Clinical trial NCT01942135
Conditions: Metastatic Breast Cancer
Keywords: Palbociclib (PD-0332991) Fulvestrant Goserelin Hormone receptor-+ HER2-negative Prior Endocrine treatment any menopausal status PALOMA-3
Sponsor: Pfizer
Start date: 2013-09-26; Completion date: 2022-09-28
Enrollment: 521 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a randomized, double blind, placebo controlled, Phase 3 clinical trial with the primary objective of demonstrating the superiority of palbociclib in combination with fulvestrant (Faslodex®) over fulvestrant alone in prolonging PFS in women with HR+, HER2 negative metastatic breast cancer whose disease has progressed after prior endocrine therapy. The safety between the two treatment arms will also be compared. During study treatment, pre- and perimenopausal women must be receiving therapy with the LHRH agonist goserelin (Zoladex® or generic).

Detailed description:

Arms: arm 1: Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. arm 2: Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.
Interventions: intervention 1: Palbociclib intervention 2: Fulvestrant intervention 3: Placebo intervention 4: Fulvestrant
Intervention descriptions: intervention 1: Palbociclib 125 mg/day orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle. intervention 2: Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle. intervention 3: Placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle. intervention 4: Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle.

Protocol documents:
Prot_000.pdf: 
PD-0332991 (Palbociclib)
A5481023 (PALOMA-3)
Final Protocol Amendment 3, 20 October2015
PFIZER CONFIDENTIAL
Page 1
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PHASE 3 TRIAL OF FULVESTRANT (FASLODEX) WITH OR WITHOUT 
PD-0332991 (PALBOCICLIB) GOSERELIN IN WOMEN WITH HORMONE 
RECEPTOR-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER 
WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE THERAPY
Compound:
PD-033,2991
Compound Name:
Palbociclib
United States Investigational New Drug
Number:
69,324
European Clinical Trial Database 
(EudraCT) Number:
2013-002580-26
Protocol Number:
A5481023
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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A5481023 (PALOMA-3)
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Document History
Document
Version Date
Summary of Changes
Amendment 3
20 October 2015

Section 1.2.4.3: Added the section to clarify the 
rationale for Amendment 3.  Upon approval, 
some of the safety and efficacy assessments
will be reduced due to: 1) completion of 
efficacy analyses including interim and final 
analysis of primary endpoint and secondary 
endpoints; 2) additional analyses of safety 
conducted to comply with Health Authorities 
requirements; 3) at the time of amendment 
approval a smaller number of patients will be 
on study treatment and patients will remain
under observation for a follow-up period of 
approximately 1 year and a half.

Protocol Summary-Background and 
Rationale/Section 1.2.1.8: Added data of 
interim analysis of present study. 

Protocol Summary-Study 
Endpoints/Section 2.2: PRO endpoints have 
been better reworded. 

Protocol Summary-Study Design/Schedule of 
Activities/Section 6.4/Section 7.2.1: Added 
clarification that tumor assessments will be 
conducted as per local practice after approval of 
Amendment 3.  As a consequence, the 
requirement of conducting tumor assessment at 
the End of Treatment visit will not be 
mandatory any longer. 

Protocol Summary-Study design/Section 7.2.3: 
Clarified that the third-party core imaging 
laboratory will not perform any longer blinded 
independent central review of PFS data.  The 
investigators will stop sending the imaging
studies to the central laboratory.

Protocol Summary-Schedule of 
Activities/Section 6.5.3/Section 7.2.4: Added 
clarification that survival follow-up visits will 
be conducted every 3 months after approval of 
Amendment 3.


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A5481023 (PALOMA-3)
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Document
Version Date
Summary of Changes

Protocol Summary-Schedule of Activities: 
Added clarification that blood chemistry will be 
performed every 3 cycles (Day 1) after approval 
of Amendment 3.  It was also clarified that, if 
an adverse event occurs that mandates blood 
chemistry to be performed (eg, hepatic function 
abnormality), the additional laboratory data will 
be recorded in the CRF.

Protocol Summary-Schedule of Activities: 
Clarified that hemoglobin A1c will be tested at 
the time of blood chemistry.

Protocol Summary-Schedule of Activities: 
Clarified that ophthalmology tests will continue 
to be collected.

Protocol Summary-Schedule of 
Activities/Section 5.3.3.1: Clarified that no time 
window is to be considered for treatment 
schedule of palbociclib/placebo and that 
hematology tests must meet retreatment criteria 
prior to administering palbociclib.

Protocol Summary-Tumor Assessment 
Requirements Flow Chart/Section 5.2: Clarified 
that, after approval of Amendment 3, tumor 
assessments will be conducted as per local 
practice, selection of imaging studies will 
depend on treating physician and radiologist as 
per local practice, and RECIST version 1.1 will 
not be mandatory any longer to evaluate 
imaging studies nor to confirm disease 
progression.   

Section 5.5.1: Clarified that strong/moderate 
CYP3A inhibitors/inducers and proton pump 
inhibitors listed in the protocol are permitted for 
those patients who permanently discontinued 
palbociclib/placebo and continue on fulvestrant 
monotherapy only.


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A5481023 (PALOMA-3)
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Document
Version Date
Summary of Changes

Section 6.5.4: The section was deleted as for 
patients who discontinued study treatment 
without an objectively documented progression, 
the tumor assessments showing progression of 
the disease will not be collected any more 
during follow-up.

Section 9: Clarified that the planned data 
analyses described in the protocol had been 
already conducted at the time of the interim 
analysis

Section 16: Added reference 41 related to 
interim analysis data of A5481023 study and 
deleted reference 60 to reflect changes made in 
the protocol.
Amendment 2
30 September 
2014

Schedule of Activities/Section 7.3.1 Laboratory 
Safety Assessments: Added prospective 
monitoring of hemoglobin A1c to characterize 
whether or not palbociclib affects glucose 
metabolism.

Schedule of Activities/Study design: Added 
clarification to the schedule of administration of 
fulvestrant and goserelin.

Schedule of Activities/Section 5.3.4.2.1/
Section 6: Language related to cycle delay 
further defined to clearly state that any new 
cycle may only start if blinded study treatment
can be resumed.  

Schedule of Activities/Section 7.3.3: Added 
clarification to the timing for physical 
examination/vital signs assessments.

Section 1.2.1.2. Human Pharmacokinetic Data: 
Updated section to add data findings to support:
1) administration of palbociclib with food; 
2) prohibition of palbociclib administered
concomitantly with proton-pump inhibitors; 
CCI
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Version Date
Summary of Changes
3) concomitant use of local antacids and H2-
receptor antagonists; 4) prohibition of 
palbociclib administered concomitantly with
strong/moderate CYP3A inducers/inhibitors; 
5) palbociclib as a weak time-dependent 
inhibitor of CYP3A.

Section 5.3.4.2.3: In Table 3, added language 
related to the criteria for treatment restart after 
the occurrence of toxicity to allow restart of 
palbociclib/placebo at the next lower dose level 
if uncomplicated Grade 3 neutropenia recurs in 
2 consecutive cycles.

Section 5.5: Editorial changes made to 
differentiate between strong and moderate 
CYP3A inducers/inhibitors. Restriction on 
CYP3A substrate removed based on updated 
information indicating that palbociclib is a 
weak time-dependent inhibitor of CYP3A.  
Lastly, local antacids and H2-receptor 
antagonists were moved under the “Permitted 
Medications” Section 5.5.3 to reflect results 
from Study A5481038 showing that H2-
receptor antagonists and local antacids given as 
defined per protocol did not impact the 
exposure of palbociclib.

Section 6.5: Added clarification of adverse 
events follow-up procedure (telephone contact)
at 28 calendar days after treatment 
discontinuation.  Additional editorial changes
made to clarify follow-up procedures for 
patients who discontinue treatment for reasons 
other than disease progression and for patients 
who discontinue treatment due to disease 
progression. 
CCI


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Document
Version Date
Summary of Changes

Sections 9.6 and 9.7: Updated to report the 
analyses to be conducted on ocular events data 
and added clarification that the method of 
sample size re-estimation will be pre-specified 
in a separate technical document to be only 
shared with the E-DMC before the interim 
analysis.

Minor editorial changes made to correct 
inconsistencies or improve text clarity 
throughout the protocol.
Amendment 1
04 April 2014

Schedule of Activities; Section 7.2.2. (Ocular 
Safety Assessments) – Added ocular safety 
assessment procedures to newly enrolled lens 
grading evaluable patients to assess the 
potential risk of palbociclib-associated lens 
changes.

Section 1.2.1.2 (Human Pharmacokinetic Data) 
– Included preliminary results from two clinical 
pharmacology studies of palbociclib supporting 
revisions of Sections 5.3.3.1
(Palbociclib/Placebo), 5.5.1 (Prohibited 
Medications), and 5.5.2 (Medications Not 
Recommended).

Section 1.2.4. (Amendment Rationale): Added 
rationale for Amendment 1.

Section 4.1 (Inclusion Criteria) - Clarified
inclusion criterion #6 and exclusion criteria #4, 
5 and 6 to address frequent questions from 
investigational sites.

Section 5.3.3.1 (Palbociclib/Placebo) – Added 
recommendation to take palbociclib with food
instead of under fasting conditions.
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Document
Version Date
Summary of Changes

Section 5.3.4.2.3 (Retreatment Criteria), 
Table 3 – Specified time period of 7 days for 
delay of neutrophil recovery qualifying for 
further dose reduction to align with remainder 
of the protocol.

Section 5.5.1 (Prohibited Medications) – Added 
prohibition to take proton-pump inhibitors 
while receiving study drug.

Section 5.5.2 (Medications Not Recommended) 
– Added instructions about administration of 
local antacids and H2-receptor antagonist as 
alternative treatment for patients requiring 
gastroprotective treatment.

Section 6.6.1 (Active Treatment Phase 
Discontinuation) – Clarified that routine safety 
assessments must continue if patient continues
study treatment despite progression of disease.

Appendix 4 (RECIST version 1.1 Guidelines) –
Aligned terminology with RECIST version 1.1.

Appendix 8 Wisconsin Age-Related Eye 
Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure added.

Editorial changes to align language throughout 
the protocol, to clarify text considered 
confusing by investigational sites, and to reflect 
the sponsor’s current protocol template.
Original protocol
24 July 2013
Not applicable.
This amendment incorporates all revisions to date.


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A5481023 (PALOMA-3)
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PROTOCOL SUMMARY 
Background and Rationale: 
Palbociclib is an orally active pyridopyrimidine, first-in-class compound that is a potent and 
highly selective reversible inhibitor of Cyclin-Dependent Kinase (CDK) 4/6. The compound 
prevents cellular Deoxyribonucleic Acid (DNA) synthesis by prohibiting progression of the 
cell cycle from G1 into the S phase, as demonstrated both in laboratory models and in early 
clinical trials. There is a strong link between the action of estradiol and the G1-S phase 
transition, where it drives transcriptional activation of cyclin D1 leading to formation of the 
cyclin D1-CDK4/6-Rb complex which facilitates the G1 to S phase transition. Preclinical 
data, both Pfizer internal data and also from other laboratories, suggest that estrogen resistant 
models are exquisitely sensitive to the combination of palbociclib with antihormonal therapy 
or palbociclib alone. 
Blockade of the Estrogen Receptor (ER) signaling pathway is synergistic with cell cycle 
arrest induction, as demonstrated by the more than doubling in median Progression Free 
Survival (PFS) observed to date in the ongoing trial evaluating ER+ metastatic breast cancer
patients treated with the combination of an aromatase inhibitor (AI) and palbociclib
compared with aromatase inhibitor alone. Overcoming resistance to endocrine therapy in 
breast cancer patients is a major challenge and there is a high unmet need for safe and 
efficacious treatment options in women resistant to endocrine therapy.
Postmenopausal women with hormone receptor (HR)+/ Human Epidermal Growth Factor 
Receptor 2(HER2)-negative breast cancer that have progressed after treatment with letrozole 
or anastrozole are now able to receive everolimus (Afinitor) in combination with 
exemestane.  However, despite promising efficacy recently demonstrated in the BOLERO-2 
trial in ER+/HER2-negative patients (median PFS 6.9 months for the everolimus-exemestane 
combination vs. 2.8 months for exemestane alone per investigator’s assessment), a high 
percentage of patients discontinued everolimus due to a challenging tolerability profile. The 
potential of everolimus to improve overall survival and clinical benefit in women with 
endocrine sensitive disease, or who present with advanced breast cancer in the pre- or 
perimenopausal status, is not yet known.
Data from the open-label Phase 2 study PALOMA-1 (A5481003) in a patient population of 
ER+/HER2-negative postmenopausal patients with newly diagnosed metastatic breast cancer 
indicate that the addition of palbociclib to letrozole significantly extends PFS with a tolerable 
safety profile. The results of two interim analyses showed a consistent trend of clinically 
meaningful improvements in PFS. In the first interim analysis (Part 1; N=66), the median 
PFS for the palbociclib plus letrozole arm was 18.2 months versus 5.7 months for the 
letrozole alone arm (Hazard Ratio (HR)=0.35; 95% confidence interval (CI): 0.17, 0.72; 
p=0.006).  The second interim analysis (N=165) demonstrated a statistically significant 
improvement in PFS (26.1 vs. 7.5 months, respectively; HR=0.37; 95% CI: 0.21, 0.63; 
p <0.001). 


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While the study included patients whose disease had relapsed at various timepoints after 
prior endocrine therapy, there is limited clinical data on the activity of palbociclib in patients 
whose disease recurred on or early after antihormonal therapy - a population that may be less 
sensitive to re-treatment with antihormonal therapy. Such patients, who could be pre-, peri-, 
or postmenopausal, comprise a large high-risk population for whom more therapeutic options 
are needed. 
Fulvestrant is a potent anti-estrogen drug that binds and degrades ER. Recent data with 
fulvestrant administered 500 mg monthly to patients with recurrent HR+/HER2-negative 
breast cancer indicate significant antitumor activity after both antiestogen and AI failure. In 
a Phase 2 study, the combination of fulvestrant and everolimus has shown efficacy in 
postmenopausal women after failure of AI treatment similar to that of the combination of 
tamoxifen with everolimus (median time to progression 7.4 months). Fulvestrant is currently 
indicated for the treatment of postmenopausal women with metastatic HR+ breast cancer 
following the failure of antiestrogen therapy.  Despite its attractive mechanism of action, it 
has not been studied extensively in pre- or peri-menopausal women. However, it is expected 
to also add benefit to the treatment of pre- and peri-menopausal women if given concurrently 
with ovarian suppression/ablation. 
Clinical experience demonstrates that ovarian ablation produces comparable outcomes to 
tamoxifen monotherapy and supports the use of goserelin (Luteinizing Hormone-Releasing 
Hormone [LHRH] agonist) concurrently with fulvestrant in premenopausal women with 
metastatic breast cancer. In fact, Phase 2 studies are currently underway evaluating the 
combination of fulvestrant with medical ovarian suppression in premenopausal women with 
breast cancer.  The growing data about the activity of fulvestrant after antihormonal therapy 
failure, together with emerging efficacy data of palbociclib support their combined use in 
women with HR+, HER2-negative metastatic breast cancer whose disease has progressed 
after prior endocrine therapy. The present study will establish the degree of added benefit of 
palbociclib in HR+/HER2-negative recurrent breast cancer patients treated with fulvestrant 
versus fulvestrant alone. 
The present study (PALOMA-3/A5481023) met its primary endpoint as per protocol at the 
interim analysis based on the recommendation of the external data monitoring committee.  
The addition of palbociclib to fulvestrant substantially improved PFS in pre/peri- and 
postmenopausal women with HR-positive, HER2-negative advanced breast cancer whose 
disease had progressed after prior endocrine therapy.  The median PFS was 9.2 months (95% 
CI, 7.5 to not estimable) in the palbociclib-fulvestrant arm and 3.8 months (95% CI, 3.5 to 
5.5) in the placebo-fulvestrant arm (HR=0.422; 95% CI, 0.318 to 0.560; 1-sided 
P<0.000001).. 
In the open-label Phase 2 study PALOMA-1 (A5481003) in patients with ER-positive, 
HER2-negative metastatic breast cancer who had never received systemic therapy for their 
advanced disease, palbociclib in combination with letrozole improved PFS compared to 
letrozole alone, suggesting palbociclib has activity when combined with endocrine therapy in 
both endocrine-naive and -resistant settings.


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In the present study, adverse events seen with palbociclib and fulvestrant were consistent 
with previously reported data.  Overall, palbociclib was well tolerated, with a discontinuation 
rate due to adverse events similar to that seen with placebo, and manageable by dosing 
interruptions, dose reductions, and/or standard medical care.  The majority of adverse events 
were mild to moderate in severity with the exception of hematological toxicties.
In addition, the patient-reported outcomes support the positive impact of palbociclib plus 
fulvestrant, maintaining global Quality of Life (QoL) on treatment and resulting in a 
statistically significantly higher on-treatment global QoL compared to placebo plus 
fulvestrant.
Double blinding of the present study will be maintained to allow ongoing collection of data 
for other pre-specified secondary endpoints including patient reported outcomes.
Study Design:
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, Phase 3 clinical trial with the primary objective of demonstrating the 
superiority of palbociclib in combination with fulvestrant (Faslodex) over fulvestrant alone 
in prolonging investigator-assessed PFS in women with HR+/HER2-negative metastatic 
breast cancer whose disease has progressed after prior endocrine therapy. The safety 
between the two treatment arms will also be compared. 
Eligible patients must have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of recurrent advanced (locally or metastatic) 
disease. Their breast cancer must have progressed during or within 12 months of completion 
of adjuvant therapy (with an AI, if postmenopausal, or with tamoxifen, if pre- or 
perimenopausal). Alternatively, it must have progressed while on, or within 1 month after 
the end of prior therapy for advanced/metastatic breast cancer (with an AI, if 
postmenopausal, or other prior endocrine treatment, if pre- or perimenopausal). One 
previous line of chemotherapy for metastatic disease is allowed. Patients must have 
measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 or 
bone disease as their only site of disease.  Tumor tissue is required for patient participation.
At least 417 patients will be randomized in a 2:1 ratio and stratified by documented 
sensitivity to prior hormonal therapy (yes vs. no), menopausal status at study entry (pre-/peri-
vs. post menopausal), and presence of visceral metastases (yes vs. no). 
Patients in Arm A (at least 278) will receive palbociclib 125 mg/day orally for 3 weeks 
followed by 1 week off plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, 
every 28 days (+/- 7 days) thereafter starting from Day 1 of Cycle 1.
Patients in Arm B (at least 139) will receive placebo orally daily for 3 weeks followed by 
1 week off plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, every 
28 days (+/- 7 days) thereafter starting from Day 1 of Cycle 1.


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In both arms, pre- and peri-menopausal women will also receive the LHRH agonist goserelin 
(Zoladexor generic).
At the time of approval of Amendment 3, patients will undergo tumor assessment according 
to local practice. . 
Patients will continue to receive assigned treatment until objective Progressive Disease (PD), 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  Crossover between treatment arms will not be allowed.  Patients showing PD 
can continue with study treatment at the discretion of the investigator as long as that is 
considered to be in the best interest of the patient and 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.
In addition, should palbociclib/placebo related toxicity mandate palbociclib/placebo 
discontinuation, patients can continue to receive fulvestrant alone. Patients discontinuing the 
active treatment phase (ie, discontinuing both palbociclib/placebo and fulvestrant) will enter 
a follow-up phase during which survival and new anti-cancer therapy information will be 
collected, every 3 months from the last dose of study treatment going forward after approval 
of Amendment 3.
An external data monitoring committee (E-DMC) will perform an early review of safety data 
from approximately the first 40 randomized patients with sufficient pharmacokinetic (PK) 
sampling to confirm safety and tolerability of the combination.  The early safety review by 
the E-DMC will also include Pharmacokinetic (PK) data from these initial approximately
40 patients to explore potential Drug-Drug-Interactions (DDIs) between fulvestrant, goserelin 
(if applicable) and palbociclib. The study will continue while these analyses and review are 
ongoing.
In addition, blood samples will be collected from all patients to assess trough concentrations 
of palbociclib for exposure/response analysis for safety and efficacy findings.
Patient Reported Outcomes (PRO) will be collected to evaluate health-related quality of life 
and health status. 
The study will also include a molecular profiling component aimed at assessing the 
relationship between breast tumor sensitivity and resistance to palbociclib and the alteration 
of cell cycle pathway-related genes and proteins in tumor tissues.
Study Objectives:
Primary Objective: 

To demonstrate the superiority of palbociclib in combination with fulvestrant (with or 
without goserelin) over fulvestrant alone (with or without goserelin) in prolonging 
investigator-assessed PFS in women with HR+/HER2-negative metastatic breast 
cancer whose disease has progressed on prior endocrine therapy. 


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Secondary Objectives:

To compare measures of tumor control between the treatment arms.

To compare safety and tolerability between the treatment arms.

To evaluate trough concentrations of palbociclib when given in combination with 
fulvestrant or fulvestrant plus goserelin, compared to historical palbociclib data.

To compare fulvestrant and goserelin trough concentrations when given in 
combination with palbociclib to those when given without palbociclib.

To explore correlations between palbociclib exposures and efficacy/safety findings in 
this patient population.

To compare Patient Reported Outcomes measures between treatment arms.

To characterize alterations in genes, proteins, and ribonucleic acids (RNAs) relevant 
to the cell cycle, drug targets, tumor sensitivity and/or resistance.

To conduct subgroup analysis for primary and secondary endpoints in stratified 
groups.
Study Endpoints:
Primary Endpoint:

Progression-Free Survival (PFS) as assessed by the Investigator. 
Secondary Endpoints:

Overall Survival (OS).

1-year, 2-year, and 3-year survival probabilities.

Objective Response (OR): Complete Response (CR) or Partial Response (PR).

Duration of Response (DR).

Clinical Benefit Response (CBR): CR or PR or Stable Disease (SD) 24 weeks.

Type, incidence, severity (as graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), seriousness and 
relationship to study medications of Adverse Events (AEs) and any laboratory 
abnormalities.

Trough plasma concentration of palbociclib, fulvestrant and goserelin (if applicable) 
in the subgroup of approximately 40 patients included in the initial safety review.


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
PRO endpoints such as global quality of life symptoms and functioning assessed 
using the European Organisation for Research and Treatment of Cancer Quality of 
Life Instrument (EORTC QLQ-C30) and European Organisation for Research and 
Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23) and Dimension 
Health State EuroQoL Score (EQ-5D)and time to deterioration (TTD) in pain
endpoint.

Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1 and 
CDKN2A, PIK3CA mutations), proteins (eg, Ki67, pRb, CCNE1), and RNA 
expression (eg, cdk4, cdk6).
Statistical Methods:
The primary objective of this study is to demonstrate that the combination of palbociclib and 
fulvestrant (goserelin) is superior to the combination of placebo and fulvestrant 
(goserelin) in prolonging investigator-assessed PFS in women with HR+/HER2-negative 
metastatic breast cancer that has progressed on prior endocrine therapy, regardless of their 
menopausal status. 
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The study is designed to have one interim analysis.  The interim analysis will be conducted to 
allow for early stopping of the study due to efficacy, or to potentially re-estimate the sample 
size of the trial based upon the primary endpoint of PFS. The safety of the combination will 
also be assessed at the interim analysis. The interim analysis of PFS will be performed after 
approximately 143 patients have documented PD or death (approximately 60% of the total 
events expected). The information fraction for the interim analysis may be adjusted if 
needed. The sample size of the study may also be adjusted as appropriate.
OS will be hierarchically tested for significance at the time of PFS analyses, provided the 
primary PFS endpoint is statistically significant at the interim and/or final PFS analyses. 
CCI


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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 patient.
Protocol Activity
Screening
Active Treatment Phasea - One Cycle = 28 days
End of 
Treatment/Withdrawalc
Post-Treatment 
Follow-Upd
Cycles 1 and 2
Cycles 3
Study Day
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1b
Day 15
Day 1
Visit Window
-2 days
2 days
7 daysa
7 days
Informed Consente
X
Medical/Oncological Historyf
X
Baseline Signs/Symptomsg
Xg
Physical Examination/Vital Signsh
X
Xb
X
X
Ophthalmic Examinationi
X
Xi
X
ECOG Performance Status
X
X
X
X
Laboratory Studies
Hematologyj
X
Xb
X
X
X
Blood Chemistryj
X
Xb
X
X (upon approval of 
Amendment 3, assessed 
every 3 cycles)
X
Pregnancy test, serum estradiol and FSH (if 
applicable) j
X
12-Lead ECG (in triplicate)
X
X
Disease Assessment
CT/MRI Scans of Chest, Abdomen, Pelvis, 
any clinically indicated sites of disease, and 
of bone lesions; Clinical evaluation of 
superficial diseasek
X
◄--►k
Upon approval of Amendment 3, performed as per local 
practice (See tumor assessment requirements flowchart)
X
X
Radionuclide Bone Scan, Whole Bodyl
X
Upon approval of Amendment 3, performed as per local 
practice  (See tumor assessment requirements flowchart)l
X
X
Other Clinical Assessments
Adverse Event Reportingm
X
X
X
X
X
X


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Protocol Activity
Screening
Active Treatment Phasea - One Cycle = 28 days
End of 
Treatment/Withdrawalc
Post-Treatment 
Follow-Upd
Cycles 1 and 2
Cycles 3
Study Day
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1b
Day 15
Day 1
Visit Window
-2 days
2 days
7 daysa
7 days
Concomitant Medications/Treatments
◄--►
Recorded from 28 days prior to the start of study treatment up to 28 days after the last dose of study treatment
Pharmacokinetics (PK)n
First 40 patients: Sampling at pre-dose on Day 1 and
Day 15 of Cycles 1 and 2, and Day 1 of Cycle 3; all other 
patients: Pre-dose sampling on Day 15 of Cycles 1 and 2
EuroQol-5D (EQ-5D) r
Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and Day 1 of 
every other cycle thereafter starting with Cycle 6 (ie, 
Cycle 6,8, 10, etc)
X
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire (EORTC-QLQ-C30) r
X
European Organisation for Research and 
Treatment of Cancer Breast Cancer Module 
(EORTC-QLQ-BR23)r
X
Survival Follow-ups
X
Study Treatment
Randomization 
X
Fulvestrant (both treatment arms)t
◄--►t
IM administration on Days 1 and 15 of Cycle 1, every 28 
days (7 days) thereafter starting from Day 1 of Cycle 1
Palbociclib or placebo (Arm A only)u
◄--►u
Orally once daily on Days 1 to 21of each Cycle followed 
by 7 days off treatment (visit windows not applicable to 
palbociclib/placebo dosing)
For pre-/peri-menopausal patients only: 
Goserelin (both treatment arms, if 
applicable)v
SC administration at least 
4 weeks before study 
treatment startv
◄--►v
SC administration every 28 days
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a.
Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers. No time window is to be considered for treatment schedule of palbociclib/placebo. 
One cycle consists of 28 days. A cycle could be longer than 28 days if persistent toxicity delays initiation of the subsequent cycle.  Day 1 of any cycle 
visit should coincide with the day the palbociclib/placebo treatment begins.  If there are delays due to toxicity, then the start of the next cycle visit 
will be delayed until the patient has recovered and can begin study treatment again.  Fulvestrant injection will be given every 28 days (+/- 7 days) with 
the exception of Cycle 1 during which it will be administered on Days 1 and 15 (2 days allowed according to the protocol visit time windows).  
Goserelin will be administered every 28 days (+/- number of days allowed according to the protocol visit time windows).  The active treatment phase is 
ongoing as long as the patient is receiving both study drugs (ie, palbociclib/placebo and fulvestrant) or fulvestrant alone.
b.
Cycle 1/Day 1: Blood chemistry, hematology, and physical examination not required if acceptable screening assessment is performed within 7 days 
prior to randomization. 
c.
End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and 
prior to initiation of any new anticancer therapy.  Obtain assessments if not completed during the previous 4 weeks on study.
d.
Post Treatment Follow-up: Patients who discontinue study treatment should be contacted 28 calendar days (7 days) after discontinuation of study 
treatment (palbociclib/placebo or fulvestrant) to assess if there have been any new adverse events and/or any change to any previously reported adverse 
events.  This follow-up should occur 28 calendar days (7 days) regardless of any new anti-cancer therapy that may have started.  Telephone contact is 
acceptable.  Follow-up visits to assess survival status will be conducted every 3 months going forward after approval of Amendment 3. See table 
footnote s (Survival Follow-up) below. 
e.
Informed Consent: Informed consent must be obtained prior to any protocol required assessments being performed (with the exception of certain 
imaging assessments if meeting the criteria defined in the Screening Section).
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.
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems and breasts, 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. Physical 
examinations will be carried out at Screening, Day 1 of every cycle and the End of Treatment/Withdrawal visit.


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i.
Ophthalmology Examinations: Upon approval of Amendment 1, newly enrolled lens grading evaluable patients will undergo an ophthalmic 
examination by an ophthalmologist at screening, during study treatment on Cycle 4 Day 1, on Cycle 7 Day 1, on Cycle 13 Day 1 (ie, after 3, 6 and 
12 months), every 12 months thereafter (ie, Days 1 of Cycles 25, 37, etc.) and at the End of Treatment/Withdrawal visit. Additional ophthalmic 
examinations may be performed as clinically indicated.  It is expected that a minimum of 100 evaluable patients will participate in these examinations.
Sites will be informed once these examinations are no longer required for patients newly enrolled in this study. Refer to the Ocular Safety Assessments
Section for further details.  Upon approval of Amendment 3, ophthalmology tests will continue to be collected.
j.
Laboratory tests: Hematology includes hemoglobin, WBC, absolute neutrophil count, platelet count.  Hematology tests must meet retreatment criteria 
prior to administering palbociclib Blood chemistry includes AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, total calcium, total 
bilirubin, blood urea nitrogen (BUN) (or urea), serum creatinine, and albumin.  Additional hematology/chemistries panels may be performed as 
clinically indicated.  Upon approval of Amendment 3, hemoglobin A1c will be measured in all patients every 3 cycles (Day 1) going forward (C7D1, 
C10D1, C13D1, etc) and at the End of Treatment/Withdrawal visit.  Pregnancy test (serum) at screening only for women of childbearing potential.  Test 
may be repeated as per request of IRB/IECs or if required by local regulations.  Serum estradiol and Follicle stimulating hormone (FSH) levels are 
analysed at screening to confirm postmenopausal status of women <60 years old and who have been amenorrheic for at least 12 consecutive months.  
Upon approval of Amendment 3, blood chemistry will be performed every 3 cycles (Day 1) going forward (C7D1, C10D1, C13D1, etc) and at the End 
of Treatment/Withdrawal visit. Hemoglobin A1c will be tested at the time of blood chemistry.  If an adverse event occurs that mandates blood 
chemistry to be performed (eg, hepatic function abnormality), the additional laboratory data will be recorded in the CRF.  
k.
CT/MRI Scans of Chest, Abdomen, Pelvis: Upon approval of Amendment 3, tumor assessments will be performed as per local practice.  Refer to the 
tumor assessment requirement flowchart.
l.
Radionuclide Bone Scan, Whole Body: Upon approval of Amendment 3, tumor assessments will be performed as per local practice.  Refer to the 
tumor assessment requirement flowchart. 
m. Adverse Events (AEs): Serious Adverse events (SAEs) must be reported from the time the patient provides informed consent through and including 
28 calendar days after the last administration of the study drug.  SAEs occurring after the active reporting period has ended should be reported if the 
investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to study 
drug are to be reported to the Sponsor.  All AEs (serious and non serious) should be recorded on the CRF from the first dose of study treatment through 
last patient visit.  It is expected that telephone contact with the patient will be made in order to assess SAEs and AEs 28 calendar days (+/- 7 days) after 
the last administration of the study drug.
n.
Pharmacokinetics (PK): In approximately the first 40 patients randomized in the study, plasma PK samples will be drawn pre-dose on Day 1 and 
Day 15 of Cycles 1 and 2, and Day 1 of Cycle 3 for DDI assessment for palbociclib and fulvestrant (and goserelin if applicable).  In all other patients, 
plasma concentrations will be drawn on Day 15 of Cycle 1 and Cycle 2 for palbociclib only.  Additional PK blood samples may be collected from 
patients experiencing unexpected or serious adverse events, or adverse events that lead to discontinuation.
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r.
Patient Reported Outcomes Assessments: 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.
s.
Survival Follow-Up: Upon approval of Amendment 3, for patients who discontinue study treatment, survival data will be collected every 3 months
going forward.  Telephone contact is acceptable. During follow-up visits the following data will be recorded in the CRF: 1) start, stop and type of new 
anticancer therapy; 2) tumor response of new anticancer therapy; 3) date of progression of the disease during or after the new antitumor agent; 
4) survival status.
t.
Fulvestrant: To be administered on-site according to the local Summary of Product Characteristics for fulvestrant (Faslodex). Fulvestrant injection 
will be given every 28 days (+/- 7 days) with the exception of Cycle 1 during which it will be administered on Days 1 and 15 (2 days allowed 
according to the protocol visit time windows).  
u.
Palbociclib or Placebo: Patients will be required to return all bottles of palbociclib/placebo as well as the completed patient diary on Day 1 of each 
cycle for drug accountability. 
v.
Goserelin (if applicable): Goserelin will be administered every 28 days (+/- number of days allowed according to the protocol visit time windows).  
Treatment with goserelin (Zoladexor generic) as per local practice for all women who are pre- or peri-menopausal at study entry.  Patients must have 
commenced treatment with goserelin or an alternative luteinizing hormone-releasing hormone (LHRH) agonist at least 4 weeks prior to randomization.  
If patients have not received goserelin as their LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial.  It is 
recommended to administer goserelin (given every 28 days) on-site when monthly fulvestrant is given.  If goserelin is administered at home by the 
patient, a patient diary will be implemented.
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TUMOR ASSESSMENT REQUIREMENTS FLOWCHART
Method
Screeninga
Treatment Periodb
End of Treatment Visitc
CT or MRI of chest, abdomen, and 
pelvis 
Required
Upon approval of Amendment 3, 
imaging studies will be 
conducted as per local practice.
Upon approval of Amendment 3, imaging studies will be 
conducted as per local practice.
CT or MRI of any other site of 
disease, as clinically indicated
Required
Upon approval of Amendment 3, 
imaging studies will be 
conducted as per local practice.
Upon approval of Amendment 3, imaging studies will be 
conducted as per local practice.
Radionuclide bone scan (whole 
body) and confirmatory imaging in 
case of any hot spots (CT, MRI or 
X-ray)
Required
Upon approval of Amendment 3, 
imaging studies will be 
conducted as per local practice.
Upon approval of Amendment 3, imaging studies will be 
conducted as per local practice.
Photographs of all superficial 
lesions as applicable
Required
Upon approval of Amendment 3, 
imaging studies will be 
conducted as per local practice.
Upon approval of Amendment 3, imaging studies will be 
conducted as per local practice.
a.
Screening scans must occur within 4 weeks (ie, 28 days) prior to randomization unless otherwise specified. 
b.
During treatment period, upon approval of Amendment 3:

tumor assessment must be done according to local practice: if tumor assessments are scheduled as per the original protocol, upon approval of 
Amendment 3 they can be performed at a different schedule if this is common practice at that institution or it is recommended by the physician 
according to the patient’s clinical conditions.

Selection of imaging studies will depend on treating physician and radiologist as per local practice.  

Upon approval of Amendment 3, RECIST 1.1 may be used to evaluate imaging assessments but will not be mandatory.  Evaluation of imaging 
studies will be conducted as per the practice at the institution.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................25
APPENDICES .........................................................................................................................26
1. INTRODUCTION ...............................................................................................................27
1.1. Indication.................................................................................................................27
1.2. Background and Rationale ......................................................................................27
1.2.1. Overview of Palbociclib .............................................................................28
1.2.1.2. Human Pharmacokinetic (PK) Data..........................................29
1.2.1.3. QT Interval Data........................................................................32
1.2.1.5. Palbociclib Dose Rationale .......................................................34
1.2.1.6. Phase 2 Trial of Palbociclib Alone in Women with 
Advanced Breast Cancer ...................................................................35
1.2.1.7. Data from Phase 1/2 Study of Palbociclib in Combination 
with Letrozole in Advanced Breast Cancer.......................................35
1.2.1.8. Interim Analysis Data from Phase 3 Study A5481023 of 
Palbociclib in Combination with Fulvestrant....................................36
1.2.2. Overview of Fulvestrant (Faslodex).........................................................37
1.2.3. Study Rationale...........................................................................................39
1.2.4. Amendment Rationale ................................................................................41
1.2.4.1. Rationale for Changes in Amendment 1 ...................................41
1.2.4.2. Rationale for Changes in Amendment 2 ...................................42
1.2.4.3. Rationale for Changes in Amendment 3 ...................................43
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................44
2.1. Objectives................................................................................................................44
2.2. Endpoints.................................................................................................................45
3. STUDY DESIGN.................................................................................................................45
4. PATIENT SELECTION......................................................................................................48
4.1. Inclusion Criteria.....................................................................................................49
4.2. Exclusion Criteria....................................................................................................51
4.3. Randomization Criteria ...........................................................................................52
4.4. Sponsor Qualified Medical Personnel.....................................................................53
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5. STUDY TREATMENTS.....................................................................................................53
5.1. Allocation to Treatment ..........................................................................................53
5.2. Breaking the Blind ..................................................................................................54
5.3. Drug Supplies..........................................................................................................54
5.3.1. Formulation and Packaging........................................................................54
5.3.1.1. Palbociclib (PD-0332991)/Placebo...........................................54
5.3.1.2. Fulvestrant.................................................................................55
5.3.2. Preparation and Dispensing........................................................................55
5.3.2.1. Palbociclib/Placebo ...................................................................55
5.3.2.2. Fulvestrant.................................................................................55
5.3.3. Administration............................................................................................56
5.3.3.1. Palbociclib/Placebo ...................................................................56
5.3.3.2. Fulvestrant.................................................................................56
5.3.4. Dose Modification ......................................................................................57
5.3.4.1. Fulvestrant.................................................................................57
5.3.4.2. Palbociclib/Placebo ...................................................................57
5.3.5. Medication Errors .......................................................................................62
5.3.6. Compliance.................................................................................................63
5.4. Drug Storage and Drug Accountability...................................................................63
5.4.1. Palbociclib/Placebo Storage and Accountability........................................64
5.4.1.1. Fulvestrant Storage and Accountability....................................64
5.5. Concomitant Medications .......................................................................................64
5.5.1. Prohibited Medications...............................................................................64
5.5.2. Medications Not Recommended.................................................................65
5.5.3. Permitted Medications................................................................................66
5.6. Concomitant Radiotherapy or Surgery....................................................................67
6. STUDY PROCEDURES .....................................................................................................67
6.1. Screening.................................................................................................................68
6.2. Screen Failure..........................................................................................................69
6.3. Active Treatment Phase ..........................................................................................69
6.4. End of Treatment Visit............................................................................................69
6.5. Follow-up Visits......................................................................................................70


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6.5.1. 28-day Post-treatment Follow-up ...............................................................70
6.5.2. Survival Follow-up.....................................................................................70
6.6. Patient Withdrawal..................................................................................................70
6.6.1. Active Treatment Phase Discontinuation ...................................................70
6.6.2. Study Discontinuation ................................................................................71
7. ASSESSMENTS..................................................................................................................72
7.1. Pregnancy Testing...................................................................................................72
7.2. Efficacy Assessments..............................................................................................72
7.2.1. Tumor Assessments....................................................................................72
7.2.2. Ocular Safety Assessments.........................................................................73
7.2.2.1. Snellen Best Corrected Visual Acuity and Refraction..............73
7.2.2.2. Intraocular Pressure Measurement............................................74
7.2.2.3. Slit-Lamp Biomicroscopy .........................................................74
7.2.2.4. Lens Grading.............................................................................75
7.2.2.5. Funduscopy (Ophthalmoscopy) ................................................75
7.2.3. Independent Review of Disease Assessments............................................76
7.2.4. Overall Survival..........................................................................................76
7.3. Safety Assessments .................................................................................................76
7.3.1. Laboratory Safety Assessments..................................................................76
7.3.2. Electrocardiogram.......................................................................................77
7.3.3. Other Safety Assessments...........................................................................77
7.4. Pharmacokinetic Assessments.................................................................................77
7.5. Patient Reported Outcomes.....................................................................................79
7.5.1. EuroQol Health Utilities Index EQ-5D ......................................................79
7.5.2. EORTC QLQ-C30......................................................................................79
7.5.3. EORTC QLQ-BR23 ...................................................................................79
8. ADVERSE EVENT REPORTING......................................................................................83
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8.1. Adverse Events........................................................................................................83
8.2. Reporting Period .....................................................................................................83
8.3. Definition of an Adverse Event...............................................................................83
8.4. Abnormal Test Findings..........................................................................................84
8.5. Serious Adverse Events...........................................................................................85
8.5.1. Protocol-Specified Serious Adverse Events...............................................85
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................86
8.6. Hospitalization ........................................................................................................87
8.7. Severity Assessment................................................................................................88
8.8. Causality Assessment..............................................................................................88
8.9. Exposure during Pregnancy ....................................................................................89
8.10. Occupational Exposure .........................................................................................90
8.11. Withdrawal Due to Adverse Events (See also the Section on Patient 
Withdrawal)...............................................................................................................90
8.12. Eliciting Adverse Event Information ....................................................................90
8.13. Reporting Requirements........................................................................................90
8.13.1. Serious Adverse Event Reporting Requirements .....................................90
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................91
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities ...................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................91
9.2. Analysis Population.................................................................................................92
9.2.1. Intent-to-Treat Population (ITT).................................................................92
9.2.2. As-Treated Population (AT).......................................................................92
9.3. Efficacy Analysis ....................................................................................................93
9.3.1. Analysis of Primary Endpoint ....................................................................93
9.3.2. Analysis of Secondary Endpoints...............................................................94
9.5. Analysis of Other Endpoints ...................................................................................96
9.6. Safety Analysis........................................................................................................97
9.7. Interim Analysis ......................................................................................................98
9.8. Data Monitoring Committee ...................................................................................98
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10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................99
11. DATA HANDLING AND RECORD KEEPING .............................................................99
11.1. Case Report Forms/Electronic Data Record .........................................................99
11.2. Record Retention.................................................................................................100
12. ETHICS............................................................................................................................100
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........100
12.2. Ethical Conduct of the Study ..............................................................................101
12.3. Patient Information and Consent.........................................................................101
12.4. Patient Recruitment.............................................................................................101
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................102
13. DEFINITION OF END OF TRIAL.................................................................................102
13.1. End of Trial in a Member State...........................................................................102
13.2. End of Trial in all other Participating Countries.................................................102
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................102
15. PUBLICATION OF STUDY RESULTS........................................................................102
15.1. Communication of Results by Pfizer ..................................................................102
15.2. Publications by Investigators ..............................................................................103
16. REFERENCES ................................................................................................................105
LIST OF TABLES
Table 1.
Palbociclib/Placebo Capsule Characteristics........................................................55
Table 2.
Available Dose Levels..........................................................................................60
Table 3.
Palbociclib/Placebo Dose Modifications for Treatment-Related Toxicities ........61
Table 4.
Palbociclib/Placebo Dose Modifications in the Event of QTc Prolongation .......62


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APPENDICES
Appendix 1. List of Abbreviations.........................................................................................111
Appendix 2. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............114
Appendix 3. List of Drugs Known to Predispose to Torsade de Pointes...............................115
Appendix 4. RECIST (Response Evaluation Criteria In Solid Tumors) Version 1.1 
Guidelines...........................................................................................................116
Appendix 8. Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure ................................................................................124
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1. INTRODUCTION
1.1. Indication
Women of any menopausal status with hormone receptor-positive (HR+), Human Epidermal 
Growth Factor Receptor 2 (HER2)-negative advanced/metastatic 1 breast cancer (BC) after 
failure of prior endocrine therapy.
1.2. Background and Rationale
HR+/HER2-negative breast cancer is the most common subset of breast cancer.1 Most 
patients are diagnosed at an early stage and remain relapse-free if treated with a prolonged 
course of endocrine therapy.  Unfortunately, not all patients respond to first-line endocrine 
therapy (primary or de novo resistance), and even patients who have a response will 
eventually relapse (acquired resistance). About one-third of all HR+/HER2-negative 
patients, diagnosed initially with early stage disease, experience disease recurrence.2 As a 
result the HR+/HER2-negative subset is responsible for the majority of breast cancer related 
deaths.  The fundamental problem is that endocrine agents are only partially effective, 
typically causing cell cycle arrest and tumor dormancy rather than true cure.  As a result, 
secondary resistance to endocrine therapy is a major clinical challenge.
In postmenopausal patients with HR+/HER2-negative metastatic BC, aromatase inhibitors 
(AIs) have become the treatment of choice in first-line therapy.3 On the contrary, most pre-
or perimenopausal women with HR+ breast cancer present with early stage disease and are 
treated with the antiestrogen tamoxifen with or without ovarian ablation (by surgery, 
chemotherapy or luteinizing hormone-releasing hormone (LHRH) ) in the adjuvant setting.4
Upon initial presentation with metastatic disease during premenopause, the recommended 
approach is to suppress ovarian function (by ovarian ablation or luteinizing 
hormone-releasing hormone (LHRH) agonist therapy),5 and then to concurrently follow 
post-menopausal treatment guidelines, switching treatment from tamoxifen to AIs or 
fulvestrant.4 Thus, in clinical practice so called “pre/perimenopausal” patients with HR+ 
metastatic breast cancer will be rendered postmenopausal by the time of first line treatment
for advanced disease.
Upon disease progression on hormonal therapy, historically the treatment options have been 
limited to a change in AIs (steroidal or nonsteroidal) or the use of the estrogen-receptor (ER) 
antagonists fulvestrant and tamoxifen.6,7
In the past few years the search for newer, non-endocrine related agents to treat recurrent 
metastatic ER+ breast cancers has expanded to include agents targeting the PI3K/mTOR 
pathway as well as cell cycle specific agents. Everolimus, recently approved in advanced, 
recurrent disease, is an example of the former,8 and palbociclib, is an example of the latter.9
In both cases, successful development of molecular patient selection criteria has so far 
proven to be elusive. More efficacious and safe therapeutic options are still needed, 
                                                          
1 The terms “advanced” and “metastatic” breast cancer are used interchangeably in this document.


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particularly in molecularly selected patient populations. Thus, HR+/HER2-negative breast 
cancer patients who have tumor progression following endocrine therapies for metastatic 
disease, represent an important unmet medical need, regardless of their menopausal status.
1.2.1. Overview of Palbociclib
PD-0332991 (palbociclib), an orally active pyridopyrimidine, is a potent first-in-class, highly 
selective reversible inhibitor of CDK 4 and CDK6 (IC50 = 11 nM; Ki = 2 nM) with a 
molecular weight of 573.67. 
The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle 
from G1 into the S phase, as demonstrated both in laboratory models and in early clinical 
trials.  CDK4 and CDK6 control G1 to S phase transit by binding to D-type cyclins.10,11,12
The CDK4/6/Cyclin D1 complex phosphorylates the retinoblastoma susceptibility (RB1) 
gene product (Rb), releasing the E2F and DP transcription factors that drive expression from 
genes required for S-phase entry.12 CDK activity and G1 progression is negatively regulated 
by Cip-Kip and INK4 family, typified by p16.13,14,15,16,17 Overexpression of p16 in cells with 
normal Rb inhibits both CDK4-and CDK6-associated kinase activity and Rb 
phosphorylation, with subsequent cell cycle arrest.18,19
Preclinical data, both Pfizer internal data and also from other laboratories, suggest that 
estrogen resistant models are exquisitely sensitive to the combination of palbociclib with 
antihormonal therapy or palbociclib alone. Blockade of the ER signaling pathway is 
synergistic with cell cycle arrest, as demonstrated by the more than doubling in median PFS 
observed to date in the ongoing trial evaluating ER+ metastatic breast cancer patients treated 
with the combination of an aromatase inhibitor and palbociclib compared with aromatase 
inhibitor alone.9 Overcoming resistance to endocrine therapy in breast cancer patients is a 
major challenge and there is a high unmet need for safe and efficacious treatment options in 
women resistant to endocrine therapy. 
There is a strong link between the actions of estradiol and the G1-S phase transition, where 
the estradiol effector is the cyclin D1-CDK4/6-Rb complex.20 Cyclin D1 is a direct 
transcriptional target of ER21,22,23,24 and microinjection of antibodies to cyclin D1 inhibits 
estrogen-induced S-phase entry.25,26,27,28,29 In addition, anti-estrogen-induced growth arrest 
of ER+ breast cancer cells is accompanied by decreased cyclin D1 expression30 while 
endocrine resistance is associated with persistent cyclin D1 expression and Rb 
phosphorylation.31 Consistent with the notion that the main function of cyclin D1 is to 
activate CDK4/6, its oncogenic activity is dependent on CDK4/6-associated kinase activity32
and CDK4/6 inhibitors are most effective in tumors with gene amplification and 
overexpression of cyclin D1,33,34,35 which is common in ER+ breast cancer.  For example,
palbociclib was most effective for ER+ breast cancer in a cell line panel,36 including those 
that exhibited anti-estrogen resistance.  Genetic aberrations leading to hyperactivation of 
cyclin D1-CDK4/6 is particularly common in ER+ breast cancer, consistent with its critical 
role in the tumorigenesis of this cancer subtype,36 making CDK4/6 inhibitors particularly 
attractive agents for ER+ breast cancer. 
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1.2.1.2. Human Pharmacokinetic (PK) Data
To date, PK data have been collected in 8 clinical studies for a total of over 250 advanced 
cancer patients and 30 healthy volunteers (A5481001, A5481002, A5481003, A5481004, 
A5481008, A5481009, A5481010, and A5481011).  In the first-in-human Study A5481001,
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 steady state, 
palbociclib was absorbed with a median Tmax of ~4 hours. The mean palbociclib Vz/F was 
2583 L, which is significantly greater than total body water (42 L), indicating that palbociclib 
extensively penetrates into peripheral tissues. Palbociclib was eliminated slowly; the mean 
elimination half-life (t1⁄2) was 28.8 hours and the mean CL/F was 63.1 L/hour. Palbociclib 
accumulated following repeated dosing with a median Rac of 2.4, which is consistent with the 
terminal half-life.
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The effect of food on the bioavailability of palbociclib when administered as the commercial 
free base capsule, was investigated in Study A5481021.  The administration of the free base 
formulation of palbociclib with food (including a high fat or a low fat meal given together 
with palbociclib, or moderate fat meals given 1 hour before and 2 hours after palbociclib) 
resulted in more uniform drug absorption and significantly reduced the intersubject 
variability in drug exposure when compared to the administration of free base formulation of 
palbociclib in a fasted state.  The relative bioavailability of the commercial free base capsule 
administered with food and the isethionate capsule administered under overnight and 
minimal fasting conditions was investigated in Study A5481036.  The two fasting conditions 
for administration of isethionate capsules represent the 2 extreme scenarios for compliant 
palbociclib dosing with regard to food intake in the pivotal Phase 1/2 efficacy trial, Study 
A5481003, in which patients were instructed to fast from 1 hour before until 2 hours after 
palbociclib dosing.  The administration of palbociclib free base capsule formulation with 
food was found to be bioequivalent to palbociclib isethionate capsule formulation given 
under both the overnight and minimal fasting conditions. As a result of these findings, 
patients should be instructed to take palbociclib with food. 
Study A5481018 showed that coadministration of palbociclib and QD doses of the proton-
pump inhibitor (PPI) rabeprazole administered under fasted condition decreased single-dose 
palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared with those after 
a single dose of palbociclib administered alone.  Another clinical trial (Study A5481038) 
showed that administration of palbociclib with famotidine and Mi-Acid Maximum Strength 
Liquid under fed conditions had no impact on the exposure of palbociclib.  Coadministration 
of a single 125-mg palbociclib dose with multiple doses of the proton pump inhibitor
(PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but it had
limited impact on AUCinf (13% decrease) compared with a single dose of palbociclib
administered alone.  The concomitant use of PPIs with palbociclib should be
avoided. 
Study A5481038, a Phase 1 study, was designed to investigate the effect of famotidine (an 
H2-receptor antagonist) given 10 hours before and 2 hours after palbociclib; rabeprazole 
sodium (a PPI) given daily for 6 days before and 4 hours prior to palbociclib; mi-acid 
maximum strength liquid given 2 hours before palbociclib; mi-acid maximum strength liquid 
given 2 hours after palbociclib on the relative bioavailability of a single oral 125 mg of 
palbociclib commercial free base hard capsule formulation dose given under fed conditions 
in healthy volunteers.  The results from this study showed that famotidine given 10 hours 
before and 2 hours after palbociclib or mi-acid maximum strength liquid (local antacid) given 
2 hours before or 2 hours after palbociclib did not impact the exposure of palbociclib. 
Additionally, the results showed that coadministration of rabeprazole and palbociclib under 
fed conditions resulted in a decrease in palbociclib exposure less dramatic than the change in 
exposure observed in Study A5481018 where palbociblib was administered under fasted 
conditions.  Palbociclib change in geometric mean Cmax in combination with daily 
administration of rabeprazole decreased by 41% under fed conditions compared to the 80% 
decrease under fasted conditions.  The change in AUCinf of palbociclib when coadministered 
with rabeprazole under the fed conditions was approximately 13% compared to palbociclib 
given alone.  Based upon these data, under fed conditions, the use of H2-receptor antagonists 


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or local antacids is now permitted as defined in Section 5.5.3.  As PPIs affect palbociclib 
Cmax and to a lesser extent AUCinf their concomitant use will remain prohibited during the 
active treatment phase as outlined in Section 5.5.1.  
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 
Cytochrome P-450 (CYP) 3A4 enzymes.  An exploratory evaluation of the circulating 
metabolites for palbociclib was conducted in plasma samples obtained from patients treated 
with palbociclib 200 mg QD (Schedule 2/1) in Study A5481001.  Preliminary assessment of 
the pooled plasma samples on Day 14 of Cycle 1 indicated that the glucuronide conjugate of 
palbociclib and the lactam of palbociclib (PF-05089326) were the main metabolites present 
in plasma.  Other metabolites observed were the glucuronide conjugates of hydroxylated 
palbociclib and the glucuronide conjugate of reduced palbociclib.  PF-05089326 was also 
observed in the circulation of rats following repeated daily oral administration of palbociclib 
at the dose levels of 50 and 100 mg/kg/day.  Plasma protein binding of palbociclib and 
PF-05089326 is ~85% and 95%, respectively. 
Pharmacokinetic data are available from an itraconazole DDI study where the effect of 
multiple dosing of a potent CYP3A4 inhibitor, itraconazole (200 mg QD), on the single-dose 
PK of palbociclib (125 mg) was evaluated in 12 healthy fasted subjects (Study A5481016). 
Median palbociclib plasma concentrations were higher in the presence of itraconazole than 
those in the absence of itraconazole. Palbociclib mean plasma AUC from time 0 to infinity 
(AUCinf ) and Cmax values increased approximately 87% and 34%, respectively, when 
administered in combination with itraconazole compared to when administered alone.
Therefore, concomitant administration of agents known to be strong/moderate inhibitors of 
CYP3A isoenzymes (such as ketoconazole, miconazole, itraconazole, posaconazole, 
clarithromycin, erythromycin, telithromycin, nefazodone, diltiazem, verapamil, indinavir, 
saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and 
grapefruit juice) should be avoided.
Pharmacokinetic data are available from a rifampin DDI study where the effect of multiple 
dosing of a potent CYP3A4 inducer, rifampin (600 mg QD), on the single-dose PK of 
palbociclib (125 mg) was evaluated in 15 healthy fasted subjects (Study A5481017). Median 
palbociclib plasma concentrations were substantially lower in the presence of rifampin than 
those in the absence of rifampin. Palbociclib mean plasma AUC from time 0 to infinity 
(AUCinf ) and Cmax values decreased approximately 85% and 70%, respectively, when 
administered in combination with rifampin compared to when administered alone. 
Therefore, co-administration of palbociclib with strong/moderate CYP3A inducers (such as 
phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, and St. John’s 
Wort) should be avoided.
Palbociclib and its metabolite PF-05089326 caused time-dependent inhibition of CYP3A in 
in vitro assays.  Pharmacokinetic data are available from a midazolam DDI study where the 
effect of multiple dosing of palbociclib (125 mg QD) on the single-dose PK of a sensitive 
CYP3A4/5 probe substrate, oral midazolam (2 mg), was evaluated in 26 healthy women of 
non-childbearing potential (Study A5481012).  When midazolam was administered with 


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palbociclib 125 mg QD at steady-state, the mean midazolam plasma Cmax and AUCinf  values 
increased approximately 38% and 61%, respectively, as compared with those determined 
after administration of midazolam alone.  These results indicated that palbociclib is a weak 
time-dependent inhibitor of CYP3A.
1.2.1.3. QT Interval Data
In vitro (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.  A preliminary pharmacokinetic/pharmacodynamic analysis has 
been conducted to explore the QT/QTc and plasma palbociclib concentration relationship for 
Study A5481001 (First in Human 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 (CI) of QTcF change from the baseline were 5.8 and 9.4 msec, 
respectively.
In order to achieve more extensive evaluation of the effect of palbociclib on QTc 
prolongation, time-matched Electrocardiogram (ECG) and PK data are being collected in a 
subset of at least 60 patients participating in Study A5481008.
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1.2.1.5. 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 toxicities (DLTs) observed in this study were related to 
myelosuppression and mainly consisted of Grade 3 neutropenia lasting more than 7 days 
after the end of the treatment cycle.  However, neutropenia was reversible and 
non-cumulative. The most common non-hematological adverse events included fatigue, 
anemia, diarrhea, constipation, vomiting and dyspnea, all with mild to moderate severity.  A 
greater proportion of patients on the 2/1 schedule had treatment-related 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 (PR) 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.  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 
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schedule was determined to be 125 mg/day.  This schedule and associated RP2D was further 
explored as a single agent and in combination with letrozole in the Phase 2 study and 
Phase ½ studies in patients with advanced breast cancer described below.
1.2.1.6. Phase 2 Trial of Palbociclib Alone in Women with Advanced Breast Cancer
A Phase 2 study is ongoing with single agent palbociclib in 36 women with advanced breast 
cancer. Preliminary results will be reported at the American Society of Clinical Oncology 
(ASCO) 2013 from 28 women who have completed Cycle 1. Palbociclib was given at 
125 mg orally, Days 1- 21 of a 28-day cycle.  Of the 28 women, 18 women are 
HR+/HER2-negative, 2 are HR+/HER2+ and 8 are HR-/HER2-negative. A total of 90% had 
prior chemotherapy for metastatic disease; 78% had prior hormonal therapy.  Therapy with 
palbociclib alone was well-tolerated, and demonstrated tumor shrinkage and prolonged SD in 
patients with all subtypes of breast cancer and despite progression on prior hormonal- and 
chemotherapy. Clinical Benefit Response rates (PR+SD 6 months) were 4/18 (23%) in the 
HR+/HER2-negative cohort, 1/2 (50%) in the HR+/HER2+ cohort, and 1/8 (13%) in the 
HR-negative/HER2-negative cohort. Toxicities were consistent with those previously seen 
with palbociclib, ie, were mostly Grade 1/2, and Grade 3/4 toxicities were limited to transient 
neutropenia (50%) and thrombocytopenia (21%).  Treatment was interrupted in 25% and 
dose was reduced in 46% of the patients for cytopenias. Translational studies examining 
molecular predictors of response are in progress.38
1.2.1.7. Data from Phase 1/2 Study of Palbociclib in Combination with Letrozole in 
Advanced Breast Cancer
A multicenter, randomized, controlled Phase 1/2 Study (A5481003) was designed to assess 
the efficacy, safety and PK 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-negative advanced breast cancer in 
postmenopausal women.  Letrozole was selected as the active control based on its worldwide 
approval and use as standard of care for the first-line hormonal treatment of postmenopausal 
women with ER+ advanced breast cancer. 
Study A5481003 was comprised of a limited Phase 1 portion, aimed at confirming the safety 
and tolerability of the combination and excluding a PK interaction with the combination, and 
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-negative advanced breast cancer.  The Phase 2 
portion consisted of 2 parts.  In Part 1, patient selection was based only on ER/HER2 status.  
In Part 2, patients were prospectively selected also taking into account tumor CCND1 
amplification and/or p16 loss.  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 portion39 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 
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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.  PRs were 
reported for 3 (33%) out of 9 patients with measurable disease (3 had bone-only disease). 
Another 5 patients (42%) had stable disease for 6 months and the clinical benefit rate 
(PR + SD 6 months) was 67%.  Eight (8) patients discontinued from the study due to 
disease progression, including 2 patients with clinical progression, 1 patient withdrew 
consent, and 3 patients are still ongoing. 
Two interim analyses for the Phase 2 portion of the study have been conducted.  The results 
of the interim analyses showed consistent trend of clinically meaningful improvements in 
PFS (primary endpoint).  In the first interim analysis (Part 1; N=66), the median PFS for the 
palbociclib plus letrozole arm was 18.2 months versus 5.7 months for the letrozole alone arm 
(HR=0.35; 95% CI: 0.17, 0.72; p=0.006).  The second interim analysis (N=165) continued to 
demonstrate a statistically significant improvement in PFS (26.1 vs. 7.5 months, respectively; 
HR=0.37; 95% CI: 0.21, 0.63; p <0.001).9, 40
These results indicate that the combination of palbociclib with letrozole is well tolerated with 
a safety profile similar to that seen with palbociclib alone.  The most frequently reported 
treatment-related adverse events included neutropenia, leukopenia, anemia, and fatigue.  
There were no cases of febrile neutropenia reported to date in this study.  Overall, 8 patients 
in the combination arm were discontinued from the study treatment due to an adverse event, 
of which 5 were considered treatment-related (Grade 3 neutropenia [n=4] and ischemic 
colitis) and 1 patient from the letrozole alone arm.  Additionally, the combination 
demonstrated antitumor activity which was consistent with the sensitivity of ER+ breast 
cancer observed in the preclinical models.
Complete information for palbociclib may be found in the Single Reference Safety 
Document for this compound which is the Investigator's Brochure (IB; November 2012).
1.2.1.8. Interim Analysis Data from Phase 3 Study A5481023 of Palbociclib in 
Combination with Fulvestrant
The present study A5481023 (PALOMA-3) met its primary endpoint at the preplanned 
interim analysis (data cutoff date of 05 December 2014) based on the recommendation of the 
external data monitoring committee.  The addition of palbociclib to fulvestrant substantially 
improved PFS in pre/peri- and postmenopausal women with HR-positive, HER2-negative 
metastatic breast cancer whose disease had progressed after prior endocrine therapy.  The 
median PFS was 9.2 months (95% CI, 7.5 to not estimable) on palbociclib-fulvestrant and 
3.8 months (95% CI, 3.5 to 5.5) on placebo-fulvestrant (HR=0.422; 95% CI, 0.318 to 0.560; 
1-sided P<0.000001).  The random sample-based BICR audit approach has shown no 
investigator bias in favor of the palbociclib plus fulvestrant arm and the analysis results of 
BICR also corroborated the results of investigator-assessed PFS.  Subgroup analyses for 
stratification factors and demographic/prognostic factors revealed consistent results.  In 
particular, relative improvements in PFS for palbociclib were similar between 
pre/perimenopausal and postmenopausal patients (HR=0.435 versus 0.409, respectively, 
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In the present study, adverse events observed with palbociclib and fulvestrant were consistent 
with previously reported data.  Overall, palbociclib was well tolerated, with a discontinuation 
rate due to adverse events similar to that seen with placebo, and manageable by dosing 
interruptions, dose reductions, and/or standard medical care.  The majority of adverse events 
were mild to moderate in severity with the exception of hematological toxicties.
In the open-label Phase 2 study PALOMA-1 (A5481003) in patients with ER-positive, 
HER2-negative metastatic breast cancer who had never received systemic therapy for their 
advanced disease, palbociclib in combination with letrozole improved PFS compared to 
letrozole alone, suggesting palbociclib has activity when combined with endocrine therapy in 
both endocrine-naive and -resistant settings.
In addition, the patient-reported outcomes support the positive impact of palbociclib plus 
fulvestrant, maintaining global quality of life (QOL) on treatment and resulting in a 
statistically significantly higher on-treatment global QOL compared to placebo plus 
fulvestrant.
Double blinding of the present study will be maintained to allow ongoing collection of data 
for other pre-specified secondary endpoints including patient reported outcomes.
1.2.2. Overview of Fulvestrant (Faslodex)
Approximately two thirds of breast cancers express ER42 and the role for estrogens in breast 
cancer etiology and progression is well established. Modification of estrogen activity or 
synthesis represents the treatment of choice for women with hormone receptor-positive 
advanced breast cancer, particularly for those with slowly progressive disease (PD) and 
limited tumor-related symptoms.43 Conversion of androgens to estrogens via aromatase 
enzyme action represents the main source of estrogens in postmenopausal women.  Women 
with disease recurring early after AI or tamoxifen therapy are candidates to receive 
fulvestrant. 
Fulvestrant (Faslodex) is a competitive ER antagonist with an affinity comparable to 
estradiol. It blocks the trophic actions of estrogens without any partial agonist (estrogen-like) 
activity, and is currently indicated for the treatment of hormone receptor positive metastatic 
breast cancer in postmenopausal women with disease progression following antiestrogen 
therapy.44
The mechanism of action is associated with down-regulation of ER protein levels. Clinical 
trials in postmenopausal women with primary breast cancer have shown that fulvestrant 
significantly down-regulates ER protein in ER-positive tumours compared with placebo. 
There was also a significant decrease in progesterone receptor (PR) expression consistent 
with a lack of intrinsic estrogen agonist effects. It has also been shown that fulvestrant 
500 mg/month downregulates ER and the proliferation marker Ki67 to a greater degree than 
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Fulvestrant is comparable to AIs in terms of efficacy and tolerability for women who have 
progressed on prior tamoxifen therapy.46 Past studies have found all AIs to be at least as 
good as tamoxifen in first-line metastatic therapy in postmenopausal women.46
Two Phase 3 clinical trials were completed in a total of 851 postmenopausal women with 
advanced breast cancer (77% of the women were ER+) who had disease recurrence on or 
after adjuvant endocrine therapy or progression following endocrine therapy for advanced 
disease.  These trials compared the safety and efficacy of monthly administration of 
fulvestrant at the lower dose of 250 mg versus the daily administration of 1 mg of the AI 
anastrozole. Monthly 250 mg fulvestrant was at least as effective as anastrozole in terms of 
PFS, OR, and time to death. The combined data showed an objective response rate for 
fulvestrant 250 mg of 19.2% compared with 16.5% for anastrozole. The median time to 
death was 27.4 months for patients treated with fulvestrant and 27.6 months for patients 
treated with anastrozole. The hazard ratio of fulvestrant 250 mg to anastrozole for time to 
death was 1.01 (95% CI 0.86 to 1.19).44
However, there is evidence to suggest that doses of fulvestrant higher than 250 mg may have 
greater pharmacodynamic activity against the ER pathway. A Phase 3 clinical trial 
(CONFIRM) was completed in 736 postmenopausal women with advanced breast cancer 
who had disease recurrence on or after adjuvant endocrine therapy or progression following 
endocrine therapy for advanced disease. The study included 423 patients whose disease had 
recurred or progressed during anti-estrogen therapy (AE subgroup) and 313 patients whose 
disease had recurred or progressed during AI therapy (AI subgroup). This trial compared the 
efficacy and safety of fulvestrant 500 mg (n=362) with those of fulvestrat 250 mg (n=374). 
PFS for fulvestrant 500 mg was 6.5 months compared to 5.5 months for fulvestrant 250 mg. 
Overall survival data from the time of final analysis showed a median time to death of 
26.4 months for fulvestrant 500 mg versus 22.3 months for fulvestrant 250 mg (HR (95%CI) 
0.81 (0.69, 0.96), p-value 0.016).47,48 Also, a pilot Japanese study showed fulvestrant 500 mg 
to have clinical activity in the treatment of advanced or recurrent breast cancer, to be well 
tolerated, and to result in plasma levels approximately double those seen with 250 mg
fulvestrant.49 Subsequently, a neoadjuvant study comparing fulvestrant 250 mg (low-dose)
and 500 mg (high-dose) reported that significantly greater Ki67 and ER downregulation was 
achieved with the high-dose compared with the low-dose regimen and that both doses were 
well tolerated.50
A randomized Phase 2 trial assessed fulvestrant with or without dasatinib in postmenopausal 
patients with HR+ metastatic BC who have previously treated with an AI, a patient 
population similar to that included in the present study.  In this trial, the median PFS for the 
fulvestrant alone arm was 5.3 months and the median PFS for the combination arm was 
6.0 months, information used to determine the sample size in the present study. (See Sample 
Size Determination Section).51
The Single Reference Safety Document for the active comparator agent, fulvestrant
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1.2.3. Study Rationale
The present study is an international,  multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, Phase 3 clinical trial with the primary objective of 
demonstrating the superiority of palbociclib in combination with fulvestrant (Faslodex) over 
fulvestrant alone in prolonging PFS in women with HR+, HER2-negative metastatic breast 
cancer whose disease has progressed after prior endocrine therapy. The safety between the 
two treatment arms will also be compared. Pre- and perimenopausal women must be 
receiving therapy with the LHRH agonist goserelin (Zoladexor generic). 
Palbociclib is an orally active pyridopyrimidine, first-in-class compound that is a potent and 
highly selective reversible inhibitor of Cyclin-Dependent Kinases 4 and 6 (CDK 4/6). The 
compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle from 
G1 into the S phase, as demonstrated both in laboratory models and in early clinical trials.  
There is a strong link between the action of estradiol on the G1-S phase transition, where it 
drives transcriptional activation of cyclin D1 leading to formation of the cyclin 
D1-CDK4/6-Rb complex which facilitates the G1 to S phase transition. In non clinical 
experiments, palbociclib synergizes with antiestrogen to cause tumor regression in in vitro 
ER+ advanced breast cancer cell lines.
Preclinical data, both Pfizer internal data and also from other laboratories,52 (unpublished
data by L.Martin, Royal Marsden, London, UK) suggest that estrogen-resistant models are 
exquisitely sensitive to the combination of palbociclib with antihormonal therapy or 
palbociclib alone. Moreover, a small set of data in patients with HR+/HER2-negative 
recurrent breast cancer treated with monotherapy palbociclib suggests that about 25% of 
patients derive some degree of clinical benefit from monotherapy.38
Blockade of ER+ signaling pathway is synergistic with cell cycle arrest induction and results 
in significant clinical benefit as measured by PFS in patients with hormonal receptor positive 
metastatic breast cancer. Overcoming resistance to endocrine therapy in breast cancer is a 
major challenge and there still is an unmet need for safe and efficacious treatment options in 
women resistant to endocrine therapy. 
Postmenopausal women with HR+/HER2-negative breast cancer that have progressed after 
treatment with letrozole or anastrozole are now able to receive everolimus (Afinitor) in 
combination with exemestane. However, despite promising efficacy recently demonstrated 
in the BOLERO-2 trial in ER+/HER2-negative patients (median PFS 6.9 months for the 
everolimus-exemestane combination vs. 2.8 months for exemestane alone per investigator’s 
assessment), a high percentage of patients discontinued everolimus due to a challenging 
tolerability profile. The potential of everolimus to improve overall survival and clinical 
benefit in women with endocrine sensitive disease, or who present with advanced breast 
cancer in the pre- or perimenopausal state, is not yet known.53
Data from the open-label Phase 2 study PALOMA-1 (A5481003) in a patient population of 
ER+/HER2-negative postmenopausal patients with newly diagnosed metastatic breast cancer
indicate that addition of palbociclib to letrozole significantly extends PFS with a tolerable 
safety profile. While the study included patients whose disease had relapsed at various 


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timepoints after prior endocrine therapy, there is limited clinical data on the activity of 
palbociclib in patients whose disease recurred on or early after antihormonal therapy, a 
population that may be less sensitive to retreatment with antihormonal therapy.  Such 
patients, who could be pre-, peri-, or postmenopausal, comprise a large high-risk population 
for whom more therapeutic options are needed. 
Fulvestrant (see Section 1.2.1.8) is a potent anti-estrogen drug that binds and degrades ER.  
Recent data with fulvestrant administered at the dose of 500 mg/monthly to patients with
recurrent HR+/HER2-negative breast cancer indicate significant antitumor activity after both 
antiestogen and aromatase inhibitor (AI) failures. In a Phase 2 study the combination of 
fulvestrant and everolimus has shown efficacy in postmenopausal women after failure of AI 
treatment similar to that of the combination of tamoxifen with everolimus (median time to 
progression 7.4 months).54 Fulvestrant is currently indicated for the treatment of 
postmenopausal women with metastatic hormone receptor positive breast cancer following 
the failure of antiestrogen therapy. Despite its attractive mechanism of action, it has not been 
studied extensively in pre- or peri-menopausal women. However, it is expected to also add 
benefit to the treatment of pre- and peri-menopausal women if given concurrently with 
ovarian suppression/ablation. Clinical experience demonstrates that medical (or surgical) 
ovarian ablation produces comparable outcomes to tamoxifen monotherapy and support the
use of goserelin (LHRH agonist) concurrently with fulvestrant in premenopausal women 
with metastatic breast cancer.5,55 In fact, Phase 2 studies are currently underway evaluating 
the combination of fulvestrant with medical ovarian suppression in premenopausal women 
with breast cancer.56
The growing data about the activity of fulvestrant after antihormonal therapy failure57
together with emerging efficacy data of palbociclib support their combined use in women 
with HR+, HER2-negative metastatic breast cancer whose disease has progressed after prior 
endocrine therapy. The present study will establish the degree of added benefit of 
palbociclib in HR+/HER2-negative recurrent breast cancer patients treated with fulvestrant 
versus fulvestrant alone. 
Potential Drug-Drug-Interactions (DDIs)
The sponsor considers the potential for a clinically significant DDI between palbociclib and 
fulvestrant to be very low. The routes of elimination for fulvestrant include combinations of 
a number of possible biotransformation pathways analogous to those of endogenous steroids, 
including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or 
sulphate.  There are no known drug-drug interactions. Fulvestrant does not significantly 
inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 
in vitro, and studies of co-administration of fulvestrant with midazolam indicate that 
therapeutic doses of fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels 
of drug metabolized by that enzyme. Although fulvestrant is partly metabolized by 
CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no effect on the 
PK of fulvestrant. Also results from a healthy volunteer study with ketoconazole, a potent 
inhibitor of CYP3A4, indicated that ketoconazole had no effect on the PK of fulvestrant and 
dosage adjustment is not necessary in patients with co-prescribed CYP 3A4 inhibitors or 
inducers.44


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Since palbociclib is not expected to affect the PK of fulvestrant, and based on the results of 
the CONFIRM study (see above)47,48 the same dose regimen for fulvestrant (ie, 500 mg, 
intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 days 
Cycle) will be used in both treatment arms, ie, palbociclib plus fulvestrant and placebo plus 
fulvestrant.
Following fulvestrant monthly dosing with an additional dose on Day 15, steady-state 
concentration of fulvestrant will be achieved within the first month of study treatment.43
Following monthly goserelin 3.6 mg SC depot (goserelin acetate implant), there is no 
significant evidence of drug accumulation.56
Likewise, the sponsor considers the potential for a clinically significant DDI between 
palbociclib and goserelin to be very low. Goserelin is a synthetic decapeptide analogue of 
gonadotropin releasing hormone whose primary route of elimination is the cleavage of 
C-terminal amino acids followed by renal excretion. No formal drug-drug interaction studies 
have been performed and no confirmed interactions have been reported between goserelin 
and other drugs.58
1.2.4. Amendment Rationale
1.2.4.1. Rationale for Changes in Amendment 1
Preliminary results from two clinical pharmacology studies A5481018 and A5481021 
suggested that palbociclib taken with food results in more consistent drug absorption and 
exposure than in a fasted state, and palbociclib exposure may be decreased in a subgroup of 
patients taking palbociclib concomitantly with proton-pump inhibitors. Therefore, the 
protocol is being amended to revise the study drug administration instructions from 
administration in a fasted state to administration with food and to prohibit the concomitant 
use of proton-pump inhibitors. 
Also, based on the limited pre-clinical and clinical data currently available, it is not known 
whether a clinical risk exists for palbociclib with regard to the development of cataracts. The 
protocol is therefore being amended to assess this potential risk by implementing prospective 
ophthalmic examinations in newly enrolled lens grading evaluable patients. Patients will be 
evaluated at baseline, during and at the end of study treatment. By adding these 
examinations the sponsor is addressing a request by the Food and Drug Administration 
(FDA) for the palbociclib program. The sponsor expects PALOMA-3 to contribute to this 
request ocular data from a minimum of 100 patients. The sponsor will inform sites as soon 
as these examinations are no longer required for this study. The results of the ophthalmic 
examinations will provide a better understanding of the potential risk of ocular adverse 
events.
Additional editorial changes are made to clarify inclusion criterion 6 and exclusion criteria 
#4, 5 and 6, to align language throughout the protocol, and to reflect the sponsor’s current 
protocol template.


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1.2.4.2. Rationale for Changes in Amendment 2
Given the observed nonclinical findings in rats and taking into account the limited laboratory 
glucose data in the current clinical dataset, the protocol was amended in order to 
prospectively characterize whether or not palbociclib affects glucose metabolism through 
monitoring of appropriate laboratory measurements. 
In order to answer the many requests of clarifications from the clinical sites, the language 
related to cycle delay was further defined to clearly state that any new cycle may only start if 
blinded study treatment can be resumed.  In addition, clarification to the schedule of 
administration of fulvestrant and goserelin was made.  Language related to the criteria for 
treatment restart after the occurrence of toxicity was also added to allow restart 
palbociclib/placebo at the next lower dose level if uncomplicated Grade 3 neutropenia recurs 
in 2 consecutive cycles.
The section reporting Human Pharmacokinetic Data was updated.  Data of clinical studies 
recently finalized have been added for the investigators to better clarify the reasons for 1) 
administration of palbociclib with food; 2) prohibition of palbociclib administered 
concomitantly with proton-pump inhibitors; 3) concomitant use of local antacids and 
H2-receptor antagonists; 4) prohibition of palbociclib administered concomitantly with 
strong/moderate CYP3A inducers/inhibitors; 5) palbociclib as a weak time-dependent 
inhibitor of CYP3A.
Further clarification was also added in the Concomitant Medications Section 5.5: editorial 
changes were made to differentiate between strong and moderate CYP3A inducers/inhibitors, 
restriction on CYP3A substrate was removed based on updated information indicating that 
palbociclib is a weak time-dependent inhibitor of CYP3A and local antacids and H2-receptor 
antagonists were moved under the “Permitted Medications” Section 5.5.3 to reflect results 
from Study A5481038 showing that H2-receptor antagonists and local antacids given as 
defined per protocol do not impact the exposure of palbociclib.  “Human Pharmacokinetic 
Data” Section 1.2.1.2 was also updated to add data findings supporting the prohibition to 
concomitantly administer palbociclib with strong/moderate CYP3A inducers/inhibitors. 
Clarification of adverse event follow-up procedure (telephone contact) at 28 calendar days 
after treatment discontinuation to assess if there have been any new adverse events and/or
any change to any previously reported adverse events was added.  Additional editorial 
changes were also made to clarify follow-up procedures for patients who discontinue 
treatment for reasons other than disease progression and for patients who discontinue 
treatment due to disease progression.
Clarification of timing for physical examination/vital signs assessments was provided.
Section 9 “Data Analysis/Statistical Methods” was updated to add the analyses to be 
conducted on ocular event data and clarify that the method of sample size re-estimation will 
be pre-specified in a separate technical document to be only shared with the E-DMC before 
the interim analysis.


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In addition, minor editorial changes were made to correct inconsistencies or improve text 
clarity.
1.2.4.3. Rationale for Changes in Amendment 3
The scope of Amendment 3 will be to reduce efficacy and safety assessments mainly due to
the following reasons: 1) the study met its primary endpoint of efficacy at the preplanned 
interim analysis; 2) additional efficacy analyses of the primary and secondary endpoints had 
been conducted upon request of Health Authorities (HAs); 3) additional analyses of safety 
had been conducted to comply with HAs requests.  At the time of the amendment a smaller
number of patients will be on study treatment and patients will remain under observation for 
a follow-up period of approximately 1 year and a half. 
A summary of efficacy results at the time of interim analysis was added.
Main modification concerns the tumor assessments that will be conducted according to local 
practice at the institutions once this amendment is approved.  The evaluation of the 
assessments as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will 
not be mandatory any longer.  Tumor lesions and their measurements will not be recoreded in 
the case report form (CRF), nor will the RECIST assessments.  Only the date of progression 
of disease will be recorded.
As a consequence of this modification, the tumor assessments showing progression of the 
disease will not be collected any more during follow-up for those patients who discontinued 
study treatment without an objectively documented progression.
Since the random sample-based BICR audit approach has shown no investigator bias in favor 
of the palbociclib plus fulvestrant arm and the analysis results of BICR also corroborated the 
results of investigator-assessed PFS, the third-party core imaging laboratory will no longer 
perform blinded independent central review of PFS data and the investigators will stop 
sending the imaging studies to the central laboratory.
Considering the safety profile of palbociclib as shown at the time of interim analysis and 
subsequent safety analyses, it was decided to perform blood chemistry only every 3 cycles
(Day 1).  However, when an adverse event occurs that mandates blood chemistry to be 
performed (eg, hepatic function abnormality), the additional laboratory data will be recorded 
in the CRF.  Hemoglobin A1c must be tested at the time of blood chemistry collection.  
Ophtalomologic examination will continue.
It was also clarified that strong/moderate CYP3A inhibitors/inducers and proton pump 
inhibitors listed in the protocol are permitted for those patients who permanently 
discontinued palbociclib/placebo and continue on fulvestrant monotherapy only.
A modification of timing for survival follow-up was added.  Survival follow-up visits will be 
conducted every 3 months from the last dose of study treatment after approval of 
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In order to answer some requests of clarifications from the clinical sites, it was clarified that 
no time window is to be considered for treatment schedule of palbociclib/placebo.
In addition, minor editorial changes were made to correct inconsistencies or improve text 
clarity.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective: 

To demonstrate the superiority of palbociclib in combination with fulvestrant (with or 
without goserelin) over fulvestrant (with or without goserelin) alone in prolonging 
investigator-assessed PFS in women with HR+/HER2- metastatic breast cancer 
whose disease has progressed on prior endocrine therapy. 
Secondary Objectives:

To compare measures of tumor control (including PFS, DR, CBR) between the 
treatment arms.

To compare safety and tolerability between the treatment arms.

To evaluate trough concentrations of palbociclib when given in combination with 
fulvestrant or fulvestrant plus goserelin compared to historical palbociclib data.

To compare fulvestrant and goserelin trough concentrations when given in 
combination with palbociclib to those when given without palbociclib.

To explore correlations between palbociclib exposures and efficacy/safety findings in 
this patient population.

To compare Patient Reported Outcomes measures between treatment arms.

To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle, 
drug targets, tumor sensitivity and/or resistance.

To conduct subgroup analysis for primary and secondary endpoints in stratified 
groups.
CCI


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2.2. Endpoints
Primary Endpoint:

Progression-Free Survival (PFS) as assessed by the Investigator.
Secondary Endpoints:

Overall Survival (OS).

1-year, 2-year, and 3-year survival probabilities.

Objective Response (OR: CR or PR).

Duration of Response (DR).

Clinical Benefit Response (CBR: CR or PR or SD 24 weeks).

Type, incidence, severity (as graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v4.0), seriousness and 
relationship to study medications of AEs and any laboratory abnormalities.

Trough plasma concentration of palbociclib, fulvestrant and goserelin (if applicable) 
in the subgroup of approximately 40 patients included in the initial safety assessment.

PRO endpoints such as global quality of life , symptoms and functioning assessed 
using the European Organisation for Research and Treatment of Cancer Quality of 
Life Instrument (EORTC QLQ-C30) and European Organisation for Research and 
Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23) and Dimension 
Health State EuroQoL Score (EQ-5D) and time to deterioration (TTD) in pain
endpoint.

Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1 and 
CDKN2A, PIK3CA mutations), proteins (eg, Ki67, pRb, CCNE1), and RNA 
expression (eg, cdk4, cdk6). 
3. STUDY DESIGN
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, Phase 3 clinical trial with the primary objective of demonstrating the 
superiority of palbociclib in combination with fulvestrant (Faslodex) over fulvestrant alone 
in in women with HR+, HER2-negative metastatic breast cancer,regardless of their 
menopausal status,  whose disease has progressed after prior endocrine therapy. The safety 
between the two treatment arms will also be compared.  Pre- and perimenopausal women 
must receive therapy with the LHRH agonist goserelin (Zoladexor generic). 


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Eligible patients must have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of recurrent (locally or metastatic) disease. 
Their breast cancer must have progressed during or within 12 months of completion of 
adjuvant therapy (with an AI, if postmenopausal, or with tamoxifen, if pre- or 
perimenopausal).  Alternatively, it must have progressed while on, or within 1 month after 
the end of prior therapy for advanced/metastatic breast cancer (with an AI, if 
postmenopausal, or other prior endocrine treatment, if pre- or perimenopausal). One 
previous line of chemo therapy for metastatic disease is allowed. Patients must have 
measurable disease as per RECIST v.1.1 (Appendix 4) or bone disease as their only site of 
disease.  Tumor tissue is required for patient participation.
Approximately 417 women will be randomly assigned on a 2:1 basis to receive either 
palbociclib plus fulvestrant (at least 278 women; investigational arm), or placebo plus 
fulvestrant (at least 139 women; comparator arm). Pre- and peri-menopausal women 
continue receiving concurrent ovarian function suppression with goserelin. 
417 patients, 
238 PFS events
Palbociclib + 
Fulvestrant 
Placebo + 
Fulvestrant
RANDOMI ZAT I ON  2:1
• HR+ Her2- recurrent 
BC
• Failure of prior 
hormonal treatment
• Progressed ≤12 months 
from prior adjuvant 
therapy with AI*/Tam
• Progressed ≤1 
month  from prior 
advanced BC therapy 
with AI*/anti-endocrine
• LHRH agonist for 
pre/peri-menopausal 
women
* for post-menopausal 
women only


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Arm A (Investigational arm): 
Palbociclib 125 mg/day orally for 3 weeks followed by 1 week off plus fulvestrant 500 mg 
intramuscularly on Days 1 and 15 of Cycle 1, every 28 days (+/- 7 days) thereafter starting 
from Day 1 of Cycle 1.
Arm B (Comparator arm): 
Placebo orally daily for 3 weeks followed by 1 week off plus fulvestrant 500 mg 
intramuscularly on Days 1 and 15 of Cycle 1, every 28 days (+/- 7 days) thereafter starting 
from Day 1 of Cycle 1.
Details of palbociclib dose modifications for toxicity will be addressed in the STUDY 
TREATMENTS section. Dosages of fulvestrant will not be modified.
Pre- and peri-menopausal women must have commenced treatment with any LHRH agonist
at least 4 weeks prior to randomization. If patients have not received goserelin as their
LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial.
Every effort should be made to administer goserelin (given every 28 days, see ZoladexPI)58
on site at the time of fulvestrant administration in order to minimize the number of clinic 
visits.
Randomization will be stratified by documented sensitivity to prior hormonal therapy (yes 
vs. no), by menopausal status at study entry (pre-/peri- vs. post menopausal), and by the 
presence of visceral metastases (yes vs. no). 
Sensitivity to prior hormonal therapy is defined as either: (i) Documented clinical benefit 
(CR, PR, SD 24 weeks) to at least one prior hormonal therapy in the metastatic setting, OR 
(ii) At least 24 months of adjuvant hormonal therapy prior to recurrence. “Visceral” refers to 
lung, liver, brain, pleural and peritoneal involvement.
Patients will continue to receive assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first. Crossover between treatment arms is not allowed.  However, patients may 
continue treatment as assigned at randomization beyond the time of 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. In this case, the patient would continue with routine 
safety relevant assessments as per the SCHEDULE OF ACTIVITIES for the active treatment 
period. In addition, should palbociclib/placebo related toxicity mandate palbociclib/placebo 
discontinuation, patients can continue to receive fulvestrant alone.
Upon approval of Amendment 3, patients discontinuing the active treatment phase will enter 
a follow-up period phase during which survival and new anti-cancer therapy information will 
be collected every 3 months from the last dose of study treatment going forward. Tumor 
response and progression to the subsequent therapy data will also be collected when 
applicable and available. The follow-up period will conclude at the time of the final OS 
analysis. 


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Upon the approval of Amendment 3, disease assessments will be performed and evaluated 
according to local practice. 
Upon approval of Amendment 3, the third-party core imaging laboratory will no longer
perform blinded independent central review (BICR) of PFS data of the subgroup of patients
that was randomly selected.  The investigators will stop sending the image studies to the core 
imaging laboratory.
Patients will undergo study-related safety and efficacy assessments as outlined in the relevant 
SCHEDULE OF ACTIVITIES located in the summary section. 
A total of 238 PFS events will be required in the two treatment arms for the study to have a 
90% power to detect an increase in PFS assuming a true HR of 0.64 (representing a 
56% increase in median PFS from 6 to 9.38 months), if tested at a 1-sided significance level 
of =0.025. 
One interim analysis is planned to re-estimate the sample size, to assess patient safety and
efficacy at 60% of the PFS events.
An external data monitoring committee (E-DMC) will perform an early review of safety data 
from approximately the first 40 randomized patients with sufficient PK sampling to confirm 
safety and tolerability of the combination.  The early safety review by the E-DMC will also 
include PK data from these initial approximately 40 patients to explore potential 
Drug-Drug-Interactions (DDIs) between fulvestrant, goserelin (if applicable) and palbociclib.  
The study will continue while these analyses and review are ongoing.
In addition, trough concentrations of palbociclib will be collected from all patients and will 
be used for exposure/response analysis for safety and efficacy findings.
Patient Reported Outcomes (PRO) will be collected in this trial to evaluate the impact on 
quality of life, functioning, symptoms and general health status using the EuroQol-5D 
(EQ-5D), (Appendix 5) European Organisation for Research and Treatment of Cancer 
Quality of Life questionnaire (EORTC-QLQ-C30), (Appendix 6) and breast cancer 
(EORTC-QLQ-BR23) (Appendix 7).
The study will also include a molecular profiling component aimed at assessing the 
relationship between breast tumor sensitivity and resistance to palbociclib and the alteration 
of cell cycle pathway-related genes and proteins in tumor tissues.
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 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. 


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4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Women 18 years of age or older, who are either:

Postmenopausal, as defined by at least one of the following criteria:

Age 60 years;

Age <60 years and cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause; and serum 
estradiol and FSH level within the laboratory’s reference range for 
postmenopausal females;

Documented bilateral oophorectomy;

Medically confirmed ovarian failure.
OR

Pre/peri-menopausal, ie, not meeting the criteria for being postmenopausal.

Pre/perimeopausal women can be enrolled if amenable to be treated with the 
LHRH agonist goserelin. Patients must have commenced treatment with 
goserelin or an alternative LHRH agonist at least 4 weeks prior to 
randomization.  But, if patients have received an alternative LHRH agonist
prior to study entry, they must switch to goserelin for the duration of the trial. 
2. Histologically or cytologically proven diagnosis of breast cancer with evidence of 
metastatic or locally advanced disease, not amenable to resection or radiation therapy 
with curative intent. 
3. Documentation of ER-positive and/or PR-positive tumor (1% positive stained cells) 
based on most recent tumor biopsy (unless bone-only disease, see below) utilizing an 
assay consistent with local standards.
4. Documented HER2-negative tumor based on local testing on most recent tumor biopsy: 
HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by 
in situ hybridization (FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or for 
single probe assessment a HER2 copy number <4.


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5. Patients must satisfy the following criteria for prior therapy: 

Progressed during treatment or within 12 months of completion of adjuvant therapy 
with an aromatase inhibitor if postmenopausal, or tamoxifen if pre- or 
perimenopausal.
OR

Progressed while on or within 1 month after the end of prior aromatase inhibitor 
therapy for advanced/metastatic breast cancer if postmenopausal, or prior endocrine 
treatment for advanced/metastatic breast cancer if pre- or perimenopausal. 
One previous line of chemotherapy for advanced/metastatic disease is allowed in 
addition to endocrine therapy.
6. Except where prohibited by local regulations, all patients must agree to provide and have 
available a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken at the 
time of presentation with recurrent or metastatic disease. A de novo biopsy is required if 
no archived tissue taken at the time of presentation with recurrent/metastatic disease is 
available. The sole exception is those patients with bone only disease for whom
provision of previous archival tissue only is acceptable. Patients who had surgery within 
the last 3 years (but without neoadjuvant chemotherapy prior to surgery) and relapsed 
while receiving adjuvant therapy may provide a tumor specimen from that surgery.
7. Measurable disease as defined by RECIST version 1.1, or bone-only disease.  Patients 
with bone-only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can 
be accurately assessed by CT or MRI. Patients with bone-only disease and blastic-only
metastasis are not eligible. Tumor lesions previously irradiated or subjected to other loco 
regional therapy will only be deemed measurable if progression at the treated site after 
completion of therapy is clearly documented.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
9. Adequate organ and marrow function defined as follows: 

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 ULN or estimated creatinine clearance 60 ml/min as 
calculated using the method standard for the institution;

Total serum bilirubin 1.5 x ULN (<3ULN if Gilbert’s disease);

AST and/or ALT 3 x ULN (5.0 x ULN if liver metastases present);


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
Alkaline phosphatase 2.5 x ULN (5 x ULN if bone or liver metastases present). 
10. Resolution of all acute toxic effects of prior therapy or surgical procedures to National 
Cancer Institute (NCI) CTCAE Grade 1 (except alopecia).
11. Evidence of a personally signed and dated informed consent document indicating that the
patient (or a legal representative) has been informed of all pertinent aspects of the study.
12. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Prior treatment with any CDK inhibitor, or fulvestrant, or with everolimus, or any agent 
whose mechanism of action is to inhibit the PI3K-mTOR pathway.
2. Patients with advanced/metastatic, 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 Central Nervous System (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 (eg, radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 
4 weeks before randomization.
4. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be 
potent CYP3A4 inducers (for examples, see the Prohibited Medications section), and 
drugs that are known to prolong the QT interval.
5. Major surgery, chemotherapy, radiotherapy, 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.
6. 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.
7. QTc interval >480 msec (based on the mean value of the triplicate ECGs), family or 
personal history of long or short QT syndrome, Brugada syndrome or known history of
QTc prolongation or Torsade de Pointes.


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8. Any of the following within 6 months of randomization: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE 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.
9. Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the 
absorption of palbociclib, such as history of GI surgery with may result in intestinal blind 
loops and patients with clinically significant gastroparesis, short bowel syndrome, 
unresolved nausea, vomiting, active inflammatory bowel disease or diarrhea of CTCAE 
Grade >1.
10. Prior hematopoietic stem cell or bone marrow transplantation.
11. Known abnormalities in coagulation such as bleeding diathesis, or treatment with 
anticoagulants precluding intramuscular injections of fulvestrant or goserelin (if 
applicable).
12. Known or possible hypersensitivity to fulvestrant, goserelin, any of their excipients or to 
any palbociclib/placebo excipients.
13. Known human immunodeficiency virus infection.
14. 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.
15. 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 patients who are Pfizer employees directly involved in the conduct of the 
trial.
16. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks before randomization in the current study.
4.3. Randomization Criteria

Patients will be randomized into the study provided they have satisfied all patient 
selection criteria. 

Prior to randomization, the site will complete a Pre-Randomization form which must 
be approved by the sponsor. On this form, information needed to stratify the patient
must be identified and completed prior to randomizing the patient.


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
The investigators or their pre-specified designee will randomize eligible patients by 
interactive randomization technology (IRT) as described in the Study Reference 
Manual. 

The central computerized system will provide the randomization number and 
treatment assignment. 
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 within the site coordinator’s manual. 
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a 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 patients 
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 patient directly and if a patient 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 and stratification factors, 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. 
Eligible patients will be randomly assigned in a 2:1 ratio to either the experimental arm: 
palbociclib plus fulvestrant, or the control arm: placebo plus fulvestrant, stratified according 
to sensitivity to prior hormonal therapy, menopausal status at study entry, and presence of 
visceral metastases.
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. 


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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
At the initiation of the trial, the trial site will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process.  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, 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 PD. 
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. 
5.3. Drug Supplies
The experimental drugs used in the course of this trial are palbociclib or placebo.  In 
addition, all patients will receive fulvestrant (Faslodex) administered at the study site. All 
three medications will be supplied by the sponsor. Goserelin is administered as per local 
standard of care and is not a study drug.
5.3.1. Formulation and Packaging
5.3.1.1. Palbociclib (PD-0332991)/Placebo
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).
Placebo will be indistinguishable from the palbociclib capsules and will be supplied as 
capsules matching in size and color the various palbociclib dosage strengths (see Table 1).  
The sponsor will supply placebo to sites in HDPE bottles. 


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Table 1.
Palbociclib/Placebo Capsule Characteristics
Dosage
Capsule color
75 mg
Sunset Yellow
100 mg 
Caramel/Sunset Yellow
125 mg
Caramel
5.3.1.2. Fulvestrant
Commercially available fulvestrant, 50mg/mL solution, will be supplied to sites by the 
sponsor.  Complete information about fulvestrant formulation can be found in the local SPC 
for Faslodex.
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. 
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.  Unused returned medication MUST NOT be 
re-dispensed to patients. 
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 a single 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.
Patients will receive a drug diary to document palbociclib/placebo intake, and an 
administration card with information about storage and administration of palbociclib/placebo.  
The completed diary must be returned to the site at the next study visit.
5.3.2.2. Fulvestrant
Fulvestrant (Faslodex) is supplied as two 5-mL clear neutral glass (Type 1) barrels, each 
containing 250 mg/5 mL of fulvestrant solution for intramuscular injection and fitted with a 
tamper evident closure. The syringes are presented in a tray with polystyrene plunger rod 
and safety needles (SafetyGlideTM) for connection to the barrel. 


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Refer to the local SPC for fulvestrant (Faslodex) for instructions and steps necessary for 
drug preparation and administration. Drug preparation and administration will be performed 
at the site by a physician, registered nurse or other qualified health care provider.
Should goserelin be self-administered by the patient at home, patient will receive also a 
second drug diary to document goserelin injection. The completed diary must 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 the patient diary.
Patients should take palbociclib/placebo with food.  Palbociclib/placebo will be administered 
orally once a day for 21 days followed by 7 days off treatment for each 28-day cycle.  No 
time window is to be considered for treatment schedule of palbociclib/placebo. Prior 
palbociclib administration hematology tests must meet retreatment criteria 
(Section 5.3.4.2.2).
Patients experiencing investigational product related toxicity may have their dose modified 
according to the Dose Modification Section.
General rules for palbociclib/placebo administration:

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 the Medication Errors Section for further details on 
medication errors and overdose.
5.3.3.2. Fulvestrant
Fulvestrant 500 mg will be administered intramuscularly into the buttocks slowly 
(1-2 minutes per injection) as two 5 mL injections, one in each buttock. Drug preparation 
and administration will be performed at the site by a physician, registered nurse or other 
qualified health care provider. Refer to the local for Faslodexfor detailed administration 
instructions. 


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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
palbociclib/placebo may need to be adjusted as described in the following sections. Dose 
adjustment is permitted for palbociclib/placebo only. The fulvestrant dose cannot be 
adjusted; its dosing can only be delayed or interrupted.
Depending on the nature of the toxicity observed, treatment interruption may be required for 
one or both study drugs in the combination.  In the event treatment interruption is deemed 
necessary for just one of the study drugs in the combination, treatment with the other study 
drug will continue as planned. 
The start of a cycle is defined as the day when palbociclib/placebo administration begins,
starting with the first palbociclib/placebo dose at baseline (Cycle 1, Day 1).  In case of 
palbociclib/placebo dose delays, administration of fulvestrant and goserelin will continue 
according to the pre-planned schedule. 
Every effort should be made to synchronize Day 1 of palbociclib/placebo administration with
the first injection of fulvestrant (and with the first on-study goserelin injection, if applicable 
and if administered at the study site) and other study related activities according to the 
SCHEDULE OF ACTIVITIES table.
5.3.4.1. Fulvestrant 
No dose adjustment for fulvestrant is permitted. A single fulvestrant injection can be skipped 
in case of a fulvestrant-related toxicity or dosing can be delayed.  Treatment delay for 
fulvestrant-related toxicities will be performed as per the investigator’s best medical 
judgment, but by no more than 7 days. If delay of longer than 7 days is required then the 
dose should be skipped. In the event of a toxicity requiring dosing delay of
palbociclib/placebo, fulvestrant can also be delayed by a maximum of 7 days.
Fulvestrant should not be administered if the platelet count is <50,000/mm3. 
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 followed by dose 
reduction, if required.


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
Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start.

At start of the new 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 fulvestrant monotherapy as per 
the investigator’s discretion. 
5.3.4.2.1. Dosing Interruptions/Delays
Patients experiencing the following adverse events will have their treatment with 
palbociclib/placebo interrupted/delayed until criteria for retreatment are met: 

Uncomplicated Grade 3 or 4 neutropenia (ANC<1000/mm3).

Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection 
or fever 38.5C.

Grade 3 or 4 thrombocytopenia (Platelet <50,000/mm3).

Non-hematologic toxicity persisting despite optimal medical treatment if either 
Grade 2 lasting more than 3 weeks, or Grade 3 (including, nausea, vomiting, and 
diarrhea).  Patients should not hold or discontinue palbociclib/placebo for 
non-hematological side effects potentially or likely related to concomitant 
antihormonal therapy (eg, Grade 3 or long lasting Grade 2 joint pain) as per the 
investigator’s judgment. 

Grade 3 QTc prolongation (QTc 501 msec on at least two separate ECGs).

Concurrent >3x ULN ALT and 2x ULN Total Bilirubin. If those occur, the dose 
needs to be held while the cause is being investigated. 
Doses should be held until toxicity resolution. Appropriate follow up assessments, as 
defined by the investigator, should be undertaken until adequate recovery occurs. Criteria 
required before treatment can resume are described in the Retreatment Criteria Section.
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 in the 
initiation of the subsequent cycle. A new cycle only starts when the retreatment criteria 
listed below are met and blinded study treatment may be administered, otherwise initiation of 
the new cycle must be delayed until such criteria are met.


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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 
treatment 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.  In these cases, Day 1 procedures 
performed before the dose of palbociclib/placebo of the new cycle will be reported in the 
CRF at Day 1 of the new 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 the Dose Reductions Section 
unless an alternative plan is expressly agreed upon 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 >3 weeks, treatment resumption will be decided in 
consultation with the sponsor.
5.3.4.2.2. Retreatment Criteria
Retreatment with palbociclib/placebo 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.

Grade 3 non-hematologic AEs (including nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment), have recovered to 
Grade 1 or baseline.

QTc 500 msec and potential reversible causes (eg, electrolyte imbalance, 
concomitant medications known to prolong QTc) corrected.  If QTc remains above 
480 msec, treatment may re-start but a cardiologist should be consulted and the ECG 
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 adjusted as clinically indicated.
If the retreatment parameters are met within 3 weeks of treatment interruption (which may 
include dose holding due do toxicity, the scheduled week off treatment and up to 7 days of 
cycle delay), palbociclib/placebo may be resumed.  Refer to the Dose Reductions section
below for adverse events requiring dose reduction at the time of treatment resumption. 


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If these parameters have not been met after 3 weeks of dosing interruption, the patient should 
permanently discontinue palbociclib/placebo treatment. Treatment resumption for patients 
recovering from treatment-related toxicity after >3 weeks of treatment interruption but 
deemed to be suitable for a trial of lower dose, is recommended but left at the investigator’s 
discretion and upon discussion and agreement with the sponsor (see below for suggested 
dose adjustments).
5.3.4.2.3. Dose Reductions
No specific dose adjustments are recommended for Grade 1 or short lasting (<3 weeks) 
treatment-related Grade 2 toxicity.  However, investigators should always manage their 
patients according to their medical judgment based on the individual clinical circumstances.
In case of a Grade 2 toxicity lasting for >3 weeks or a Grade 3 toxicity (both assessed in the 
presence of maximum supportive care as judged by the investigator), dose reduction is 
recommended for the subsequent cycles. Dose reduction of palbociclib/placebo by one, and, 
if needed, by two dose levels (Table 2) is recommended depending on type and severity of 
the toxicity.  Patients requiring more than two dose reductions will be allowed to receive 
75 mg/day for 2 weeks on followed by 2 weeks off study treatment (if, per the investigator’s 
judgment, and in consulation with the sponsor, such a change in schedule is manageable and 
preferable to permanent palbociclib/placebo discontinuation and treatment continuation with 
fulvestrant only). All dose modifications/adjustments must be clearly documented in the 
patient's source notes and Investigational product administration CRF. 
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that 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)
Fulvestrant monthly dosing schedule
Starting dose
125 mg/d
2x 250 mg/injection
-1
100 mg/d
2x 250 mg/injection
-2
75 mg/d*
2x 250 mg/injection
* Palbociclib/placebo dose de-escalation below 75 mg/d is not allowed, but the schedule may be changed to 
75 mg/day two weeks on followed by two weeks off (2/2 schedule).
Palbociclib/placebo dose modifications for treatment-related toxicities requiring treatment 
interruption/delay despite optimal medical treatment are described in Table 3.


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Table 3.
Palbociclib/Placebo Dose Modifications for Treatment-Related Toxicities
Toxicity
Palbociclib/Placebo Treatment at:
Uncomplicated Grade 3 neutropenia (ANC 500 
- <1000/mm3)
Same dose level; 1 dose level if 
neutrophil recovery is delayed
beyond 7 days *, **
Grade 3 neutropenia (ANC<1000/mm3) 
associated with a documented infection or fever 
38.5C
1 Dose Level; 2 dose levels***
if neutrophil recovery is delayed
beyond 7 days *
Grade 4 neutropenia (ANC<500/mm3)
1 Dose Level; 2 dose levels***
in case of recurrent grade 4 event *
Grade 3 or 4 thrombocytopenia (Platelet count 
<50,000/mm3)
1 Dose Level; 2 dose levels***
in case of recurrent grade 3 event
Grade 3 non-hematologic toxicity (including, 
nausea, vomiting, diarrhea, and hypertension only 
if persisting despite optimal medical treatment)
1 Dose Level; 2 dose levels***, 
if repeated toxicity is seen in the 
next cycle or if recovery from grade 
3 is delayed beyond 7 days *
* If recovery of neutrophils to 1000/mm3 or platelet count to 50,000/mm3 takes longer than 2 weeks (which
may include dose holding due do toxicity, the scheduled week off treatment and up to 7 days of cycle delay), 
then reduce by 2 dose levels.
** If uncomplicated Grade 3 neutropenia recurs in 2 consecutive cycles, after recovery as per retreatment 
criteria (ANC 1000/mm3 and no fever), treatment may restart at the next lower dose level at investigator’s
discretion.
*** If no further dose reduction is possible (ie, patient is already receiving 75 mg/d according to schedule 3/1) 
consider changing the schedule to 75/mg/d 2 weeks on/2 weeks off), or discontinue palbociclib/placebo and 
continue with fulvestrant alone.
5.3.4.2.4. QTc prolongation management
In the event of QTc prolongation of >480 and 500 msec, possible reversible causes such as 
serum electrolytes abnormalities, or usage of concomitant medications with the potential to 
prolong the QTc interval 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 with the potential to prolong the QT 
interval [see Appendix 3]). 
Dose modifications in the event of QTc prolongation are provided in Table 4.


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Table 4.
Palbociclib/Placebo Dose Modifications in the Event of QTc Prolongation
Toxicity (NCI CTCAE Grade, Version 4.0)
Grade 2 QTc prolongation
(>480 and 500 msec)
Grade 3 QTc prolongation
(501 msec)
Grade 4 QTc 
prolongation 
(501 msec or 
>60 msec change 
from baseline AND 
life-threatening 
signs including 
Torsades de 
Pointes)
Reversible 
cause 
identified 
Treat reversible cause 
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc 480 msec 
Continue at the same dose level (1)
Treat reversible cause 
Withhold treatment until QTc 
500 msec 
Resume treatment at the same dose 
level.
Monitor ECG more frequently as per 
investigator’s best medical judgment 
until QTc 480 msec.  
Permanently 
discontinue
palbociclib/placebo
No 
reversible 
cause 
identified
Consult cardiologist and 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 
500 msec 
Resume treatment at the next lower 
dose level (2)
Consult cardiology and monitor ECG 
more frequently as per investigator’s 
best medical judgment until QTc 
480 msec.
Permanently 
discontinue
palbociclib/placebo
1.
If the QTc remains >480 msec and 500 msec for 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 recurs after one dose reduction, further dose adjustment 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.
5.3.5. Medication Errors
Medication errors may result in this study from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page and on the Serious Adverse Event 
(SAE) form when appropriate.  In the event of medication dosing error, the sponsor should 
be notified immediately.


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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page, and if applicable, any associated AE(s) are captured on AE CRF page. 
5.3.6. Compliance
Patients will be required to return all bottles of palbociclib/placebo as well as the completed 
patient diary at the beginning of each cycle for drug accountability.  Drug accountability will 
be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.  The 
number of remaining capsules/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 during the study.  Dose adjustments must follow instructions provided in the 
dose adjustment guidelines section. 
Fulvestrant will be administered by qualified study personnel at the site in accordance with 
the fulvestrant label. Fulvestrant administration will be documented on the corresponding 
study drug administration CRF.
5.4. Drug Storage and Drug Accountability 
Storage conditions stated in the Single Reference Safety Document (ie, Investigator’s 
Brochure (IB), United States Package Insert (USPI), Summary of Product Characteristics 
(SPC), or Local Product Document (LPD)) will 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 
correctly as required for proper storage of investigational products.  These include 
thermometers for both the room storage and refrigerator storage.  Any temperature 
excursions must be reported to the sponsor.  The investigational products 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 
fulvestrant) must be quarantined and not used until the sponsor provides documentation of 
permission to use the investigational products. 


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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 Storage and Accountability
Palbociclib/placebo capsules should be stored at controlled room temperature (15-30C, 
59-86F) in their original container.
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication should be stored separately from 
medication that needs to be dispensed.
To ensure adequate records, palbociclib/placebo capsules will be accounted for as instructed 
by 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. 
5.4.1.1. Fulvestrant Storage and Accountability
Fulvestrant must be stored according to the instructions described in the local package insert. 
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 
products 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 fulvestrant (and goserelin for pre- and 
perimenopausal women) will be permitted during the active treatment phase.  In 
general, any drugs containing “for the treatment of breast cancer” on the product label 
are not permitted on study.


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
Potent (Strong/Moderate) CYP3A inhibitors/inducers: Palbociclib is metabolized to 
multiple metabolites in a qualitatively similar manner in rat, dog and human liver 
microsomes.  In vitro, palbociclib is primarily metabolized by CYP3A4 enzymes.  
Co-administration with drugs that are strong CYP3A inhibitors and inducers may 
change the plasma concentrations of palbociclib in humans.  The concurrent use of
the following compounds is not allowed in the study:

Strong CYP3A inhibitors, including, boceprevir, clarithromycin, conivaptan, 
delavirdine, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
suboxone, telaprevir, telithromycin, voriconazole, and grapefruit, grapefruit juice 
or any product containing grapefruit, 

Strong CYP3A inducers, including carbamazepine, phenytoin, primidone, 
rifampin, rifapentin, and St. John’s wort, 

Only the following moderate CYP3A inhibitors: amprenavir, atazanavir,
diltiazem, erythromycin, fosamprenavir, verapamil and moderate CYP3A 
inducers: felbamate, nevirapine, phenobarbital, rifabutin.

Drugs known to cause QT interval prolongation are prohibited during the active 
treatment phase (refer to Appendix 3). 

Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators
(eg, raloxifene) are prohibited during the active treatment phase.

Anticoagulants: if patient is receiving anticoagulants, refer to the FaslodexPI.44

Proton-pump inhibitors (PPIs): The concomitant use of PPIs with palbociclib/placebo 
is prohibited, including but not limited to dexlansoprazole, esomeprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole. Should the use of PPIs be 
required for a given patient, please contact the Sponsor for an assessment of the best 
treatment choice.  Alternative acid-reducing recommendations are provided in
Section 5.5.3.
Strong/moderate CYP3A inhibitors/inducers and PPIs listed above, are now permitted ONLY 
for patients who permanently discontinued palbociclib/placebo and continue on fulvestrant 
monotherapy only.
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. 


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If one of the following treatments is deemed necessary, consultation and agreement with 
the sponsor is required prior to treatment initiation. 

The concurrent use of dexamethasone is not recommended. 

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. 
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 patient’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 ASCO guideline.59
If neutropenic complications are observed in a cycle in which primary prophylaxis 
with CSFs was not received, secondary prophylaxis may be given at the discretion of 
the investigator, but only if dose reduction or delay are not considered a reasonable 
alternative.

Erythropoietin may be used at the investigator's discretion for the supportive 
treatment of anemia. 

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.


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
H2-receptor antagonists (including, but not limited to, cimetidine, famotidine, 
nizatidine, ranitidine); palbociclib/placebo treatment should occur at least 10 hours 
after H2-receptor antagonist evening dose and 2 hours before H2-receptor antagonist 
morning dose.
5.6. Concomitant Radiotherapy or Surgery
Any concurrent radiotherapy (except palliative radiotherapy as specified below) or 
cancer-related surgery is 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.
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 the Screen Failure Section) 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.
One cycle consists of 28 days.  A cycle could be longer than 28 days if persistent toxicity 
delays initiation of the subsequent cycle.


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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); 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 SCHEDULE OF 
ACTIVITIES.
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.
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.
Any suspicious abnormalities (ie, hotspots) identified on the bone scans at baseline and on 
subsequent bone scans shall be confirmed by X-ray, CT or MRI to confirm its tumor-related 
malignancy.  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, Week 8 7 days from randomization) as for all other lesions.  
Areas that have received palliative radiotherapy cannot be used to assess response to study 
treatment. 
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.
Once Amendment 1 is approved, a minimum of 100 lens grading evaluable, newly enrolled 
patients will undergo the following ophthalmic procedures at screening:

Best corrected distant visual acuity (Snellen);


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
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 - pupil dilated examination). 
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. 
All ophthalmic examinations will be performed by an ophthalmologist. Refer to
Section 7.2.2. Ocular Safety Assessments for further details on these procedures. Sites and 
patients will be informed as soon as these ocular examinations are no longer required for the
study.
For details on baseline procedures, see the SCHEDULE OF ACTIVITIES. 
6.2. Screen Failure
Patients who completed the informed consent process but do not meet one or more eligibility 
criteria and therefore are not randomized will be considered as screen failures. 
For all screen failures, clinical sites must provide the following information using the 
appropriate CRFs: screening number, demographic data as well as the final patient summary 
including the reason for failing the screening process.
Ineligible patients are allowed to be re-screened a single time only. When re-screened they 
must be reconsented and will be assigned a new study patient identification (ID). 
6.3. Active Treatment Phase
For details on procedures during the active treatment phase, see the SCHEDULE OF 
ACTIVITIES tables. 
6.4. End of Treatment Visit
The end of treatment visit will be performed as soon as possible but no later than 4 weeks
from last dose of investigational products and prior to the initiation of any new anticancer 
therapy.
Obtain these assessments if not completed during the previous 4 weeks on study.


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For details on procedures to be performed at the End of Treatment visit, see the SCHEDULE 
OF ACTIVITIES tables. 
6.5. Follow-up Visits
6.5.1. 28-day Post-treatment Follow-up
Patients who discontinue study treatment should be contacted 28 calendar days (+/- 7 days) 
after discontinuation of investigational product (palbociclib/placebo or fulvestrant) to assess 
if there have been any new adverse events and any change to any previously reported adverse 
events.  This follow-up should occur 28 calendar days (7 days) regardless of any new anti-
cancer therapy that may have started. Telephone contact is acceptable.  The telephone 
contact will be documented in the patient’s file.
6.5.2. Survival Follow-up
After discontinuation of study treatment, post-study survival status (including start, stop and 
type of post study anticancer therapies, tumor response and date of progression of the disease 
during or after the subsequent anticancer therapy) will be collected every 3 months from the 
last dose of study treatment going forward after approval of Amendment 3 Telephone contact 
is acceptable.
For details on follow-up visit procedures, see the SCHEDULE OF ACTIVITIES tables. 
6.6. Patient Withdrawal
6.6.1. 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, 
ie, discontinues treatment of palbociclib/placebo AND fulvestrant.  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);

Symptomatic deterioration (ie, global deterioration of health status without objective 
evidence of disease progression);

Need for new or additional anticancer therapy not specified in the protocol;

Unacceptable toxicity; 

Investigator’s conclusion that discontinuing therapy is in the patient’s best interest;

Lost to follow-up;


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
Patient choice to withdraw from treatment (follow-up permitted by patient);

Withdrawal of patient consent (cessation of follow-up);

Death.
*
Patients may continue treatment as assigned at randomization beyond the time of 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. In this case, the patient would continue with routine safety-relevant assessments as per the SCHEDULE OF 
ACTIVITIES during the treatment period.
Patients 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 products 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. 
6.6.2. 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 patient consent (ie, refuses tumor assessments or follow-up on survival 
status after the 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 returns all unused investigational product(s), request the patient returns for 
a final visit, if aplicable, and follow-up with the patient regarding any unresolved AEs.
Data to be collected for the end of study treatment/withdrawal are described in the 
SCHEDULE OF ACTIVITIES. 


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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 footnotes to the SCHEDULE OF ACTIVITIES.
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. Pregnancy Testing
For women of childbearing potential, a serum pregnancy test, with a sensitivity of at least 
25 mIU/mL will be performed before starting investigational products at screening and 
repeated at the baseline visit.  A negative pregnancy result is required before the patient may 
receive the study treatment. 
No routine pregnancy test will be carried out after baseline as patients will be rendered 
postmenopausal by the administration of goserelin and fulvestrant. However, pregnancy 
tests will also be done whenever a potential pregnancy is suspected. In the case of a positive 
hCG test, the patient will be withdrawn from study medication but may remain on study for 
survival follow up.  Pregnancy tests may also be repeated as per request of Institutional 
Review Board (IRB)/IECs or if required by local regulations. 
In this protocol, a woman is defined of childbearing potential if pre- or perimenopausal at the 
time of consenting to study enrollment (see Inclusion Criterion n.1 for details).
Additionally, for women who are <60 years old and have been amenorrheic for at least 
12 consecutive months, serum estradiol and FSH levels will be analysed pre-dose at baseline 
to confirm postmenopausal status. 
7.2. Efficacy Assessments
7.2.1. Tumor Assessments 
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:

CT or MRI scan of the chest, abdomen, and pelvis.


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
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 as only site 
of disease 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 the Screening Section for further 
details on timing allowance for baseline brain and bone scans. 
Post-baseline tumor assessments.  Upon approval of Amendment 3, tumor 
assessments/imaging studies will be performed according to local practice.  
If tumor assessments are scheduled as per the original protocol, upon approval of 
Amendment 3, they can be performed at a different schedule if this is common practice at 
that institution or it is recommended by the physician according to the patient’s clinical 
conditions.  
Upon approval of Amendment 3, selection of imaging studies will depend on treating 
physician and radiologist as per local practice. RECIST 1.1 may be used to evaluate imaging 
assessments but will not be mandatory.  Evaluation of imaging studies will be conducted as 
per the practice at the institution.
Tumor lesions [ie, target lesion(s), non-target lesion(s) and target lymph node(s)] will no 
longer be recoreded in the CRF, nor will the RECIST assessments.  Only the date of 
progression of disease will be recorded.  
7.2.2. Ocular Safety Assessments
Amendment 3 will not affect ocular safety assessments which will continue to be collected as 
per the SCHEDULE OF ACTIVITIES.
7.2.2.1. 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.  


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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.
7.2.2.2. 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).
7.2.2.3. 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
No cells
1 to 5 
cells
6 to 10 cells
11 to 20 cells
>20 cells
a
Evaluation of Anterior Chamber Inflammation (modified from Hogen et al.)60:
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.


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During the study, any new finding or deterioration from baseline findings should be reported 
as an adverse event.
7.2.2.4. Lens Grading
When doing lens grading, graders must be aware of their bias, either conscious or 
unconscious, 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.61 (Appendix 8).  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 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.
7.2.2.5. 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.  
Any new findings or deterioration from baseline findings will be reported as an adverse 
event.


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7.2.3. Independent Review of Disease Assessments 
Upon approval of Amendment 3, the third-party core imaging laboratory will stop 
performing blinded independent central review (BICR) of PFS data of the subgroup of 
patients that was randomly selected.  The investigators will stop sending the image studies to 
the core imaging laboratory.
7.2.4. Overall Survival
Upon approval of Amendment 3, after the End of Treatment visit, survival status will be 
collected in all patients (telephone contact is acceptable) every 3 months from the last dose of 
study treatment going forward.  Information on start, stop and type of subsequent anticancer 
therapy as well as the date of disease progression during or after the anticancer therapy will 
also be collected.
7.3. Safety Assessments
Safety assessment will consist of monitoring of all AEs, including SAEs, regular monitoring 
of hematology, serum chemistry, and routine monitoring of ECGs, physical examinations, 
vital signs, and ECOG performance status. 
Adverse event assessment will include type, incidence, severity, timing, seriousness, and 
relatedness. Severity will be graded by the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.0, see Severity Assessment section. 
Baseline cancer 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.
7.3.1. Laboratory Safety Assessments
Blood tests include the following:
Hematology Panel
Blood Chemistry Panel
Hormonal Status (if 
applicable)
1
Hemoglobin
1
ALT
1
Serum Beta-HCG*
2
Platelets
2
AST
2
Serum estradiol**
3
WBC
3
Alkaline Phosphatase
3
FSH**
4
Absolute Neutrophil
Count
4
Sodium
5
Potassium
6
Total Calcium
7
Magnesium
8
Total Bilirubin
9
BUN or Urea
10
Serum Creatinine
11
Albumin
12
Hemoglobin A1c
* For women of childbearing potential.
** For postmenopausal status confirmation of women <60 years old who have been amenorrheic for at least 12 consecutive 
months.


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Blood tests will be drawn at the time points described in the SCHEDULE OF ACTIVITIES
table, and analyzed at local laboratories.  
Hematology tests must meet retreatment criteria prior to administering palbociclib/placebo. 
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. 
7.3.2. Electrocardiogram
All Electrocardiograms (ECGs) will be performed using a 12-lead (with a 10-second rhythm 
strip) tracing.  ECG measurements will include PR interval, QT interval, RR interval, and 
QRS complex.  It is preferable that the machine used has a capacity to calculate the standard 
intervals automatically. 
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents. 
Additional ECGs may be performed as clinically indicated at any time.
For the purpose of the study, triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart at the protocol specified timepoints (see 
SCHEDULE OF ACTIVITIES table for details) to determine the mean QTc interval. 
Refer to the Dose Modification Section for details on dose management in case of abnormal 
ECGs considered related to investigational product. 
7.3.3. Other Safety Assessments
A full physical examination including an examination of all major body systems and breasts, 
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, Day 1 of every cycle and End of Treatment/Withdrawal visit.
Symptom directed physical examinations, blood pressure and pulse rate may be performed at
interim cycle visits at the Investigator’s discretion.
Performance Status: The ECOG performance status scale will be used (see Appendix 2). 
7.4. Pharmacokinetic Assessments
In the initial approximately 40 patients included in the early safety review, plasma PK 
samples will be drawn at predose on Day 1 and Day 15 of Cycle 1 and Cycle 2, and Day 1 of 
Cycle 3 for DDI assessments. 


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Review of the PK data will be done by the E-DMC once all planned PK samples from 
theseapproximately 40 patients have been analyzed. The study will continue while PK 
analysis and data review are ongoing. Details of the analysis (along with other safety data 
included in the early safety review) will be provided in the E-DMC charter.
For patients who receive palbociclib and fulvestrant, PK samples will be analyzed for 
palbociclib and fulvestrant concentrations.  For patients who receive fulvestrant and placebo, 
PK samples will be analyzed for fulvestrant. For pre- and perimenopausal women also 
receiving goserelin, PK samples will be analyzed for palbociclib, fulvestrant AND goserelin 
concentrations. For patients who receive fulvestrant, goserelin and placebo, PK samples will 
be analyzed for fulvestrant and goserelin. Concentrations of fulvestrant and Goserelin will 
be compared between the palbociclib and placebo subgroups.  The concentrations of 
palbociclib will be compared with historical data. 
In these approximately 40 patients, two (combinations without goserelin) or three 
(combinations with goserelin) 3 mL samples of venous blood will be collected in 
appropriately labeled collection tubes for assessment of palbociclib, fulvestrant, and/or 
goserelin levels at the protocol-specified times, as described above. 
In all other patients (not participating the early safety review), plasma concentrations will be 
drawn on Day 15 of Cycle 1 and Cycle 2 for palbociclib determination. These trough 
concentrations will be used for exposure/response analysis for safety and efficacy findings.  
From those patients, one 3 mL sample of venous blood will be collected in appropriately 
labeled collection tubes for assessment of palbociclib.  Samples will be analyzed using 
validated analytical methods in compliance with Pfizer standard operating procedures. 
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 son 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 
missing dose should also be recorded in the CRF. 
Additional PK blood samples for palbociclib and fulvestrant (and goserelin if applicable) 
may be collected 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. 
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7.5. Patient Reported Outcomes 
Patient reported outcomes of health-related quality of life and health status will be assessed 
using the EQ-5D instrument, the EORTC QLQ-C30, and EORTC QLQ-BR23 (Appendix 5, 
Appendix 6, Appendix 7, respectively).
Patients will complete each instrument at pre-dose on Day 1 of Cycles 1-4, then on Day 1 of 
every other subsequent Cycle starting with Cycle 6 (eg, Cycles 6, 8, 10, 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 instruments will be given to the patient in the 
appropriate language for the site. 
7.5.1. EuroQol Health Utilities Index EQ-5D 
The EuroQol-5D (EQ-5D) (version 3L) (see Appendix 5) 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 (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.
7.5.2. EORTC QLQ-C30
The EORTC-QLQ-C30 (see Appendix 6) is a 30-item questionnaire composed of five 
multi-item functional subscales (physical, role, cognitive emotional, and social functioning), 
three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global health/quality 
of life (QOL) subscale, and six single items assessing other cancer-related symptoms 
(dyspnea, sleep disturbance, appetite, diarrhea, constipation, and the financial impact of 
cancer).  The questionnaire employs 28 4-point Likert scales with responses from “not at all” 
to “very much” and two 7-point Likert scales for global health and overall QOL.  For 
functional and global QOL scales, higher scores represent a better level of functioning and 
are converted to a 0 to 100 scale.  For symptom-oriented scales, a higher score represents 
more severe symptoms.
7.5.3. EORTC QLQ-BR23 
The EORTC-QLQ-BR23 (see Appendix 7) is a 23-item breast cancer-specific companion 
module to the EORTC-QLQ-C30 and consists of two functional scales (body image and 
sexuality); three symptom subscales (arm/hand, breast, and systemic side effects) and single 
items covering sexual enjoyment, distress at hair loss, and future perspective.


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7.6. Biomarker Assessments
Tumor tissues are required from all patients for study participation. 
HR and HER2 status for eligibility will be based on local results utilizing an assay consistent 
with local standards for entry into the trial and for reporting of the efficacy endpoints.
Central assessment of ER, PR, and HER2 on suitable samples will be performed 
retrospectively at a qualified central laboratory.
A biomarker will be nominated as the primary marker for analysis using data external to the 
current study. The interaction between this primary marker (eg, pRb or other from a set of 
biomarkers to be analyzed) and benefit from palbociclib in terms of prolongation of PFS will
be examined. In addition, other tumor tissue biomarkers, including DNA, RNA and protein 
analytes, will be analyzed to investigate possible associations with resistance/sensitivity to 
treatment with palbociclib.  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 are not limited to, CCND1 and CDKN2A gene copy number, cdk4 
and cdk6 RNA expression, and Ki67, pRb, cyclin E and p16 protein expression. The 
relationship between centrally reported ER/PR and HER2 status and resistance/sensitivity to 
treatment with palbociclib will also be assessed. 
All patients with archived samples need to provide a FFPE tissue blocks of adequate size to 
allow for three 0.6 mm diameter x 5 mm deep core punchesthat will be used to generate a 
tissue microarray.  If FFPE tissue block cannot be provided, a minimum of 12 unbacked 
glass slides each containing an unstained 5-micron FFPE tissue section, will be required for 
patient participation.  Archived FFPE specimen from the metastatic or recurrent tumor tissue 
will be collected and sent to the sponsor-designated central laboratories for assessment of 
biomarkers potentially associated with sensitivity and/or resistance to palbociclib (eg, Ki67,
p16/CDKN2A, pRb, PIK3CA, CCNE1). 
Plasma samples will be collected for analyses of circulating free DNA or RNA, and the 
relationship with resistance/sensitivity to treatment with Palbociclib/placebo.
If archived FFPE tissue from a recurrent tumor or distant metastasis is unavailable, a de novo 
biopsy is required for patient participation, except those with bone metastasis only, when, in 
the investigator’s judgment, such biopsy is feasible and can be safely performed.  Original 
diagnostic tumor tissue will be used for biomarker analyses in the event that patients have 
bone disease only. Patients who had surgery (but without neoadjuvant chemotherapy prior to 
surgery) within the last 3 years and relapsed while receiving adjuvant therapy may provide 
tissue from that surgery. Provision of de novo metastatic tissue in these cases is strongly 
encouraged but not mandated. 
Detailed information about biomarker sample collection, preparation, storage, labeling, and 
shipment is indicated in the central laboratory manual.


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7.6.1. Optional Tumor Tissue Biopsy for Molecular Profiling
An optional de novo 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.
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an 
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 patient 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all 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 the patient’s last 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.
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;


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
Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an AE by the investigator or sponsor.


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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 
SAE with Common Terminology Criteria for Adverse Events (CTCAE) Grade 5 (see Section 
on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes the 
important medical event should be reported as serious.
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 the Section on Serious Adverse Event Reporting Requirements).


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8.5.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis 
and an alkaline phosphatase 2 X ULN or not available.

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller).

Concurrent with:

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.  For oncology studies 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, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 


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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 of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.

Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical exam);

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;


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
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.
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
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 CTCAE document but may be used in certain circumstances.)  
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences: urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
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 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the 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.


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8.9. Exposure during Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product. An example of environmental exposure
would be a case involving direct contact with a Pfizer product in a pregnant woman
(eg, a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (SAE) Form and 
Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE has occurred.  In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) using the 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).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination) and notify Pfizer of the outcome as a follow up to 
the initial 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;


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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 the 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.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a 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 investigator site file.
8.11. Withdrawal Due to Adverse Events (See also the Section on 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 
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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, 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.
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 
have been documented in a Statistical Analysis Plan (SAP), which have been 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.  The planned data analysis in this section was 
performed when the study A5481023 (PALOMA-3) met its primary endpoint at the 
preplanned interim analysis from the data with the cutoff date of 05 December 2014.  With 
the ongoing data collection of overall survival (OS) information, the planned OS interim 
analysis and final analysis will be performed based on the detailed plan described in the SAP.  
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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/placebo or fulvestrant), 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
Efficacy analyses will be based on ITT population.  Analysis of DR will be based upon the 
responders (CR or PR) from ITT population. All analyses will be performed by using SAS
Version 9.1.3 or higher. 
All primary and secondary endpoints based on radiological (and photographical where 
applicable) assessments of tumor burden (ie, PFS, OR, DR, CBR) will be derived using the 
local radiologist’s/investigator’s assessment.  Radiographic images (approximately 40%, 
randomly collected) and clinical information collected on-study will also be reviewed by a 
blinded independent third-party core imaging laboratory to verify investigator reported tumor 
assessments.  This information will be used for supportive analyses.
In addition to analyses driven by the study objectives, subset analyses may be conducted, for 
example, by age, regions, race, performance status, line of therapy in metastatic setting, 
biomarkers, and others as deemed appropriate.
All of the above secondary analyses will be conducted at a one-sided 0.025 level of 
significance.  Additional sensitivity analyses will be outlined in the SAP.
9.3.1. Analysis of Primary Endpoint 
The primary endpoint is PFS 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 the duration of one 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. Patients with documentation of PD or death 
after an unacceptably long interval (ie, 2 or more incomplete or non-evaluable assessments) 
since the last tumor assessment will be censored at the time of last objective assessment that 
did not show PD.
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 factors used to conduct the stratified log-rank test for 
the primary analysis 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.  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 and the stratified long-rank test (one-sided, 
=0.025) will be used. 


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9.3.2. Analysis of Secondary Endpoints
Overall Survival (OS)
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.  OS will be hierarchically 
tested for significance at the time of PFS analysis, provided the primary PFS endpoint is 
statistically significant at the interim and/or final analyses.  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 treatment 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% CI.
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 using the Greenwood’s formula, 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) 
OR is defined as a complete response (CR) or partial response (PR) according to 
RECIST v.1.1 (Appendix 4) 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 CR or 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. 
The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the 
number of patients with OR (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 of 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 
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In addition, the Best Overall Response for each patient will be summarized by treatment 
arm. Refer to the end of Appendix 4 for definitions of Best Overall Response based upon 
RECIST v. 1.1.
Duration of Response (DR) 
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 
OR.  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. 
Clinical Benefit Response (CBR)
CBR is defined as CR or PR or SD 24 weeks according to the RECIST version 1.1 
(Appendix 4) recorded in the time period between randomization and disease progression or 
death of any cause. 
The CBR rate 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 CBR rates will be provided.  CBR 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 CBR 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. 
Patient Reported Outcomes (PRO)
Breast cancer-specific quality of life scores and change from baseline scores will be 
compared between the treatment arms using a mixed model repeated measures 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. 
In addition to the above analyses, an examination of the time to deterioration (TTD) 
composite endpoint will be carried out using survival analysis methods.  A composite 
definition for deterioration based on death, tumor progression, and/or breast cancer-specific 
quality of life subscale MIDs may be used.


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9.5. Analysis of Other Endpoints
Pharmacokinetic Analysis
For approximately the initial 40 patients included in the early safety review, the 
concentration data of palbociclib, fulvestrant and goserelin will be listed by analyte, patient, 
collection time and day and treatment arm (combination).  Summary statistics will be 
provided for concentrations by analyte, collection time and day, and treatment arms 
(combination).
For all patients on the palbociclib treatment arm, palbociclib trough concentrations will be 
listed by patient, collection time and day, and unique combination.  Summary statistics will 
be provided by collection time and day, and unique combination.  If fulvestrant or goserelin 
does not have an effect on the palbociclib PK, an average of the two trough concentrations of 
palbociclib will be listed by patient for the corresponding combination, and summary 
statistics will be provided.  If both fulvestrant and goserelin has no effect on palbociclib PK, 
summary statistics will be provided including average trough concentration from all patients 
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across combinations.  The relationship between trough concentration and potential covariates 
will 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.  
Refer to Statistical Analysis Plan for details of the analyses.
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 SAP for details of the analyses. The results of these modeling analyses 
may be reported separately from the clinical study report. 
Biomarker Analysis 
For baseline continuous endpoint data, descriptive statistics, including the mean, standard 
deviation, median, minimum, and maximum values, will be provided by treatment arm. 
For baseline categorical data, the number and percentage of patients in each category will be 
provided by treatment arm. 
Appropriate statistical methods may be used to investigate any possible relationship of 
biomarker levels with palbociclib plus fulvestrant anti-tumor efficacy. 
9.6. 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 v. 15.1) 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 
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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.  
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. 
9.7. Interim Analysis 
The study is designed to have one interim analysis. The interim analysis will be conducted to 
allow for early stopping of the study due to efficacy, and to allow for potential re-estimating
the sample size of the trial based upon the primary endpoint of PFS. The safety of the 
combination will also be assessed at the interim analysis. The efficacy boundary of PFS will 
also be pre-specified.  The Haybittle-Peto boundary63,64 will be used (alpha=0.00135 is to be 
spent at interim analysis) in developing the efficacy boundary of the interim analysis of PFS. 
The total Type I error rate will be well preserved.  Specific details regarding the efficacy 
boundary will be described in the SAP.
The interim analysis of PFS will be performed after approximately the first 143 patients have 
documented PD or death (approximately 60% of the total events expected). The information 
fraction (60% currently) for the interim analysis may be adjusted if needed. As appropriate, 
the sample size of the study may be adjusted using the method outlined by Cui, Hung, and 
Wang65 and applied to the PFS endpoint.  The technical details of sample size re-estimation 
approach will be pre-specified in a separate technical document that is to be shared only with 
the E-DMC before the interim analysis.
OS will be hierarchically tested for significance at the time of PFS analyses, provided the 
primary PFS endpoint is statistically significant at the interim and/or final PFS analyses. 
Further details, along with a table of nominal alpha for the interim and final PFS analysis and 
for OS will be included in the SAP.
9.8. Data Monitoring Committee 
The study will use an External Data Monitoring Committee (E-DMC).  The E-DMC 
membership and governance is outlined in a separate charter.
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of patients 
in the study according to the Charter.  The E-DMC will make a recommendation as to 
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the E-DMC will also evaluate interim efficacy data and make a recommendation regarding 
study continuation based on observed results of the study.  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, which may include summaries of aggregate analyses of 
endpoint events and of safety data which are not endpoints, to regulatory authorities, as 
appropriate.  The sponsor will designate a biostatistician not affiliated with the project to 
prepare data for E-DMC review.  Only if action or consultation with Health Authorities is 
required will other sponsor staff be involved.  Clinical sites will be restricted from access to 
study results until the conclusion of the study. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent 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 IRB/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 
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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.
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.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 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.
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, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient's 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). 
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.


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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.
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.


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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, Food and Drug Administration (FDA)-approved 
products, Pfizer posts results within one year of the primary completion date. For studies 
involving products approved in any country, but not FDA approved, Pfizer posts results one 
year from last patient, last visit:
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.
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 last subject last visit (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 
Drug.  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.


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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.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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Konecny GE, Winterhoff B, Kolarova T, et al. Expression of p16 and retinoblastoma 
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Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 
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Molecular cancer therapeutics. 2004; 3: 1427-1438.
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Cen L, Carlson BL, Schroeder MA, et al. p16-Cdk4-Rb axis controls sensitivity to a 
cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. 
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Finn RS, Dering J, Conklin D, et al. PD-0332991, a selective cyclin D kinase 4/6 
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PD0332991 in advanced breast cancer. ASCO 2013, Abstract 519.


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Slamon DJ, Hurvitz SA, Applebaum S, et al. Phase I study of PD-0332991, cyclin-D 
kinase (CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of
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PD 0332991, a Cyclin-Dependent Kinase 4/6 inhibitor, in combination with letrozole 
for first line treatment of patients with postmenopausal, ER-positive, HER2-negative 
advanced breast cancer.  Poster; SABCS; Dec 6-10, 2011; San Antonio, Texas.
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Breast Cancer.  The New England journal of medicine; online publication Jun 01, 2015.
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Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by 
immunohistochemistry is superior to the ligand-binding assay for predicitng response to 
adjvuant endocrine therapy in breast cancer. J Clin Oncol. 1999 Vol 17, No5, pp 
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Hellman S, Rosenberg SA, editor(s). Cancer: principles and practice of oncology. 
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Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM Phase III trial 
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Di Leo A, Jerusalem G, Petruzelka L, et al. Final analysis of overall survival for the 
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postmenopausal Japanese women with hormone receptor-positive (HR+) advanced 
(ABC) or recurrent breast cancer (RBC). 2007 ASCO Breast Cancer Symposium: 
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or without Dasatinib in Postmenopausal Patients with Hormone Receptor-Positive 
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mediate resistance to estrogen deprivation in human breast cancer. Cancer Discovery 
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RAD001 (everolimus) in metastatic estrogen receptor (ER) positive breast cancer after 
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Appendix 1. List of Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferases 
AI
Aromatase Inhibitor
ANC
Absolute Neutrophil Count
AREDS
Age-Related Eye Disease Study
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferases 
AUC
Area under the concentration curve
BICR
Blinded Independent Central Review
BUN
Blood Urea Nitrogen
CBR
Clinical Benefit Response
CCND1
Cyclin D1
CDK
Cyclin-Dependent Kinase
CI
Confidence Interval
CISH
Chromogenic In Situ Hybridization
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
DD
Differential discordance
DICOM
Digital Imaging and Communications in Medicine
DISH
Dual in situ hybridization 
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
E-DMC
External Data Monitoring Committee
EDR
Early discrepancy rate
EDTA
Ethylenediaminetetraacetic acid
EIU
Exposure In Utero
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire
EORTC-QLQ-BR23
European Organisation for Research and Treatment of Cancer 
breast cancer module  


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EQ-5D
Dimension Health State EuroQoL Score
ER
Estrogen Receptor
FDA
US Food and Drug Administration 
FDAAA
US Food and Drug Administration Administration Amendments
FFPE
Formalin Fixed Paraffin Embedded
FISH
Fluorescent In Situ hybridization
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
HDPE
High Density Polyethylene
HER
Human Epidermal Growth Factor Receptor
hERG
Human Ether-à-Go-Go
HR
Hazard Ratio
IB
Investigator’s Brochure
IC50
Concentration of 50% Inhibition 
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ID
Identification
IEC
Independent Ethics Committee
IOP
Intraocular Pressure
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
ITT
Intent-to-treat 
LDR
Late discrepancy rate
LFT
Liver Function Test
LHRH
Luteinizing Hormone-Releasing Hormone
LPD
Local Product Document
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival
PK
Pharmacokinetic 
PR
Partial Response or Progesterone Receptor (depending on context)
PR interval (in 
context of ECG)
The PR interval is measured from the beginning of the P wave to 
the beginning of the QRS complex.
PRO
Patient Reported Outcome
PSC
Posterior Subcapsular Cataract


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PT
Prothrombin Time
RR interval (in the 
context of ECG)
The PR interval is measured from the peak of one QRS complex to 
the peak of the next QRS complex.
QD
Quaque Die (once daily)
QOL
Quality of Life
QRS
Name for the combination of three of the graphical deflections seen 
on a typical electrocardiogram
QT
Time between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett's fomula
QTcF
QT interval corrected for heart rate using Fridericia's fomula
RANKL
Receptor Activator of Nuclear Factor Kappa B Ligand
RB/Rb
Retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
RR
The interval between an R wave and the next R wave
Rac
Accumulation Ratio
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease 
SPC
Summary of Product Characteristic
t½
Terminal Elimination Half-life
Tmax
Time for Cmax
TTD
Time to deterioration
ULN
Upper Limit of Normal
USPI
United States Package Insert
Vz/F
Apparent Volume of Distribution
WBC
White Blood Cells


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Appendix 2. Eastern Cooperative Oncology Group (ECOG) Performance Status
Description
Grade
Fully active, able to carry on all pre-disease performance 
without restriction.
0
Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature, ie, 
light house work, office work.
1
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours.
2
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
3
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair.
4


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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.azcert.org/medical-pros/drug-lists/bycategory.cfm#.  This list is not meant to be considered all 
inclusive.  See website for current list. 


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Appendix 4. 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
Upon approval of Amendment 3, RECIST version 1.1 will no longer be mandatory to 
evaluate tumor assessments.


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Final Protocol Amendment 3, 20 October2015
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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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SAP_001.pdf: 
Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
Protocol A5481023 
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PHASE 3 TRIAL OF FULVESTRANT (FASLODEX®) WITH OR WITHOUT 
PD-0332991 (PALBOCICLIB) ± GOSERELIN IN WOMEN WITH HORMONE 
RECEPTOR-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER 
WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE THERAPY  
 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
Version: 
2.1. 
Author:  
 
Date:  
January 10, 2018 
 
 
This document contains confidential information belonging to Pfizer Inc. Except as may be otherwise agreed to 
in writing, by accepting or reviewing these materials, you agree to hold such information in confidence and not 
to disclose it to others (except where required by applicable law), nor to use it for unauthorized purposes. In the 
event of actual or suspected breach of this obligation, Pfizer Inc. should be promptly notified. 
PPD


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Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 2 
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSIONS ....................................................................6 
1.1. Version 2.1 ......................................................................................................................6 
1.2. Version 2.0 ......................................................................................................................6 
2. INTRODUCTION .......................................................................................................................6 
2.1. Study Design ...................................................................................................................6 
2.2. Study Objectives .............................................................................................................8 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................9 
3.1. Progression Free Survival ...............................................................................................9 
3.2. Overall Survival ............................................................................................................10 
3.3. Data Monitoring Committee .........................................................................................11 
3.4. Blinding .........................................................................................................................11 
3.4.1. Early Safety and PK Unblinding ......................................................................11 
4. HYPOTHESES AND DECISION RULES ...............................................................................11 
4.1. Statistical Hypotheses ...................................................................................................11 
 
 
 
 
5. ANALYSIS SETS .....................................................................................................................13 
5.1. Intent-to-Treat Population (Full Analysis Set) ..............................................................13 
5.2. As-Treated (AT) Population (Safety Analysis Set) .......................................................13 
5.3. Other Analysis Sets .......................................................................................................13 
5.3.1. Pharmacokinetic Analysis Sets .........................................................................13 
5.3.2. Biomarker Analysis Set ....................................................................................13 
5.3.3. Patient Reported Outcome (PRO) Evaluable Population (PRO 
Analysis Set) ................................................................................................14 
5.4. Treatment Misallocations ..............................................................................................14 
5.5. Protocol Deviations .......................................................................................................14 
5.5.1. Protocol Deviations Assessed Prior to Randomization ....................................14 
5.5.2. Protocol Deviations Assessed Post Randomization .........................................14 
6. ENDPOINTS AND COVARIATES .........................................................................................14 
6.1. Efficacy Endpoints ........................................................................................................14 
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6.1.1. Primary Endpoint ..............................................................................................14 
6.1.2. Secondary Endpoints ........................................................................................15 
 
 
6.3. Safety Data ....................................................................................................................18 
6.3.1. Treatment Emergent Adverse Event .................................................................18 
6.3.2. Treatment Related Adverse Event ....................................................................19 
6.3.3. Laboratory Safety Assessments ........................................................................19 
6.3.4. Electrocardiogram (ECG) .................................................................................19 
6.3.5. Other Safety Assessment ..................................................................................20 
6.4. Other Data .....................................................................................................................20 
6.4.1. Pharmacokinetic Data .......................................................................................20 
6.4.2. Biomarkers ........................................................................................................21 
6.4.3. Patient Reported Outcome Endpoints ...............................................................22 
6.4.3.1. EORTC QLQ-C30 ...........................................................................22 
6.4.3.2. EORTC QLQ-BR23 ........................................................................22 
6.4.3.3. EQ-5D .............................................................................................22 
6.5. Covariates and Stratification Factors ............................................................................23 
6.5.1. Covariates .........................................................................................................23 
6.5.2. Stratification Factors .........................................................................................23 
7. HANDLING OF MISSING VALUES ......................................................................................23 
7.1. Missing Dates ................................................................................................................23 
7.2. Missing Tumor Assessments .........................................................................................23 
7.3. Missing Data in PFS Derivation ....................................................................................24 
7.4. Missing Values in Patient Reported Outcomes .............................................................24 
7.5. Missing Values in PK Data ...........................................................................................25 
7.5.1. Concentrations below the limit of quantification .............................................25 
7.5.2. Deviations, missing concentrations and anomalous values ..............................25 
7.6. Missing and/or Duplicate Values in Biomarker Data ...................................................25 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................25 
8.1. Statistical Methods ........................................................................................................25 
8.1.1. Analyses for Time-to-Event Data .....................................................................25 
8.1.2. Analyses for Binary Data ..................................................................................26 
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8.1.3. Analyses of Continuous Data ...........................................................................26 
8.1.4. Analyses for Categorical Data ..........................................................................26 
8.1.5. Evaluation of BICR Data ..................................................................................26 
8.2. Statistical Analyses .......................................................................................................29 
8.2.1. Primary Efficacy Analysis ................................................................................29 
8.2.2. Sensitivity Analyses for the Primary PFS Endpoint .........................................29 
8.2.3. Secondary Analyses ..........................................................................................32 
8.2.4. Supportive Efficacy Analyses ...........................................................................35 
8.2.5. Standard Analyses ............................................................................................37 
8.2.6. Safety Analyses ................................................................................................39 
8.2.6.1. Adverse Events ................................................................................39 
8.2.6.2. Laboratory abnormalities ................................................................41 
8.2.7. Patient Reported Outcomes Analyses ...............................................................41 
8.2.8. QTc Analyses ....................................................................................................42 
8.2.9. Analyses for Ocular Assessment Data ..............................................................43 
8.2.9.1. Snellen Best Corrected Visual Acuity and Refraction ....................43 
8.2.9.2. Intraocular Pressure Measurement ..................................................43 
8.2.9.3. Slit-Lamp Biomicroscopy ...............................................................44 
8.2.9.4. Lens Grading ...................................................................................44 
8.2.9.5. Funduscopy (Ophthalmoscopy) ......................................................44 
8.2.10. Pharmacokinetic Analyses ..............................................................................44 
8.2.10.1. Baseline Characteristics Analyses .................................................45 
8.2.10.2. Drug-Drug Interaction Analyses ...................................................45 
8.2.10.3. Exposure/Response Analysis ........................................................46 
8.2.10.4. Adverse Events with PK Analyses ................................................46 
8.2.10.5. Pharmacokinetic Analyses Reporting ...........................................47 
 
8.3. Summary of Key Efficacy Analyses .............................................................................50 
9. REFERENCES ..........................................................................................................................52 
10. APPENDICES .........................................................................................................................54 
10.1. Schedule of Activities .................................................................................................54 
10.2. RECIST (Response Evaluation Criteria in Solid Tumors) version 
1.1 Guidelines .............................................................................................................61 
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10.3. Rules for Determining PFS Status and Date ...............................................................66 
10.4. Data Derivation Details ...............................................................................................67 
10.5. Study Treatment Modification and Compliance .........................................................68 
10.5.1. Dose Modification ..........................................................................................68 
10.5.2. Summarizing Relative Dose (RD) and Relative Dose Intensity 
(RDI) ............................................................................................................68 
10.6. List of Abbreviation ....................................................................................................72 
 


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1. AMENDMENTS FROM PREVIOUS VERSIONS  
1.1. Version 2.1 
This version amends the statistical analysis plan dated December 17, 2014.  
 
Since more patients have been randomized in the study than it was original planned, the 
previously determined final OS analysis based on 198 deaths (only 38% deaths out of 521 
patients) becomes insufficient and inadequate to answer the overall survival question for the 
patient population. Therefore, the time of final OS analysis is shifted to when approximately 
60% deaths are observed in the 521 randomized patients.   
 
1.2. Version 2.0  
This version amends the statistical analysis plan dated August 28, 2013.  Changes have been 
made to incorporate relevant updates from protocol amendment 1 (dated April 4, 2014) and 
protocol amendment 2 (dated September 30, 2014). 
 
Other major changes include the following items: 
• the summary of early safety and PK unblinding plan was added; 
• clarifications on statistical analysis models for drug-drug interaction were provided; 
• the analysis plan for PK data was updated; 
• the analysis plan for PRO data was updated; 
• the plan of sensitivity analysis on PFS was updated; 
• clarifications on subset analyses were provided; 
• the analysis plan for ocular assessment data was added;  
• the summary of key efficacy analyses table was updated. 
2. INTRODUCTION 
This is the Statistical Analysis Plan (SAP), Amendment 1, for study A5481023.  This 
analysis plan is meant to supplement the study protocol.  Any deviations from this analysis 
plan will be described in the Clinical Study Report.  
2.1. Study Design 
This is an international,  multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, Phase 3 clinical trial with the primary objective of demonstrating the 
superiority of palbociclib in combination with fulvestrant (Faslodex®) over fulvestrant alone 


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in prolonging investigator-assessed PFS in women with HR+/HER2-negative metastatic 
breast cancer whose disease has progressed after prior endocrine therapy.  The safety 
between the two treatment arms will also be compared.  
Eligible patients 
with: 
-HR+/HER2- 
recurrent BC 
-failure of prior 
hormonal 
treatment  
- progressed ≤ 
12 months from 
prior adjuvant 
therapy with 
AI*/Tam 
- progressed ≤ 
1 month from 
prior advanced BC 
therapy with 
AI*/anti-endocrine 
 - LHRH agonist 
for pre/peri 
menopausal 
women 
* for post 
menopausal 
women only 
Stratification: 
Documented 
sensitviity to prior 
hormonal therapy 
(yes vs. no) 
Menopausal status 
at study entry 
(pre/peri- vs. post 
menopausal)  
Presence of 
visceral 
metastatses (yes 
vs. no) 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
(2:1) 
Blinded:  
Palbociclib 
+ 
Fulvestrant 
(N=278) 
 
Or 
 
Placebo + 
Fulvestrant 
(N=139) 
 
Treatment until:  
 
Progressive disease per 
RECIST v1.1 
Or Symptomatic 
deterioration 
Or 
Need for new additional 
anticancer therapy not 
specified in the protocol 
Or 
Unacceptable toxicities 
Or 
Investigator’s conclusion 
that discontinuing therapy 
is in the patient’s best 
interest 
Or 
Lost to follow-up 
Or 
Patient choice to withdraw 
from treatment 
Or 
Withdrawal of patient 
consent 
Or 
Death 
All Patients 
should be 
followed 
for:  
 
 
Subsequent 
anti-cancer 
therapy 
(including 
type, 
start/stop 
dates, 
progression 
date, best 
response to 
the 
subsequent 
therapy)  
 
And 
 
Overall 
survival 
 
Eligible patients must have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of recurrent advanced (locally or metastatic) 
disease.  Their breast cancer must have progressed during or within 12 months of completion 
of adjuvant therapy (with an AI, if postmenopausal, or with tamoxifen, if pre- or 
perimenopausal).  Alternatively, it must have progressed while on, or within 1 month after 
the end of prior therapy for advanced/metastatic breast cancer (with an AI, if 
postmenopausal, or other prior endocrine treatment, if pre- or perimenopausal).  One 
previous line of chemotherapy for metastatic disease is allowed.  Patients must have 
measurable disease as per RECIST v.1.1 (Eisenhauer et al. 2009) or bone disease as their only 
site of disease.  Tumor tissue is required for patient participation. 
At least 417 patients will be randomized in a 2:1 ratio and stratified by documented 
sensitivity to prior hormonal therapy (yes vs. no), menopausal status at study entry (pre-/peri- 
vs. post menopausal), and presence of visceral metastases (yes vs. no).  


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Patients in Arm A (at least 278) will receive palbociclib 125 mg/day orally for 3 weeks 
followed by 1 week off plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, 
every 28 days (+/- 7 days) thereafter starting from Day 1 of Cycle 1. 
Patients in Arm B (at least 139) will receive placebo orally daily for 3 weeks followed by 
1 week off plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, every 
28 days (+/- 7 days) thereafter starting from Day 1 of Cycle 1. 
In both arms, pre- and peri-menopausal women will also receive the LHRH agonist goserelin 
(Zoladex® or generic). 
Patients will undergo tumor assessment at Week 8, and then every 8 weeks for the first year, 
and then every 12 weeks, calculated from the date of randomization.  
Patients will continue to receive assigned treatment until objective Progressive Disease (PD), 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  Crossover between treatment arms will not be allowed.  Patients showing 
RECIST-defined PD can continue with study treatment at the discretion of the investigator as 
long as that is considered to be in the best interest of the patient and 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. 
In addition, should palbociclib/placebo related toxicity mandate palbociclib/placebo 
discontinuation, patients can continue to receive fulvestrant alone.  Patients discontinuing the 
active treatment phase (ie, discontinuing both palbociclib/placebo and fulvestrant) will enter 
a follow-up phase during which survival and new anti-cancer therapy information will be 
collected, initially every 3 months and then every 6 months. 
An external data monitoring committee (E-DMC) will perform an early review of safety data 
from approximately the first 40 randomized patients with sufficient pharmacokinetic (PK) 
sampling to confirm safety and tolerability of the combination.  The early safety review by 
the E-DMC will also include Pharmacokinetic (PK) data from these initial approximately 
40 patients to explore potential Drug-Drug-Interactions (DDIs) between fulvestrant, goserelin 
(if applicable) and palbociclib.  The study will continue while these analyses and review are 
ongoing. 
In addition, blood samples will be collected from all patients to assess trough concentrations 
of palbociclib for exposure/response analysis for safety and efficacy findings. 
Patient Reported Outcomes (PRO) will be collected to evaluate global quality of life and 
general health status.  
The study will also include a molecular profiling component aimed at assessing the 
relationship between breast tumor sensitivity and resistance to palbociclib and the alteration 
of cell cycle pathway-related genes and proteins in tumor tissues. 
2.2. Study Objectives 
Primary Objective:  


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To demonstrate the superiority of palbociclib in combination with fulvestrant (with or 
without goserelin) over fulvestrant (with or without goserelin) alone in prolonging 
investigator-assessed PFS in women with HR+/HER2- metastatic breast cancer whose 
disease has progressed on prior endocrine therapy.  
Secondary Objectives: 
• To compare measures of tumor control (including PFS, DR, CBR) between the 
treatment arms; 
• To compare safety and tolerability between the treatment arms;  
• To evaluate trough concentrations of palbociclib when given in combination with 
fulvestrant or fulvestrant plus goserelin and compare them to historical data; 
• To compare fulvestrant and goserelin trough concentrations when given in 
combination with palbociclib to those when given without palbociclib; 
• To explore correlations between palbociclib exposures and efficacy/safety findings in 
this patient population; 
• To compare Patient Reported Outcomes measures between treatment arms;  
• To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle, 
drug targets, tumor sensitivity and/or resistance; 
• To conduct subgroup analysis for primary and secondary endpoints in stratified 
groups. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
3.1. Progression Free Survival 
The study is designed to have one interim analysis and the final analysis at 238 events based 
on the primary PFS endpoint with the investigator assessment.  The interim analysis will be 
conducted to allow for early stopping of the study due to efficacy or to potentially re-estimate 
the sample size of the trial based upon the primary endpoint of PFS.  The safety of the 
combination will also be assessed at the interim analysis.  The analysis will be performed 
after approximately 143 investigator-assessed PFS events (documented progressive disease 
or death; approximately 60% of the total events expected).  The information fraction for the 
interim analysis may be adjusted if needed.  
• The Haybittle-Peto efficacy boundary (Haybittle 1971; Peto et al. 1976) is to be used at 
the IA.  If the value of the test-statistic from the log-rank test for PFS exceeds the 
efficacy boundary (z ≥ 3, p ≤ 0.00135) the trial may be stopped for efficacy.  It is 
assumed that a hazard ratio less than 1.0 is in favor of the palbociclib plus fulvestrant 
arm. 


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• As appropriate, the sample size of the study may be adjusted using the method outlined 
by Cui et al. (1999) and applied to the PFS endpoint.  Using the Cui method guarantees 
that the overall type I error will still be preserved after a sample size increase.  The 
technical details of sample size re-estimation approach will be pre-specified in a separate 
technical document that is to be shared only with the E-DMC before the interim analysis. 
• If the results of the interim analysis indicate serious safety concerns, the sponsor will 
communicate with the Health Authorities regarding stopping the clinical trial. 
• The final analysis of PFS will be performed after approximately 238 PFS events have 
been observed if the trial continues and the sample size is not adjusted after the IA . 
Efficacy Stopping Boundary of PFS for Rejecting Null Hypothesis Expressed as Z Scales 
and p-values 
Analysis 
Number of Event (%) 
Z Scale 
p-value (1-sided) 
Interim 
143 (60%) 
3 
0.00135 
Final 
238(100%) 
1.9644 
0.02474 
 
3.2. Overall Survival 
Interim analyses of efficacy are also planned for the secondary OS endpoint and OS will be 
tested in a hierarchically approach.  The analysis will be performed at the time of the interim 
or final PFS analyses if the primary analysis for PFS is positive.  The nominal significance 
levels for the interim and final analyses of OS will be determined by the Lan-DeMet 
spending function based upon the O’Brien-Fleming boundary.  The overall significance level 
for the efficacy analysis of OS will be preserved at 0.025 (one-sided test). 
• Only one interim analysis of OS is planned.  Although the first possible time for OS 
interim analysis could be at the time of the PFS IA, it is anticipated that the number of 
deaths could be low at PFS IA and yield non-robust analysis results.  Therefore, the 
OS interim analysis will be planned at approximately 97 deaths (at the estimated time 
for planned PFS final analysis).  If OS is not significant at the interim analysis, a final 
analysis will be performed after 198 deaths have been observed. 
• If PFS is not significant at its final analysis, the formal conclusion on OS statistical 
significance will not be drawn. 
Efficacy Stopping Boundary of OS for Rejecting Null Hypothesis Expressed as Z  
Scales and p-values 
Analysis 
Number of Event (%) 
Z Scale 
p-value (1-sided) 
Interim 
97 (49%) 
3.0141 
0.0013 
Final 
198 (100%) 
1.9673 
0.0246 
 


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3.3. Data Monitoring Committee 
The study will use an External Data Monitoring Committee (E-DMC).  The E-DMC 
membership and governance are outlined in a separate charter.The E-DMC will be 
responsible for ongoing monitoring of the efficacy and safety data from patients in the study 
according to the Charter.  The E-DMC will make recommendation as to whether or not the 
trial should continue based on ongoing reviews of safety data.  In addition, the E-DMC will 
also evaluate interim efficacy data and make a recommendation regarding study continuation 
based on observed results of the study.  The Sponsor will designate a biostatistician not 
affiliated with the project to prepare data for E-DMC review.  Only if action or consultation 
with Health Authorities is required will other sponsor staff be involved in the data 
preparation.  Clinical sites will be restricted from access to study results until the conclusion 
of the study.  More details can be found in the E-DMC charter. 
3.4. Blinding  
At the initiation of the trial, the trial sites will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process.  Blinding codes should only 
be broken in emergency situations to preserve the 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, only if deemed essential to allow the 
investigator to select the patient's next treatment regimen and after discussion and agreement 
with the sponsor.  Codes 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. 
3.4.1. Early Safety and PK Unblinding 
There will be an early review of safety and PK data from approximately the first 
40 randomized patients with sufficient pharmacokinetic (PK) sampling.  A separate PK 
Unblinding Plan explains how the study will remain blinded while PK data are explored for 
potential Drug-Drug-Interactions (DDIs) between palbociclib + fulvestrant ± goserelin versus 
placebo + fulvestrant ± goserelin compared to historical palbociclib data and whether dosing 
adjustments are necessary.  The study will continue while these analyses and review are 
ongoing. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
The primary objective of this study is to demonstrate that the combination of palbociclib and 
fulvestrant is superior to the combination of placebo and fulvestrant in prolonging 


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Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 12 
investigator-assessed PFS in women with HR+/HER2-negative metastatic breast cancer that 
has progressed on prior endocrine therapy, and regardless of their menopausal status.  
The study is designed to test the null hypothesis that the true PFS distributions for both 
palbociclib plus fulvestrant and placebo plus fulvestrant arms are the same with a median 
PFS 6.0 months versus the alternative hypothesis that the true PFS distribution has a median 
that is longer than 6.0 months for the palbociclib plus fuvestrant arm. 
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5. ANALYSIS SETS 
5.1. Intent-to-Treat Population (Full Analysis Set) 
The intent-to-treat (ITT) population or full analysis set will include all patients who are 
randomized, with study drug assignment designated according to initial randomization, 
regardless of whether patients receive study drug or receive a different drug from that to 
which they were randomized.  The ITT population will be the primary population for 
evaluating all efficacy endpoints and patient characteristics. 
5.2. As-Treated (AT) Population (Safety Analysis Set) 
The as-treated (AT) population or safety analysis set will include all patients who receive at 
least 1 dose of study medication, 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 and clinical benefit endpoints may 
be assessed in this population as well. 
5.3. Other Analysis Sets 
5.3.1. Pharmacokinetic Analysis Sets 
There will be at least two PK analysis sets: 
1. Early Safety Review Set: The 40 patients participating in the early safety review, who are 
treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ± goserelin and 
have at least one measured plasma drug concentration. 
2. Palbociclib PK Analysis Set: All patients (including those in the Early Safety Review 
Set) who have PK blood samples collected for palbociclib and have at least one measured 
plasma drug concentration. 
PK/Adverse Event Analysis Set (if applicable): patients experiencing unexpected or serious 
adverse events, or adverse events that lead to discontinuation who have PK blood samples 
collected for palbociclib or fulvestrant (or goserelin if applicable) and have at least one 
measured plasma drug concentration. 
5.3.2. Biomarker Analysis Set 
A subset of AT patients, who have both baseline and at least one follow-up values for at least 
one biomarkers. 
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5.3.3. Patient Reported Outcome (PRO) Evaluable Population (PRO Analysis Set) 
The PRO –evaluable population is defined as a subset of ITT patients, who have completed a 
baseline and at least one post –baseline PRO assessment prior to end of study treatment. 
5.4. Treatment Misallocations  
• If patients were randomized but not treated, then they will be reported under their 
randomized treatment group for efficacy analyses.  However, they are by definition 
excluded from the safety analyses. 
• If patients were randomized but took incorrect treatment, then they will be reported 
under their randomized treatment group for efficacy analyses, but will be reported 
under the treatment they actually received at the time of onset of toxicity for all safety 
analyses.  
5.5. Protocol Deviations 
All deviations will be described when they appear and relate to the statistical analyses or 
populations. 
5.5.1. Protocol Deviations Assessed Prior to Randomization 
Deviations prior to randomization are not allowed (ie, no waivers are allowed).  There is no 
distinction between acceptable and unacceptable, minor or major deviations.  Selected 
eligibility violations may be described in a listing,but no patient will be excluded from the 
primary analyses based on eligibility  
5.5.2. Protocol Deviations Assessed Post Randomization  
Treatment not started.  Patients who do not start treatment will not be included in the safety 
analysis.  However, those patients will still be included in the primary efficacy analyses.  
Randomized treatment on the wrong arm.  In such cases efficacy is analyzed according to the 
assigned treatment arm, not the arm received (intent-to-treat principle).  For safety, results 
are analyzed as treated at the time of the onset of the toxicity.  
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoints 
6.1.1. Primary Endpoint  
Progression Free Survival (PFS) 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.  If tumor progression 
data include more than 1 date, the first date will be used.  Documentation of progression must 
be objective disease assessment.  Objective disease assessments are based on Response 
Evaluation Criteria in Solid Tumor (RECIST) v1.1 guidelines. 
The length of PFS will be calculated as 
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Censorship:  Patients last known to be 1) alive 2) not to have started new (non-protocol) 
anti-cancer treatment and 3) progression-free,  and who have a baseline and at least one 
disease assessment after dosing, are censored at the date of the last objective disease 
assessment that verified lack of disease progression.  Patients with inadequate baseline 
disease assessment are censored at the date of randomization. 
• Patients with no disease assessments after dosing are censored at the date of 
randomization unless death occurred prior to the first planned assessment (in which 
case the death is an event).  
• Patients starting new anti-cancer treatment prior to progression are censored at the 
date of last objective disease assessment documenting no progression prior to the new 
treatment. 
• If patients are removed from the study (withdrew the consent, lost to follow up, etc.) 
prior to progression and death, then censorship is at the date of the last objective 
disease assessment that verified lack of disease progression. 
• Patients with documentation of progression or death after an unacceptably long 
interval (ie, 2 or more incomplete or indeterminate assessments) since the last tumor 
assessment will be censored at the time of last objective assessment documenting no 
progression. 
Other scenarios for defining event/censoring may be investigated in supportive analyses (eg, 
if a substantial number of patients has questionable failure or censorship dates). 
6.1.2. Secondary Endpoints  
• 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.  For patients lacking survival data beyond the 
date of their last follow-up, the OS time will be censored on the last date they were 
known to be alive.  Patients lacking survival data beyond randomization will have their 
OS times be censored at randomization.  The length of OS will be calculated as 
OS time (months) = [death date (censor date) – randomization date + 1]/30.4. 
• One-, Two- or Three-year Survival Probability is defined as the probability of survival 
1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate. 
• Objective Response (OR) is defined as the overall complete response (CR) or partial 
response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 
version 1.1) Objective Response Rate (ORR) is defined as the proportion of patients 
with CR or PR relative to (1) all randomized patients and (2) randomized patients with 
measurable disease at baseline.  Designation of best response of stable disease (SD) 
requires the criteria to be met at least 8 weeks after randomization.  Patients who do not 
have on-study radiographic tumor re-evaluation, who receive anti-tumor treatment other 
than the study medication prior to reaching a CR or PR, or who die, progress, or drop out 


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for any reason prior to reaching a CR or PR will be counted as non-responders in the 
assessment of ORR. 
• Clinical Benefit Response (CBR) is defined as the overall complete response (CR), 
partial response (PR) , or stable disease (SD) ≥24 weeks according to the Response 
Evaluation Criteria in Solid Tumors (RECIST version 1.1).  Clinical Benefit Response 
Rate is defined as the proportion of patients with CR, PR, or SD ≥24 weeks relative to 
(1) all randomized patients and (2) randomized patients with measurable disease at 
baseline.  Designation of best response of SD ≥24 weeks requires the criteria to be met at 
least 24 weeks after randomization.  Patients who do not have on-study radiographic 
tumor re-evaluation, who receive anti-tumor treatment other than the study medication 
prior to reaching a CR or PR, a best response of SD ≥24 weeks, or who die, progress, or 
drop out for any reason prior to reaching a CR or PR and a best response of SD 
≥24 weeks will be counted as non-responders in the assessment of CBR. 
• 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 disease progression or 
to death due to any cause, whichever occurs first.  If tumor progression data include more 
than 1 date, the first date will be used.  DR will be calculated as [the date response ended 
(ie, date of PD or death) –  first CR or PR date + 1)]/30.4.  DR will only be calculated for 
the subgroup of patients with an objective tumor response. 
Responders last known to be 1) alive 2) not to have started new (non-protocol) anti-cancer 
treatment and 3) progression-free are censored at the date of the last objective disease 
assessment that verified lack of disease progression. 
• Patients starting new anti-cancer treatment prior to progression are censored at the 
date of last objective disease assessment documenting no progression prior to the new 
treatment. 
• If patients are removed from the study (withdrew the consent, lost to follow up, etc.) 
prior to progression and death, then censorship is at the date of the last objective 
disease assessment that verified lack of disease progression. 
• Patients with documentation of progression or death after an unacceptably long 
interval (ie, 2 or more incomplete or indeterminate assessments) since the last tumor 
assessment will be censored at the time of last objective assessment documenting no 
progression. 
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6.3. Safety Data 
Overall safety profile as characterized by type, frequency, severity of adverse events as 
graded by NCI Common Toxicity Criteria for Adverse Events version 4 (NCI CTCAE v.4.0), 
timing and relationship to treatment on each arm, and laboratory abnormalities observed. 
Serious and Non-serious Adverse events (AEs), hematology, blood chemistry, ECG and vital 
signs will be assessed as described in the Schedule of Activities of the protocol. 
Adverse events will be classified using the MedDRA classification system.  The severity of 
the toxicities will be graded according to the NCI CTCAE version 4.  For labs without 
CTCAE grade definitions, results are summarized as normal or abnormal (per Pfizer Data 
Standards (PDS)) or not done.  For other AEs without specific CTCAE definitions, results 
are identified according to CTCAE “other” categories.  The “Schedule of Activities” in the 
protocol lists all safety parameters to be collected. 
Adverse events leading to discontinuation of trial treatment, events classified using NCI 
CTCAE v.4.0 as Grade 3 or higher, trial drug related events, and serious adverse events will 
be considered with special attention. 
Laboratory results will be graded according to the NCI CTCAE v.4.0 severity grade.  For 
parameters for which an NCI CTCAE v.4.0 scale does not exist, the frequency of patients 
with values below, within, and above the normal range for the local lab will be summarized.  
Each patient will be summarized by the worst severity grade observed for a particular 
laboratory parameter.  This will be provided for all cycles as well as by cycles.  Patients who 
start treatment are assessed for toxicities up to 28 days after the final dose of treatment or 
start of new treatment (whichever comes first).  Toxicities observed beyond 28 days and 
recorded in the database per Sponsor's agreement will be included in the summaries. 
A 3-tier approach will be used to summarize AEs.  Under this approach, AEs are classified 
into 1 of 3 tiers.  Different analyses will be performed for different tiers (See Section 8.2.6).  
6.3.1. Treatment Emergent Adverse Event 
An adverse event is considered treatment emergent if: 
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• The event occurs for the first time after the start of study treatment and up to 28 days 
after final dose of study treatment and was not seen prior to the start of treatment or 
• The event was seen prior to the start of treatment but increased in NCI CTCAE v.4.0  
grade during study treatment. 
• Disease progression is not considered a treatment emergent adverse event unless the 
patient dies of disease prior to 28 days after discontinuation of treatment. 
6.3.2. Treatment Related Adverse Event 
Adverse events defined as treatment emergent adverse events with cause possibly, probably 
or definitely related to treatment as judged by the investigator are defined as treatment related 
adverse events.  Events that are continuation of baseline abnormalities are not considered 
treatment related unless there is an increase in grade, or if there is an increase following a 
decrease, and the increase is judged by the investigator to be caused by the treatment. 
6.3.3. Laboratory Safety Assessments 
Laboratory assessment will be assigned to cycles based on the collection date of the sample 
relative to the start dates of cycles from the study drug administration as described in the 
Schedule of Activities table in Appendix 10.1. 
Baseline evaluations for laboratory are those collected 
• Within 28 days prior to or on first day of study drug and 
• If there is more than one baseline evaluation, closest to but any time prior to the 1st 
dosing on the first day of study treatment. 
6.3.4. Electrocardiogram (ECG) 
All Electrocardiograms (ECGs) will be performed using a 12-lead (with a 10-second rhythm 
strip) tracing.  ECG measurements will include PR interval, QT interval, RR interval, and 
QRS complex.  It is preferable that the machine used has a capacity to calculate the standard 
intervals automatically.  
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents.  
Additional ECGs may be performed as clinically indicated at any time. 
For the purpose of the study, triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart at the protocol specified timepoints (see Schedule 
of Activities table) to determine the mean QTc interval.  
Refer to the Dose Modification Section for details on dose management in case of abnormal 
ECGs considered related to investigational product.  


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6.3.5. Other Safety Assessment 
A full physical examination including an examination of all major body systems and breasts, 
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 every cycle and at End of Treatment. 
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits. 
Performance Status: The ECOG performance status scale will be used. 
6.4. Other Data  
6.4.1. Pharmacokinetic Data  
For the first approximately 40 patients participating in the early safety review, PK samples 
will be drawn at pre-dose on Day 1 and Day 15 of Cycle 1 and Cycle 2, and Day 1 of Cycle 
3 for DDI assessments.  Two (combinations without goserelin) or three (combinations with 
goserelin)  
3-mL samples of venous blood will be collected in appropriately labeled collection tubes for 
assessment of palbociclib, fulvestrant, and/or goserelin levels at the protocol-specified times.  
In all other palbociclib patients (not participating in the early safety review), plasma 
concentrations will be drawn on Day 15 of Cycle 1 and Cycle 2 for palbociclib 
determination.  For these patients, one 3 mL sample of venous blood will be collected in 
appropriately labeled collection tubes for assessment of palbociclib.  
All palbociclib concentrations will be used for exposure/response analysis for safety and 
efficacy findings.  
The endpoint for these analyses is palbociclib steady state trough plasma concentration 
(Ctrough) which will be compared as follows: palbociclib and fulvestrant with/without 
goserelin versus placebo and fulvestrant with/without goserelin compared to historical 
palbociclib data from studies A5481001, A5481002, and A548003.  The historical 
palbociclib data will be A5481001 (epharm artifact ID 8146749), A5481002 (epharm artifact 
ID 8145916) and A5481003 (epharm artifact ID 8149001).  A5481001 was conducted in all 
comer patients and resulted in lower exposures for palbociclib, A5481002 was a pilot 
open-labeled clinical study in 17 patients with previously treated mantle cell lymphoma and 
A5481003 was conducted in breast cancer patients and resulted in higher exposures for 
palbociclib.  These studies provide the “normal” palbociclib exposure ranges. 
Palbociclib steady state trough plasma concentration (Ctrough) is defined as pre-dose plasma 
concentration following at least 8 consecutive days of 125 mg daily dose without dosing 
interruption.  The time window for the PK collection should be between 22 and 26 hrs after 
the dose (the day prior to PK collection) and no more than 1 hr postdose on the day of 
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Covariates for this PK per PMAR-EQDD-A548b-DP4-269 are: age and baseline body 
weight. 
Additional PK blood samples for palbociclib and fulvestrant (and goserelin if applicable) 
may be collected from patients experiencing unexpected or serious adverse events, or adverse 
events that lead to discontinuation. 
Samples will be analyzed using validated analytical methods in compliance with Pfizer 
standard operating procedures.  
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 products on that day will be 
considered protocol compliant.  
6.4.2. Biomarkers 
Tumor tissues are required from all patients for study participation.  
HR (ER and PR) and HER2 status for eligibility will be based on local results utilizing an 
assay consistent with local standards for entry into the trial and for reporting of the efficacy 
endpoints.  Central assessment of ER, PR, and HER2 on suitable samples will be performed 
retrospectively at a qualified central laboratory. 
A biomarker will be nominated as the primary marker for analysis using data external to the 
current study.  The interaction between this primary marker (eg, pRb or other from a set of 
biomarkers to be analyzed) and benefit from palbociclib in terms of prolongation of PFS will 
be examined.  In addition, other tumor tissue biomarkers, including DNA, RNA and protein 
analytes, will be analyzed to investigate possible associations with resistance/sensitivity to 
treatment with palbociclib.  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 are not limited to, CCND1 and CDKN2A gene copy number, 
cdk4 and cdk6 RNA expression, and Ki67, pRb, cyclin E and p16 protein expression.  The 
relationship between centrally reported ER/PR and HER2 status and resistance/sensitivity to 
treatment with palbociclib will also be assessed.  
Plasma samples will be collected for analyses of circulating free DNA or RNA, and the 
relationship with resistance/sensitivity to treatment with Palbociclib/placebo. 
If archived FFPE tissue from a recurrent tumor or distant metastasis is unavailable, a de novo 
biopsy is required for patient participation, except those with bone metastasis only, when, in 
the investigator’s judgment, such biopsy is feasible and can be safely performed.  Original 
diagnostic tumor tissue will be used for biomarker analyses in the event that patients have 
bone disease only.  Patients, who relapsed while receiving adjuvant therapy and had surgery 
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within the last 3 years, may provide tissue from that surgery.  Provision of de novo metastatic 
tissue in these cases is strongly encouraged but not mandated.  
Detailed information about biomarker sample collection, preparation, storage, labeling, and 
shipment is indicated in the Study Reference Manual. 
6.4.3. Patient Reported Outcome Endpoints  
Patient reported outcomes of functioning, global quality of life and general health status will 
be assessed using the he EORTC QLQ-C30, EORTC QLQ-BR23 and EQ-5D.  
Patients will complete each instrument at pre-dose on Day 1 of Cycles 1-4, then on Day 1 of 
every other subsequent Cycle starting with Cycle 6 (eg, Cycles 6, 8, 10, 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 instruments will be given to the patient in the 
appropriate language for the site.  
6.4.3.1. EORTC QLQ-C30 
The EORTC-QLQ-C30 (see Protocol Appendix 6) is a 30-item questionnaire composed of 
five multi-item functional subscales (physical, role, emotional, cognitive , and social 
functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global 
quality of life (QOL) subscale, and six single item symptom scales assessing other 
cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, , 
and the financial impact of cancer).  The questionnaire employs 28 4-point Likert scales with 
responses from “not at all” to “very much” and two 7-point Likert scales for global health 
and overall QOL.  Responses to all items are then converted to a 0 to 100 scale.  For 
functional and global QOL scales, higher scores represent a better level of functioning/QOL.  
For symptom-oriented scales, a higher score represents more severe symptoms.  A 10-point 
or higher change in scores from baseline is considered clinically significant. 
6.4.3.2. EORTC QLQ-BR23  
The EORTC-QLQ-BR23 (see Protocol Appendix 7) is a 23-item breast cancer-specific 
companion module to the EORTC-QLQ-C30 and consists of four functional scales (body 
image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales ( 
systemic side effects, breast symptoms, arm symptoms, upset by hair loss). 
6.4.3.3. EQ-5D 
The EuroQol-5D (EQ-5D) (version 3L) (see Protocol Appendix 5) is a brief 
self-administered, validated instrument consisting of 2 parts.  The first part consists of 
5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and 
anxiety/depression); a patient is asked to rate each state on a three level scale (1=no problem, 


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2=some problem, and 3=extreme problem) with higher levels indicating greater 
severity/impairment Published weights are available that allow for the creation of a single 
summary score called the EQ-5D index, which basically ranges from 0 to 1 with low scores 
representing a higher level of dysfunction and 1 as perfect health.  The second part consists 
of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS).  The 
EQ-5D VAS measures the patient’s self-rated health status on a scale from 0 (worst 
imaginable health state) to 100 (best imaginable health state). 
6.5. Covariates and Stratification Factors 
6.5.1. Covariates  
The potential influences of baseline patient characteristics such as age, ethnic origin, ECOG 
performance status, geographical region, selected biomarkers, and stratification factors on the 
primary PFS, OS, and OR endpoints may be evaluated. 
6.5.2. Stratification Factors  
Randomization will be stratified by documented sensitivity to prior hormonal therapy (yes 
vs. no), by menopausal status at study entry (pre-/peri- vs. post menopausal), and by the 
presence of visceral metastases (yes vs. no).  Sensitivity to prior hormonal therapy is defined 
as either: 1) documented clinical benefit (complete response [CR], partial response [PR], 
stable disease [SD] ≥24 weeks) to at least 1 prior hormonal therapy in the metastatic setting, 
OR 2) at least 24 months of adjuvant hormonal therapy prior to recurrence. “Visceral” refers 
to lung, liver, brain, pleural, and peritoneal involvement. 
7. HANDLING OF MISSING VALUES 
7.1. Missing Dates 
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (eg, date of onset cannot be prior to day one 
date).  In this case, the date resulting in 1 day duration will be used.  If the day of the month 
and the month are missing for any date used in a calculation, eg, January 1 will be used to 
replace the missing date. 
Missing dates for adverse events will be imputed based on the similar principle. 
If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date, and provided the event is not a serious 
adverse event. 
7.2. Missing Tumor Assessments 
If baseline tumor assessment is inadequate the patient cannot be assessed for response. 
Inadequate baseline assessment may include  


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• Not all required baseline assessments were done 
• Assessments were done outside the required window  
• Measurements were not provided for one or more target lesions 
• One or more lesions designated as target were not measurable. 
If measurements for one or more target lesions are missing for an evaluation and disease does 
not qualify as progression (or symptomatic deterioration if applicable), the objective status 
for that evaluation is Indeterminate. 
If non-target disease was not assessed, then objective status cannot be a CR even if all target 
disease has disappeared.  Otherwise, missing non-target disease assessments do not 
necessarily affect response determination.  Such cases will be reviewed carefully. 
If a lesion measurement is missing because it is documented as too small to measure, the 
value 5 mm will be assigned and objective status calculated accordingly.  
In the assessment of OR, patients who do not have on study radiographic tumor 
re-evaluations will be counted as non-responders. 
7.3. Missing Data in PFS Derivation 
PFS cannot be assessed in patients with inadequate baseline tumor assessment.  PFS cannot 
be assessed in patients who have no on-study assessments unless death occurs prior to the 
first planned assessment time.  
If a substantial number of patients have questionable failure or censorship dates for either 
PFS definition (such as progression or death not documented until after multiple missing 
assessments) scenarios such as best case (failure at time of documentation) and worst case 
(progression at earliest possible planned assessment date) will be investigated.  
For PFS analysis, no values will be imputed for missing data.  For time to event endpoints, 
non-event observations will be censored as defined in Section 6.1.1.  
7.4. Missing Values in Patient Reported Outcomes 
For the QLQ-C30, QLQ-BR23 and EQ-5D, in cases where two answers are given to one 
item, the more severe answer will be counted.  For QLQ-C30 and QLQ-BR23, if at least half 
of the constituent items for the multi-item functional or symptom scale have been answered, 
then the score for that scale may be pro-rated based on the non-missing items.  For the 
EQ-5D, the index score is considered missing if the answer to any of the 5 items is missing.  .  
For subsequent analysis purposes, missing items will be considered missing; they will not be 
imputed. 


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7.5. Missing Values in PK Data 
7.5.1.  Concentrations below the limit of quantification 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  In listings, BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification. 
7.5.2. Deviations, missing concentrations and anomalous values 
In summary tables, statistics will be calculated having set concentrations to missing if 1 of 
the following cases is true: 
1. A concentration has been noted as ND (ie, not done) or NS (ie, no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
3. A predose concentration has no actual collection time relative to the dosing due to 
missing dosing time or missing sampling time. 
7.6. Missing and/or Duplicate Values in Biomarker Data 
Missing biomarker data will not be imputed.  Duplicate biomarker data is not expected.  If 
any is received, the study team will determine which record will be used or if an average of 
the duplicate records will be used, depending upon the type of data.  A flag will be included 
in the biomarker data indicating the value used for biomarker analyses. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1. Analyses for Time-to-Event Data 
Time-to-event endpoints between the 2 treatment arms will be compared with a 1-sided 
stratified log-rank test adjusting for presence of visceral metastases and sensitivity to prior 
hormonal therapy (two of the baseline stratification factors as listed in Section 6.5.2) and/or a 
1-sided unstratified log-rank test at the α=0.025 overall significance level.  Hazard ratios and 
2-sided 95% confidence intervals (subject to the multiplicity adjustment at the final analysis 
for PFS and OS) will be estimated using Cox proportional hazards regression. 
Cox proportional hazard models will also be used to explore the potential influences of the 
baseline stratification factors (as listed in Section 6.5.2) on time-to-event endpoints.  In 
addition, potential influences of baseline patient characteristics such as age, race, ethnic 
origin, ECOG performance status, geographical region, and selected biomarkers on the 
endpoints may be evaluated.  A backward selection process (with treatment in the model) 
will be applied to these variables to identify the final set of relevant factors.  
Treatment-by-factor interactions will be explored only for the set of factors included in the 


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final model.  The estimated hazard ratio and 2-sided 95% confidence interval will be 
provided.  Additionally for each treatment arm, the median event time and a 2-sided 95% 
confidence interval will be provided for each level of stratification factors or baseline 
characteristics.  
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence interval for 
each median will be provided.  
The X-year survival probability will be estimated using the Kaplan-Meier method and a 
2-sided 95% confidence interval for the log [-log(X-year survival probability)] will be 
calculated using a normal approximation and then back transformed to give a confidence 
interval for the X-year survival probability itself. 
Since patients in both treatment arms may receive other available treatments after disease 
progression, the treatment effect on overall survival may not be able to estimate properly by 
above defined methods because of these confounding factors.  Therefore, the proper testing 
statistics such as Wilcoxon test and methods like Rank-Preserving Structural Failure Time 
Model (RPSFTM) proposed by Robins and Tsiatis (1991) will be applied to the overall 
survival analysis. 
8.1.2. Analyses for Binary Data 
The odds ratio estimator (with the corresponding 2-sided 95%) and the 1-sided stratified 
exact test will be used to compare the rates of binary endpoints for the two treatments.  In 
addition, point estimates of the rates for each treatment arm will be provided along with the 
corresponding exact 2-sided 95% confidence intervals using the exact method based on 
Clopper-Pearson method.  
8.1.3. Analyses of Continuous Data 
Descriptive statistics, including the mean, standard deviation, median, minimum, and 
maximum values, will be provided for continuous endpoints.  
8.1.4. Analyses for Categorical Data  
The number and percentage of patients in each category will be provided for categorical 
variables. 
8.1.5. Evaluation of BICR Data 
NCI Method: 
The auxiliary estimator of the log-hazard ratio that combines the information from 
patient-level data by investigator assessment on all the cases and the retrospective random 
sample BICR audit cases will be calculated.  
More specifically, here are some notations: 


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CA
θˆ
 = an estimator of the log-hazard ratio (based on the proportional hazards model) using 
BCIR data of the audited subset; 
LA
θˆ
 = an estimator of the log-hazard ratio (based on the proportional hazards model) using 
investigator assessment data of audited subset; 
__
ˆ
LA
θ
 = an estimator of the log-hazard ratio (based on the proportional hazards model) using 
investigator assessment data of non-audited subset; 
CA
Vˆ
 = an estimator of the variance of log-hazard ratio using BICR data of the audited subset; 
L
Vˆ  = an estimator of the variance of log-hazard ratio using investigator assessment data of 
the total population; 
δ  = proportion of study participants audited assuming the number of events in the audit is 
proportional to the sampled audit size; 
ρˆ  = a bootstrap estimator of the correlation between 
LA
θˆ
 and 
CA
θˆ
 . 
ρˆ  will be estimated using a bootstrap approach.  Within the randomly selected sample (of 
size m) for BICR audit,  a bootstrap sample of m patients will be sampled with replacement.  
The two sample-based log-hazard ratio estimates (investigator-based vs. BICR –based) will 
be estimated for the bootstrap sample.  The procedure will be repeated 1000 times to obtain 
1000 bootstrap samples.  Consequently, 1000 pairs of sample estimates of log(HR) 
(investigator-based vs. BICR-based) will be calculated.  The sample correlation coefficient 
between the investigator-based log(HR) estimates and BICR-based log(HR) estimates will be 
used for ρˆ  in calculating the auxiliary estimator and the corresponding one-sided 95% CI.  
The auxiliary estimator, 
C
θ~ , will be calculated as 
)
ˆ
ˆ
(
ˆ
ˆ
)
1(
ˆ
ˆ
~
__
LA
LA
L
CA
CA
C
V
V
θ
θ
δ
δ
ρ
θ
θ
−
−
+
=
 
The estimate of variance of 
C
θ~  will be calculated as  
)}
1(
ˆ
1
{
ˆ
~
2
δ
ρ
−
−
=
CA
C
V
V
. 
Assuming asymptotic normality of 
C
θ~  , the upper bound of one-sided 95% CI of this 
estimator will consequently be calculated as 
C
C
V
Z
~
~
05
.0
1−
+
θ
, where 
05
.0
1−
Z
 is the 95% 
quantile of a standard normal distribution.  


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The NCI method may be used to evaluate the BICR data only if the BICR approach is 
conducted for the randomly selected sample.  In the circumstances where the BICR approach 
is conducted for the total population upon the request of the health authorities or the study 
sponsor, NCI method will not be implemented to evaluate the BICR data.  
PhRMA Method 
Differential discordance will be evaluated using two measures, the early discrepancy rate 
(EDR) and late discrepancy rate (LDR).  The agreement between the investigator and the 
blinded independent central review within a treatment arm is represented in a tabular form 
below 
 
Blinded Independent Core Imaging Laboratory 
Investigator 
PD 
No PD 
PD 
a=a1+a2+a3 
b 
No PD 
c 
d 
a1: number of agreements on timing and occurrence of PD. 
a2: number of times investigator declares PD later than BICR 
a3: number of times investigator declares PD earlier than BICR
 
The early discrepancy rate (EDR) is defined as: 
EDR = (b + a3) / (a + b) 
The EDR represents the positive predictive value of investigator assessment and quantifies 
the frequency with which the investigator declares progression early relative to blinded 
independent central review within each arm as a proportion of the total number of 
investigator assessed PD’s. 
The late discrepancy rate (LDR) is defined as: 
LDR = (c + a2) / (b + c + a2 + a3) 
The LDR quantifies the frequency that investigator declares progression later than blinded 
independent central review as a proportion of the total number of discrepancies within the 
arm.  If the distribution of discrepancies is similar between the arms then this suggests the 
absence of evaluation bias favoring a particular arm. 
The EDR and LDR will be calculated for each treatment arm and the differential discordance 
around each measure will be summarized as the rate on the experimental arm minus the rate 
on the control arm.  A negative differential discordance for the EDR and/or positive 
differential discordance for the LDR are suggestive of a bias in the investigator favoring the 
experimental arm. 


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8.2. Statistical Analyses  
All efficacy analyses will be based on intent-to-treat (ITT) population.  Some efficacy 
sensitivity analyses will also be performed on AT populations.  All analyses will be 
performed by using SAS® Version 9.2 or higher.  
The primary and secondary analyses of endpoints dependent on disease assessments (PFS, 
OR, DR, and CBR) will be based on investigator assessments of disease response and 
progression.  
The BICR review as described in section 6.2. will be implemented as an auditing tool with 
the objective being to corroborate the analysis results of the primary endpoint (ie, 
investigator-assessed PFS) and to assist in the evaluation of potential bias.  The analyses 
based on the BICR data are considered as supportive.  The BICR audit approach is not 
intended to provide an alternative means of definitive analysis.  
All primary, secondary, and supportive analyses will be tested at a significance level of 
0.025 (1-sided test).  No adjustments are planned for multiple testing/comparisons in the 
secondary and supportive hypothesis tests except OS. 
8.2.1. Primary Efficacy Analysis 
PFS based on the assessment of investigator will be summarized in the ITT population using 
the Kaplan-Meier method and displayed graphically where appropriate.  The median event 
time and corresponding 2-sided 95% confidence interval for the median will be provided for 
PFS.  The hazard ratio and its 95% Confidence interval (subject to the multiplicity 
adjustment at the final analysis) will be estimated.  A log-rank test (1-sided, α=0.025) 
stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy 
(two of the baseline stratification factors as listed in Section 6.5.2) will be used to compare 
PFS between the two treatment arms.  
8.2.2. Sensitivity Analyses for the Primary PFS Endpoint 
The primary efficacy analysis on the primary PFS endpoint is based on well-documented and 
verifiable progression events and deaths due to any cause.  Other data are censored at the 
time of the last tumor assessment documenting absence of progressive disease and death.  In 
addition, the sensitivity analysis (SA) on the primary PFS endpoint will be performed in 
determining whether the result of the primary PFS analysis is robust.  
Sensitivity Analysis 1: Influence of Analysis Population - A sensitivity analysis will be 
performed to investigate whether the analysis population influenced the outcome of the 
primary endpoint PFS.  The stratified log-rank test (1-sided, α=0.025) and Cox regression 
model will be used to evaluate the primary efficacy endpoint, PFS, in the AT population. 
Sensitivity Analysis 2: Influence of the Use of Stratified Statistical Methods - A 
sensitivity analysis will be performed to investigate whether the use of stratified statistical 
methods influenced the outcome of the primary endpoint PFS.  The unstratified log-rank test 


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(1-sided, α=0.025) and Cox regression model will be used to evaluate the primary endpoint 
of PFS in the ITT population. 
Sensitivity Analysis 3: Influence of Stratification Factors and Covariates - A sensitivity 
analysis will be performed to investigate whether the stratification factors and important 
covariates (Section 6.5.1) influenced the outcome of the primary endpoint PFS.  The 
multivariate Cox regression model will be used to evaluate the primary endpoint of PFS in 
the ITT population. 
Sensitivity Analysis 4: Influence of Disease Assessment Scheduling - A sensitivity 
analysis will be performed to investigate whether deviations in disease assessment 
scheduling influenced the outcome of the primary endpoint PFS.  If disease progression is 
documented between 2 scheduled tumor assessments, then the date of progression will be 
assigned to the earlier scheduled tumor assessment.  In the event of death, the date of the 
endpoint will not be adjusted.  Handling of missed disease assessments will be similar to that 
in the primary analysis except that any missed assessment will result in censoring.  The 
stratified log-rank test (1-sided, α=0.025) and Cox regression model will be used to evaluate 
the investigator-assessed PFS with the modified event/censoring definitions in the ITT 
population. 
Sensitivity Analysis 5: Influence of Deviations in Tumor Lesion Assessment - A 
sensitivity analysis will be performed to investigate whether deviations in tumor lesion 
assessment influenced the outcome of the primary endpoint PFS.  If a lesion is classified as 
Indeterminate (IND) at Time Point X, and is adequately evaluated as PD at the next Time 
Point (X+1), then PD will be assigned to the Time Point X or earlier (the first date of the 
consecutive INDs) instead of the date of the next Time Point (X+1) as the primary analysis.  
The stratified log-rank test (1-sided, α=0.025) and Cox regression model will be used to 
evaluate the investigator-assessed PFS with the modified event/censoring definitions in the 
ITT population 
Sensitivity Analysis 6: Influence of Bone-only Disease Patients - Three sensitivity 
analyses will be performed to investigate whether addition of bone-only disease patients 
influenced the outcome of the primary endpoint PFS.  
1. For patients with bone-only disease, progression is defined as the appearance of 
≥1 new lesions after the first on-study bone scan.  In the following cases the patient 
will be censored at the date of prior tumor assessment with no PD in addition to the 
censoring rules defined in Section 6.1.1:  
• On-study fracture; or 
• On-study management of pain (palliative radiation therapy, palliative 
surgery); or 
• Clinical worsening not objectively confirmed (ECOG performance status 
increase from baseline by at least 2 points in 2 assessments); or 


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• On-study change of therapy 
2. For patients with bone-only disease, progression is defined as the appearance of 
≥1 new lesions after the first on-study bone scan.  The following cases the patient will 
be considered as PD:  
• On-study fracture; or 
• On-study management of pain (palliative radiation therapy, palliative 
surgery);  
or  
• Clinical worsening not objectively confirmed (ECOG performance status 
increase from baseline by at least 2 points in 2 assessments); or 
• On-study change of therapy 
3. Excluding bone-only disease patients from the analysis of the primary PFS endpoint. 
Sensitivity Analysis 7: Influence of Missing Data - A sensitivity analysis will be performed 
to investigate whether the missing PFS data due to various reasons (eg, new anticancer 
treatment, lost to follow-up, and consent withdrawal, etc.) influenced the outcome of the 
primary endpoint of PFS.  The following missing PFS data that may result in the censored 
PFS data in the primary analysis will be considered PFS events in addition to the documented 
PD and death in this sensitivity analysis: 
• new anti-cancer treatment; 
• lost to follow up;  
• consent withdrawal (ie, no long willing to participate in study) 
• Medication error without associated AE 
The stratified log-rank test (1-sided, α=0.025) and Cox regression model will be used to 
evaluate the investigator-assessed PFS with the modified event/censoring definitions in the 
ITT population.  
Sensitivity Analysis 8 (Supportive Analysis): Influence of Potential Investigator Bias - A 
sensitivity analysis will be performed to investigate whether the potential investigator (INV) 
bias on tumor assessment may influence the outcome of the primary endpoint of PFS.  BICR 
and investigator PFS (event) data will be combined.  For events identified by both BICR and 
INV, BICR data is to be used to determine event time.  For patients who are censored by both 
BICR and INV, BICR (when applicable) data is to be used to determine the censoring time.  
The stratified log-rank test (1-sided, α=0.025) and Cox regression model will be used to 
evaluate the combined PFS data in the ITT population.  This analysis will be conducted only 


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if the BICR is done for all the patients upon the request of the sponsor or the regulatory 
agencies. 
8.2.3. Secondary Analyses 
OS will be summarized in the ITT population using the Kaplan-Meier methods and displayed 
graphically where appropriate.  The median event time and 2-sided 95% confidence interval 
for the median will be provided.  A stratified (by the presence of visceral metastases and 
sensitivity to prior hormonal therapy) log-rank test will be used to compare OS between two 
treatment arms and the hazard ratio and its 95% confidence interval (subject to the 
multiplicity adjustment at the final analysis) will be estimated.  
OS will be hierarchically tested for significance at the time of PFS analyses, provided the 
primary endpoint, PFS, is statistically significant at the interim and/or final PFS analyses.  If 
OS does not yield a significant result at these analyses, OS will be tested at the final OS 
analysis.  If PFS is not significant at the interim and/or final PFS analyses, the statistical 
significance of OS results will not be evaluated.  
A naive hierarchical testing strategy is to test the secondary endpoint (OS) only if the 
primary endpoint (PFS) is significant, using the same level of significance α that was used to 
test PFS.  However, as shown recently (Hung, Wang, and O'Neill, 2007) this hierarchical 
strategy when applied in a group sequential design does not control the overall type I error 
rate in the strong sense.  
An alternative strategy is to apply the hierarchical group sequential testing with separate 
error spending functions at level 0.025 for PFS (primary) and OS (secondary) hypotheses 
proposed in this study to protect the family-wise error rate (FWER) strongly at level 0.025.  
Under this strategy, the secondary hypothesis for OS can be tested only when the primary 
hypothesis for PFS is rejected.  That is, only if the primary hypothesis has been rejected 
(positive PFS) at the pre-planned interim analysis (or the final PFS analysis), the secondary 
hypothesis for OS can be tested on partial data at an interim analysis as well and again at the 
OS final analysis, if it is not significant before.  
More specifically, here are some notations: 
• let H0p and H0o denote the null hypotheses for testing PFS and OS, 
respectively; 
• let αp(t) and αo(t) denote the alpha-spending functions for PFS and OS, 
respectively, at information fraction t; 
• let T₁ <T₂* < T₃ denote the time points for: 
T₁: pre-planned PFS interim analysis (driven by PFS events), 
T₂:planned final analysis of PFS and expected interim analysis of OS,  
T₃: planned final analysis of OS; 


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• let tp(T₁), tp(T₂) represent information fractions for PFS at time points T₁, T₂, 
respectively; 
• let to(T₂), to(T₃) represent information fractions for OS at time points T₂ and 
T₃, respectively; 
• let up(t) and uo(t) are the efficacy stopping boundaries for PFS and OS, 
respectively, at information fraction t. 
* In a special case when PFS is statistically significant at T₁, the timing of T₂ will no longer be driven 
by the targeted number of PFS events but rather by the number of OS events expected to be observed 
at time of planned final analysis of PFS.  In other words, the timing of T₂ can change but the 
information fraction to(T₂) should remain approximately the same. 
Using the following testing algorithm or strategy, it is expected that the overall type-I 
error rate can be controlled at level 0.025 across both endpoints if the proper error 
spending approaches, each at level 0.025, are applied separately to both endpoints.  
1. Interim Analysis of PFS at T₁: Test PFS with αp(tp(T₁))  
If up(tp(T₁)) is crossed, then H0p is rejected and go to Bullet 3  
If uo(to(T₁)) is not crossed, go to Bullet 2. 
2. Final Analysis of PFS at T₂ and Interim Analysis of OS at T₂: Test PFS at 
αp(tp(T₂)) adjusting for αp(tp(T₁)) and Test OS with αo(to(T2)) at T₂* 
If up(tp(T₂)) is crossed, then H0p is rejected and IA of OS is conducted at T₂: 
if uo(to(T₂)) is crossed, H0o is rejected; 
else if uo(to(T₂)) is not crossed, go to Bullet 4. 
If up(tp(T₂)) is not crossed, the study does not meet the primary endpoint of 
PFS and no testing for OS statistical significance will be done.  
3. Interim Analysis of OS at T₂: Test OS with αo(to(T2)) at T₂*  
If H0p is rejected at IA,  OS will be tested at T₂: 
if uo(to(T₂)) is crossed, H0o is rejected; 
else if uo(to(T₂)) is not crossed, go to Bullet 4. 
4. Final Analysis of OS at T₃: Test OS with αo(to(T₃)) adjusting for αo(to(T₂)). 
If uo(to(T₃)) is crossed, H0o is rejected; 
else if uo(to(T₃)) is not crossed, statistical significance is not established for 
OS results.  
* Although the formal statistical inference of OS result is not going to be drawn at T1, a small alpha 
can be theoretically spent at T1 for OS based on the pre-specified O’Brien-Fleming boundary generated 
by the Lan-DeMets spending function.  It is expected that only approximately 47 OS events from both 


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arms will be observed at T1; consequently, the theoretical alpha that can be spent for OS at T1 is highly 
close to 0 and therefore is negligible.  
The 1-year, 2-year and 3-year survival probabilities will be provided with their 95% 
confidence intervals. 
After the final results of Study A5481003 were communicated in April 2014, the enrollment 
rate of Study A5481023 accelerated significantly. Over 200 patients were enrolled into the 
study in the last two months of the enrollment period. Thus, 521 patients instead of the 
planned approximately 417 patients were randomized. 
 
An interim analysis of OS was triggered by the significant PFS results observed at the 
planned PFS interim analysis. At the time of the analysis 19 (5.5%) patients had died in the 
palbociclib plus fulvestrant arm and 9 (5.2%) patients had died in the placebo plus fulvestrant 
arm. No conclusions on OS could be drawn due to immature OS data with such a small 
number of deaths. 
 
The second interim OS analysis was performed based on 112 deaths and managed by the 
DMC. No detail interim analysis results have been shared with the sponsor and were not 
available to the public. The DMC only informed the sponsor that the analysis results did not 
cross the pre-specified O’Brien-Fleming efficacy boundary and therefore no conclusions 
regarding OS could be drawn at the time.  As the investigator and patients are still blinded to 
the treatment, collection of OS data for the final OS analysis is being continued in the study,  
Since more patients have been randomized in the study than it was originally planned, the 
previously determined final OS analysis based on 198 deaths becomes insufficient and 
inadequate in terms of the follow up time and data maturity. It would be difficult to answer 
the overall survival question for the patient population with 38% deaths (198 events out of 
521 patients). Therefore, the time of final OS analysis is shifted from when the study reaches 
198 deaths to approximately 60% deaths are observed in the 521 randomized patients.  This 
adjustment will not only ensure more matured the survival data with longer follow-up time to 
be included in the final analysis, but also protect the study integrity and address the clinical 
question with much more robust results.   
 
The nominal significance level for the final analyses of OS is determined by the Lan-DeMet 
spending function based on the O’Brien-Fleming boundary with the consideration of two 
interim analyses.  The overall significance level for the efficacy analysis of OS will be 
preserved at 0.025 (one-sided test). 
The number and proportion of patients achieving objective response (CR or PR) will be 
summarized in the ITT population and the ITT population with measurable disease at 
baseline along with the corresponding exact 2-sided 95% confidence interval calculated 
using a method based on Clopper-Pearson method.  The odds ratio estimator and the 
corresponding 2-sided 95% will be calculated to contrast the treatment effects on response 
rates.  A stratified 1-sided exact test will be used to compare ORR between two treatment 
arms. 


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The subgroup analyses will be conducted for the key efficacy endpoints that include PFS, 
OS, and ORR.  For the time-to-event endpoints, the median (and other quartiles) of each 
treatment arm and the corresponding 2-sided 95% CIs will be provided.  The HR estimate 
from the Cox model, the corresponding 2-sided 95% CI, and the p-value from the score test 
will also be provided for all the subgroups.  The response rate of each treatment arm will also 
be summarized for each subgroup and presented along with the corresponding exact 2-sided 
95% CI.  The odds ratio estimator (with the corresponding 2-sided 95%) and the 1-sided 
stratified exact test may also be used to compare ORR between the treatment arms in each 
subgroup.  
The following subgroups may be considered: 
• subgroups defined by stratification factors and baseline patient characteristics 
(section 6.5.1) 
• subgroups defined by ER mutation status (yes vs. no) using plasma DNA data 
when available 
• subgroups defined by bone-only (yes vs. no) patients 
The number and proportion of patients achieving clinical benefit response (CR or PR and 
SD≥24 weeks) will be summarized in the ITT population and the ITT population with 
measurable disease at baseline along with the corresponding exact 2-sided 95% confidence 
interval calculated using a method based on Clopper-Pearson method.  The odds ratio 
estimator (with the corresponding 2-sided 95%) and the 1-sided stratified exact test may also 
be used to compare clinical benefit response rate between the treatment arms in each 
subgroup.  
DR will be summarized using the Kaplan-Meier methods and displayed graphically where 
appropriate.  DR will be calculated for the subgroup of patients with objective disease 
response.  The median event time and 2-sided 95% confidence interval for the median will be 
provided.  
8.2.4. Supportive Efficacy Analyses  
The independent third-party core imaging laboratory assessment data will be evaluated as 
described in Section 8.1.5.  Additional supportive analyses for the time-to event endpoints 
such as PFS and DR and ORR will be performed in the ITT population based on the 
independent third-party core imaging laboratory assessment as described in Sections 8.2.1 - 
8.2.3.  In addition, discordance rates between the investigator and independent Core imaging 
laboratory on assessing PFS data will be summarized by treatment arms.  Concordance 
between the investigator and independent Core imaging laboratory assessments of tumor 
response will be summarized by treatment arms as well.  
If sufficient data is available, outcome to subsequent treatments in terms of objective 
response rate and PFS after next line of treatment (PFS2) may be summarized by treatment 
arm in the ITT population.  PFS2 is defined as the time from randomization to second 


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objective disease progression or death from any cause, whichever first.  Patients alive and for 
whom a second objective disease progression has not been observed should be censored at 
the last time known to be alive and without second objective disease progression.  Median 
PFS2 and the confidence interval for each arm will be estimated.  If PFS2 cannot be reliably 
be determined, the outcome in terms of end-of-next-line treatment may be summarized by the 
treatment arm in the ITT population.  For this analysis, an event is defined as end or 
discontinuation of next-line treatment, second objective disease progression, or death from 
any cause, whichever first.  Time to end-of-next-line-treatment is defined as the time from 
randomization to the event defined in the previous sentence.  Patients alive and for whom a 
second objective disease progression and end/discontinuation of next-line treatment have not 
been observed should be censored at the last time known to be alive and without second 
objective disease progression and end/discontinuation of next-line treatment.  Median time to 
end-of-next-line-treatment and the confidence interval for each arm will be estimated. 
In order to study the effect of the combination of palbociclib and an anti-hormonal agent (ie, 
fulvestrant or exemestane) on overall survival for women with HR+/HER2- advanced breast 
cancer, a supportive pooled OS analysis of individual patient data from this study and a 
collaborative IIR study (GEICAM /2013-02 “PEARL” Study) may be conducted.  . The 
collaborative IIR study (subsequently referred to as PEARL study) is a Phase 3 study of 
exemestane plus palbociclib versus chemotherapy (i.e., capecitabine) in HR+/HER2- 
metastatic breast cancer patients with resistance to non-steroidal aromatase inhibitors.  PFS is 
the primary endpoint and OS is one of the key secondary endpoints for PEARL study.  
Although a qualitative interaction is not anticipated, no pooled analysis will be performed if 
the qualitative interaction does exist between the two studies.  A qualitative interaction is 
defined as the heterogeneity between the two studies where the estimated hazard ratio of OS 
demonstrates a statistical significance in favor of palbociclib arm in one study and a 
statistical significance in favor of the control arm in the other study.  
The same definition of OS, which is the time from date of randomization to date of death due 
to any cause, will be shared between this study and PEARL study and will be used in the 
pooled analysis.  The pooled analysis will be conducted on an intent-to-treat (ITT) basis.  
The experimental group in the pooled analysis will include the patients in the ITT population 
of this study with the designated study drug assignment of palbociclib + fulvestrant and the 
patients in the ITT population of PEARL study with the designated study drug assignment of 
palbociclib + exemestane.  The control group in the pooled analysis will include the patients 
in the ITT population of this study with the designated study drug assignment of fulvestrant 
and the patients in the ITT population of PEARL study with the designated study drug 
assignment of exemestane. 
A log-rank test stratified by study will be used to compare the OS between the experimental 
and control groups based upon the pooled data and the two-sided p-value of the log-rank test 
will be calculated.  Kaplan-Meier survival curves will be presented for the two groups and 
the median OS times and 95% CIs will be estimated using the pooled data.  The 1-year 
survival probability will also be estimated using the Kaplan-Meier method based upon the 
pooled data and a two sided 95% CI for the log [-log(1 year survival probability)] will be 
calculated using a normal approximation with the Greenwood’s formula, and then back 


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transformed to give a CI for the 1-year survival probability itself (Brookmeyer and Crowley 
1982).  The 2-year, and 3-year survival probabilities will be estimated similarly based upon 
the pooled data.  
A fixed effects meta-analysis proportional hazard model (Whitehead 2002), stratified by 
study, will be used to estimate the HR of experimental group to control group.  Patient-level 
covariates including the important prognostic factors and baseline characteristics will be 
prospectively specified and consistently defined for both studies and be adjusted as fixed 
effects in the proportional hazard model.  
The quantitative heterogeneity between the two studies will be assessed by fitting a 
proportional hazard model which included an additional study by treatment interaction term.  
The interaction term will be tested with a chi-squared distribution with 1 degree of freedom.  
The graphical techniques (eg, forest plot) may also be used to further explore the 
heterogeneity between the two studies. 
It is expected that the interim OS data be analyzed and summarized separately when the final 
analysis of PFS in the individual study is conducted.  Consequently, the planned pooled 
analysis may be performed on the interim OS data only if the final analysis of PFS has been 
completed and the interim OS results generated separately for both studies.  The pooled 
analysis may also be performed on the final OS data when the results of final OS analyses are 
available for each individual study.  No multiple testing adjustments will be made in the 
pooled OS analysis. 
8.2.5. Standard Analyses  
Descriptive statistics will be used to summarize study conduct and patient disposition, 
baseline characteristics, and treatment administration/compliance.  
• Study Conduct and Patient Disposition - an accounting of the study patients will be 
tabulated including randomized (per stratification factors), treated, accrual by study 
center, assessed for AEs, laboratory data, biomarkers, PK, and QTc, etc.  Patients not 
meeting the eligibility criteria will be identified.  Patients not completing the study will 
be listed along with the reason for their premature discontinuation.  Reasons for 
premature discontinuation will be summarized.  Randomization errors and stratification 
errors will be described. 
• Baseline Characteristics - patient characteristics such as patient age, height, weight, 
race, ethnicity, ECOG performance status, primary diagnosis, HR and HER2 status, prior 
therapy (radiotherapy, surgery, systemic therapy), baseline disease site, prior medication, 
medical history, and signs and symptoms at study entry will be summarized in frequency 
tables, and descriptive statistics will be provided for quantitative variables.  
• Treatment Administration and Compliance  
• Extent of Treatment 
The extent of treatment will be summarized as follows: 
• The number and % of patients on treatment and off for each reason 


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• Treatment assigned vs. actual received  
• The number and percent of patients beginning 1, 2, 3, 4, 5+ cycles of either study 
drug  
• The number of cycles started (median, minimum, maximum) will be reported 
(overall and by study treatment).  
• Duration of treatment (weeks) (overall and by study treatment) 
• Cumulative dose and relative dose intensity (see Appendix 10.6 for details) 
(overall and by cycle; by study treatment)  
• Treatment Delays and Dose Modifications 
Dose adjustment is permitted for palbociclib/placebo only.  The fulvestrant dose 
cannot be adjusted, its dosing can only be delayed or interrupted.  However, a single 
fulvestrant injection can be skipped in case of a fulvestrant-related toxicity.  
Treatment delays and dose modifications of study treatments will be summarized as 
follows including number and percent: 
• The number of patients with at least one palbociclib dose reduction and the 
number of patients with at least one palbociclib or fulvestrant dose omission at 
any time during drug administration will be reported. 
• The number of patients with at least one palbociclib dose reduction due to an 
adverse event will be reported. 
• The number of patients with at least one palbociclib dose delay (ie, start of 
following cycle is delayed) and percentage due to each reason for the delay will 
be reported  
• Concomitant medications and Non-drug treatments 
Concomitant and non-drug treatments refer to all drug and non-drug treatments taken 
while on active treatment (during the effective duration of study treatment), whether 
or not they are recorded at baseline (ie, have stop day greater than or equal to day 
1 relative to first dose of study drug).  Concomitant medication will be summarized in 
frequency tables by treatment.  All the collected data of goserelin (including the start 
and stop date for each dose of goserelin) will be listed in a separate table.  In addition, 
the duration of goserelin will be summarized for pre/peri-menopausal patients by the 
general descriptive statistics including mean, median, standard deviation and range.  
The number of pre/peri-menopausal women who took goserelin prior to 
randomization and the number of pre/peri-menopausal women who took goserelin 
during the study will also be provided.  
• Follow-Up Therapy  


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Follow-up cancer therapy will be summarized by treatment as patients with number 
of regimens (0, 1, 2, ≥3), and patients with particular agents. 
8.2.6. Safety Analyses 
Listings of AE, SAE, death, lab data, vital signs, and physical examinations will be provided 
according to reporting standard. 
8.2.6.1. Adverse Events 
All patients treated with at least one dose of study treatment (ie, palbociclib/Placebo or 
fulvestrant) will be included in all the safety analyses.  
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v.4.0 whenever possible (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events.  Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. 
 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 v.4.0 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 discontinuation of trial treatment, events classified as NCI CTCAE 
v.4.0 Grade 3 or higher, trial drug related events, and serious adverse events will be 
considered with special attention. 
The percentage of patients with an event will be calculated using the number of patients in 
the as-treated population as the denominator.  The denominator for summary tables for each 
laboratory parameter will be all patients in the as-treated population with at least one 
evaluable cycle for that parameter. 
A 3-tier approach will be used to summarize AEs. 
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s Safety Review Plan. 
Tier-2 events: These are events that are not tier-1 but are “common”.  A MedDRA preferred 
term is defined as a tier-2 event if there are at least 10% for all a grades in any treatment 
CCI
CCI
CCI


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group.  For grade 3/4/5 analysis, the events should be reported in at least 5% patients in any 
treatment group. 
Tier-3 events: These are events that are neither tier-1 nor tier-2 events. 
• For Tier-1 events, the MedDRA preferred term, treatment arm, n (%) for each 
MedDRA preferred term per arm, risk difference, 95% confidence interval and 
P-values for the risk difference will be provided.  Graphical format may be presented 
as well.  Presented in descending p-value order. 
• For Tier-2 events, the MedDRA preferred term, treatment arm, n (%) for each 
MedDRA preferred term per treatment arm, risk difference and 95% confidence 
intervals for the risk difference will be provided in tabular format.  Table by AE for 
All Grade and for Grade 3/4/5 will be provided.  Graphical format may be presented 
as well.  Presented in descending risk difference order. 
• Tier-3 events will be presented by observed event proportions.  The following will be 
provided: 
• Incidence and grades of treatment emergent (all causality, preferred term, and 
by System Organ Class) AEs for all cycles combined. 
• Incidence and grades of treatment emergent (all causality, preferred term) AEs 
for all cycles combined in descending frequency order. 
• Incidence and grades of treatment emergent (treatment related, preferred term 
and by System Organ Class) AEs for all cycles combined. 
• Incidence and grades of treatment emergent (treatment related, preferred term) 
AEs for all cycles combined in descending frequency order. 
• Disease progression will not be included 
• There will be no adjustment for multiplicity 
The following summaries of treatment emergent adverse events will also be provided by arm: 
• Discontinuations Due to Adverse Events including causality: all cause, treatment 
related, including relationship to specific study treatment of fulvestrant, palbociclib, 
and placebo 
• Temporary Discontinuations or Dose Reductions Due to Adverse Events including 
causality and relationship to specific study treatment of fulvestrant, palbociclib, and 
placebo 
• Treatment-Emergent Adverse Events (All Causality, and Treatment Related) 
including the number of patients evaluable for adverse events, total number of 
adverse events (counting each unique preferred term across all patients), number of 


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patients with serious adverse events, number of patients with Grades 3 and 4 adverse 
events, number of patients with Grade 5 adverse events, and number with dose 
reductions or temporary discontinuations due to adverse events 
• Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Maximum NCI CTCAE v.4.0 Grade (All Causality, and Treatment related) 
• Treatment-Emergent Adverse Events by MedDRA Preferred Term sorted by 
Descending Order of AE Frequency (All Causality, and Treatment related) 
• Treatment-Emergent Adverse Events by Preferred Term – Grade 3/4/5 events with 
number of patients experienced Grade 3-5 AEs and total number of Grade 3-5 AEs, 
sorted by Descending Order of AE Frequency (All Causality, and Treatment Related) 
A summary of Serious Adverse Events and listing of deaths reported as serious adverse 
events will be provided. 
8.2.6.2. Laboratory abnormalities 
Hematologic, chemistry and urinalysis laboratory data will be summarized by cycle.  The 
hematologic and chemistry laboratory results will be graded according to the NCI CTCAE 
v.4.0 severity grade.  For parameters for which an NCI CTCAE v.4.0 scale does not exist, the 
frequency of patients with values below, within, and above the normal range for the local lab 
will be summarized.  Each patient will be summarized by the worst severity grade observed 
for a particular laboratory parameter.  This will be provided for all cycles as well as by 
cycles. 
8.2.7. Patient Reported Outcomes Analyses 
Analysis of the PRO endpoints will be based on the PRO evaluable population.  
The PRO analysis endpoints will be based on the instruments QLQ-C30, QLQ-BR, and 
EQ-5D.  . For each treatment group and at each time point, the number and percentage of 
patients who completed these instruments will be summarized, as will the reasons for 
non-completion of these measures.  An instrument is considered completed if at least one 
item was answered by the patient.  
EORTC QLQ-C30. 
This questionnaire contains 30 questions organized into 5 multi-item functional scales, 
3 multi-item symptom scales, a global quality of life scale, and 6 single item symptom scales.  
For each of the 15 scales, the results will be summarized using means (and standard 
deviation), 95% confidence interval, and medians (and range) for each treatment group at 
each time point.  This will be done based on the observed values as well as changes from 
baseline where both within group and between group differences will be displayed.  
For each of the 15 scales, statistical comparison between the two treatment groups will be 
based on a longitudinal repeated measures analysis using a mixed effects model.  The 
variables in the model will be treatment, time, treatment-by-time, with baseline used as a 
covariate.  Parameter estimates will be based on a restricted maximum likelihood method and 


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an unstructured covariance matrix will be used.  No adjustments for multiple comparisons 
will be made. 
For the symptom scale of pain, a time to deterioration (TTD) analysis will be carried out 
using survival analysis methods.  Deterioration will be defined increase in score of 10 points 
or greater from baseline. .  
For each of the 15 scales, a graphical display of means over time as well as mean changes 
from baseline over time will also be provided. 
EORTC QLQ-BR23. 
This questionnaire contains 23 questions organized into 4 functional scales and 4 symptom 
scales.  As with C30, the analysis of the BR23 scales will consist of descriptive statistics on 
means and changes from baseline, and a between treatment comparison using a longitudinal 
mixed effects model.  Also, as with C30, graphical displays of means and changes from 
baseline over time will also be provided for each BR23 scale. . 
EQ-5D Health Index 
Analysis of the EQ-5D health index will consist of descriptive statistics on means and 
changes from baseline, a between treatment comparison using a longitudinal mixed effects 
model, and graphical displays of means and changes from baseline over time,  as with the 
EORTC scales.  In addition, there will be a health status profile analysis consisting of a 
display of the number and percentage of patients in each of the 3 response levels for each of 
the 5 dimensions at each visit.  
EQ-5D General Health Status (EQ-5D VAS) 
Analysis of EQ-5D general health status will consist of descriptive statistics on means and 
changes from baseline, a between treatment comparison using a longitudinal mixed effects 
model, and graphical displays of means and changes from baseline over time, as with the 
EORTC scales.  
8.2.8. QTc Analyses 
All ECGs obtained during the study will be evaluated for safety 
Baseline will be defined as the average of the triplicate readings closest prior to dosing on the 
first day that study medication is administered 
Baseline and changes from baseline in RR, PR, QT, QTc, QTcF, QRS and heart rate will be 
summarized by treatment and time post-dose. 
ECG endpoints and changes from baseline (QTc, QTcF, PR, QRS RR and HR), over all 
measurements taken post-dose, will also be summarized descriptively by treatment using 
categories as defined in ICH E14 (ie, QTcF (ms): 450-480; 480-500; ≥500)  Numbers and 
percentages of subjects meeting the categorical criteria will be provided and individual 


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values listed in the study report.Unplanned ECGs are captured when there are AE suggestive 
of arrhythmia, and such unplanned records will not be included as part of the summaries.  All 
ECG recordings will be included in the listings 
8.2.9. Analyses for Ocular Assessment Data  
Ocular assessment data will be summarized only if sufficient data are collected from the 
study.  All the collected ocular assessment data will be listed.  The data may be combined 
with the ocular assessment data collected from other palbociclib studies to generate the 
pooled results that are not to be included in this clinical study report. 
8.2.9.1. 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 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 and included in the AE tables.  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.  The adverse event of visual acuity will be 
reported in the AE tables.  If sufficient data are collected in the study, a table may be created 
to summarize the number of subjects (and the proportions of subjects) with visual acuity of 
improvement, no change, decrease by 1 line, 2 line and >2 lines by treatment groups and 
left/right eyes.  
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 and included in the AE tables.  
8.2.9.2. 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 and included in the AE tables.  If sufficient 
data are collected in the study, a summary table that presents the descriptive statistics (eg, 


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mean, median, and range) of IOP and the maximum IOP change from baseline by treatment 
arm and left/right eyes may be created. 
8.2.9.3. 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.  Intraocular Inflammation Grading 
Scale for Biomicroscopy will be u sed.  During the study, any new finding or deterioration 
from baseline findings should be reported as an adverse event and be included in the AE 
tables. 
8.2.9.4. Lens Grading 
The Wisconsin AREDS 2008 Clinical Lens Opacity Grading Procedure will be used.  Each 
type of opacity will be graded in half steps from <1 to >3 (1=mild, 2=moderate and 
3=severe).  If sufficient data are collected in the study, a table that summarizes the lens 
grading results by treatment arm, left/right eyes, different types of opacity, and visit may be 
created.  
8.2.9.5. 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.  Any new findings or deterioration from 
baseline findings will be reported as an adverse event and included in the AE tables. 
8.2.10. Pharmacokinetic Analyses 
For the pharmacokinetic analyses, four unique drug combinations will be studied: 1) 
fulvestrant + placebo, 2) fulvestrant + goserelin + placebo, 3) fulvestrant + palbociclib, and 
4) fulvestrant + goserelin + palbociclib.  
In the early safety review, the first approximately 40 patients will have the concentration data 
of palbociclib, fulvestrant and goserelin listed by analyte, patient, collection time and day and 
unique drug combination.  Summary statistics will be provided for concentrations by analyte, 
collection time (Nominal Study Day), and unique drug combination.  For fulvestrant and 
goserelin concentrations, graphical comparisons will be provided (box-plot by treatment) as 
described below.  
For all patients on the palbociclib treatment arm (including those in the early safety review), 
palbociclib trough concentrations will be listed by patient, collection time (Nominal Study 
Day), and unique drug combination.  Summary statistics will be provided by collection time 
(Nominal Study Day), and unique drug combination.  If fulvestrant or goserelin do not have 
an effect on palbociclib PK, an average of the trough concentrations of palbociclib on Day 
15 of Cycles 1 and 2 will be listed by patient for the corresponding unique drug combination, 
and summary statistics will be provided.  If both fulvestrant and goserelin have no effect on 
palbociclib PK, summary statistics will be provided including the average of the trough 


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concentrations of palbociclib on Day 15 of Cycles 1 and 2 from all patients across all unique 
drug combinations.  
The relationship between palbociclib trough concentrations (on Day 15 of Cycles 1 and 2) 
and potential covariates will be evaluated.  If there is no treatment effect, data from all 
treatment groups will be combined for covariate analysis, and the mean of the Cycle 1 Day 
15 and Cycle 2 Day 15 palbociclib troughs for each patient will be used in the analysis.  
Analysis of Covariance (ANCOVA) may be used to analyze the effect of baseline 
characteristics on pharmacokinetic parameters.  The ANCOVA may include baseline 
characteristics (such as age, gender, race, renal impairment status, etc.) as covariates. 
8.2.10.1. Baseline Characteristics Analyses 
Patient characteristics such as age, gender, weight, height, BMI, ethnicity, diagnosis, extent 
of disease, ECOG performance status, smoking history and creatinine clearance will be 
summarized for the PK evaluable population per unique drug combination and study. 
8.2.10.2. Drug-Drug Interaction Analyses 
The drug combination effect on palbociclib, fulvestrant and goserelin will be determined by 
constructing 90% confidence intervals around the estimated difference between the Test and 
Reference treatments using the models specified below for analyzing natural log transformed 
Ctrough data.  The statistical analyses models are pre-specified below, but not limited to 
these models.  The validity of pre-specified analyses will be evaluated by the unblinded 
pharmacokineticist and statistician.  Additional analyses may also be conducted if warranted 
by the data. 
Three analytes will be compared: palbociclib, fulvestrant and goserelin.  For palbociclib, 
Ctrough data from study A5481023 will be the Test while palbociclib Ctrough from 
historical data will be the Reference.  For fulvestrant, fulvestrant± goserelin+palbociclib 
combination will be the test while fulvestrant±goserelin+ placebo combination will be the 
reference.  For goserelin, fulvestrant+goserelin+palbociclib combination will be the test 
while fulvestrant+goserelin+ placebo combination will be the reference.  Estimates of the 
adjusted mean differences (Test-Reference) and corresponding 90% confidence intervals (CI) 
obtained from the models will be exponentiated to provide estimates of the ratio of adjusted 
geometric means (Test/Reference) and 90% CIs for the ratios. 
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals versus predicted values and normal probability plots of 
residuals.  A summary of findings will be described in the data summary from these analyses 
but will not be included in the report.  If there are major deviations from normality then the 
effect of these on the conclusions will be investigated through alternative transformations 
and/or analyses excluding outliers.  Justification for any alternatives to the planned analyses 
will be given in the report. 
8.2.10.2.1. Palbociclib 
• Base model: One-way analysis of variance (ANOVA) will be used to analyze the 
natural log transformed Ctrough with unique drug combination as a single factor.  


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The statistical summary table for the base model will provide the least square mean 
(lsm) for the test and reference, geometric mean ratio (Test/Reference) and its 90% 
CI. 
• Full model: Analysis of covariance (ANCOVA) will be used to analyze the natural 
log transformed Ctrough with unique drug combination as a main effect along with 
age and baseline body weight as covariates.  The statistical summary table for the full 
model will provide the lsm for the test and reference, adjusted geometric mean ratio 
(Test/Reference) and its 90% CI. 
• Final model: Regression analysis will be performed on natural log transformed 
Ctrough against unique drug combination and covariates identified by backward 
selection process from the full model at significance level of 10%.  If unique drug 
combination is identified as one of the significant predictors, a statistical summary 
table for the final model will be provided with the lsm for the test and reference, 
adjusted geometric mean ratio (Test/Reference) and its 90% CI. 
8.2.10.2.2. Fulvestrant 
• Base model: One-way analysis of variance (ANOVA) will be used to analyze the 
natural log transformed Ctrough with unique drug combination as a single factor.  
The statistical summary table for the base model will provide the least square mean 
(lsm) for the test and reference, geometric mean ratio (Test/Reference) and its 90% 
CI. 
8.2.10.2.3. Goserelin 
• Base model: One-way analysis of variance (ANOVA) will be used to analyze the 
natural log transformed Ctrough with unique drug combination as a single factor.  
The statistical summary table for the base model will provide the least square mean 
(lsm) for the test and reference, geometric mean ratio (Test/Reference) and its 90% 
CI. 
8.2.10.3. Exposure/Response Analysis 
The relationship between exposure and efficacy/safety endpoints will be explored, as 
necessary, based on emerging efficacy and safety data.  All patients treated with palbociclib 
(Palbociclib PK Analysis Set) and for whom drug plasma concentration results (from at least 
1 visit) are available will be included in the analysis.  The results of these modeling analyses 
may be reported separately from the clinical study report.  
8.2.10.4. Adverse Events with PK Analyses 
For patients experiencing unexpected or serious adverse events, or adverse events thatlead to 
discontinuation who have PK blood samples collected for palbociclib or fulvestrant (or 
goserelin, if applicable) and have at least one measured plasma drug concentration: 
Concentration data of palbociclib,fulvestrant and goserelin listed by analyte, patient, 
collection time and day and unique drug combination as well as the corresponding adverse 


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event analysis data.  This will be done, if applicable, and separately for the early safety 
review data set and for the palbociclib PK analysis data set. 
8.2.10.5. Pharmacokinetic Analyses Reporting 
The study report will include, but not be limited to, the following listings, tables, and figures 
for PK data and analysis. 
For the first approximately 40 patients participating in the early safety review: 
1. Summary statistics of PK Subject Evaluation Groups and their Demographic 
Characteristics 
2. Summary statistics of plasma predose concentration (ng/mL) for palbociclib, fulvestrant 
and goserelin, respectively, versus time (Nominal Study Day) by unique combination 
3. Summary statistics of plasma mean predose concentrations (ng/mL) for Day 1 and Day 
15 of Cycles 1, 2 and 3 visits for palbociclib by unique drug combination 
4. Summary statistics of plasma mean predose concentrations (ng/mL) for palbociclib 
(125 mg dose only) historical control by study and all studies combined (A5481001-3). 
5. Summary statistics of plasma mean predose concentrations (ng/mL) for Day 1 and Day 
15 of Cycles 1, 2 and 3 visits for fulvestrant and goserelin by unique drug combination, 
respectively  
6. Box-plot of the plasma predose concentration (ng/mL) versus study day for palbociclib, 
fulvestrant and goserelin, respectively, by unique combination - mean (+/- SD); median 
and individual.  For palbociclib Ctrough box-plot, historical control (combined data from 
studies A5481001-3 should be also plotted as reference. 
7. Box-plot of the plasma predose concentration (ng/mL) versus unique drug combination 
for palbociclib, fulvestrant and goserelin, respectively, by unique study day - mean (+/- 
SD); median and individual 
8. Box-plot of the mean plasma predose concentrations (ng/mL) of the Day 15 of Cycles 
1 and 2 visits for palbociclib (ng/mL) by unique combination - mean (+/- SD); median 
and individual.  Corresponding historical control data (combined from studies 
A5481001-3 should be also plotted as reference.  
9. Box-plot of the mean plasma predose concentrations (ng/mL) of the Day 15 of Cycles 
1 and 2 visits for palbociclib (ng/mL) by unique combination - mean (+/- SD); median 
and individual.  Corresponding historical control data from studies A5481001-3 should 
each be plotted as reference. 
10. Box-plot of the mean plasma predose concentrations (ng/mL) of the Day 15 of Cycle 
1 for palbociclib (ng/mL) by unique combination - mean (+/- SD); median and individual.  
Corresponding historical control data from studies A5481001-3 should each be plotted as 
reference. 


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11. Box-plot of the mean plasma predose concentrations (ng/mL) of the Day 15 of Cycle 
2 for palbociclib (ng/mL) by unique combination - mean (+/- SD); median and individual.  
Corresponding historical control data from studies A5481001-3 should each be plotted as 
reference. 
12. Box-plot of the mean plasma predose concentrations (ng/mL) of Day 1 and Day 15 of 
Cycles 1, 2 and 3 visits for fulvestrant (ng/mL) by unique combination - mean (+/- SD); 
median and individual, respectively 
13. Box-plot of the mean plasma predose concentrations (ng/mL) of Day 1 and Day 15 of 
Cycles 1, 2 and 3 visits for goserelin (ng/mL) by unique combination - mean (+/- SD); 
median and individual, respectively 
14. Statistical comparison of adjusted geometric mean of palbociclib Ctrough (ANCOVA 
and/or ANOVA analysis summary) 
15. Statistical comparison of adjusted geometric mean of fulvestrant Ctrough (ANOVA 
analysis summary) 
16. Statistical comparison of adjusted geometric mean of goserelin Ctrough (ANOVA analysis 
summary) 
17. Listing of plasma predose concentration (ng/mL) of palbociclib, fulvestrant and goserelin 
versus time by visit 
18. Listing and descriptive summary of plasma mean predose concentrations (ng/mL) of the 
Day 15 of Cycles 1 and 2 visits for palbociclib by unique drug combination 
19. Listing and descriptive summary of plasma mean predose concentrations (ng/mL) of the 
Day 1 of Cycles 2 and 3 visits for fulvestrant and goserelin by unique drug combination, 
respectively  
20. Listing of plasma sample time deviation and sample comments for palbociclib, 
fulvestrant and goserelin assay 
21. Listing of Plasma Samples for Palbociclib (PD-0332991), Fulvestrant, and Goserelin 
Assays That Are Excluded From the Analysis  
For all patients participating in the palbociclib PK analysis set: 
1. Summary statistics of PK Subject Evaluation Groups and their Demographic 
Characteristics 
2. Summary statistics of plasma predose concentration (ng/mL) for palbociclib, versus time 
(Nominal Study Day) by unique combination 
3. Summary statistics of plasma mean predose concentrations (ng/mL) of the Day 15 of 
Cycles 1 and 2 visits for palbociclib by unique drug combination 


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4. Box-plot for the plasma predose concentration (ng/mL) versus study day for palbociclib 
by unique combination - mean (+/- SD); median and indi vidual 
5. Box-plot for the plasma predose concentration (ng/mL) versus unique drug combination 
for palbociclib by unique study day - mean (+/- SD); median and individual 
6. Box-plot of the individual patient mean plasma predose concentrations (ng/mL) of the 
Day 15 of Cycles 1 and 2 visits for palbociclib (ng/mL) by unique combination - mean 
(+/- SD); median and individual 
7. Box-plot of the plasma predose concentration (ng/mL) for palbociclib by significant 
covariate(s) if applicable - mean (+/- SD); median and individual 
8. Listing of plasma predose concentration (ng/mL) of palbociclib versus time by visit 
9. Listing and descriptive summary of plasma mean predose concentrations (ng/mL) of the 
Day 15 of Cycles 1 and 2 visits for palbociclib by unique drug combination 
10. Listing of plasma sample time deviation and sample comments for palbociclib assay (all 
patients)  
11. Listing of Plasma Samples for Palbociclib (PD-0332991), Fulvestrant, and Goserelin 
Assays That Are Excluded From the Analysis  
12. ANCOVA and/or ANOVA analysis summary table (if applicable) 
For the PK/Adverse Event Analysis Set (if applicable, and separate for early safety review 
data set and palbociclib PK analysis set): 
1. Listing of plasma predose concentration (ng/mL) of palbociclib, fulvestrant and 
goserelin by analyte, patient, collection time and day and unique drug combination as 
well as the corresponding adverse event data (suspect drug/dose, action taken, 
discontinuation day, discontinuation date or event onset date, event onset day, event 
stop day, AE term, investigator causality, clinical outcome/seriousness). 
CCI


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8.3. Summary of Key Efficacy Analyses  
Type of 
Analysis 
Endpoint 
Analysis Set 
Statistical Method  
Primary 
Analysis  
PFS 
ITT  
Investigator 
assessment 
• Stratified log-rank test (stratified by the presence 
of visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value), 
• K-M method (median and 95% CIs) 
• HR and 95% CIs from the stratified Cox model 
Sensitivity 
analysis 1 
PFS 
AT 
Investigator 
assessment 
• Stratified log-rank test (stratified by the presence 
of visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value), 
• K-M method (median and 95% CIs) 
• HR and 95% CIs from the stratified Cox model 
Sensitivity 
analysis 2 
PFS  
ITT  
Investigator 
assessment  
• Unstratified log-rank test (1-sided p-value),  
• K-M method (median and 95% CIs) 
• HR and 95% CIs from the Cox model 
Sensitivity 
analyses 3 
PFS  
ITT  
Investigator 
assessment  
• HR 95% CIs from the multivariate Cox model 
Sensitivity 
analysis 4-7 
PFS 
ITT  
Investigator 
assessment  
• Stratified log-rank test (stratified by the presence 
of visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value), 
• K-M method (median and 95% CIs) 
• HR and 95% CIs from the stratified Cox model 
Supportive 
Analysis 
Sensitivity 
analysis 8  
PFS 
ITT  
Investigator 
assessment and BICR 
(only if 100% BICR is 
conducted) 
•  Stratified log-rank test (stratified by the presence 
of visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value), 
• K-M method (median and 95% CIs) 
• HR and 95% CIs from the stratified Cox model 
Supportive 
Analysis 
PFS 
ITT 
BICR 
• Stratified log-rank test (stratified by the presence 
of visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value). 
• K-M method (median and 95% CIs) 
• HR and 95% CIs from the stratified Cox model 
• Unstratified log-rank test (1-sided p-value). 
• HR and 95% CIs from the stratified Cox model 
Supportive 
Analysis 
PFS 
ITT 
BICR 
• PhRMA and NCI estimation results 
• Concordance/Discordance summary results 
Secondary 
analyses  
OS  
ITT  
 
• Stratified log-rank test (stratified by the presence 
of visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value) 
• K-M method (median and 95% CI) 
• HR and 95% CIs from the stratified Cox model 
• Wilcoxon test and RPSFT method (when 
appropriate) 
1, 2, and 
3-year 
survival 
ITT  
• K-M method (95% CI) 


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Type of 
Analysis 
Endpoint 
Analysis Set 
Statistical Method  
Secondary 
analyses 
OR  
ITT  
Investigator 
assessment  
• Stratified exact test (stratified by the presence of 
visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value),  
• Exact CI based on Clopper-Pearson method (95% 
CI)  
• Odds ratio and 95% CI 
Supportive 
analyses 
OR  
ITT  
BICR  
• Stratified exact test (stratified by the presence of 
visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value),  
• Exact CI based on Clopper-Pearson method (95% 
CI)  
• Odds ratio and 95% CI 
Secondary 
analyses 
OR  
ITT  
Investigator 
assessment  
• Stratified exact test (stratified by the presence of 
visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value),  
• Exact CI based on Clopper-Pearson method (95% 
CI)  
• Odds ratio and 95% CI 
Supportive 
analyses 
OR  
ITT  
BICR  
• Stratified exact test (stratified by the presence of 
visceral metastases and sensitivity to prior 
hormonal therapy, 1-sided p-value),  
• Exact CI based on Clopper-Pearson method (95% 
CI)  
• Odds ratio and 95% CI 
Secondary 
analyses 
DR 
 
ITT patients with a CR 
or PR  
Investigator 
assessments  
• K-M method (median and 95% CI) 
Supportive 
analyses 
DR 
ITT patients with a CR 
or PR  
BICR 
• K-M method (median and 95% CI) 
Abbreviations: AT=as-treated; BICR=Blinded, Independent Central Review; CBR=clinical benefit rate; 
CR=complete response; CI=confidence interval; DR=duration of response; HR=hazard ratio; 
ITT=intent-to-treat; K-M=Kaplan-Meier; OR=objective response; OS=overall survival; PFS=progression-free 
survival; PR= partial response; SD=stable disease;  
 


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9. REFERENCES  
1. 
Amit O, Mannino F, Stone AM, et al: “Blinded independent central review of 
progression in cancer clinical trials: results from a meta-analysis”. European Journal of 
Cancer. 2011; 47:1772-1778. 
2. 
Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  
Biometrics 1982; 38:29-41. 
3. 
Cui L, Hung HMJ, Wang S, et al. Modification of sample size in group-sequential 
clinical trials. Biometrics. 1999; 55: 853-7. 
4. 
Dodd LE, Korn EL, Freidlin B, et al.  Blinded independent central review of 
progression-free survival in phase III clinical trials: important design element or 
unnecessary expense?  J Clin Oncol 2008;26:3791-6. 
5. 
Dodd E L, Korn L E, Freidlin B, Gray R, Bhattacharya S. An audit strategy for 
progression-free survival. Biometrics, Vol 67, Issue 3; 1092-99, 2011. 
6. 
Dmitrienko A, Tamhane AC, Bretz F (2010). Multiple Testing Problems in 
Pharmaceutical Statistics. Chapman and Hall/CRC, Boca Raton.  
7. 
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised 
RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. 
8. 
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Brit. 
J. Radiology 1971; 44:793-797. 
9. 
National Cancer Institute (NCI). Common Terminology Criteria For Adverse Events 
(CTCAE). http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
10. Peto, R., Pike, M. C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, 
N., McPherson, K., Peto, J., Smith, P.G. Design and Analysis of Randomized Clinical 
Trials Requiring Prolonged Observation of Each Patient: I. Introduction and Design. 
Brit. J. Cancer 1976; 34:585–612. 
11. Robins JM, and Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics. - Theory 
and Methods. 1991; 20:2609-2631.  
12. Whitehead, A. Meta-Analysis of Controlled Clinical Trials; John Wiley & Sons, Ltd: 
Chichester, England, 2002. 


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13. Wright GL, Blum J, Krekow LK, et al. Randomized Phase II Trial of Fulvestrant with 
or without Dasatinib in Postmenopausal Patients with Hormone Receptor-Positive 
Metastatic Breast Cancer Previously Treated with an Aromatase Inhibitor. Cancer 
Research: December 15, 2011; Volume 71, Issue 24, Supplement 3 doi: 
10.1158/0008-5472.SABCS11-PD01-01 
14. Zhang, J, Chen H, He K, et al.  Evaluation of blinded independent central review of 
tumor progression in oncology clinical trials: a meta-analysis. Therapeutic Innovation & 
Regulatory Science. 2012 DOI: 10.1177/0092861512459733 


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10. APPENDICES  
10.1. 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 patient. 
Protocol Activity 
Screening 
Active Treatment Phase a - One Cycle = 28 days 
End of 
Treatment/Withdrawal c
Post-Treatment 
Follow-Up d 
Cycles 1 and 2 
Cycles ≥3
Study Day 
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1 b
Day 15
Day 1
Visit Window 
±-2 days 
±2 days 
±7 days a 
 
±7 days 
 
Informed Consent e 
X 
 
 
 
 
 
Medical/Oncological History f 
X 
 
 
 
 
 
Baseline Signs/Symptoms g 
 
X g 
 
 
 
 
Physical Examination/Vital Signs h 
X 
X b 
 
X 
X 
 
Ophthalmic Examinationi 
X 
 
 
X i 
X 
 
ECOG Performance Status 
X 
X 
 
X 
X 
 
Laboratory Studies 
Hematology j 
X 
X b 
X 
X 
X 
 
Blood Chemistry j 
X 
X b 
X 
X 
X 
 
Pregnancy test, serum estradiol and FSH (if 
applicable) j 
X 
 
 
 
 
 
12-Lead ECG (in triplicate) 
X 
 
 
 
X 
 
Disease Assessment 
CT/MRI Scans of Chest, Abdomen, Pelvis, 
any clinically indicated sites of disease, and 
of bone lesions; Clinical evaluation of 
superficial disease k 
X 
◄--►k 
Performed every 8 weeks (±7 days) for the first year, and 
then every 12 weeks (±7 days) from the date of 
randomization (See tumor assessment requirements 
flowchart) 
X 
X 
Radionuclide Bone Scan, Whole Body l 
X 
As clinically indicated or to confirm complete response.  
(See tumor assessment requirements flowchart) l 
X 
X 


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Protocol Activity 
Screening 
Active Treatment Phase a - One Cycle = 28 days 
End of 
Treatment/Withdrawal c
Post-Treatment 
Follow-Up d 
Cycles 1 and 2 
Cycles ≥3
Study Day 
Within 28 days prior to 
randomization unless 
specified otherwise
Day 1 b
Day 15
Day 1
Visit Window 
±-2 days 
±2 days 
±7 days a 
 
±7 days 
Other Clinical Assessments 
Adverse Event Reporting m 
X 
X 
X 
X 
X 
X 
Concomitant Medications/Treatments 
◄--► 
Recorded from 28 days prior to the start of study treatment up to 28 days after the last dose of study treatment
 
Pharmacokinetics (PK) n 
 
First 40 patients: Sampling at pre-dose on Day 1 and Day 
15 of Cycles 1 and 2, and Day 1 of Cycle 3; all other 
patients: Pre-dose sampling on Day 15 of Cycles 1 and 2
 
 
EuroQol-5D (EQ-5D) r 
 
Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and Day 1 of 
every other cycle thereafter starting with Cycle 6 (ie, 
Cycle 6,8, 10, etc) 
X 
 
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire (EORTC-QLQ-C30) r 
 
X 
 
European Organisation for Research and 
Treatment of Cancer Breast Cancer Module 
(EORTC-QLQ-BR23) r 
 
X 
 
Survival Follow-up s 
 
 
 
 
 
X 
Study Treatment 
Randomization  
 
X 
 
 
 
 
Fulvestrant (both treatment arms) t 
 
◄--►t 
IM administration on Days 1 and 15 of Cycle 1, every 
28 days (±7 days) thereafter starting from Day 1 of Cycle 
1 
 
 
Palbociclib or placebo (Arm A only) u 
 
◄--►u 
Orally once daily on Days 1 to 21of each Cycle followed 
by 7 days off treatment 
 
 
For pre-/peri-menopausal patients only: 
Goserelin (both treatment arms, if applicable) 
v 
SC administration at least 
4 weeks before study 
treatment start v 
◄--►v 
SC administration every 28 days 
 
 
 
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a. 
Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers.  One cycle consists of 28 days.  A cycle could be longer than 28 days if persistent 
toxicity delays initiation of the subsequent cycle.  Day 1 of any cycle visit should coincide with the day the palbociclib/placebo treatment begins.  
If there are delays due to toxicity, then the start of the next cycle visit will be delayed until the patient has recovered and can begin study treatment 
again.  Fulvestrant injection will be given every 28 days (+/- 7 days) with the exception of Cycle 1 during which it will be administered on Days 1 and 
15 (±2 days allowed according to the protocol visit time windows).  Goserelin will be administered every 28 days (+/- number of days allowed 
according to the protocol visit time windows).  The active treatment phase is ongoing as long as the patient is receiving both study drugs 
(ie, palbociclib/placebo and fulvestrant) or fulvestrant alone. 
b. Cycle 1/Day 1: Blood chemistry, hematology, and physical examination not required if acceptable screening assessment is performed within 7 days 
prior to randomization.  
c. 
End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and 
prior to initiation of any new anticancer therapy.  Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 
8 weeks or 12 weeks [as applicable] for disease assessments).  
d. Post Treatment Follow-up:  Patients who discontinue study treatment should be contacted 28 calendar days (±7 days) after discontinuation of study 
treatment (palbociclib/placebo or fulvestrant) to assess if there have been any new adverse events and/or any change to any previously reported adverse 
events.  Telephone contact is acceptable.  Patients who discontinue active study treatment for any reason other than objective disease progression or 
death will continue to have tumor assessments performed every 8 weeks (±7 days) for the first year, and then after 1 year every 12 weeks (±7 days) 
(calculated from the date of randomization) until documented progression or onset of new anticancer therapy.  See Tumor Assessment Requirements 
Flowchart for details.  For patients who discontinue study treatment due to objective disease progression, see table footnote s (Survival Follow-up) 
below.  
e. 
Informed Consent: Informed consent must be obtained prior to any protocol required assessments being performed (with the exception of certain 
imaging assessments if meeting the criteria defined in the Screening Section of the study protocol amendment 2). 
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. Physical Examination/Vital signs: A full physical examination including an examination of all major body systems and breasts, 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. Physical 
examinations will be carried out at Screening, Day 1 of every cycle and the End of Treatment/Withdrawal visit. 


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i. 
Ophthalmology Examinations: Upon approval of Amendment 1, newly enrolled lens grading evaluable patients will undergo an ophthalmic 
examination by an ophthalmologist at screening, during study treatment on Cycle 4 Day 1, on Cycle 7 Day 1, on Cycle 13 Day 1 (ie, after 3, 6 and 
12 months), every 12 months thereafter (ie, Days 1 of Cycles 25, 37, etc.) and at the End of Treatment/Withdrawal visit.  Additional ophthalmic 
examinations may be performed as clinically indicated.  It is expected that a minimum of 100 evaluable patients will participate in these examinations.  
Sites will be informed once these examinations are no longer required for patients newly enrolled in this study. Refer to the Ocular Safety Assessment 
Section of the study protocol amendment 2 for further details. 
j. 
Laboratory tests: Hematology includes hemoglobin, WBC, absolute neutrophil count, platelet count.  Blood chemistry includes AST/ALT, alkaline 
phosphatase, sodium, potassium, magnesium, total calcium, total bilirubin, blood urea nitrogen (BUN) (or urea), serum creatinine, and albumin.  
Additional hematology/chemistries panels may be performed as clinically indicated.  Upon approval of Amendment 2, hemoglobin A1c will be 
measured in all patients every 3 months from the date of randomization (ie, C4D1, C7D1, C10D1, etc), and at the End of Treatment/Withdrawal visit.  
Pregnancy test (serum) at screening only for women of childbearing potential.  Test may be repeated as per request of IRB/IECs or if required by local 
regulations.  Serum estradiol and Follicle stimulating hormone (FSH) levels are analysed at screening to confirm postmenopausal status of women 
<60 years old and who have been amenorrheic for at least 12 consecutive months. 
k. CT/MRI Scans of Chest, Abdomen, Pelvis: Refer to the tumor assessment requirement flowchart for details and timing of procedures. 
l. 
Radionuclide Bone Scan, Whole Body: Refer to the tumor assessment requirement flowchart for all details and timing of procedures.  
m. Adverse Events (AEs): Serious Adverse events (SAEs) must be reported from the time the patient provides informed consent through and including 
28 calendar days after the last administration of the study drug.  SAEs occurring after the active reporting period has ended should be reported if the 
investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to 
study drug are to be reported to the Sponsor.  All AEs (serious and non serious) should be recorded on the CRF from the first dose of study treatment 
through last patient visit.  It is expected that telephone contact with the patient will be made in order to assess SAEs and AEs 28 calendar days (+/- 
7 days) after the last administration of the study drug. 
n. Pharmacokinetics (PK): In approximately the first 40 patients randomized in the study, plasma PK samples will be drawn pre-dose on Day 1 and 
Day 15 of Cycles 1 and 2, and Day 1 of Cycle 3 for DDI assessment for palbociclib and fulvestrant (and goserelin if applicable).  In all other patients, 
plasma concentrations will be drawn on Day 15 of Cycle 1 and Cycle 2 for palbociclib only.  Additional PK blood samples may be collected from 
patients experiencing unexpected or serious adverse events, or adverse events that lead to discontinuation. 
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r. 
Patient Reported Outcomes Assessments: 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.  
s. 
Survival Follow-Up: For patients who discontinue study treatment due to objective disease progression, survival data (ie, patient status along with 
start, stop and type of new anticancer therapy) will be collected every 3 months for the first 9 months (Month 3, 6, and 9, ±14 days), then every 
6 months starting at Month 15 (±14 days), calculated from the last dose of study treatment.  Telephone contact is acceptable. 
t. 
Fulvestrant: To be administered on-site according to the local Summary of Product Characteristics for fulvestrant (Faslodex®).  Fulvestrant injection 
will be given every 28 days (+/- 7 days) with the exception of Cycle 1 during which it will be administered on Days 1 and 15 (±2 days allowed 
according to the protocol visit time windows).   
u. Palbociclib or Placebo: Patients will be required to return all bottles of palbociclib/placebo as well as the completed patient diary on Day 1 of each 
cycle for drug accountability.  
v. Goserelin (if applicable):  Goserelin will be administered every 28 days (+/- number of days allowed according to the protocol visit time windows).  
Treatment with goserelin (Zoladex® or generic) as per local practice for all women who are pre- or peri-menopausal at study entry.  Patients must have 
commenced treatment with goserelin or an alternative luteinizing hormone-releasing hormone (LHRH) agonist at least 4 weeks prior to randomization.  
If patients have not received goserelin as their LHRH agonist prior to study entry, they must switch to goserelin for the duration of the trial.  It is 
recommended to administer goserelin (given every 28 days) on-site when monthly fulvestrant is given.  If goserelin is administered at home by the 
patient, a patient diary will be implemented. 


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Tumor Assessment Requirements Flowchart 
Method 
Screening a 
Treatment Periodb 
End of Treatment Visit c 
CT d or MRI of chest, abdomen, 
and pelvis  
Required e 
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 confirmatory imaging in 
case of any hot spots (CT, MRI or 
X-ray) 
Required g,h 
As clinically indicated or to 
confirm complete response 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 every 8 weeks (±7 days) for the first year during the treatment period, then after 1 year (6 assessments) every 12 weeks 
(±7 days) from the date of randomization until radiographically and/or clinically (ie, for photographed or palpable lesions) documented PD as per the 
Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1, (Protocol Appendix 4) 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 8 weeks (±7 days) for the first year, then after 1 year (6 assessments) every 
12 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 and pelvis 


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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 a few days 
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) (Protocol Appendix 4) 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.  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) 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, Week 8 ±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. 
Bone lesions identified at baseline as the only sites of a patient’s disease will be followed by X-ray/CT scan/MRI every 8 weeks (±7 days) for the first 
year, and then after 1 year every 12 weeks (±7 days) during the active treatment phase (calculated from the date of randomization) and at the time of CR 
confirmation.  If no bone lesions were identified at baseline, or if bone is not the only site of a patient’s disease, bone scans will only be repeated during 
the active treatment phase 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 at the time of CR confirmation.  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 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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10.2. 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. 
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. 


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


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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; 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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Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 64 
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.  
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: 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 65 
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 
Best Overall Response 
The best overall response (BOR) is the best response recorded from the randomization until 
disease progression or death due to any cause.  This is derived from the sequence of objective 
statuses.  Objective statuses are not considered after objective progression is documented or 
after start of the first anticancer treatment post discontinuation of protocol treatment.  BOR 
for each patient will be derived as one of the following categories.  
• Complete response (CR): At least one objective status of CR documented before 
progression. 
• Partial response (PR): At least one objective status of PR documented before 
progression. 
• Stable disease (SD): At least one objective status of stable documented at least 
8 weeks after randomization date and before progression but not qualifying as CR, 
PR. 
• Progressive Disease (PD): Objective status of progression within 16 weeks of 
randomization, not qualifying as CR, PR or SD.  
• Indeterminate (IND): Progression not documented within 16 weeks after 
randomization and no other response category applies.  


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 66 
10.3. Rules for Determining PFS Status and Date 
Situation 
Date of Progression/Censoring1 
Outcome 
Inadequate baseline 
assessment  
Randomization date (Day 1) 
Censored 
No on-study assessments 
Randomization date (Day 1) 
Censored 
Alive and no Progression  
Date of last objective tumor assessment 
documenting no progression 
Censored 
Progression Documented on 
or between scheduled tumor 
assessments 
Date of first objective tumor assessment 
documenting objective progression 
 
Progressed 
(Event) 
Patients are removed from 
the study (withdrew the 
consent, lost to follow up, etc.)  
prior to progression or death 
Date of last objective tumor assessment 
documenting no progression 
Censored 
New anticancer treatment 
prior to progression or death 
Date of last objective tumor assessment 
documenting no progression prior to 
new anticancer treatment 
Censored 
Death prior to first planned 
tumor assessment  
Date of death 
Death (Event)         
Death without objective 
progression prior to 
treatment discontinuation2 
Date of death 
Death (Event) 
                   
Death or progression after 
2 or more missed tumor 
assessments 
Date of last objective tumor assessment 
documenting no progression prior to the 
event 
Censored 
1 For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date. 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 67 
10.4. Data Derivation Details 
Enrollment/Randomization  
Date of assignment of the randomization number 
Study Day 1 
Randomization day 
Treatment start 
Day 1 of Cycle 1 
Day 1 (cycle start date) 
Day 1 of a cycle is every 28 days unless there is a 
dosing delay. 
Cycle length (all but final cycle) 
Cycle length is 28 days (previous cycle length may 
exceed planned length if there is a delay in study 
treatment administration). 
Final cycle 
For patients off treatment, from Day 1 of final cycle to 
28 days after final dose or until start of new anticancer 
treatment (whichever comes first).  
For patients on treatment, from Day 1 of most recent 
cycle start to protocol specified cycle length. 
Follow-up Period for AEs 
From 28 days after final dose until start of new 
anticancer treatment (whichever comes first).   
Baseline lab values 
From date closest to, but prior to, start of study 
treatment.  
 
 
Tumor assessment baseline values 
From date closest but prior to first dose.   
 
 
Measurable disease 
Defined by RECIST 
Adequate baseline tumor 
assessment 
Within 35 (28 + 7) days prior to first dose or 28 days 
prior to the randomization date with the exception of 
bone scan (within 12 weeks prior to randomization). 
Maximum diameter reported for each target lesion 
listed.  Each target lesion is measurable, unless bone 
only disease.  All required pre-treatment scans done. 
Cycle k treatment delayed. 
If study treatment administration is delayed for cycle k 
then cycle k-1 is extended.  
 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 68 
10.5. Study Treatment Modification and Compliance  
10.5.1. Dose Modification 
No dose adjustment for fulvestrant is permitted but dosing interruptions are allowed.  
Treatment interruption for fulvestrant-related toxicities will be performed as per the 
investigator’s best medical judgment. 
In the event of significant treatment-related toxicity, palbociclib/placebo dosing may be 
interrupted or delayed and/or reduced as described below. 
• 
A treatment delay is defined as any delay of the cycle start date, based on the previous 
cycle’s start date.  
• 
A dose reduction is defined as a day when the actual dose taken is less than the initial 
prescribed dose for any reason with the exception that a day with total dose administered 
of 0mg is not considered a dose reduction. 
• 
A dose interruptions/missed dose is defined as a planned dosing day with 0 mg 
administered. 
10.5.2. Summarizing Relative Dose (RD) and Relative Dose Intensity (RDI)  
The following types of summaries are proposed for administration of palbociclib 
(palbociclib) and fulvestrant with the proposed dosing schedule in the protocol, which is  
Palbociclib 125 mg/day orally for 3 weeks followed by 1 week off plus fulvestrant 500 mg 
intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28-day 
cycle: 
• RDI for palbociclib: by Cycle and Overall  
• RD for fulvestrant: by Cycle and Overall 
Note: the denominator for tables summarizing “fulvestrant” will be all patients who took at 
least a dose of fulvestrant and for tables summarizing “palbociclib” will be all patients who 
took at least a dose of palbociclib 
Examples for the summaries described in above are included in the tables below. 
Conventions: 
• The Intended Dose Intensity is the same for all cycles: the daily dose is fixed at the 
start of treatment rather than start of a cycle and the intended treatment duration is the 
same for the entire dosing period, including last cycle (eg, for a 3/1 dosing schedule, 
all cycles have an intended duration of 4 weeks);  
• Actual Dose Intensity is calculated based on actual cycle length in all but last cycle 
where it is fixed at the intended length (eg, 4 weeks for a 3/1 dosing schedule) 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 69 
Table 1 
Treat
ment / 
Summ
ary 
Type  
Calculation of RD/RDI 
Example 
Cyclic
al 
palboc
iclib / 
Overal
l  
 
 
 
                                       
                                   
100
*
 
 
 
 
Dose
Total
Intended
Dose
Total
Actual
RD =
% 
 
 
Actual Total Dose = (Sum over all cycles of the 
“Actual Total Dose per cycle”) 
 
Intended Total Dose =  (Intended Total Dose per 
cycle†) * (Total number of cycles per CRF) 
 
Note: Calculation of RD is optional 
 
† = Calculated based on prescribed dose at the 
beginning of the study 
• palbociclib is to be dosed at 
125 mg QD on a 3/1 Schedule  
• Actual palbociclib dosing: 
3/1 in Cycle 1, 3/2 in Cycle 
2 and 2/2 in Cycle 3 (with 
7 days dose interruption from 
Day 8 to Day 14) 
Actual Total Dose = 
(125*7*3)*2 + (125*7*2)  (same 
dosing in the first 2 cycles) = 
7,000 mg 
 
Intended Total Dose= (125*7*3) 
* 3 (same dosing in all 3 cycles) 
=7,875 mg 
 
RD = (7,000 / 7,875) * 100% = 
88.9% 
                            
100
*
 
 
 
 
 
 
Intensity
Dose
Overall
Intended
Intensity
Dose
Overall
Actual
RDI =
% 
 
 
Actual Overall Dose Intensity = (Sum over all cycles 
of the “Actual Total Dose per cycle”) / (Sum over all 
cycles of the “Actual number of weeks in cycle” ♣), 
where ♣ is calculated as presented in Table 2 
 
Intended Overall Dose Intensity = Intended Dose 
Intensity (per week per cycle) - calculated as 
presented in Table 3 
 
• palbociclib is to be dosed at 
125 mg QD on a 3/1 Schedule  
• Actual palbociclib dosing: 
3/1 in Cycle 1, 3/2 in Cycles 
2 and 2/2 in Cycle 3 (with 
7 days dose interruption from 
Day 8 to Day 14) 
Actual Overall Dose Intensity =  
(2,625 + 2,625 + 1,750) / (4 + 5 + 
4) = 538.46 
                                                        
Intended Overall Dose 
Intensity=656.25  
 
RDI = (538.46 / 656.25) *100% = 
82.1% 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 70 
Table 2 
Treatm
ent / 
Summa
ry Type  
Calculation of RD/RDI 
Example 
Cyclical 
palbocic
lib / By 
Cycle  
 
 
 
 
                                 
100
*
 
 
 
 
Intensity
Dose
Intended
Intensity
Dose
Actual
RDI =
% 
 
Actual Dose Intensity (per week) = (Actual Total 
Dose per cycle) / (Actual number of weeks in cycle) 
 
Actual Number of Weeks in Cycle = (Start date of 
next cycle – Start date of current cycle) / 7.  
 
Intended Dose Intensity (per week) = (Intended 
Total Dose per cycle) / (Intended number of weeks 
in cycle) 
  
• palbociclib is to be dosed at 
125 mg QD on a 3/1 Schedule  
• Actual palbociclib dosing: 
3/1 in Cycle 1 and 3/2 in Cycle 
2 and 2/2 in Cycle 3 (with 
7 days dose interruption from 
Day 8 to Day 14) 
Intended Dose Intensity = 
(125*7*3) / 4 = 656.25 mg/wk 
 
Cycle 1:  
Actual Dose Intensity = 
(125*7*3) / 4 = 656.25 mg/wk 
RDI = (656.25/656.25) * 100% = 
100% 
 
Cycle 2:  
Actual Dose Intensity = 
(125*7*3) / 5 = 525 mg/wk 
RDI = (525/656.25) * 100% = 
80% 
 
Cycle 3:  
Actual Dose Intensity = 
(125*7*2) / 4 = 437.5 mg/wk 
RDI = (437.5/656.25) * 100% = 
66.7% 
 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 71 
Table 3 
Treatment 
/ Summary 
Type  
Calculation of RD/RDI 
Example 
fulvestrant 
By Cycle & 
Overall 
 
 
 
  
                                 
100
*
 
 
)
(
Dose
Intended
Dose
Actual
Cycle
RD
=
%  
 
Actual Dose  = Actual Dose received within a 
specific cycle 
 
Intended Dose  = Intended Dose within a 
specific cycle  
 
 
100
*
 
 
)
(
Dose
Total
Intended
Dose
Total
Actual
Overall
RD
=
% 
 
Actual Total Dose = Actual dose received over 
all cycles 
 
Intended Total Dose = Intended dose (1000 mg 
for Cycle 1 and 500 mg for the rest cycles) 
overall cycles  
 
IM administration on Days 1 and 15 of Cycles 1, and then 
on Day 1 of each subsequent Cycle 
• Fulvestrant is to be IM 
administered on Days 1 and 
15 of Cycles 1, and then on 
Day 1 of each subsequent 
Cycle  
• Actual fulvestrant dosing: 
D1 on Cycle 1; D1 in Cycle 2  
 
• Intended Dose is 1000 mg in 
Cycle 1 
• Actual Dose is 500 mg in 
Cycle 2 
• Actual Total Dose is 1000 mg 
over 2 cycles.  
 
Cycle 1: 
Actual Dose = 500 mg 
 
Intended Dose = 1000 mg 
 
RD= (500 /1000) * 100% =50% 
 
Cycle 2: 
Actual Dose = 500 mg 
 
Intended Dose = 500 mg 
 
RD=(500/500)*100%=100% 
 
Overall: 
Actual Total Dose = 500 + 500 = 
1000 mg  
 
Intended Total Dose = 1000 + 
500 = 1500 mg  
 
RD= (1000 / 1500) 
*100%=66.7% 
 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 72 
10.6.  List of Abbreviation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferases  
AI 
Aromatase Inhibitor 
AST 
Aspartate Aminotransferases  
AT 
As Treated  
AUC 
Area Under the Curve 
BC 
Breast Cancer 
BUN 
Blood Urea Nitrogen 
CBR 
Clinical Benefit Response 
CCND1 
Cyclin D1 
CDK 
Cyclin-Dependent Kinase 
CDKN2A, p16Ink4A 
Cyclin-Dependent Kinase Inhibitor 2A 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
CMH 
Cochran Mantel Haenszel 
CR 
Complete Response 
CRF 
Case Report Form 
CSF 
Colony-Stimulating Factors 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
DNA 
Deoxyribonucleic Acid 
DR 
Duration of Response 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
E-DMC 
External Data Monitoring Committee 
EDR 
The early discrepancy rate 
EQ-5D 
Dimension Health State EuroQoL Score 
ER 
Estrogen Receptor 
FFPE 
Formalin Fixed Paraffin Embedded 
G-CSF 
Granulocyte Colony Stimulating Factor 
HER 
Human Epidermal Growth Factor Receptor 
HR 
Hazard Ratio 
HR 
Hormone Receptor 
ICH 
 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat  
LDR 
The late discrepancy rate 
MedDRA 
Medical Dictionary for Regulatory Activities 


Protocol A5481023  
Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 73 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
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 
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 
Rb 
Retinoblastoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RPSFTM 
Rank-Preserving Structural Failure Time Model 
RR 
The interval between an R wave and the next R wave 
SAE 
Serious Adverse Event 
SD 
Stable Disease or Standard Deviation (depending on context) 
WBC 
White Blood Cell