treatment arms;

To evaluate the safeties and tolerability of the treatment arms;

To determine trough Palbociclib plasma concentration in this patient population and
explore the correlations between exposure and response and/or safety findings;To 
compare health-related quality of life between the treatment arms;

To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle, 
drug targets, and tumor sensitivity and/or resistance in tumor tissues;

To explore the relationship between germline polymorphism in CDK6 gene and 
palbociclib treatment related neutropenia.
2.2. Endpoints
Primary Endpoint

Progression-Free Survival (PFS) based on investigator’s assessment.
Secondary Endpoint(s)

Progression-Free Survival (PFS) based on blinded independent central review 
(BICR);

Objective Response (OR);

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
Duration of Response (DR);

Disease Control Rate (DCR);

Overall Survival (OS);

1-year, 2-year, and 3-year Survival Probabilities;

Trough plasma concentration of Palbociclib;

Quality of life assessments: EuroQol (EQ-5D) Score (see Appendix 5) and Functional 
Assessment of Cancer Therapy - Breast (FACT-B) (See Appendix 6);

Type, incidence, severity (as graded by NCI CTCAE v4.0), seriousness and 
relationship to study medications of adverse events (AE) and any laboratory 
abnormalities;

Tumor tissue biomarkers, including genes, proteins, and RNA expression (eg, ER, 
Ki67).
3. STUDY DESIGN
This is an international, multicenter, randomized(1:1), double-blind, placebo-controlled, 
parallel-group, Phase 3 clinical trial comparing the efficacy and safety of Palbociclib in 
combination with letrozole versus placebo in combination with letrozole in postmenopausal 
Asian women with ER(+)/HER2 (-) advanced breast cancer. Eligible patients will have 
histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of locoregionally recurrent or metastatic disease and will be candidates to receive
letrozole as first-line treatment for their advanced disease. In order to avoid inclusion of 
patients who are refractory or resistant to non-steroidal aromatase inhibitors, patients who 
received anastrozole or letrozole as a component of their (neo)adjuvant regimen may only 
enter the study if their disease did not progress while on or within 12 months from 
completion of their anastrozole/letrozole-containing (neo)adjuvant therapy. Patients will not 
have received any prior systemic anti-cancer therapy for their advanced disease and will not 
be candidates for curative therapies. Patients must have measurable disease as per 
RECIST v.1.1 or bone disease as their only site of disease.  Tumor tissue availability is 
required for patient participation.

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At least approximately 330 eligible patients will be randomized 1:1 to receive either 
Palbociclib plus letrozole (Arm A: at least approximately 165 patients) or placebo plus 
letrozole (Arm B: at least approximately 165 patients). Among these approximately 
330 patients, at least 264 patients will be from China and the rest of the patients will be from 
other Asia countries. Patients will be stratified at randomization by region (China vs other),
by site of disease (visceral* vs non-visceral**), by disease-free interval since completion of 
prior (neo)adjuvant therapy (de novo metastatic; ≤12 months; >12 months), and by the nature 
of prior (neo)adjuvant anticancer treatment received (prior hormonal therapy; no prior 
hormonal therapy).
*"Visceral" refers to any lung and/or liver involvement. 
**"Non-visceral" refers to absence of lung and/or liver involvement.
Patients randomized to Arm A (investigational arm) will receive: 

Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle 
followed by 7 days off treatment;
in combination with 

Letrozole, 2.5 mg, orally once daily (continuously). 
Patients randomized to Arm B (comparatorl arm) will receive: 

Placebo orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 
7 days off treatment;
in combination with 

Letrozole, 2.5 mg, orally once daily (continuously). 
Patients will continue to receive assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  However, patients may continue treatment as assigned at randomization beyond 
the time of RECIST-defined disease progression at the discretion of the investigator if that is 
considered to be in the best interest of the patient and as long as no new anticancer treatment 
is initiated. In this case, the patient would continue with routine safety relevant assessments 
as per the Schedule of Activities for the active treatment period.

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The importance of timely and complete disease assessments in this study cannot be 
overstated. Disease assessments will be performed every 12 weeks (± 7 days) from the date 
of randomization. Patients with bone lesions identified at baseline will also have repeat bone 
scans performed every 24 weeks (± 7 days) from the date of randomization.  Each assessment 
will be performed as scheduled according to the calendar regardless of any dosing delay to 
prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the 
required disease assessments will result in the inability to determine disease status for that 
time point.  Tumor assessments will be performed until radiographically and/or clinically (ie, 
for photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment 
discontinuation (for patients continuing treatment beyond RECIST-defined disease 
progression), initiation of new anticancer therapy or discontinuation of patient from overall 
study participation (eg, death, patient's request, lost to follow-up), whichever occurs first.  A
series of incomplete disease assessments will result in censoring of the primary endpoint of 
PFS back to the time of the last full assessment that did not show progression. 
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie for photographed or palpable lesions) documented PD as per RECIST v.1.1 will 
continue to have tumor assessments performed during the follow-up visits every 12 weeks 
(± 7 days) and bone scans (if applicable) every 24 weeks (± 7 days) until RECIST-defined 
disease progression, initiation of new anticancer therapy or discontinuation of patient from 
overall study participation (eg, death, patient's request, lost to follow-up), whichever occurs 
first.
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as primary data source. However, a blinded independent third-party core 
imaging laboratory will complete a retrospective review of radiographic images and clinical 
information collected on-study to verify the protocol-defined endpoints of disease response 
and progression as assessed by the investigator.
Patients discontinuing the active treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every 6 months from the 
last dose of investigational product. The follow-up period will conclude at the time of the 
final OS analysis. Crossover will not be allowed in the trial.
Patients will undergo study-related safety and efficacy assessments as outlined in the relevant 
Schedule of Activities located in the summary section. 

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The study also includes molecular profiling components aimed at characterizing alterations 
in genes, proteins, and RNAs relevant to the cell cycle, drug targets, and tumor sensitivity 
and/or resistance in tumor tissues, and assessing the relationship between germline 
polymorphism in CDK6 gene and palbociclib treatment related neutropenia. 
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 the protocol treatment is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1.
Adult Asian women (ages 18-70 years, inclusive) with proven diagnosis of 
adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic 
disease not amenable to resection or radiation therapy with curative intent and for whom 
chemotherapy is not clinically indicated.
2.
Documentation of histologically or cytologically confirmed diagnosis of 
estrogen-receptor positive (ER+) breast cancer based on local laboratory results. 
3.
Previously untreated with any systemic anti-cancer therapy for their locoregionally 
recurrent or metastatic ER+ disease.
4.
Postmenopausal status defined as :

Prior bilateral surgical oophorectomy, or

Medically confirmed post-menopausal status defined as spontaneous cessation of 
regular menses for at least 12 consecutive months or follicle-stimulating hormone 
(FSH) and estradiol blood levels in their respective postmenopausal ranges with no 
alternative pathological or physiological cause.

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5.
Measurable disease as defined per RECIST v.1.1 (see Appendix 7) or bone-only disease.  
Tumor lesions previously irradiated or subjected to other locoregional therapy will only 
be deemed measurable if disease progression at the treated site after completion of 
therapy is clearly documented.
6.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see 
Appendix 1).
7.
Adequate organ and bone marrow function defined as follows: 

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);

Serum creatinine ≤1.5 x Upper Limit of Normal (ULN) or estimated creatinine 
clearance ≥ 60 mL/min as calculated using the method standard for the institution;

Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease);

AST and/or ALT ≤3 x 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). 
8.
Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to 
NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator's discretion).
9.
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures.
10. All patients must agree to provide tumor tissues for centralized retrospective 
confirmation of ER status and to evaluate correlation between genes, proteins, and RNAs 
relevant to the cell cycle pathways and sensitivity/resistance to the investigational agents.  
Freshly biopsied, recurrent/metastatic tumor samples must be provided whenever 
possible.  If such a biopsy is not feasible or cannot be safely performed, then an archived 
tumor sample may be accepted.  In either case a formalin fixed, paraffin embedded 
(FFPE) block or 12 unstained FFPE slides (highly recommend to submit tissue block or 

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12 unstained slides, but if there would be technical difficulties or other issues refraining 
from obtaining tissue block or 12 unstained slides, however, it is still mandatory 
to collect a minimum 7 unstained slides) are required for patient participation.
11. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1.
HER2-positive tumor as defined by documentation of erbB-2 gene amplification by FISH 
(as defined by a HER2/CEP17 ratio ≥2) or chromogenic in situ hybridization (CISH, as 
defined by the manufacturer’s kit instruction) or documentation of HER2-overexpression 
by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local 
laboratory results utilizing one of the sponsor-approved assays (see Appendix 2). If 
HER2 status is unavailable or was determined using a test other than a sponsor-approved 
assay, then testing must be performed/repeated using one of these assays prior to 
randomization. If tissue sample from both primary and recurrent/metastatic tumors are 
available, HER2 assessment from the most recent sample (ie, recurrent/metastatic 
sample) should be used to define eligibility whenever feasible.
2.
Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening 
complications in the short term (including patients with massive uncontrolled effusions 
[pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver 
involvement).
3.
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, 
or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or 
progressive growth.  Patients with a history of CNS metastases or cord compression are 
eligible if they have been definitively treated with local therapy (eg, radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 
4 weeks before randomization.
4.
Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (ie,
anastrozole or letrozole) with disease recurrence while on or within 12 months of 
completing treatment.

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5.
Prior treatment with any CDK4/6 inhibitor.
6.
Patients treated within the last 7 days prior to randomization with:

Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, 
boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, 
fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice);

Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, 
nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and 
St. John’s wort);

Drugs that are known to prolong the QT interval (see Appendix 3).
7.
Major surgery, chemotherapy, radiotherapy, any investigational agents, or other 
anti-cancer therapy within 2 weeks before randomization. Patients who received prior 
radiotherapy to ≥25% of bone marrow are not eligible independent of when it was 
received (see Appendix 4).
8.
Diagnosis of any other malignancy within 3 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.
9.
Machine-read QTc >480 msec (based on the mean value of the triplicate 
Electrocardiogram, ECGs), family or personal history of long or short QT syndrome, 
Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging 
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
11. Any of the following within 6 months of randomization: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE
version 4.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident including transient 
ischemic attack, or symptomatic pulmonary embolism.

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12. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any 
upper gastrointestinal surgery including gastric resection.
13. Known hypersensitivity to letrozole, or any of its excipients, or to any 
Palbociclib/placebo excipients.
14. Known human immunodeficiency virus infection.
15. Other severe acute or chronic medical or psychiatric condition (including recent 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.
16. Patients who are investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the 
trial.
17. Participation in other studies involving investigational drug(s) (Phase 1-4) within 4 weeks 
before the current study begins and/or during study participation in the active treatment 
phase of the trial.
4.3. Randomization Criteria

Patients will be randomized into the study provided they have satisfied all patient 
selection criteria. 

The investigators or their pre-specified designee will randomize eligible patients by 
interactive randomization technology (IRT) as described in the Study Reference 
Manual. 

At the time of randomization, information about patient demographics and 
stratification factors [ie, region (China vs other), site of disease (visceral vs 
non-visceral), disease-free interval since the end of the (neo)adjuvant treatment to 
disease recurrence (de novo metastatic vs ≤12 months vs >12 months), nature of prior 
(neo)adjuvant anticancer therapies (prior hormonal therapy vs no prior hormonal
therapy)] will be requested. 

The central computerized system will provide the randomization number and 
treatment assignment. 

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4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the team sharepoint site.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects 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 help desk 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 subjects 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used 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 help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site.  
5. STUDY TREATMENTS
5.1. Allocation to Treatment
If the patient is found to be eligible for the study, she should be randomized using a 
centralized internet/telephone registration system no more than 4 business days before 
administration of the first dose of investigational product. 
After a patient has provided written informed consent, has completed the necessary baseline
assessments, and is found to be eligible for the study, the clinical site must complete a Patient 
Pre-Randomization Form which includes key eligibility criteria (eg, breast cancer diagnosis, 
stage of disease at initial diagnosis and at screening, hormonal receptor and HER2 status as 
per local results, prior systemic therapy, disease free interval (DFI) from prior (neo)adjuvant 
letrozole or anastrozole (if applicable)) and send it to the sponsor for approval of
randomization.  Upon receipt of the sponsor’s approval the site must contact a centralized 
internet/telephone registration system as described in the Study Reference Manual, to enroll 
the patient on study (see Section 4.3). 

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Eligible patients will be randomly assigned in a 1:1 ratio to either Arm A (investigational 
arm: Palbociclib plus letrozole) or Arm B (comparator arm: placebo plus letrozole) stratified 
according to region, site of disease, disease-free interval since completion of prior 
(neo)adjuvant therapy, and nature of prior (neo)adjuvant anticancer treatment received (see 
Section 4.3).
Clinical sites must complete the screening case report forms (CRFs) for all registered and 
randomized patients, even if the patient is not subsequently treated in this study.
At the time of registration, the clinical site staff must provide site and patient identifiers and
demographic information. The IRT will assign a unique patient identification number.  The
IRT system will also be used to assign study medication.
If a patient does not receive the correct study treatment for their allocated treatment arm, the 
reason must be clearly documented in CRF. The patient will remain on study, baseline data 
will be collected and follow up will continue as described in the relevant Schedule of 
Activities table.
5.2. Breaking the Blind
This study will be patient and investigator blinded. At the initiation of the trial, the trial site 
will be instructed on the method for breaking the blind. The method will be by contacting 
the interactive response technology (IRT) provider. Blinding codes should only be broken in 
emergency situations for reason of patient safety. Blinding codes may also be broken after a 
patient discontinues treatment due to disease progression, as determined by the treating 
investigator using RECIST v.1.1 criteria, but only if deemed essential to allow the 
investigator to select the patient's next treatment regimen and after discussion and agreement 
with the sponsor.  Code should not be broken in the absence of emergency situations or 
progressive disease as per RECIST v.1.1 (eg, in case of clinical deterioration, increase in 
tumor markers or any other evidence suggestive of disease progression but in the absence of 
RECIST-defined disease progression).  When the blinding code is broken, the date and 
reason for unblinding must be fully documented in source documents and entered on the case 
report form. However, every effort should be made by the site staff to ensure that the 
treatment arm in which the unblinded patient is assigned is not communicated to any sponsor
personnel or designee involved in the conduct of the trial. 

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5.3. Drug Supplies
The investigational drug used in the course of this trial is Palbociclib/placebo. In addition, 
all patients will receive letrozole.  All three medications will be supplied by the sponsor.
5.3.1. Formulation 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 sponsor will supply the oral drug formulation to sites 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/Placebo Capsule Characteristics
Dosage
Capsule color
Capsule size
75 mg
Sunset Yellow/Sunset Yellow
2
100 mg
Caramel/Sunset Yellow
1
125 mg
Caramel/Caramel
0
5.3.1.2. Placebo
Placebo will be indistinguishable from the Palbociclib capsules and will be supplied as 
capsules matching in size and color the various Palbociclib formulations (see Table 1). The 
sponsor will supply placebo to sites in HDPE bottles. 
5.3.1.3. Letrozole
Commercially available letrozole 2.5 mg film-coated tablets will be supplied to sites by the 
sponsor. Complete information about letrozole formulation can be found in the local package 
insert.
5.3.2. Preparation and Dispensing
5.3.2.1. Palbociclib/Placebo
Palbociclib will be provided in non-patient-specific bottles containing either 75 mg, 100 mg 
or 125 mg capsules. Matching placebo capsules will be provided in non-patient-specific 
bottles as to be indistinguishable from Palbociclib. 

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The patient number should be recorded on the bottle label in the spaces provided by site 
personnel at the time of assignment to patient.  Site personnel must ensure that patients 
clearly understand the directions for self-medication.  Patients should be given a sufficient 
supply to last until their next study visit.  Unused drug and/or empty bottles should be 
returned to the site at the next study visit. Returned unused medication MUST NOT be 
re-dispensed to patient. 
Palbociclib/placebo is an agent that must be handled and administered with care.  Patients 
should be instructed to keep their medication in the bottles provided and not transfer it to any 
other container.  Due to possible unknown hazards associated with topical and environmental 
exposure to experimental agents, capsules must not be opened and/or emptied into any 
vehicle for oral ingestion; capsules must be swallowed intact.
Only one capsule strength will be dispensed to the patient at each dispensing visit. In the
event of dose modification, request should be made of the patient to return all previously 
dispensed medication to the clinic and new capsules will be dispensed.
5.3.2.2. Letrozole
Letrozole should be prepared and dispensed according to the package insert or standard 
practice at the study site. 
The patient number should be recorded on the bottle label in the spaces provided by site 
personnel at time of assignment to patient.  Site personnel must ensure that patients clearly 
understand the directions for self-medication.  Patients should be given a sufficient supply to 
last until their next study visit.  Unused drug and/or empty bottles should be returned to the 
site at the next study visit.
5.3.3. Administration
5.3.3.1. Palbociclib/Placebo
Patients should be instructed to swallow Palbociclib/placebo capsules whole and not to chew 
them prior to swallowing.  No capsule should be ingested if it is broken, cracked, or 
otherwise not intact.  Patients should be encouraged to take their dose at approximately the 
same time each day.  Patients should be instructed to record daily administration of the study 
drugs in a patient diary.

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Palbociclib/placebo will be administered together with letrozole. Patients should take 
Palbociclib /placebo with food. Palbociclib/placebo will be administered orally once a day 
for 21 days of every 28-day cycle followed by 7 days off treatment.
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section 5.3.4.
5.3.3.2. Letrozole
Letrozole will be administered orally once daily continuously together with 
Palbociclib/placebo.
Refer to the local package insert for Letrozole for additional administration instructions.
5.3.3.3. General Rules
For both Palbociclib/placebo and letrozole: 

Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the 
next day.

Patients who vomit anytime after taking a dose must be instructed NOT to “make it 
up,” and to resume treatment the next day as prescribed. 

Patients who inadvertently take 1 extra dose during a day must be instructed to skip 
the next day’s dose. Also refer to Section 5.3.5 for further details on medication 
errors and overdose.
5.3.4. Dose Modification
Every effort should be made to administer study treatment on the planned dose and schedule.  
However, in the event of significant treatment-related toxicity, administration of study drugs 
(Palbociclib/placebo or letrozole) may need to be adjusted as described in the following 
sections. Depending on the nature of the toxicity observed, dosing adjustment may be 
required for just one or both study drugs in the combination.  In the event treatment 
interruption is deemed necessary for just one of the study drugs in the combination, treatment 
with the other study drug will continue as planned. 

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5.3.4.1. Letrozole 
No dose adjustment for letrozole is permitted but dosing interruptions are allowed.  
Treatment interruption for letrozole-related toxicities will be performed as per the 
investigator’s best medical judgment.
Patients discontinuing letrozole treatment due to treatment-related toxicity will be 
discontinued from the active treatment phase of the study and enter the follow-up phase.
5.3.4.2. Palbociclib/Placebo
In the event of significant treatment-related toxicity, Palbociclib/placebo dosing may be 
interrupted or delayed and/or reduced as described below.  In the event of multiple toxicities, 
dose modification should be based on the worst toxicity observed.  Patients are to be 
instructed to notify Investigators at the first occurrence of any adverse sign or symptom.
Dose modifications may occur in three ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle;

Between cycles: next cycle administration may be delayed due to persisting toxicity
when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
Patients discontinuing Palbociclib/placebo treatment due to treatment-related toxicity may 
continue on the active treatment phase of the study receiving letrozole monotherapy as per 
the investigator’s discretion. 
5.3.4.2.1. Dosing Interruptions
Patients experiencing the following adverse events should have their treatment 
interrupted/delayed: 

Uncomplicated Grade 3 neutropenia (ANC<1000/mm3);

Grade 3 neutropenia (ANC<1000/mm3) associated with a documented infection or 
fever 38.5C;

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
Grade 4 neutropenia (ANC<500/mm3);

Grade 4 thrombocytopenia (Platelet count <25,000/mm3);

Grade 3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment);

Grade 3 QTc prolongation (QTc ≥501 msec on at least two separate ECGs).
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator.  Criteria required before treatment can resume are described in 
Section 5.3.4.2.2.
Doses may be held as needed until toxicity resolution.  Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed.  Doses omitted for toxicity are not replaced within the 
same cycle.  The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in Section 5.3.4.2.3 Dose Reductions unless expressly agreed 
otherwise following discussion between the investigator and the sponsor.  If a dose reduction 
is applied in the same cycle, the patient will need to return to the clinic to receive new drug 
supply.
In the event of a treatment interruption for reasons other than treatment-related toxicity (eg, 
non-cancer related surgery) lasting >2 weeks, treatment resumption will be decided in 
consultation with the sponsor.
5.3.4.2.2. Dose Delay
Retreatment following treatment interruption for treatment related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met:

Platelet count 50,000/mm3;

ANC 1000/mm3 and no fever;

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
Grade 3 or higher treatment-related non-hematologic AEs (including, nausea, 
vomiting, diarrhea, and hypertension only if persisting despite optimal medical 
treatment), with the exception of alopecia, have recovered to Grade ≤ 1 or baseline 
(or, at the investigator’s discretion, Grade ≤ 2 if not considered a safety risk for the 
patient).

QTc <501 msec and potential reversible causes (eg, electrolyte imbalance, 
concomitant medications known to prolong QTc) corrected.  If QTc remains above 
480 msec, ECG should be monitored more frequently as per the investigator’s best 
medical judgement until QTc≤480 msec.
If a treatment delay results from decline in hematologic parameters, the frequency of blood 
count assessments should be increased as clinically indicated.
If these parameters are met within 2 weeks of treatment interruption or cycle delay, 
Palbociclib/placebo may be resumed. Please refer to Section 5.3.4.2.3 Dose Reductions for 
adverse events requiring dose reduction at the time of treatment resumption. 
If these parameters have not been met after 2 weeks of dose interruption (including the 
scheduled 1 week off treatment) or 2 weeks of cycle delay, permanent discontinuation of 
Palbociclib/placebo treatment should be considered.  Treatment resumption for patients 
recovering from treatment-related toxicity after > 2 weeks of treatment interruption or cycle 
delay but deemed to be deriving obvious clinical benefit per the investigator’s best medical 
judgment is left at the investigator’s discretion.
5.3.4.2.3. Dose Reductions
Following dose interruption or cycle delay the Palbociclib/placebo dose may need to be 
reduced when treatment is resumed.
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.
Dose reduction of Palbociclib /placebo by 1 and, if needed, 2 dose levels (Table 2) will be 
allowed depending on the type and severity of toxicity encountered.  Patients requiring more 
than 2 dose reductions will be discontinued from the study and entered into the follow-up 
phase. All dose modifications/adjustments must be clearly documented in the patient's 
source notes and Investigational product administration CRF. 

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Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Dose re-escalation 
is not allowed.
Table 2.
Available Dose Levels
Dose Level
Palbociclib/Placebo for 3 out of 4 
weeks (3/1 schedule)
Letrozole on a continuous daily 
dosing regimen
Starting dose
125 mg/d
2.5 mg/d
-1
100 mg/d
2.5 mg/d
-2
75 mg/d*
2.5 mg/d
Discontinue Study Treatment
* Palbociclib/placebo dose de-escalation below 75 mg/d is not allowed.
Palbociclib/placebo recommended dose modifications for treatment related toxicities 
requiring treatment interruption/delay or persisting despite optimal medical treatment are 
described in Table 3 and Table 4.
Table 3.
Palbociclib/Placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal 
Medical Treatment.
Type and Grade of Toxicity:
Restart Palbociclib/Placebo 
Treatment at:
Uncomplicated Grade 3 neutropenia (ANC<1000/mm3)
Same dose level
Grade 3 neutropenia (ANC<1000/mm3) associated with a 
documented infection or fever 38.5C
1 Dose Level
Grade 4 neutropenia (ANC<500/mm3)
1 Dose Level
Grade 4 thrombocytopenia (Platelet count <25,000/mm3)
1 Dose Level
Grade 3 non-hematologic toxicity (including, nausea, 
vomiting, diarrhea, and hypertension only if persisting 
despite optimal medical treatment)
1 Dose Level

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Table 4.
Palbociclib/Placebo Dose Modifications for Hematologic Toxicities (by
CTCAE Grade and on Day of Treatment)a
Day of treatment
CTCAE Grade
Dose modifications
Cycle 1 Day 14
Grade 1, 2, and 3b
No dose adjustment is required
Grade 3c with documented 
infection or fever 38.5C
Grade 4
d
Withhold until recovery to Grade ≤2, then 
resume at next lower dose at start of next cycle
Cycle 1 Day 21
Grade 1, 2, and 3b
No dose adjustment is required
Grade 3c with documented 
infection or fever 38.5C  
Grade 4
d
Withhold until recovery to Grade ≤2, then 
resume at next lower dose at start of next cycle
Cycle 2 Day 1
Grade 1 and 2
No dose adjustment is required
Grade 3
b
Withhold until recovery to Grade ≤2, then 
resume at current dose
Grade 3c with documented 
infection or fever 38.5C
Grade 4
d
Withhold until recovery to Grade ≤2, then 
resume at next lower dose
Cycle 2 Day 21
Grade 1, 2, and 3b
No dose adjustment is required
Grade 3c with documented 
infection or fever 38.5C
Grade 4
d
Withhold until recovery to Grade ≤2, then 
resume at next lower dose at start of next cycle
Day 1 of subsequent 
cycles
Grade 1 and 2
No dose adjustment is required
Grade 3
b
Withhold until recovery to Grade ≤2, then 
resume at current dose
Grade 3c with documented 
infection or fever 38.5C
Grade 4
d
Withhold until recovery to Grade ≤2, then 
resume at next lower dose
   Grading according to CTCAE Version 4.0.
   ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events.
a
Monitor complete blood count prior to starting Palbociclib and on Day 14 and 21 of the first 
cycle. Obtain complete blood count at the start of, and on Day 21 of the second cycle.
Continue monthly monitoring of complete blood count at the beginning of each cycle for at 
least 4 subsequent cycles. Once complete blood count has stabilized, monitor as clinically 
indicated.
b
Patients experiencing uncomplicated Grade 3 neutropenia (ANC<1000/mm3) should still 
have their treatment interrupted/delayed until recovery to Grade≤2, then resume at the same 
current dose. 
c
Patients with Grade 3 neutropenia (ANC<1000/mm3) associated with a documented 
infection or fever 38.5C should have their treatment interrupted/delayed until recovery to 
Grade≤2 and fever is no longer present, then resume at next lower dose.
d
Except lymphopenia (unless associated with clinical events, eg, opportunistic infections).

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QTc prolongation management
In the event of QTc prolongation of, possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong 
the QTc interval should be evaluated. 
If such reversible causes are identified, then they should be corrected accordingly (ie, 
correction of electrolyte abnormalities with supplements to within normal limits and/or
discontinuation (if possible) of concomitant medications known to prolong the QT interval). 
Recommended dose modifications in the event of QTc prolongation are provided in Table 5. 
Table 5.
Palbociclib/Placebo Dose Modifications in the Event of QTc Prolongation
Toxicity (NCI CTC Grade, Version 4.0)
Grade 2 QTc prolongation
Grade 3 QTc prolongation
Grade 4 
QTc 
prolongation
Reversible 
cause 
identified
Treat reversible cause
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical
judgment until QTc≤480 msec
Continue at the same dose level (1)
Treat reversible cause
Withhold treatment until QTc<501 msec
Resume treatment at the same dose level.
Monitor ECG more frequently as per 
investigator’s best medical judgment
until QTc≤480 msec.
Permanently 
discontinue
No 
reversible 
cause 
identified
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc≤480 msec
Continue at the same dose level (1)
Withhold treatment until QTc<501 msec
Resume treatment at the next lower dose
level (2)
Monitor ECG more frequently as per 
investigator’s best medical judgment 
until QTc≤480 msec.
Permanently 
discontinue
1.
If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the 
absence of other alternative causes or despite correction of alternative causes, dose adjustment and/or 
discontinuation should be considered in consultation with a cardiologist and the study medical monitor, 
taking into account the emerging safety data from Palbociclib trials and the investigator’s best medical 
judgment.
2.
If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment and/or 
discontinuation should be discussed with study medical monitor in consultation with a cardiologist, taking 
into consideration the emerging safety data from Palbociclib trials and the investigator’s best medical 
judgment.

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5.3.5. Medication Errors and Overdose
Medication errors may result in this study from the administration or consumption of the 
wrong drug, 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 
case report form (CRF) which is a specific version of the adverse event (AE) page and on the 
serious adverse event (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 should be captured on the medication error version of the 
adverse event (AE) page and, if applicable, any associated adverse event(s) are captured on 
an adverse event (AE) CRF page.
5.3.6. Compliance
Patients will be required to return all bottles of Palbociclib/placebo and all bottles of letrozole 
as well as the completed patient diary at the beginning of each cycle for drug accountability.  
Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug 
supply for the next cycle.  The number of remaining capsules/tablets will be documented and 
recorded.
To be considered compliant, each study patient must have received at least 80% of the 
planned number of doses of primary therapy based on the number of days of actual dose 
administration. Dose adjustments must follow instructions provided in the dose adjustment 
guidelines section. 
5.4. Drug Storage and Drug Accountability
Storage conditions stated in the Study Reference Safety Document (ie, Investigator’s
Brochure (IB) or Local Product Document (LPD)) may be superseded by the label storage.
Investigators and site staff are reminded to check temperatures daily (ie, manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 

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correctly as required for proper storage of investigational products (See Sections 5.4.1 & 
5.4.2).  These include thermometers for both the room storage and refrigerator storage.  Any 
temperature excursions should be reported to the sponsor.  The investigational product(s) 
must be stored as indicated.  Deviations from the storage requirements, including any actions 
taken, must be documented and reported to the sponsor.  Once a deviation is identified, the 
investigational products (Palbociclib/placebo or letrozole) MUST be quarantined and not 
used until the sponsor provides documentation of permission to use the investigational 
product. 
At the end of the trial, the sponsor will provide instructions as to disposition of any unused 
investigational product.  If the sponsor authorizes destruction at the trial site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by the sponsor.  
Destruction must be adequately documented.
5.4.1. Palbociclib/Placebo
Palbociclib/placebo capsules should be stored at controlled room temperature (15-30C, 
59-86F) in their original container.
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication should be stored separately from 
medication that needs to be dispensed.
To ensure adequate records, Palbociclib/placebo capsules will be accounted for as instructed 
by the sponsor. Patients are requested to return previously dispensed containers as well as 
their completed patient diary to the clinic at each visit for accountability purposes even if 
they will not be issued with new medication at that visit.
5.4.2. Letrozole
Letrozole tablets must be stored according to the instructions detailed in the local package 
insert. 
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication should be stored separately from 
medication that needs to be dispensed.

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To ensure adequate records, letrozole tablets will be accounted for as instructed by the 
sponsor.  Patients are requested to return previously dispensed containers as well as their 
completed patient diary to the clinic at each visit for accountability purposes even if they will 
not be issued with new medication at that visit.
5.5. Concomitant Medications
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.  Any medications
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior 
to the start of study treatment and up to 28 days following the last dose of investigational 
product and the reason for their administration must be recorded on the CRF. 
Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded.  Anesthetics used for any 
surgical procedures performed during the patient’s participation in the study can be recorded 
as “unspecified anesthesia” on the concomitant treatment records; it is not necessary to list 
the specific anesthetics.  Palliative and supportive care for cancer-related symptoms will be 
offered to all patients in this study.
5.5.1. Prohibited Medications
The following treatments are prohibited throughout the duration of the active treatment 
phase: 

Anticancer agents: No additional investigational or commercial anticancer agents 
such as chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy other than letrozole will be permitted during the 
active treatment phase.  In general, any drugs containing “for the treatment of breast 
cancer” on the product insert are not permitted on study. No Chinese anti-cancer 
herbal medicines will be permitted, any usage of Chinese herbal medicine should be 
recorded.

Strong CYP3A inhibitors/inducers: Palbociclib is metabolized to multiple 
metabolites in a qualitatively similar manner in rat, dog and human liver microsomes.  
In vitro, Palbociclib is primarily metabolized by CYP3A4 enzymes.  
Co-administration with drugs that are CYP3A inhibitors and inducers may change the 
plasma concentrations of Palbociclib in humans.  The concurrent use of CYP3A 

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inhibitors, including amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, 
delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, 
ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, 
voriconazole, and grapefruit, grapefruit juice or any product containing grapefruit, are 
not allowed in the study.  The concurrent use of CYP3A inducers, including 
carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, 
rifampin, rifapentin, and St. John’s wort, are not allowed in the study.

Drugs known to cause QT interval prolongation are prohibited during the active 
treatment phase.  Refers to Appendix 3 for a list of drugs known to predispose to 
Torsade de Pointes.

Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (eg,
raloxifene) are prohibited during the active treatment phase.

Proton-pump inhibitors: the concomitant use of proton-pump inhibitors (including, 
but not limited to, dexlansoprazole, esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole) with Palbociclib/placebo is prohibited. Further 
recommendations about the use of antacids are provided under Section 5.5.2.
5.5.2. Medications Not Recommended 
The following treatments are not recommended throughout the duration of the active 
treatment phase. Alternative therapies should be considered whenever possible. If usage of 
the following treatments is deemed necessary, consultation and agreement with the sponsor is 
required prior to treatment initiation. 

Moderate CYP3A Inducers: The concurrent use of moderate CYP3A inducers such 
as dexamethasone or omeprazole is not recommended. 

CYP3A Substrates: Palbociclib and its oxidative metabolite, 
PF-05089326, demonstrated little or no inhibition of 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 enzyme activities 
and thus, showed low potential for CYP-mediated pharmacokinetic drug interactions.  
However, Palbociclib and PF-05089326 caused time-dependent inhibition of CYP3A 
midazolam 1’-hydroxylase and testosterone 6β hydroxylase activities with Ki and 

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kinact values for Palbociclib of 10 µM, 0.036 min-1 and 19 µM, 0.087 min-1 and for 
PF 05089326 of 7.0 µM, 0.094 min-1 and 6.4 µM, 0.15 min-1, respectively.  
Therefore, Palbociclib and its metabolite may have the potential for pharmacokinetic 
drug interactions with compounds for which CYP3A-mediated metabolism 
constitutes the primary mechanism of clearance.  While the clinical significance of 
this inhibitory effect is yet to be investigated, caution must be exercised in patients 
receiving Palbociclib in combination with drugs that are predominantly metabolized 
by CYP3A.  In particular, co-administration of Palbociclib with CYP3A4 substrates 
with narrow therapeutic index including, but not limited to alfentanil, aripiprazole,
cyclosporine, ergotamine, fentanyl, halofantrine, pimozide, quinidine, sirolimus, 
tacrolimus, triazolam, astemizole*, cisapride*, and terfenadine* are not recommended 
during the active treatment phase of the trial. Alternative therapies should be used 
when available.

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 use of herbal medicine is not recommended during the active treatment phase
(anticancer herbal medicine is prohibited).

Local antacids may decrease Palbociclib absorption and exposure; however, if 
needed, local antacid should be given at least 2 hours before or after Palbociclib
/placebo administration.

H2-receptor antagonists: no data on the potential effect of these agents (including, 
but not limited to, cimetidine, famotidine, nizatidine, ranitidine) on Palbociclib
exposure has been collected. As acid lowering agents, they could potentially affect 
Palbociclib exposure. If needed, administer these agents with a staggered dosing 
regimen (twice daily). The dosing of Palbociclib/placebo should occur at least 
10 hours after H2-receptor antagonist evening dose and 2 hours before the H2-
receptor antagonist morning dose.

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5.5.3. Permitted Medications
The following treatments are permitted throughout the duration of the active treatment phase:

Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care 
(eg, analgesics, antidiarrheals, antidepressants) may also be used at the investigator’s 
discretion. All medications should be recorded. 

Bisphosphonates and receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitors for the treatment of osteoporosis or management of existing 
bone metastases may be continued for patients who have been receiving them at a 
stable dose for at least 2 weeks prior to randomization. However the need to initiate 
or increase the dose of these therapies during the study will be considered as 
indicative of disease progression leading to the discontinuation of patient from the 
active treatment phase unless disease progression can be completely ruled out and the 
exact reason for the use of these therapies clearly documented in the subject’s source 
documentation.

Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic 
use of granulocyte-colony stimulating factors is not permitted but they may be used to 
treat treatment-emergent neutropenia as indicated by the current American Society of 
Clinical Oncology (ASCO) guideline.73  If neutropenic complications are observed in 
a cycle in which primary prophylaxis with CSFs was not received, secondary
prophylaxis may be given at the discretion of the investigator, but only if dose 
reduction or delay are not considered to be a reasonable alternative.

Erythropoietin may be used at the investigator's discretion for the supportive 
treatment of anemia. 
5.6. Concomitant Radiotherapy or Surgery
Any concurrent radiotherapy (except palliative radiotherapy as specified below) or 
cancer-related surgery are prohibited throughout the duration of the active treatment phase of 
the study. Patients requiring any of these procedures will be discontinued from the active 
treatment phase and will enter the follow-up phase.

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Palliative radiotherapy is permitted for the treatment of painful bony lesions provided that the 
lesions were known to be present at the time of study entry and the investigator clearly 
documents that the need for palliative radiotherapy is not indicative of disease progression.  
In view of the current lack of data about the interaction of Palbociclib with radiotherapy, 
Palbociclib/placebo treatment should be interrupted during palliative radiotherapy, stopping 
1 day before and resuming treatment 1 week after. For patients with bone involvement, it is 
suggested to institute palliative radiotherapy before study initiation if possible and clinically 
appropriate (eg, lesions at risk for spontaneous micro-fractures or painful lesions).  Palliative 
radiotherapy during the active treatment phase will be considered alternative cancer therapy 
and will result in censoring of the PFS endpoint. The dates on which palliative radiotherapy 
is administered should be recorded on the appropriate CRFs.
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/placebo is recommended at least 7 days prior to 
elective surgery.  Postoperatively, the decision to reinitiate Palbociclib/placebo treatment 
should be based on a clinical assessment of satisfactory wound healing and recovery from 
surgery.
6. STUDY PROCEDURES
Prior to undergoing any study specific procedures (with the exception of certain imaging 
assessments if meeting the criteria defined in Section 6.1), patients must read and sign the 
consent form. All study procedures and the timing when they must be performed are detailed 
in the Schedule of Activities tables. All data obtained for these assessments must be 
supported in the patients' source documentation.
For the purpose of this trial one cycle = 28 days. 
6.1. Screening
Voluntary, written, dated, and signed informed consent must be obtained before any study 
specific procedures are performed (with the exception of certain imaging assessments if 
meeting the criteria defined in this section); however, it may be obtained more than 28 days 
before randomization. 

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Radiographic tumor assessments (as documented on the Tumor Assessment Requirement 
Flowchart) that were performed before the signing of the informed consent form as routine 
procedures (but within 28 days prior to randomization) do not need to be repeated and may 
be used as baseline assessments, as long as:

The tests were performed per the method requirements outlined in the 
Tumor Assessment Requirement Flowchart, the Efficacy Assessments sections. 

Appropriate documentation indicating that these radiographic tumor assessments 
were performed as standard of care is available in the patient’s source notes.
Bone scans performed as routine procedures within 12 weeks prior to randomization may 
also be accepted as baseline assessment if they meet the same requirements listed above.
Brain scans performed as routine procedures within 6 weeks prior to randomization may also 
be accepted as baseline assessment if they meet the same requirements listed above.
All lens grading evaluable patients will undergo the following ophthalmic procedures at 
screening: 

Best corrected distant visual acuity (Snellen);

Refractive error associated with best corrected distant visual acuity;

Intraocular pressure (IOP - one reading);

Slit lamp biomicroscopy of the anterior segment including cell count and flare 
grading;

Lens grading with the Wisconsin Age-Related Eye Disease Study (AREDS) 2008 
Clinical Lens Opacity Grading Procedures using a laminated reference pocket card 
(See Appendix 8) - (pupil dilated examination);

Funduscopy (Ophthalmoscopy – pupils must be dilated). 
Patients with ophthalmic conditions (eg, anophthalmus, phthisis, aphakia, pseudophakia) that 
would prevent grading of the lens in both eyes will not be considered evaluable for this 
ophthalmic assessment and do not need to undergo these ophthalmic procedures. Reasons 
for not being evaluable must be clearly documented in the patient source notes. 

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All ophthalmic examinations will be performed by an ophthalmologist. Refer to Section 
7.2.3. Ocular Safety Assessments for further details on these procedures.
For details on baseline procedures, see the Schedule of Activities tables. 
6.1.1. Screen Failure
Patients who completed the informed consent process but do NOT meet all eligibility criteria 
and therefore are NOT randomized to either treatment arm will be considered as screen 
failures. 
Clinical sites must provide for all screen failures the following information using the 
appropriate case report forms (CRFs): screening number, demographic data as well as the 
final subject summary including the reason for screening failure.
6.2. Active Treatment Phase
For details on procedures during the active treatment phase, see the Schedule of Activities
tables. 
In the event that the start of a new cycle is delayed due to treatment-related toxicity,
procedures required on Day 1 of the given cycle will be performed when Palbociclib/placebo 
is resumed. New cycle Day 1 procedures (ie, physical examination, ECOG performance 
status, ECG, Quality of Life questionnaires, blood chemistry, hematology) that were 
performed prior to knowing the need to delay the start of the cycle do not need to be repeated 
(1) if not required to determine whether study drug may be resumed and (2) if performed 
within 7 days prior to study drug resumption.
All lens grading evaluable patients randomized will repeat screening ophthalmic procedures 
also during the active treatment phase after 3 months (Cycle 4 Day 1), 6 months (Cycle 7 
Day 1), 12 months (Cycle 13 Day 1) then every 12 months (Day 1 of Cycles 25, 37, etc.) 
thereafter. Additional ophthalmic examinations may be repeated during the study as 
clinically indicated. 
6.3. End of Treatment Visit
The end of treatment visit will be performed as soon as possible but no later than 4 weeks (ie,
28 days) ± 7 days from last dose of investigational product and prior to the initiation of any 
new anticancer therapy.

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All lens grading evaluable patients randomized will repeat screening ophthalmic procedures 
also at the End of Treatment visit.  
For details on procedures to be performed at the End of Treatment visit, see the Schedule of 
Activities tables. 
6.4. Follow-up Visit
After discontinuation of study treatment, post-study survival status (including post study 
anticancer therapies) will be collected approximately every 6 months (±7 days) from the last 
dose of study treatment.  Telephone contact is acceptable.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented disease progression as per 
RECIST definitions will continue to have tumor assessment performed during the follow-up 
visits every 12 weeks (± 7 days) and bone scans (as applicable) every 24 weeks (± 7 days) 
from the date of randomization until disease progression, initiation of new anticancer therapy 
or discontinuation of patient from overall study participation (eg, death, patient's request, lost 
to follow-up), whichever occurs first. 
For details on follow-up visit procedures, see the Schedule of Activities tables. 
6.5. Patient Withdrawal
6.5.1. Active Treatment Phase Discontinuation
The term "interruption" refers to a patient stopping the investigational product during the 
course of the study, but then re-starting it at a later time in the study.  The reason for dosing 
interruption will be collected on the appropriate CRF. 
The term "discontinuation" refers to a patient's withdrawal from the active treatment phase.  
The reason for discontinuation from treatment will be collected on the appropriate CRF. 
Patients may be withdrawn from the active treatment phase in case of:

Disease progression as per RECIST v.1.1;

Symptomatic deterioration (ie, global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression as per 
RECIST v.1.1);

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
Need for additional anticancer therapy not specified in the protocol;

Unacceptable toxicities;

Investigator conclusion that it is in the patient’s best interest to discontinue therapy 
(eg, poor compliance with either protocol monitoring or with taking the study 
medications, etc);

Lost to follow-up*;

Patient choice to withdraw from treatment (follow-up permitted by patient);

Withdrawal of patient consent (cessation of follow-up);

Death.
*If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. If after 3 unsuccessful attempts to contact the patient, one of which is by registered 
letter, the patient should be considered “lost to follow-up”. Steps taken to contact the patient 
(eg, dates of telephone calls, registered letters, etc) must be clearly documented in the source 
documents.
Patient who discontinue from the active treatment phase must have end of 
treatment/withdrawal evaluations performed as soon as possible but no later than 4 weeks 
from the last dose of investigational product and prior to initiation of any new anticancer 
therapy.  Data to be collected for the end of study treatment/withdrawal are described in the 
Schedule of Activities tables. 
If a patient opts to discontinue from the active treatment phase as a result of an unacceptable 
adverse drug reaction, "withdrawal of consent" should not be the reason for discontinuation.  
Instead, the reason for discontinuation of active treatment phase, must be recorded as 
"Unacceptable toxicity" and an appropriate action taken must be assigned on the AE CRF to 
the adverse event leading to the patient’s withdrawal of consent.

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6.5.2. Study Discontinuation
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.
Patients will be withdrawn from study in the case of:

Withdrawal of consent (ie, refuses tumor assessments or survival status after end of 
treatment);

Lost to follow-up*;

Death.

*If a patient does not return for a scheduled visit, every effort should be made to 
contact the patient.  If after three unsuccessful attempts to contact the patient, one of 
which is by registered letter, the patient should be considered “lost to follow-up”.  
Steps taken to contact the patient (eg, dates of telephone calls, registered letters, etc) 
must be clearly documented in the source documents.  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 the patient to return for a final visit, if 
applicable, and follow-up with the patient regarding any unresolved adverse events 
(AEs).
Data to be collected for the end of study treatment/withdrawal are described in the Schedule 
of Activities tables. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
All study procedures are described in the Schedule of Activities tables footnotes.

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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 
which he/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.
7.1. Efficacy Assessments
7.1.1. Independent Review of Disease Assessments
A blinded independent third-party core imaging laboratory will perform a retrospective
review of radiographic images and clinical information collected on-study to verify the 
protocol defined endpoints of disease response and progression as assessed by the 
investigator. 
It is important to the integrity of the study that all imaging studies and clinical information 
(including photographs) are forwarded to the independent core imaging laboratory as each 
patient enrolls and progresses through the study.
Materials to be forwarded for independent review are the following:

All imaging studies performed on study, preferably in digital format on compact disc 
or optical disc.  All digital media must be in Digital Imaging and Communications in 
Medicine (DICOM) format.  Films may be forwarded for review if necessary; all 
films must be originals (second original films acceptable) rather than copies of films. 

Photographs of sites of disease assessed using clinical methods.  Details concerning 
clinically assessed lesions will be collected on the CRFs and made available to the 
core imaging laboratory. 
Further information on materials to be forwarded for independent review, correct procedures 
for the coding/blinding of the patient’s name/identity and the return of the source 
data/documents to the site is provided in the core imaging laboratory Study Coordinator 
Manual.

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7.1.2. Tumor Assessments
The importance of timely and complete disease assessments in this study cannot be
understated. Disease assessments must be performed as scheduled according to the calendar, 
regardless of treatment delays resulting from toxicity, to prevent the introduction of bias into 
the assessment of efficacy.  Failure to perform any of the required disease assessments will
result in the inability to determine disease status for that time point. A series of incomplete
disease assessments will result in censoring of the primary endpoint of PFS back to the time
of the last full assessment that did not show progression. Frequent off schedule or
incomplete disease assessments have the potential to weaken the conclusion of this clinical
trial.
Radiographic tumor assessments may be done at any time if there is clinical suspicion of 
disease progression at the discretion of the investigator.  If progressive disease is confirmed 
per RECIST v.1.1, patients are expected to discontinue study therapy and begin the follow-up 
phase of the trial.  However, patients may continue treatment as assigned at enrollment 
beyond the time of RECIST-defined PD at the discretion of the investigator if that is 
considered to be in the best interest of the patient and as long as no new anticancer treatment 
is initiated.
Screening/baseline tumor assessment will be carried out within 28 days of randomization 
(unless otherwise specified below).
Disease assessment for all patients at baseline will include:

Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan of the 
chest, abdomen, and pelvis (CAP).

CT or MRI scan of any other sites of disease as clinically indicated.

Clinical assessment of superficial disease which will include photographs of all 
superficial metastatic lesions.  All lesion measurements must be recorded in the CRF.

Bone scans in order to detect bony sites of disease. Any suspicious abnormalities (ie,
hotspots) identified on the bone scans at baseline must be confirmed by X-ray, CT 
scan with bone windows or MRI. Bone lesions identified at baseline will follow the 
same assessment schedule as for measurable lesions. Baseline brain CT or MRI are 
only required in case signs and symptoms suggest the presence of metastatic brain 
disease. Refer to Section 6.1 for further details on timing allowance for baseline 
brain and bone scans. 

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Post-baseline tumor assessments will be performed every 12 weeks (± 7 days) and bone 
scans (as applicable) every 24 weeks (±7 days) from randomization until radiographically 
and/or clinically (ie, for photographed or palpable lesions) documented PD as per 
RECIST v.1.1, study treatment discontinuation (for patients continuing treatment beyond 
RECIST-defined disease progression), initiation of new anticancer therapy, or 
discontinuation of patient from overall study participation (eg, death, patient's request, lost to 
follow-up). Imaging assessments are to be scheduled using the randomization date as the 
reference date for all time-points and are NOT to be scheduled based on the date of the 
previous imaging time-point.  Imaging assessment delay to conform to treatment delay is not 
permitted.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented disease progression as per
RECIST definitions will continue to have tumor assessment performed during the follow-up 
visits every 12 weeks (± 7 days) and bone scans (as applicable) every 24 weeks (±7 days) 
until documented disease progression, initiation of new anticancer therapy or discontinuation
of patient from overall study participation (eg, death, patient's request, lost to follow-up), 
whichever occurs first. Every effort should be made to perform a last tumor assessment 
before starting a new anticancer therapy.  Additional unscheduled tumor assessments may be 
performed as clinically indicated at any time. 
Post-baseline tumor assessments will include:

CT or MRI scan of the chest, abdomen, and pelvis (CAP).

CT or MRI scan of any other sites of disease identified at baseline.

Clinical assessment of sites of superficial disease identified at baseline. Clinical 
assessment of superficial disease must coincide with the imaging studies and will 
include photographs of all superficial metastatic lesions. All lesion measurements 
must be recorded in the CRF.

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
Bone lesions imaging:

If bone lesions were identified at baseline the following assessment must be 
performed:

X-ray/CT scan/MRI every 12 weeks (± 7 days) from the date of 
randomization using the same modality used to confirm the bone lesions at 
baseline. Areas that have received palliative radiotherapy on study cannot be 
used to assess response to study treatment.

Bone scans every 24 weeks (± 7 days) from the date of randomization and to 
confirm complete response. Abnormalities found on subsequent bone scans 
must also be confirmed by X-ray, CT scan, or MRI.

If no bone lesions were identified at baseline, bone scans should be performed as 
clinically indicated (ie, patient describes new or worsening bone pain, or has 
increasing alkaline phosphatase level, or other signs and symptoms of 
new/progressing bone metastases) but are required to confirm complete response.  
Abnormalities found on subsequent bone scans must also be confirmed by X-ray, CT 
scan, or MRI.

Repeat brain scans will be required only if metastases are suspected.
The CT scans, including brain CT scan if applicable, should be performed with contrast 
agents unless contraindicated for medical reasons. If IV contrast is medically 
contraindicated, the imaging modality to be used to follow the disease (either CT without 
contrast or MRI) should be the modality which best evaluates the disease, and the choice 
should be determined by the investigator in conjunction with the local radiologist. MRI of 
the abdomen and pelvis can be substituted for CT if MRI adequately depicts the disease.
However, MRI of the chest should not be substituted for CT of chest even if IV contrast is 
contraindicated.  In such case CT will be performed without contrast. If MRI is used to 
follow-up bone lesion(s) it must be performed before any treatment that may affect 
bone-marrow cellularity (eg, G-CSF).75
The same method and technique should be used to characterize each lesion identified and 
reported at baseline, during the study treatment period and during follow-up.  The use of 
plain-film X-rays (with the exception of bone X-rays as detailed above) is discouraged. The 
use of positron emission tomography (PET) imaging as the only imaging modality is not 
permitted.

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For patients having effusions or ascites, cases having cytological proof of malignancy should 
be recorded as non-target lesions on the tumor assessment CRFs.  Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be recorded on 
the non-target lesion CRF.
Objective tumor response will be measured using the Response Evaluation Criteria in Solid 
Tumors (RECIST Version 1.1, see http://www.eortc.be/recist/default.htm). Also please refer 
to Appendix 7. All measurements should be recorded in metric notation using a ruler or 
calipers.
For patients with bone-only disease:

Treatment outcome will be recorded in the CRF as complete response (CR), stable 
disease (SD) or progression (PD). 
Interpretation will be PD if:

The malignant nature of one or more new lesions identified with bone scan is
confirmed with X-ray, or CT, or MRI scan,

Flare observed in bone scan is followed by confirmation of progression with other
imaging modalities,

Clinical worsening of the disease is assessed by bone scan and disease progression
(ie, new lesion(s)) is confirmed with other imaging modalities.

Unequivocal progression of existing bone lesions.
Interpretation will be SD if:

The malignant nature of all the new lesions identified with bone scan is not
confirmed.
In the following cases the patient will be censored at the date of prior tumor assessment with 
no PD: 1) on-study fracture; 2) on-study management of pain (palliative radiation therapy, 
palliative surgery), 3) clinical worsening not objectively confirmed; 4) on-study change of 
therapy. In all the censored cases (no objectively documented PD) tumor assessment will be 
performed until PD. Also, it will be at the discretion of the investigator to discontinue the 
study treatment.

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It is suggested to institute palliative radiotherapy (eg, lesions at risk for spontaneous 
micro-fractures or painful lesions) before study initiation as well as palliative surgery if 
possible and clinically appropriate.
7.1.3. Overall Survival
Following the End of Treatment visit, survival status will be collected in all patients 
(telephone contact is acceptable) every 6 months (± 7 days) from the last dose of study 
treatment. Information on subsequent anticancer therapy will also be collected.
7.2. Safety assessments
Safety assessment will consist of monitoring of all adverse events (AEs), including serious 
adverse events (SAEs), regular monitoring of hematology, serum chemistry, and routine 
monitoring of ECGs, physical examinations, vital signs, ECOG performance status, and chest 
CTs. 
Adverse event assessment will include type, incidence, severity (graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], 
Version 4.0, see Severity Assessment section), timing, seriousness, and relatedness.
Baseline tumor-related signs and symptoms will be recorded at the Cycle 1 Day 1 visit and 
then reported as adverse events during the trial if they worsen in severity or increase in 
frequency.
7.2.1. Laboratory Safety Assessments
Blood tests will include the following:
Hematology Panel
Blood Chemistry Panel
1
Hemoglobin
1
ALT
2
Platelets
2
AST
3
WBC
3
Alkaline Phosphatase
4
Absolute Neutrophils
4
Sodium
5
Potassium
6
Total Calcium
7
Magnesium
8
Total Bilirubin
9
BUN or Urea
10
Serum Creatinine
11
Albumin

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Blood tests will be drawn at the time points described in the Schedule of Activities table.  
Additional blood tests may be performed at the investigator's discretion as clinically 
indicated for the purpose of planning treatment administration, dose modification, or 
following adverse events. 
7.2.2. Electrocardiogram (ECG)
12-lead ECG monitoring will be undertaken in all patients enrolled in the trial. At each time 
point (see SCHEDULE OF ACTIVITIES), 3 consecutive ECGs will be performed 
approximately 2 minutes apart to determine the mean machine-read QTc interval.  If the 
mean QTc interval is prolonged (>500 msec), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation.  Additional triplicate ECGs may be performed 
as clinically indicated.
7.2.3. Ocular Safety Assessments
7.2.3.1. Snellen Best Corrected Visual Acuity and Refraction
Snellen visual acuity will be assessed by using a standard wall or projection chart before 
implementing any procedures that can affect vision (eg, pupil dilation, tonometry, and 
gonioscopy).  The same optotype will be used throughout the study for a specific patient, and 
the right eye should be tested first.  The refractive error will be determined at the Screening 
visit.  The examiner should ensure that patients are seated comfortably and that they do not 
move their head forward or backward during testing.  Patients will be told that the chart 
contains only letters.
The line read with 2 or fewer errors will be recorded.  If 3 of the 5 letters on a line are read 
correctly, the patient will be given credit for that line.  For example, if the patient reads 20/25 
+3, 20/20 will be recorded.  
A decrease in best-corrected visual acuity of 3 lines or more from the Screening visit will be 
reported as an adverse event.  An adverse event of visual acuity will be counted from the 
following lines: 20/20 or better, 20/25, 20/30, 20/40, 20/50, 20/60, 20/70, 20/80, 20/100, 
20/125, 20/150, and 20/200.  If the acuity at screening is better than 20/20, the decrease will 
be calculated from 20/20.  
In the event of a decrease in visual acuity of 3 lines or more from screening, refraction will 
be rechecked at all subsequent study visits.  A change in refraction power (spherical or 
cylindrical) of +/– 1.25 diopters compared with the screening examination will be reported as 
an adverse event.

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7.2.3.2. Intraocular Pressure Measurement
Intraocular pressure (IOP) will be measured using a calibrated Goldmann applanation 
tonometer.  Both eyes will be tested, with the right eye preceding the left eye.  The operator 
will initially set the dial at 10 mm Hg, then look through the slit lamp and adjust the dial to 
take the reading, and then record the results, including the time assessment is made. 
Any IOP increase of greater than 10 mmHg above baseline or any IOP that increases above 
25 mm Hg will be reported as an adverse event (AE).
7.2.3.3. Slit-lamp Biomicroscopy
Slit-lamp biomicroscopy with fluorescein will be performed.  At each scheduled visit, 
deposition of pigment on the corneal endothelial layer or the lens capsule or any 
abnormalities of the lids, conjunctivae, cornea, anterior chamber, iris, or lens (see lens 
grading) will be graded as mild, moderate, or severe.  Slit-lamp biomicroscopy should 
precede IOP measurement and the administration of any pupil-dilating agent for 
ophthalmoscopy.
Cells and flare in the anterior chamber should be noted during the slit-lamp examination.
Intraocular Inflammation Grading Scale for Biomicroscopy:
Grade
0
1
2
3
4
Grading of 
aqueous flarea
Completely 
Absent
Barely 
Detectable
Moderate (iris 
and lens details 
clear)
Marked (iris 
and lens 
details hazy)
Intense (formed 
fibrin in 
aqueous)
Grading of cells in 
the aqueousa,b
No cells
1 to 5 
cells
6 to 10 cells
11 to 20 cells
>20 cells
a
Evaluation of Anterior Chamber Inflammation:
1.
Examination of the anterior chamber for cells must be performed before either dilation or 
applanation tonometry.
2.
The light intensity of the slit lamp is turned to the maximum tolerated by the patient.
3.
High magnification and 1 x 2 mm slit are used.
4.
The ray of light as directed at an angle of approximately 45to the plane of the iris.
b
Modified from Hogan et al. 195976  .
During the study, any new finding or deterioration from baseline findings should be reported 
as an adverse event.

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7.2.3.4. Lens Grading
When doing lens grading, graders must be aware of their bias, either conscious or 
subconscious, that cataract is a unidirectional disease that steadily gets worse with age. 
Because of this bias, if one knows the baseline or any prior lens grade, it is likely that the 
grade assigned at a follow-up visit will be higher. To avoid this potential observation bias, 
the grader will remain masked to earlier lens grading and should always start with a blank 
case report form (CRF).  The Wisconsin AREDS 2008 Clinical Lens Opacity Grading 
Procedure will be used.74  Once the pupils are dilated to at least 5 mm, use slit lamp with 
~10X magnification and brightest beam intensity.

Nuclear opacity:

Orient beam at 45° to viewing axis;

Adjust slit beam to standard parameters: 8 mm height and 0.3 mm width;

Compare opalescence of nucleus with those on the provided pocket card of 
standard photos.

Cortical and Posterior Subcapsular Cataract (PSC) opacities:

Select wide slit beam setting optimum for retro-illumination of lens;

Visualize lens opacities against red fundus reflex background;

Count only opacities definitely visible against red reflex;

Mentally combine all cortical opacities into one contiguous area;

Compare total opacity area with those on the provided pocket card of standard 
photos;

Grade each type of opacity in half steps from <1 to >3 (1=mild, 2=moderate and 
3=severe) using the scale defined on the provided pocket card of standard photos.
7.2.3.5. Funduscopy (Ophthalmoscopy)
Funduscopy (Ophthalmoscopy) will be performed after dilation of the pupils to examine the 
vitreous body, retina, and optic nerve head.  At screening, any abnormalities and pathologic 
findings will be graded as mild, moderate, or severe.  

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Any new findings or deterioration from baseline findings will be reported as an adverse 
event.
7.2.4. Other Safety Assessments
A full physical examination including an examination of all major body systems, height (at 
screening only), weight, blood pressure and pulse rate which may be performed by a 
physician, registered nurse or other qualified health care provider, will be required at 
screening, and Day 1 of Cycles 1 and 2. 
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits.
Performance Status: The Eastern Cooperative Oncology Group (ECOG) performance status 
scale will be used (see Appendix 1). 
A recent publication by Lee et al., (2014)77 suggests a potential role of Cyclin D1-CDK4 in 
controlling glucose metabolism; accordingly glucose levels will be monitored in all patients 
(fasting glucose, fasting insulin and HgbA1c) at various intervals as outlined in the Schedule 
of Activities. Fasting lipid panel [including total Cholesterol, HDL (High Density 
Lipoprotein), LDL( Low Density Lipoprotein) and triglycerides] will also be monitored at 
baseline and at the End of Treatment visit as outlined in the Schedule of Activities.
7.3. Pharmacokinetic Assessments
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time
relative to dosing. However, samples obtained within 10% of the nominal time AND 
collected prior to administration of the investigational product on that day will be considered 
protocol compliant. Patients must be instructed to withhold their daily dose of study drugs 
on PK sampling days until the pre-dose PK sample and safety assessessments (ie 
hematology, blood chemistry, and ECGs) have been completed. The exact time of the
sample collection and the most recent dosing time will be recorded on the CRF. The date of
any missing dose(s) should also be recorded in the CRF.  One 3 mL sample of venous blood 
will be collected in appropriately labeled K2 EDTA collection tubes for assessment of 
Palbociclib (PD-0332991) levels at the protocol-specified times. Samples will be analyzed 
using validated analytical methods in compliance with Pfizer standard operating procedures.

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Blood samples will be collected from all participating patients for PK assessments of
Palbociclib on Day 14 of Cycles 1 and Cycle 2 before administration of investigational
product on that day (24 hours after the dose on previous day). In the event a pre-dose sample 
cannot be/is not collected on Day 14 of Cycle 1 or Cycle 2 as scheduled, every effort should 
be made to collect a makeup pre-dose sample between Day 15 and Day 21 of the same cycle 
or between Day 14 and Day 21 of any subsequent cycles beyond Cycle 2 following the same 
rules described above.
Additional blood samples may be requested from patients experiencing unexpected or serious
adverse events, or adverse events that lead to discontinuation.
 
 
Refer to the Study Manual for detailed collection, processing and shipping procedures.
7.4. Patient Reported Outcomes
Patient reported outcomes of health-related quality of life and health status will be assessed 
using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol-5D 
(EQ-5D) instruments. 
Patients will complete each instrument pre-dose on Day 1 of Cycle 1 through 3, then on 
Day 1 of every other subsequent cycles starting with Cycle 5 (eg, cycles 5, 7, 9, etc), and 
then at the end of treatment visit.  Completed questionnaires are always considered source 
document and must be filed accordingly.
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 FACT-B and EQ-5D will be given to the patient in 
the appropriate language for the site. 
7.4.1. EuroQol Health Utilities Index EQ-5D (Appendix 5)
The EuroQol-5D (EQ-5D) is a 6 item instrument designed to assess health status in terms of 
a single index value or utility score.  It consists of 5 descriptors of current health state 
CCI

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(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.  It also 
includes 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).  
Published weights are available that allow for the creation of a single summary score.  
Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction 
and 1 as perfect health.
7.4.2. Functional Assessment of Cancer Therapy-Breast (FACT-B) [Version 4]
(Appendix 6)
The Functional Assessment of Cancer Therapy (FACT) is a modular approach to assess 
patient health-related quality of life using a ‘core’ set of questions (FACT-G) as well as a 
cancer site-specific module. 
The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical 
Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. 
The FACT-B consists of the FACT-G (27-items) and a breast-specific module: a 10-item 
instrument designed to assess patient concerns relating to breast cancer.  Patients are asked to 
respond to a likert scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 
4=very much.
7.5. Biomarker Assessment
Tumor tissues are required from all patients for study participation.
Retrospective confirmatory testing of tumor tissue samples for ER status will be performed 
in a central laboratory designated by the sponsor using an FDA-cleared (local standard) test. 
Results from this testing will be used for sensitivity analyses and will not be made available 
to the sites. In addition, tumor tissue biomarkers, including DNA, RNA and protein analytes, 
will be analyzed to investigate possible associations with resistance/sensitivity to treatment 
with study drugs. Biomarkers that will be analyzed will be selected based on their known 
relevance to mechanisms involved in cell cycle regulation. Examples of such biomarkers 
include but not limited to Ki67, ER protein expression.

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Submission of formalin-fixed paraffin embedded (FFPE) tumor samples (blocks) of adequate 
size to allow for three 0.6 mm diameter x 5 mm deep cores that will be used to generate a 
tissue microarray are needed. If FFPE tissue block cannot be provided, 12 glass slides each 
containing an unstained 5-micron FFPE tissue section (highly recommend to submit tissue 
block or 12 unstained slides, but if there would be technical difficulties or other issues 
refraining from obtaining tissue block or 12 unstained slides, however, it is still mandatory to 
collect a minimum 7 unstained slides), will be required for patient participation. Archived 
FFPE specimen from the original diagnostic tumor tissue will be collected and sent to the 
sponsor-designated central laboratories for assessment of biomarkers associated with 
sensitivity and/or resistance to Palbociclib (eg, Ki67, ER). Tissue sample from a metastatic 
or recurrent tumor lesion, if available, will also be collected for restrospective confirmation 
of ER status by the central laboratory. If a tissue sample from a recurrent tumor or distant 
metastasis is unavailable, a de novo fresh biopsy is recommended when, in the investigator’s 
judgment, such biopsy is feasible and can be safely performed. Original diagnostic tumor 
tissue will be used for confirmation of ER status in the event that a recurrent/metastatic tissue 
sample is not available and a fresh biopsy of the recurrent/metastatic lesion is not feasible.
Tissue samples from all patients will be used for additional biomarker analyses. Detailed 
information about biomarker sample collection, preparation, storage, labeling, and shipment 
is indicated in the Study Reference Manual.
7.5.1. Optional Tumor Tissue Biopsy for Molecular Profiling
An optional fresh metastatic/recurrent tumor biopsy sample should be collected at the end of 
treatment visit for patients who discontinue treatment due to disease progression. The tumor 
tissue will be used to determine possible mechanisms of resistance to study treatment.
7.6. CDK6 Genotyping
In order to explore the relationship between CDK6 polymorphism and the neutropenia 
associated with Palbociclib treatment, germline polymorphism of CDK6 will be analyzed. A 
single 4 mL blood sample (Prep D1; K2 EDTA whole blood collection optimized for DNA 
analysis) will be collected pre-dose at the Cycle 1 Day 1. A SNP rs445 as defined in the 
NCBI database in the CDK6 gene will be analyzed.

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7.7. Banked Biospecimen
7.7.1. Markers of Drug Response
Variation in genetic markers and other biomarkers may help to explain some of the 
variability in response seen with some drugs among different individuals. This is referred to 
as pharmacogenomic/biomarker research. Comparing the DNA, RNA, protein, and 
metabolite variation patterns of patients who respond well and those who respond poorly to 
treatment may help to better define the most appropriate group of patients in which to target a 
given treatment. Collecting biospecimens for pharmacogenomic/biomarker analyses and 
retaining them in a Pfizer BioBank makes it possible to better understand the drug’s 
mechanism of action and to seek explanations for differences in, for example, exposure, 
efficacy, tolerability, or safety not anticipated prior to the beginning of the study. Providing 
these biospecimens is a required study activity for study sites and subjects, unless prohibited 
as such by local regulations or ethics committee decision.  
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study ID number.  Samples will be kept in a facility 
accessible only by badge-swipe.  Data will be stored on password-protected computer 
systems.  The key between the code and the subject’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information.  Biospecimens will only 
be used for the purposes described here and in the informed consent document/patient 
information sheet; any other uses require additional ethical approval.  Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also post-marketing 
research.  Subjects can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses.  It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants.  Subjects are notified in the informed consent document/patient 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator.  Results will not be 
provided to family members or other physicians; nor will they be recorded in the subject’s 
medical record.  There is no intention to contact subjects after completion of the clinical trial.

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A 4 mL blood biospecimen Prep D1 (K2 edetic acid (ethylenediaminetetraacetic acid) (EDTA)
whole blood collection optimized for DNA analysis) will be collected at the pre-dose at the 
Cycle 1, Day 1 visit to be retained for potential pharmacogenomic/biomarker analyses related 
to drug response or adverse drug reactions, unless prohibited by local regulations or ethics 
committee decision.  
The Banked biospecimen will be collected from all patients unless prohibited by local 
regulations or ethics committee decision. Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/patient information sheet that 
they will not be compensated in this event.
 
 
 
 
 
 
 
 
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. 
CCI

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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 
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 non-serious adverse event 
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.  Serious adverse events occurring to a subject 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the Sponsor.
AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the 
time the patient has taken at least one dose of study treatment through last patient visit.
If a patient begins a new anticancer therapy, the AE reporting period for non-serious 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.

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8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breast feeding;

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.

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8.4. 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.
8.5. Serious Adverse Events
An SAE 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 

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SAE with Common Terminology Criteria (CTC) 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 subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
8.5.1. 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 SAE Reporting Requirements) 
8.5.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with 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 (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 (X ULN) concurrent with a total bilirubin values 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase values 2 X ULN or not available.

For patients with preexisting ALT or AST or total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

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
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 X ULN, or 8 X ULN 
(whichever is smaller).
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin increased from baseline by an amount of at least one time the upper limit of 
normal or if the value reaches ≥3 times the upper limit of normal (whichever is 
smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen(paracetamol), recreational drug 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 and E infection and liver 
imaging (eg, biliary tract) may be warranted. Acetaminophen levels may be indicated. 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.
8.6. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 

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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 
work-up of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned 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.

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Diagnostic and therapeutic non-invasive 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.
8.7. Severity Assessment
As required on the AE CRFs, the investigator will report adverse events using concise 
medical terminology (verbatim) as well as collect on the CRF the appropriate Common 
Terminology Criteria for Adverse Events (CTCAE) (version 4.0, Publish Date: May 28, 
2009, http://ctep.cancer.gov/reporting/ctc.html) and will use the following definitions of 
severity to describe the maximum intensity of the adverse event.
GRADE
Clinical Description of Severity
0 
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 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 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.
8.8. 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 serious adverse 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 

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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 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.
8.9. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy  
occurs if:

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).

A male subject 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 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 a Serious Adverse Event Form and Exposure in Utero (EIU).  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 EIU 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 EIU 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 EIU 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, 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 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested 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.
8.10. 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 adverse event.

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An occupational exposure is reported to safety within 24 hours of 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 subject enrolled in the study, the information is not reported 
on a Case Report Form (CRF); however, a copy of the completed SAE Report form is 
maintained in the study master file.
8.11. Withdrawal Due to Adverse Events (See Also Section 6.5 Patient Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.13. 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.
8.13.1. 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 timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, and 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/her first awareness of the AE.

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For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes 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.
8.13.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event 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 dated and maintained 
by the sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment.
9.1. Sample Size Determination
The primary purpose of this study is to compare the combination of Palbociclib with 
letrozole versus placebo plus letrozole in prolonging PFS in Asian postmenopausal women 
with ER (+), HER2 (-) ABC who have not received any prior systemic anti-cancer treatment 
for advanced disease.  

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The sample size for this study is determined based on the assumptions that the median PFS 
for ABC patients receiving placebo plus letrozole in the first-line treatment setting is 9 
months and it is desired to detect a risk reduction of 36% (hazard ratio 0.64), equivalent to an 
improvement in median PFS to 14 months in subjects receiving Palbociclib plus letrozole 
treatment.  A total of approximately 213 events are required in the 2 arms of the study based 
on a 1:1 randomization to have 90% power to detect a difference assuming a true hazard ratio 
of 0.64 in favor of the Palbociclib plus letrozole arm using a one-sided, log-rank test at a 
significance level of 0.025. Assuming a 10% drop-out rate on either treatment arm, an
accrual accomplished over a 19-month period and follow-up for about 12 months after the 
last patient is enrolled, a total sample size of approximately 330 patients (approximately 
165 in the Palbociclib plus letrozole arm and approximately 165 in the placebo plus letrozole 
arm) is required.
The sample size described above will also allow the assessment of differences in the 
secondary endpoint of OS. The OS outcomes of a Phase 3 clinical trial in a similar patient 
population demonstrated a median OS of 34 months for the arm receiving letrozole.  Using 
this value as an assumption with a hypothesized 30% risk reduction (a hazard ratio of 0.7) or 
43% improvement in median OS (from 34 months to 48.6 months) in patients randomized to 
receive palbociclib plus letrozole and a follow-up period of approximately 61 months, 330
patients will provide approximately 247 events for 80% power to detect such a difference 
using a 1-sided, log-rank test at a significance level of 0.025.
9.2. Analysis Population
9.2.1. Intent-to-Treat Population (ITT)
The ITT population will include all patients who are randomized, with study drug assignment 
designated according to initial randomization.  The ITT population will be the primary 
population for evaluating all efficacy endpoints and patient characteristics.
9.2.2. As-Treated Population (AT)
The AT population will include all patients who receive at least 1 dose of study treatment (ie, 
Palbociclib/letrozole or placebo/letrozole ), with treatment assignments designated according 
to actual study treatment received. The AT population will be the primary population for 
evaluating treatment administration/compliance and safety.  Efficacy endpoints may be 
assessed in this population as well.

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9.3. Efficacy Analysis
All efficacy analyses will be based on intent-to-treat (ITT) population.  Some efficacy 
analyses will also be performed on the AT population.  All primary and secondary endpoints 
based on radiological (and photographical where applicable) assessments of tumor burden 
(ie, PFS, OR, DR, DC) will be derived using the local radiologist’s/investigator’s assessment.  
Radiographic images and clinical information collected on-study will also be reviewed 
retrospectively by a blinded independent third-party core imaging laboratory to verify 
investigator reported tumor assessments.  This information will be used for supportive 
analyses.
9.3.1. Analysis of Primary Endpoint
The primary endpoint is PFS based on investigator’s assessment which is defined as the time 
from the date of randomization to the date of the first documentation of objective progression 
of disease (PD) or death due to any cause in the absence of documented PD, whichever 
occurs first.  PFS data will be censored on the date of the last tumor assessment on study for 
patients who do not have objective tumor progression and who do not die while on study. 
Patients lacking an evaluation of tumor response after randomization will have their PFS 
time censored on the date of randomization with a duration of 1 day. Additionally, patients 
who start a new anti-cancer therapy prior to documented PD will be censored at the date of 
the last tumor assessment prior to the start of the new therapy. 
The primary analyses of PFS will be performed in the ITT population. A stratified log-rank 
test (one-sided) will be used to compare PFS time between the 2 treatment arms at the 
interim and/or final analyses with the overall significance level preserved at 
0.025 (one-sided).  The stratification factor(s) will be specified in the SAP.  PFS time 
associated with each treatment arm will be summarized for the ITT population using the 
Kaplan-Meier method and displayed graphically where appropriate.  Confidence intervals 
(CIs) for the 25th, 50th and 75th percentiles of the event-free time will be reported.  The Cox 
proportional hazards model will be fitted to compute the treatment hazard ratio and the 
corresponding 95% CI.
PFS will also be evaluated in the AT population.
As the emphasis of the study is on the estimation of treatment effect in Asia region, various 
analysis methods might be used to obtain more information about the treatment effect.  Data 
from Asian patients in global study A5481008 will be used with A5481027 data for the 

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combined analysis.  Other methods (for example, the weighted Z-test proposed by Lan et al. 
2005) may also be explored to combine the global study data and the regional study data.  
Details about these analyses will be specified in the SAP.
9.3.2. Analysis of Secondary Endpoints
PFS analyses will be repeated on ITT population based on the review of the blinded 
independent third-party core imaging laboratory as secondary supportive analysis.  
The other secondary efficacy endpoints are:
Overall Survival 
Overall Survival (OS) is defined as the time from date of randomization to date of death due 
to any cause. In the absence of confirmation of death, survival time will be censored to last 
date the patient is known to be alive. 
All patients randomized will be considered evaluable for OS. A stratified log-rank test (using 
the same stratification factors as for the PFS analysis) will be used to compare OS between 
the treatment arms.  OS for the two arms will be assessed using Kaplan-Meier methods and 
displayed graphically where appropriate. The median event times and 95% CIs will be 
estimated.  Cox regression models will be used to estimate the treatment hazard ratio and its 
95% confidence interval.
The 1-year survival probability will be estimated using the Kaplan-Meier method and a two 
sided 95% CI for the log [-log(1 year survival probability)] will be calculated using a normal 
approximation, and then back transformed to give a CI for the 1-year survival probability 
itself.  The 2-year, and 3-year survival probabilities will be estimated similarly. 
Objective Response (OR)
Objective response is defined as a complete response (CR) or partial response (PR) according 
to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1; Appendix 7) 
recorded from randomization until disease progression or death due to any cause. 
A patient will be considered to have achieved an OR if the patient has a sustained complete 
response (CR) or partial response (PR) according to RECIST v.1.1 definitions. Otherwise, 
the patient will be considered as non-responders in the OR rate analysis.  Additionally, 
patients with inadequate data for tumor assessment (eg, no baseline assessment or no 
follow-up assessments) will be considered as non-responders in the OR rate analysis. 

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The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the 
number of patients with objective response (CR or PR) by the number of patients randomized 
to the respective treatment arm (“response rate”). A 95% CI for the response rates will be 
provided.  Response rate comparisons between the 2 treatment arms as randomized will be 
assessed using Cochran-Mantel-Haenszel (CMH) test with the same stratification factors as 
for the PFS analysis. 
Analyses for ORR will be performed on the ITT population based on the investigator’s 
assessment as well and also on the review of the blinded independent third-party core 
imaging laboratory.
In addition, the best overall response for each patient will be summarized by treatment arm.
Disease Control (DC)
Disease control (DC) is defined as complete response (CR), partial response (PR), or stable 
disease (SD) ≥24 weeks according to the RECIST version 1.1(Appendix 7) recorded in the 
time period between randomization and disease progression or death to any cause. 
The DC rate (DCR) on each randomized treatment arm will be estimated by dividing the 
number of patients with CR, PR, or SD ≥24 weeks by the number of patients randomized to 
the treatment arm. A 95% CI for the DC rates will be provided.  DC rate comparison 
between the two treatment arms as randomized will be assessed using CMH test with the 
same stratification factors as for the PFS analysis.
Analyses for DCR will be performed on the ITT population based on the investigator’s 
assessment as well and also on the review of the blinded independent third-party core 
imaging laboratory.
Duration of Response (DR)
Duration of response (DR) is defined as the time from the first documentation of objective 
tumor response (CR or PR) to the first documentation of objective tumor progression or to 
death due to any cause, whichever occurs first. DR data will be censored on the date of the 
last tumor assessment on study for patients who do not have objective tumor progression and 
who do not die due to any cause while on study. 
DR will only be calculated for the subgroup of patients with an objective response. 

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DR for the two treatment arms will be summarized using Kaplan-Meier methods and 
displayed graphically, where appropriate. The median event time and 95% CI for the median
will be provided for each endpoint.
Additional sensitivity analyses will be outlined in the SAP. 
Additional secondary endpoints include:
Patient Reported Outcomes (PRO)
Breast cancer-specific quality of life scores and change from baseline scores will be 
compared between the treatment arms at various time points using a mixed model repeated 
measures (MMRM) approach adjusting for specified covariates. In addition, analyses will be 
performed to determine if the change from baseline scores achieve the appropriate minimally 
important difference (MID) cut-off for the scale being examined.  Patients from the ITT
population who completed a baseline assessment and at least one post-baseline assessment 
will be considered evaluable for the patient reported outcome analysis.
Pharmacokinetic Analysis
Individual and Average Palbociclib trough concentrations will be listed by patient. Summary 
statistics will be provided for trough concentrations by study cycle and for average trough 
concentrations by patient. The relationship between trough concentration and potential 
covariates may be evaluated. All patients treated with Palbociclib and for whom drug plasma 
concentration results (from at least 1 visit) are available will be included in the analysis.
Exposure/Response Analysis: In addition, the relationship between exposure and 
efficacy/safety endpoints will be explored, as necessary, based on emerging efficacy and 
safety data. Refer to the SAP for details of the analyses. The results of these modeling 
analyses may be reported separately from the the clinical study report.
9.4. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, efficacy endpoints, safety parameters, and biomarkers.  Data will 
also be displayed graphically, where appropriate. 

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9.5. Safety Analysis
The AT population will be the primary population for safety evaluation. Summaries of AEs 
and other safety parameters will be provided as appropriate.
Adverse Events
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 v4.0 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html). 
Adverse events will be summarized by treatment and 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 v4.0 Grade.  
Adverse events will be summarized by cycle and by relatedness to trial treatment.  Detailed 
information collected for each AE will include a description of the event, duration, whether 
the AE was serious, intensity, relationship to study drug, action taken, and clinical outcome.  
Emphasis in the analysis will be placed on AEs classified as treatment emergent.
Adverse events leading to death or discontinuation of trial treatment, events classified as NCI 
CTCAE v4.0 Grade 3 or higher, trial drug-related events, and serious adverse events will be 
considered with special attention. 
Laboratory Abnormalities 
Hematology and chemistry laboratory data will be summarized by treatment and by cycle.  
The laboratory results will be graded according to the NCI CTCAE v4.0 severity grade.  The 
frequencies of the worst severity grade observed will be displayed by study treatment.  Shift 
tables will be provided to examine the distribution of laboratory toxicities. For parameters 
for which an NCI CTCAE v4.0 scale does not exist, the frequency of patients with values 
below, within, and above the normal ranges will be summarized by treatment. 
Ocular Events
Ocular events will be reported as part of the adverse event analysis described above.
Additionally, changes in lens grading while on study treatment will be analyzed as described
in the Statistical Analysis Plan.

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Analysis of Electrocardiogram Measurements 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. QT measurements corrected for heart rate 
(QTc) using Bazett’s (QTcB) and Fridericia’s (QTcF) method will be used for the data 
analysis and interpretation. Data will be summarized and listed for QT, HR, RR, PR, QRS
and QTcF by treatment and dose.  Individual QTc (all evaluated corrections) intervals will be 
listed by time and dose.  Descriptive statistics (n, mean, median, standard deviation, 
minimum, and maximum) will be used to summarize the absolute QTc value and changes 
from baseline in QTc after treatment by day and time point.
9.6. Interim Analysis
The study is designed to have one interim analysis and the final analysis based on the 
primary PFS endpoint. The purposes of the interim analysis are to allow early stopping of 
the study for efficacy, and to assess safety of the combination regimen. The analysis will be 
performed after approximately 139 patients have documented progressive disease or die 
(approximately 65% of the total events expected). 
A formal efficacy boundary  for rejecting the null hypothesis is constructed by using the 
spending function methodology of the power family design with Δ=-0.5. To protect the 
integrity of the study and to preserve the type-1 error rate, a fraction of alpha for efficacy will 
be spent at the interim analysis and accounted for in the overall type I error rate. For 
logistical and administrative reasons the actual number of events at the interim and final
analyses might differ slightly from those that have been pre-specified above. In that case
appropriate adjustments will be made to the efficacy boundaries based on the power family
spending functions. The overall significance level for the efficacy analysis of PFS will be 
preserved at 0.025 (1-sided test).
At the interim analysis, if the result exceeds the efficacy boundary, the trial may be stopped 
for efficacy.  Alternatively, as appropriate, the sample size of the study may be adjusted 
using the method outlined by Cui et al. 
If the results of the interim analysis indicate serious safety concerns, the sponsor will 
communicate with the Health Authorities regarding stopping the clinical trial.

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An interim analysis of efficacy is also planned for the secondary endpoint OS.  The analysis 
will be performed at the same time of the final analysis of PFS.  Even if the improvement in 
PFS is significant at its interim and the study is stopped due to the overwhelming resutls, the 
interim OS analysis will still be performed at the approximately planned PFS final analysis 
time.  The nominal significance levels for the interim analysis of OS will be determined by 
using the Lan-Demets procedure with an O’Brien-Flemming stopping rule.  The overall 
significance level for the efficacy analysis of OS will be preserved at 0.025 (one-sided test).  
Details of the analysis will be provided in the SAP. 
In order to control the overall type I error rate, OS will be hierarchically tested for 
significance at the time of final PFS analysis, provided the primary endpoint PFS is 
statistically significant at the interim or final PFS analysis.  If OS does not yield a significant
results at this analysis, OS will be tested at the final OS analysis.  If PFS is not significant at 
the final PFS analyses, OS will not be statistically evaluated.  
9.7. Data Monitoring Committees
An independent third party External Data Monitoring Committee (E-DMC) will monitor the 
safety data on a periodic basis. The E-DMC will make recommendation as to whether the 
trial should continue based on ongoing reviews of safety data. The E-DMC will also evaluate 
efficacy at the interim analysis and make a recommendation regarding study continuation 
based on observed results of the study.  The Sponsor will designate an external third-party 
biostatistician not affiliated with the project to prepare data for DMC review which will be 
kept confidential to the EDMC. The E-DMC membership and governance is outlined in a
separate charter.
The DMC will be responsible for ongoing monitoring of the efficacy and safety of subjects in 
the study according to the Charter.  The recommendations made by the DMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data which are not endpoints, to regulatory authorities, as appropriate.  
The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision. Pfizer will forward such decisions, to regulatory 
authorities, as appropriate. Clinical sites will be restricted from access to study results until 
the conclusion of the study.

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10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agents will conduct periodic monitoring visits 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 is 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.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), 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.
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 is true.  Any corrections to entries made in the CRFs, 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 investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, 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 International Conference on Harmonisation (ICH), 
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)/Independent Ethics Committee (IEC)
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/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.

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The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC 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 Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (ICH 1996), and the Declaration of 
Helsinki (World Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient. In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  The investigator, or a 
person designated by the investigator, will obtain written informed consent from each patient
or the patient's legal representative before any study-specific activity is performed.  The 
investigator will retain the original of each patient's signed consent document.  The patient 
will be provided with a copy of the signed informed consent form(s).

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12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.
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 which 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
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Last Patient Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug 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.

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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), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations.
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.
The timing of the posting depends on whether the Pfizer product is approved for marketing in 
any country at the time the study is completed:
For studies involving products applicable under the US Food and Drug Administration 
Amendments Act of 2007 (FDAAA), ie, FDA approved products, Pfizer posts results within 
one year of the primary completion date (PCD).  For studies involving products approved in 
any country, but not FDA approved, Pfizer posts results one year from last subject, last visit 
(LSLV);
For studies involving products that are not yet approved in any country, Pfizer posts the 
results of already-completed studies within 30 days of US regulatory approval, or one year 
after the first ex-US regulatory approval of the product (if only submitted for approval 
ex-US);
For studies involving products whose drug development is discontinued before approval, 
Pfizer posts the results within one year of discontinuation of the program (if there are no 
plans for outlicensing or within two years if outlicensing plans have not completed).
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 pre-specified protocol or was 
terminated.

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www.pfizer.com
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored interventional 
studies in patients that assess the safety and/or efficacy of an FDA-approved  Pfizer product 
with a LSLV on or after 27-Sep-2007 for which Basic Results were posted on 
www.clinicaltrials.gov.
EudraCT
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on clinical 
trials in relation to the implementation of Article 57(2) of Regulation (EC) No 726/2004 and 
Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in the European 
Economic Area and with LSLV on or after 01-May-2004, regardless of the marketing status 
of the compound.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigators of any information collected or 
generated by Investigators, whether or not the results are favorable to the Investigational 
Product.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigators will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigators will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) 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, Investigators agree to delay the 
disclosure for a period not to exceed an additional 60 days.
Investigators will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigators agree that the first publication is to 
be a joint publication covering all centers.  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, Investigators are free to publish separately, subject to the other 
requirements of this Section.

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For all publications relating to the Study, Institutions 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.

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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. Sponsor Approved HER2 Assays
HER2 results based on 1 of the following commercial kit assays are acceptable (for the 
purposes of study entry)
IHC Approved Assay
FISH Approved Assay
CISH Approved Assay
HercepTest
Pathvysion HER2 DNA 
Probe Kit
SPOT-Light® HER2 CISH 
Kit
Pathway
INFORM HER2/neu Probe
-
-
HER2 FISH PharmDx™Kit
-

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Appendix 3. List of Drugs Known to Predispose to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone®, Pacerone®
Arsenic trioxide
Trisenox®
Astemizole
Hismanal®
Azithromycin
Zithromax®
Bepridil
Vascor®
Chloroquine
Aralen®
Chlorpromazine
Thorazine®
Cisapride
Propulsid®
Citalopram
Celexa®
Clarithromycin
Biaxin®
Disopyramide
Norpace®
Dofetilide
Tikosyn®
Domperidone
Motilium®
Droperidol
Inapsine®
Erythromycin
Erythrocin®, E.E.S.®
Flecainide
Tambocor®
Halofantrine
Halfan®
Haloperidol
Haldol®
Ibutilide
Corvert®
Levomethadyl
Orlaam®
Mesoridazine
Serentil®
Methadone
Dolophine®, Methadose®
Moxifloxacin
Avelox®
Pentamidine
Pentam®, NebuPent®
Pimozide
Orap®
Probucol
Lorelco®
Procainamide
Pronestyl®, Procan®
Quinidine
Cardioquin®, Quinaglute®
Sotalol
Betapace®
Sparfloxacin
Zagam®
Terfenadine
Seldane®
Thioridazine
Mellaril®
Vandetanib
Caprelsa®
Adapted from the University of Arizona Cancer Center for Education and Research on Therapeutics: "Torsades 
List: Drugs with a Risk of Torsades de Pointes," drugs that are generally accepted by the QTdrugs.org Advisory 
Board to carry a risk of Torsades de Pointes on the University of Arizona CERT website: 
http://www.crediblemeds.org/.  This list is not meant to be considered all inclusive.  See website for current list.

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Appendix 4. Bone Marrow Reserve in Adult
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol.  5, 255-258, 1961
MARROW DISTRIBUTION OF THE ADULT
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head:
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle :
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs: 
82.6
1 pair
10.2
All 0.4
4.1
2 
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8

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MARROW DISTRIBUTION OF THE ADULT (CONT'D)
SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar):
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0

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Appendix 5. EuroQol Health Utilities Index EQ-5D 

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Appendix 6. Functional Assessment of Cancer Therapy-Breast (FACT-B) [Version 4] 

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Appendix 7. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247
Categorizing Lesions at Baseline.
Measurable Lesions  

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.  

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment.

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Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above.  If 
non-cystic lesions are also present, these are preferred as target lesions.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.

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Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
< 10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  All 
target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate. Progression has not been documented, and 

one or more target measurable lesions have not been assessed,

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
or assessment methods used were inconsistent with those used at baseline,

or one or more target lesions cannot be measured accurately (eg, poorly visible unless 
due to being too small to measure),

or one or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels.  
All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or 
PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline.

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New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 

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Table 1. Objective Response Status at each Evaluation 
   Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease 
Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD

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Appendix 8. Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure

Dilate pupils to at least 5 mm diameter;

Use slit lamp with ~10X magnification;

Use brightest beam intensity.

Nuclear opacity:

Orient beam at 45° to viewing axis;

Adjust slit beam to standard parameters: 8 mm height and 0.3 mm width;

Compare opalescence of nucleus with that in standard photos.

Cortical and PSC opacities:

Select wide slit beam setting optimum for retro-illumination of lens;

Visualize lens opacities against red fundus reflex background;

Count only opacities definitely visible against red reflex;

Mentally combine all cortical opacities into one contiguous area;

Compare total opacity area with that in standard photos.

Classify each opacity with scale defined by 3 standard photos.

Select nearest half-step:

Similar to standard or between two standards;

Obviously less than mildest standard or greater than most severe.

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Appendix 9. List of Abbreviation
ABC
Advanced Breast Cancer
ASCO
American Society of Clinical Oncology
AE
Adverse Event
ALT
Alanine Aminotransferases 
AI
Aromatase Inhibitor
ANC
Absolute Neutrophil Count
AREDS
Age-Related Eye Disease Study
AST
Aspartate Aminotransferases 
AT
As Treated 
AUC
Area Under the Curve
BC
Breast Cancer
BUN
Blood Urea Nitrogen
CAP
Chest, Abdomen, Pelvis OR College of American Pathologists 
depending on context.
CCND1
Cyclin D1
CDK
Cyclin-Dependent Kinase
CDKN2A, p16Ink4A
Cyclin-Dependent Kinase Inhibitor 2A
CFDA
China Food and Drug Administration
CI
Confidence Interval
CISH
Chromogenic In Situ Hybridization
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
CR
Complete Response
CRF
Case Report Form
CSA
Clinical Study Agreement
CSF
Colony-Stimulating Factors
CT
Computed Tomography
CTA
Clinical Trial Application
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P-450
DC
Disease Control
DCR
Disease Control Rate
DFI
Disease Free Interval
DICOM
Digital Imaging and Communications in Medicine
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group

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E-DMC
External Data Monitoring Committee
EDTA
Ethylenediaminetetraacetic acid
EIU
Exposure In Utero
EQ-5D
Dimension Health State EuroQoL Score
ER
Estrogen Receptor
FACT
Functional Assessment of Cancer Therapy
FACT-B
Functional Assessment of Cancer Therapy - Breast
FACT-G
Functional Assessment of Cancer Therapy - General
FDA
US Food and Drug Administration 
FDAAA
US Food and Drug Administration Administration Amendments
FFPE
Formalin Fixed Paraffin Embedded
FIH
First in Human
FISH
Fluorescent In Situ hybridization
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
Hb
Hemoglobin
HDL
High Density Lipoprotein
HDPE
High Density Polyethylene
HER
Human Epidermal Growth Factor Receptor
hERG
Human Ether-à-Go-Go
HR
Heart Rate
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
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International Normalized Ratio
Internal DMC
Internal Data Monitoring Committee
IOP
Intraocular Pressure
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
ITT
Intent-to-treat 
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LPD
Local Product Document
LSLV
Last Subject Last Visit
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose

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N/A
Not Applicable
NCI
National Cancer Institute
OBU
Oncology Business Unit
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PCD
Primary Outcome Completion Date
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival
PK
Pharmacokinetic 
PR
Partial Response or Progesterone Receptor (depending on context)
PR
The PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex.
PS
Performance Status
PSC
Posterior Subcapsular Cataract
PRO
Patient Reported Outcome
PT
Prothrombin Time
QD
Quaque Die (once daily)
QRS
The QRS complex is a name for the combination of three of the 
graphical deflections seen on a typical electrocardiogram.
The QRS complex reflects the rapid depolarization of the right and left 
ventricles.
QT
Time between the start of the Q wave and the end of the T wave in the 
heart's electrical cycle
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett's fomula
QTcF
QT interval corrected for heart rate using Fridericia's fomula
RANKL
Receptor Activator of Nuclear Factor Kappa B Ligand
RB/Rb
Retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
RR
The interval between an R wave and the next R wave
Rac
Accumulation Ratio
SABCS
San Antonio Breast Cancer Symposium
SAE
Serious Adverse Event
SD
Stable Disease or Standard Deviation (depending on context)
SPC
Summary of Product Characteristic
t½
Terminal Elimination Half-life
TdP
Torsade de Pointes
TEAE
Treatment Emergent Adverse Event
Tmax
Time for Cmax

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ULN
Upper Limit of Normal
US
United States
VAS
Visual Analogue Scale
Vz/F
Apparent Volume of Distribution
WBC
White Blood Cell