Clinical trial NCT01740427
Conditions: Breast Neoplasms
Keywords: breast cancer postmenopausal women estrogen-receptor positive HER2 negative locoregionally recurrent metastatic Palbociclib (PD-0332991) PALOMA-2
Sponsor: Pfizer
Start date: 2013-02-22; Completion date: 2023-11-09
Enrollment: 666 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to compare the clinical benefit following treatment with letrozole in combination with PD-0332991 versus letrozole in combination with placebo in postmenopausal women with ER(+)/HER2(-) advanced breast cancer who have not received prior systemic anti cancer therapies for their advanced/metastatic disease.

Detailed description:

Arms: arm 1: PD-0332991, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment in combination with Letrozole, 2.5mg, orally once daily (continuously). arm 2: Placebo, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment in combination with Letrozole, 2.5mg, orally once daily (continuously).
Interventions: intervention 1: PD-0332991 intervention 2: Letrozole intervention 3: Placebo intervention 4: Letrozole
Intervention descriptions: intervention 1: PD-0332991, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment intervention 2: Letrozole, 2.5mg, orally once daily (continuously) intervention 3: Placebo, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment intervention 4: Letrozole, 2.5mg, orally once daily (continuously)

Protocol documents:
Prot_000.pdf: 
PD-0332991
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PFIZER CONFIDENTIAL
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A RANDOMIZED, MULTICENTER, DOUBLE-BLIND PHASE 3 STUDY OF 
PD-0332991 (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS PLACEBO 
PLUS LETROZOLE FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN 
WITH ER (+), HER2 (-) BREAST CANCER WHO HAVE NOT RECEIVED ANY 
PRIOR SYSTEMIC ANTI-CANCER TREATMENT FOR ADVANCED DISEASE
Compound:
PD-0332991
Compound Name:
Palbociclib
US IND Number:
69,324
European Clinical Trial Database 
(EudraCT) Number:
2012-004601-27
Protocol Number:
A5481008
Phase:
3
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disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
 


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Document History
Document
Version Date
Summary of Changes
Amendment 8
21 May 2018
1. Protocol Summary – Background and 
Rationale: Added summary of the results 
from the primary analysis to support changes 
made in the body of the protocol.
2. Protocol Summary-Study Design, Section 3, 
Section 6.2, Section 7.1.2, and Appendix 10: 
Clarified that tumor assessments will be 
performed as per local institutional practice 
after IRB/IEC approval of Amendment 8.  
As a consequence, the requirement of 
conducting tumor assessment at the End of 
Treatment visit will no longer be mandatory.
Referenced Appendix 10 for new Schedule 
of Activities.
3. Protocol Summary-Study design, Section 3
and Section 7.1.1: Clarified that the third 
party core imaging laboratory will no longer
perform blinded independent central review 
of tumor imaging scans and thus, the 
investigators will no longer be required to
send the scans to the independent core 
imaging laboratory.
4. Protocol Summary-Schedule of Activities, 
Section 6.2, and Appendix 10: Referred 
reader to Appendix 10 for Schedule of 
activities for patients continuing to receive 
active treatment after IRB/IEC approval of 
Amendment 8. Revised frequency of blood 
chemistry and hematology monitoring as 
follow: (1) blood chemistries will be 
monitored on Day 1 of every 3 cycles and as 
clinically indicated, (2) hematology will be 
monitored on Day 1 of every 3 cycles and as 
clinically indicated for patients with 
maximum Grade 1 or 2 neutropenia in the 
first 6 cycles but will remain required on 
Day 1 of every cycles for patients who 
experienced maximum Grade 3 or 
4 neutropenia in the first 6 cycles, 
 


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(3) hemoglobin A1c laboratory test will no 
longer be obtained while patients are on-
treatment but will still be obtained at End of 
Treatment visit.
5. Protocol Summary-Tumor Assessment 
Requirements Flow Chart, and Section 6.5.1, 
Appendix 10: Refered reader to Appendix 10 
for tumor assessment requirements for 
patients continuing to receive active 
treatment after IRB/IEC approval of 
Amendment 8. Changes made to reflect that 
tumor assessments and selection of imaging 
studies will now depend on the treating 
physicians and radiologists as per local 
institutional practice, and RECIST 
version 1.1 will no longer be mandatory to 
evaluate imaging studies nor to confirm 
disease progression.  
6. Section 5.3.4.2.2, Section 6.2 and 
Appendix 10: Clarified that upon IRB/IEC
approval of Amendment 8, 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 unless 
required to determine whether study drug 
may be resumed.
7. Section 1.2.5.2, and Section 5.5.1: Language 
edited to reflect that the concomitant use of 
proton-pump inhibitors (PPIs) is now 
allowed during study treatment. PPI related 
language is removed from Section 5.5.1 
Prohibited medication and included in 
section 5.5.3 Permitted Medications.
8. Section 1.2.5.3 and Section 5.5.1: Language 
edited to provide rationale and reflect that 
the concomitant use of  drugs known to 
cause QT interval prolongation are now 
 


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allowed during study treatment. Drugs 
known to cause QT interval prolongation 
related language is removed from 
Section 5.5.1 Prohibited Medications and 
included in section 5.5.3 Permitted 
Medications.
9. Section 1.2.7.8: Provided rationale for 
changes made in Amendment 8.  
10. Section 5.3.4.2.3: Corrected a typographical 
error in Table 3.
11. Section 6.4, and Appendix 10: Editorial 
change to clarify the duration of the follow-
up period. 
12. Section 5.2 and Section 6.5.1: Removed 
mention of RECIST 1.1 criteria to reflect 
changes made to the tumor assessment 
requirements.
13. Section 7.1.2: Added reference to new 
Schedule of Activities in Appendix 10 for 
tumor assessment requirements.
14. Section 7.2 Safety Assessments: Chest CT 
scans will no longer be a required safety 
assessment to reflect that the choice of 
modality for tumor assessment is left at the 
investigator’s discretion upon approval of 
Amendment 8. 
15. Section 9: Added information about the 
planned data analysis being performed.
16. Section 16: Added 2 references.
17. Appendix 9: Added 2 abbreviations.
18. Appendix 10: Provide Schedule of Activities 
to be followed for patients continuing to 
receive active treatment after IRB/IEC
approval of Amendment 8.
 


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Amendment 7
15 October 2015
1. Protocol Summary/Schedule of 
Activities/Section 3 Study Design/
Section 6.4 Follow-up Visit: Changes 
reflecting the collection of disease
progression dates on subsequent anti-cancer 
therapies to better understand the potential 
influence of palbociclib on response to 
subsequent anti-cancer therapies. 
2. Schedule of Activities / Section 5.3.3.1: 
PD-0332991/Placebo: Language added to 
clarify that the 7-day off treatment period in 
any given cycle should always be respected.
3. Schedule of Activities: Editorial changes.
4. 1.2.7.7. Rationales for Changes in 
Amendment 7, 15 October 2015: Provide 
rationale for changes made in Amendment 7.
Amendment 6
07 April 2015
1. Protocol Summary/Scheduled of 
Activities/Section 3 Study design/Section 6.4 
Follow-up Visit/Section 7.4 Patient Reported 
Outcomes/Section 9.3.2 Analysis Secondary 
Endpoints: Changes reflecting the collection 
of Patient Reported Outcome data during the 
post-progression follow-up period to assess 
potential impact of post-progression status 
on patient’s quality of life. 
2. Section 1.2.7.6 Rationale for Changes in 
Amendment 6, 07 April 2015: Provide 
rationale for changes in Amendment 6. 
3. Section 8 Adverse Event 
Reporting/Section 10 Quality Control and 
Quality Assurance/Section 15 Publication of 
Study Results: Editorial changes to reflect 
current Sponsor’s protocol template.
 


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Amendment 5
02 December 2014
1. Study Design/Section 9.6 Interim Analysis: 
Changed the interim analysis efficacy 
boundary from O’Brien-Fleming to 
Haybittle-Peto boundary to ensure that the 
study would only be stopped at the interim 
analysis if the primary analysis (PFS) results 
are statistically significant, and clinically 
meaningful.
2. Section 1.2.7.5 Rationale for Changes in 
Amendment 5, 02 December 2014: Added 
the rationale for changes in Amendment 5.
3. Section 5.4 Drug Storage and Drug 
Accountability: Editorial changes to 
reflect current instructions for
investigational product destruction at the end 
of the trial. 
4. Section 5.5.1 Prohibited Medications: 
Strong/Moderate CYP3A inducers/inhibitors 
and proton-pump inhibitors are allowed for
patients who permanently discontinue 
blinded therapy and continue on study with
letrozole monotherapy only. 
5. Section 9.3.1 Analysis of Primary Endpoint: 
Editorial change to clarify planned analyses.
Amendment 4
18 September 2014
1. Schedule of Activities/Section 7.2.1
Laboratory Safety Assessments: Added 
prospective monitoring of hemoglobin A1c 
to characterize whether or not palbociclib 
affects glucose metabolism.
2. Section 1.2.5.4 Ocular Preclinical Date: 
Updated section to report emergent data 
findings from the 27-week rat toxicity study 
suggesting that cataract pathogenesis in rats 
may be related to altered glucose 
metabolism.
3. Protocol Summary/Study 
Design/Section 9.7: updated to reflect 
Sponsor’s decision to no longer require 
 


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safety review by an internal oncology 
business unit safety data monitoring 
committee (IOBU-SDMC) for studies 
already monitored by an external data 
monitoring committee (E-DMC). 
4. Schedule of Activities/Section 
5.3.4.2.2./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.
5. Section 1.2.5.2: Provided results from study 
A5481038 designed to investigate the effect 
of H2-receptor antagonists, proton pump 
inhibitors and local antacids 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.
6. Section 1.2.7.4 Added the rationale for 
changes in Amendment 4.
7. Section 5.5: Editorial changes 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. 
8. Section 8.2: Editorial changes to reflect
current Sponsor protocol template. 
 


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Amendment 3
21 March 2014
1. Schedule of Activities/Section 6 Procedures: 
Added ophthalmic procedures for all 
evaluable newly enrolled patients to assess 
the potential risk of palbociclib-associated 
crystalline lens changes.  
2. Section 1.2.5.4 Ocular Preclinical Data: 
Included preliminary results from a 
preclinical ocular study with palbociclib in 
rats.
3. Section 1.2.7 Amendment Rationale: Section 
added to provide rationales for each protocol 
amendment. 
4. Section 3 Study Design: Clarified that safety 
related assessments must continue if patients 
continue study treatment beyond 
RECIST-defined disease progression.
5. Section 4.4 Sponsor’s Qualified Medical 
Personnel: Section related to Sponsor’s 
qualified medical personnel added to align 
with updated protocol template. 
6. Section 5.3.5 Medication Errors and 
Overdose: Updated to match updated 
Protocol template.
7. Section 7.2.2 Electrocardiogram: Definition 
of “evaluable” patient revised to ensure that 
the required number of patients are enrolled 
in order to appropriately power the analysis 
in Group 1. 
8. Section 7.2.3 Ocular Safety Assessment: 
Section added to provide details on the 
ophthalmic procedures to be performed for 
all newly enrolled, lens grading evaluable 
patients. 
9. Section 8 Adverse Event Reporting: Section 
updated to reflect current protocol template. 
 


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10. Section 9.1 Sample Size Determination: 
Sample size was revised to account for the 
possible decrease in palbociclib exposure 
with concomitant use of proton-pump 
inhibitors and fasted state prior to 
Amendment 2.  To mitigate the potential 
impact on the treatment effect in the ITT 
population an additional 200 patients will be 
enrolled and required number of PFS events 
for final analysis will be increased to 347. 
This will allow the trial to maintain 90% 
power to detect statistically significant 
difference assuming a true hazard ratio of 
0.69 in favor of the palbociclib plus letrozole 
arm.
11. Section 9.1 Sample Size Determination/ 
Section 9.6 Interim Analysis: Corresponding 
to the sample size revision, the final analysis 
will require 347 PFS events and the Interim 
Analysis will be performed after 
approximately 226 PFS events 
(approximately 65% of total PFS events).
12. Section 15.1 Communication of Results by 
Pfizer: Updated to match updated Protocol 
Template.
13. Appendix 6 FACT-B: updated.
14. Appendix 8 Wisconsin Age-Related Eye 
Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure added.
Amendment 2
03 January 2014
1. Clarification of inclusion criterion #10 to 
emphasize the importance of collecting 
recurrent/metastatic tissue whenever 
possible.
2. Clarification of exclusion criterion #1 to 
highlight the need to confirm HER2 status 
on the most recent tumor sample whenever 
possible. 
 


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3. Clarification of inclusion criterion #4 to 
clarify that patients with FSH/estradiol blood 
levels within the post-menopausal range may 
be eligible. 
4. Clarification of exclusion criterion #17 to 
only exclude patient participating in the 
active treatment phase of other interventional 
trials within the protocol defined period.
5. Section 1.2.5.2 – Added preliminary results 
from two clinical pharmacology studies 
supporting revisions of Sections 5.3.3, 5.5.1, 
and 5.5.2.
6. Section 5.3.3 - Added recommendation to 
take palbociclib with a meal instead of under 
minimal fasting conditions.
7. Section 5.5.1 - Added prohibition to take 
proton-pump inhibitors while receiving study 
drugs.
8. Section 5.5.2 - Added recommendation to 
use local antacids as well as H2-receptor 
antagonist as alternative treatment for 
patients requiring gastroprotective treatment.
9. Editorial changes to address typo and align 
protocol language with clarified criteria.
Amendment 1 
01 October 2013
1. For France only: Clarification of inclusion 
criterion #10 in Section 4.1 “Inclusion 
Criteria” to emphasize that every effort
should be made to collect tissue sample from 
the recurrent/metastatic tumor at baseline at 
the request of the competent authority in 
France: Agence Nationale de Securité du 
Médicament (ANSM). 
Original protocol
30 October 2012
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/external review boards 
(IRBs)/(ERB), etc.  
 


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PROTOCOL SUMMARY
Indication:
Estrogen receptor-positive (ER(+)), HER2-negative (HER2(-)) Advanced Breast Cancer
(ABC).
Background and Rationale:
Breast cancer (BC) is the most common invasive cancer in women, with more than one 
million cases and over 411,000 deaths occurring worldwide annually. Although age-adjusted 
mortality from breast cancer has been decreasing since 1990, the median survival for patients 
with metastatic disease is still only approximately 18-24 months and the medical need for 
more active agents in this clinical setting remains very high. 
The role of estrogens in breast cancer etiology and progression is well established.  
Modification of estrogen activity or synthesis represents the treatment of choice for 
postmenopausal women with hormonal receptor positive advanced breast cancer, particularly 
for those with slowly progressive disease and limited tumor-related symptoms. Letrozole 
(Femara®) is an oral nonsteroidal aromatase inhibitor approved worldwide for the first-line 
treatment of postmenopausal women with hormone receptor-positive advanced breast cancer 
(ABC).
PD-0332991 (palbociclib) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has 
been under investigation in Phase 1 and 2 clinical trials in multiple indications. PD-0332991 
prevents cell cycle progression from G1 to S phase and has shown antitumor activity in 
multiple preclinical models, including in estrogen receptor-positive (ER+) luminal breast 
cancer cell lines. 
Furthermore, pre-clinical exploration using a breast cancer cell line panel has demonstrated 
presence of retinoblastoma (Rb) protein and upregulation of cyclin D1 as well as decreased 
CDKN2A (p16) that were associated with sensitivity to PD-0332991 as well as with its 
effects upon cell cycle and growth inhibition.  These gene expression findings were also 
associated with the luminal subtype versus basal-like subtype of BC. 
These results, together with published data on the interaction of estrogens and CDKs and the 
important role of cell cycle-related proteins in the genesis and maintenance of breast cancer, 
led to the initiation of a randomized Phase 2 clinical trial (A5481003) investigating the 
antitumor activity of PD-0332991 in combination with letrozole and single-agent letrozole in 
the first-line treatment of ER(+)/HER2(-) ABC patients.  The Phase 2 study was divided into 
2 parts. In Part 1, patient selection was based only on ER/HER2 status while in
Part 2, patients were additionally prospectively selected taking into account tumor 
CCND1 amplification and/or CDKN2A (p16) loss.
 


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After a median follow-up of 16.5 months, preliminary results from Part 1 of this Phase 2 trial 
suggest that the combination of PD-0332991 with letrozole is superior to letrozole alone in 
the selected patient population as demonstrated by prolonged progression-free survival (PFS)
(median 18.2 months vs 5.7 months, respectively), and improved objective response and 
disease control rates (52% vs 32% and 76% vs 47%, respectively) in patients treated with the 
combination.  Results from the Phase 2 Part 2 are not yet mature.
The combination therapy was generally well tolerated when compared to letrozole alone with 
AEs similar to those seen with PD-0332991 and letrozole when administered alone. 
Uncomplicated neutropenia, leucopenia, and fatigue were the most frequent adverse events,
and the most commonly reported Grade 3 treatment-related adverse events were neutropenia 
(54%) and leucopenia (21%) in patients treated with the combination therapy. 
Grade 4 events included neutropenia and fatigue each reported for 6% of patients treated with 
PD-0332991 + letrozole.  No Grade 4 events were reported in the letrozole alone arm.
Treatment-related Grade 1/2 AEs reported more frequently in patients in the 
PD-0332991 + letrozole arm compared with the letrozole alone arm included leukopenia, 
anemia, fatigue, alopecia, arthralgia, nausea, neutropenia, and thrombocytopenia.  Hot flush 
was the most common Grade 1/2 treatment-related AE reported in patients enrolled in the 
letrozole alone arm.
Overall, 3 (9%) patients in the PD-0332991 + letrozole arm and 1 (3%) patient in the 
letrozole alone arm discontinued the Phase 2 Part 1 of Study A5481003 due to AEs including
1 patient with Grade 4 fatigue (not related to PD-0332991) and 2 patients with 
Grade 3 neutropenia in the PD-0332991 + letrozole arm and 1 patient with Grade 2 nausea in
the letrozole alone arm. The median duration of treatment was 13.7 months in the 
PD-0332991 + letrozole arm vs 5.4 months in the letrozole alone arm, with 
PD-0332991 dosing interruptions and dose reductions due to AEs reported in 61% and 
39% of patients enrolled in the PD-0332991 + letrozole arm respectively.  The median 
duration of dosing interruptions was 4.5 days, and the median time to first dosing interruption 
was 55.5 days.  Despite the dosing interruptions and dose reductions, the median dose 
intensity for PD-0332991 was 87% across all cycles.
This randomized Phase 3 Study (A5481008) provides the opportunity to confirm the clinical 
benefit of the combination of PD-0332991 with letrozole observed in the randomized 
Phase 2 study. This study is designed to demonstrate that the combination of 
PD-0332991 with letrozole provides superior clinical benefit compared to letrozole in 
combination with placebo in postmenopausal women with ER(+)/HER2(-) ABC who have 
not received any prior systemic anti-cancer therapies for their advanced disease.
The present study met its primary objective of improving investigator-assessed PFS at the 
final analysis (data cutoff of 26 February 2016), demonstrating that in postmenopausal 
women with ER-positive/HER2-negative ABC who had not received any prior systemic 
anti-cancer therapies for their advanced/metastatic disease, the addition of palbociclib to 
letrozole resulted in statistically significant, robust, and clinically meaningful 10-month 
improvement in median PFS (42% risk reduction) as compared with placebo plus letrozole 
(24.8 months vs 14.5 months, HR=0.576 [95% CI: 0.463, 0.718], 1 sided p<0.000001). 
 


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Prolongation of PFS in the palbociclib plus letrozole arm was also demonstrated in multiple 
sensitivity analyses and, importantly, was consistently observed in individual patient 
subgroups defined by stratification factors and baseline demographics and disease 
characteristics, supporting the robustness and internal consistency of PFS benefit findings 
within the study. The blinded independent central review (BICR) showed no investigator 
bias in favor of the palbociclib plus letrozole arm and the analysis results of BICR 
corroborated the results of investigator-assessed PFS.
Palbociclib plus letrozole was generally well tolerated with toxicities that were manageable 
by temporary discontinuations (including cycle delays) (335 [75.5%] patients), dose 
reduction (160 [36.0%] patients), and/or standard medical therapy.  The observed AEs were 
generally consistent with the known safety profile of palbociclib when administered with 
letrozole and when letrozole is administered as monotherapy; there were no unexpected 
major safety findings in this study population. The most common adverse events in the 
palbociclib plus letrozole group were neutropenia, leukopenia, fatigue, nausea, arthralgia, 
and alopecia. The majority of adverse events  were mild to moderate in severity with the 
exception of neutropenia and leukopenia.76  Additionally, palbociclib, when added to 
letrozole, did not prolong QT interval to a clinically meaningful extent.77
Double-blinding of the present study will be maintained to allow ongoing collection of data 
for other pre-specified secondary endpoints including overall survival (OS) and patient 
reported outcomes.
Given the completion of the primary objective and most of the secondary objectives of the 
study, the management of patients who are still receiving active treatment is being modified. 
Upon Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval of 
Amendment 8, clinical assessments will be reduced in scope and the required schedule of 
activities are provided in Appendix 10. 
Objectives:
Primary Objective:
•
To demonstrate that the combination of PD-0332991 with letrozole is superior to 
placebo plus letrozole in prolonging progression-free survival (PFS) in 
postmenopausal women with ER(+)/HER2(-) advanced breast cancer who have not 
received any prior systemic anti-cancer therapies for their advanced disease. 
Secondary Objectives:
•
To compare measures of tumor control duration and overall survival between the 
treatment arms;
•
To compare safety and tolerability between the treatment arms;  
•
To compare health-related quality of life between the treatment arms;
 


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•
To characterize the effects of PD-0332991 at therapeutic doses in combination with 
letrozole on QT interval in this patient population;
•
To determine trough PD-0332991 plasma concentration in this patient population and 
explore the correlations between exposure and response and/or safety findings;
•
To characterize alterations in genes, proteins, and ribononucleic acids (RNAs)
relevant to the cell cycle (eg, CCND1 amplification, CDKN2A deletion), drug targets 
(eg, CDK 4/6), and tumor sensitivity and/or resistance (eg, Ki67, pRb) in tumor 
tissues.
Study Design:
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group Phase 3 trial comparing the efficacy and safety of PD-0332991 in combination 
with letrozole versus placebo plus letrozole in postmenopausal women with ER(+)/HER2(-)
ABC. Eligible patients will have histologically or cytologically proven diagnosis of 
adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease 
and will be candidates to receive letrozole as first-line treatment for their advanced disease.
In order to avoid inclusion of patients who are refractory or resistant to non-steroidal 
aromatase inhibitors, patients who received anastrozole or letrozole as a component of their 
(neo)adjuvant regimen may only enter the study if their disease did not progress while on or 
within 12 months from completion of their anastrozole/letrozole-containing (neo)adjuvant 
therapy. Patients will not have received any prior systemic anti-cancer therapies for their 
advanced disease and will not be candidates for curative therapies. Patients must have 
measurable disease as per the Response Evaluation Criteria in Solid Tumor (RECIST) v.1.1 
or bone disease as their only site of disease.  Tumor tissue availability is required for patient 
participation.  At least 650 patients will be randomized 2:1 between the experimental arm 
(Arm A: at least 433 patients treated with PD-0332991 plus letrozole) and the control arm 
(Arm B: at least 217 patients treated with placebo plus letrozole).
Patients will be stratified by site of disease (visceral vs non-visceral), by disease-free interval 
since completion of prior (neo)adjuvant therapy (de novo metastatic; ≤12 months; 
>12 months) and by the nature of prior (neo)adjuvant anti-cancer treatment received (prior 
hormonal therapy; no prior hormonal therapy).
Patients randomized to Arm A (experimental arm) will receive: 
•
PD-0332991, 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle 
followed by 7 days off treatment;
in combination with
•
Letrozole, 2.5 mg, orally once daily (continuously). 
 


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Patients randomized to Arm B (control arm) will receive: 
•
Placebo orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 
7 days off treatment;
in combination with
•
Letrozole, 2.5 mg, orally once daily (continuously). 
Patients will continue to receive their assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  However, patients may continue treatment as assigned at randomization beyond 
the time of disease progression at the discretion of the investigator if that is considered to be 
in the best interest of the patient and as long as no new anti-cancer treatment is initiated. In 
this case, the patient would continue with routine safety assessments as per the Schedule of 
Activities for the active treatment period.
The importance of timely and complete disease assessments in this study cannot be 
overstated.  Disease assessments will be performed every 12 weeks (±7 days) from the date 
of randomization.  Patients with bone lesions identified at baseline will also have repeat bone 
scans performed every 24 weeks (±7 days) from the date of randomization.  Each assessment 
will be performed as scheduled according to the calendar regardless of any dosing delay to 
prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the 
required disease assessments will result in the inability to determine disease status for that 
time point.  Tumor assessments will be performed until radiographically and/or clinically 
(ie, for photographed or palpable lesions) documented PD as per RECIST v.1.1, study 
treatment discontinuation (for patients continuing treatment beyond RECIST-defined disease 
progression), initiation of new anti-cancer therapy or discontinuation of patient from overall 
study participation (eg, death, patient's request, lost to follow-up), whichever occurs first.  
A series of incomplete disease assessments will result in censoring of the primary endpoint of 
PFS back to the time of the last full assessment that did not show disease progression.  Off 
schedule or incomplete disease assessments have the potential to weaken the conclusion of 
this clinical trial and must be avoided wherever possible.  Upon approval of Amendment 8, 
tumor assessments may be performed at a different schedule than the original protocol 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 institutional practice.  RECIST 1.1 may continue to be used to 
evaluate imaging assessments at the investigator’s discretion but will no longer be 
mandatory.  Assessments of tumor lesions [ie, target lesion(s), non-target lesion(s) and target 
lymph node(s)] will no longer be recorded in the case report form (CRF), nor will the 
RECIST assessments.  Only the date of progression of disease will be recorded.
Patients discontinuing the active treatment phase will enter a follow-up period during which
Functional Assessment of Cancer Therapy – Breast (FACT-B), survival and new anti-cancer 
therapy information (including regimen number, name of therapy, start/stop dates, and dates 
of disease progression on subsequent anti-cancer therapies) will be collected every 6 months 
 


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from the last dose of investigational product. The follow-up period will conclude at the time 
of the final OS analysis.  Crossover will not be allowed in the trial.
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as the primary data source. However, a blinded independent third-party core 
imaging laboratory will complete a retrospective review of radiographic images and clinical 
information collected on-study to verify the protocol-defined endpoints of disease response 
and progression determinations as assessed by the investigator.  Upon IRB/IEC approval of 
Amendment 8, retrospective blinded independent central review of radiographic images and 
clinical information will be discontinued.
An independent third party External Data Monitoring Committee (E-DMC) will monitor the 
safety data on a periodic basis.  The E-DMC will make recommendation as to whether the 
trial should continue based on ongoing reviews of safety data. The E-DMC will also 
evaluate efficacy at the interim analyses and make a recommendation regarding study 
continuation based on observed results of the study.  The E-DMC membership and 
governance is outlined in a separate charter.
Endpoints:
Primary Endpoint
•
Progression-Free Survival (PFS).
Secondary Endpoint(s)
•
Overall Survival (OS);
•
1-year, 2-year, and 3-year Survival Probabilities;
•
Objective Response (OR: Complete Response or Partial Response);
•
Duration of Response (DR);
•
Disease Control (DC: CR + PR + Stable disease ≥24 weeks);
•
Corrected QT interval (QTc);
•
Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1, CDKN2A), 
proteins (eg, Ki67, pRb), and RNA expression (eg, cdk4, cdk6);
•
Trough plasma concentration of PD-0332991;
•
EuroQol (EQ-5D) Score (see Appendix 5);
•
Functional Assessment of Cancer Therapy - Breast (FACT-B) (See Appendix 6);
 


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•
Type, incidence, severity (as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0), seriousness and 
relationship to study medications of adverse events (AE) and any laboratory 
abnormalities.
Statistical Methods:
The primary purpose of this study is to demonstrate that the combination of 
PD-0332991 with letrozole is superior to placebo plus letrozole in prolonging PFS in 
postmenopausal women with ER (+), HER2 (-) ABC who have not received any prior 
systemic anti-cancer treatment for advanced disease. All primary and secondary endpoints 
based on radiological (and photographical where applicable) assessments of tumor burden 
(ie PFS, OR, DR, DC) will be derived using the local radiologist’s/investigator’s assessment. 
Tumor assessments will also be performed in retrospective by a blinded independent 
third-party core imaging laboratory and the data will be used for secondary supportive 
analyses. The study is designed to test the null hypothesis that the true PFS distributions for 
both PD-0332991 plus letrozole and placebo plus letrozole arms are the same with a median 
PFS of 9 months versus the alternative hypothesis that the true PFS distribution has a median
that is longer than 9 months for the PD-0332991 plus letrozole arm. 
The sample size for this study is determined based on the assumptions that the median PFS 
for ABC patients receiving placebo plus letrozole in the first-line treatment setting is 
9 months and a risk reduction by 31% (hazard ratio of 0.69) or an improvement by 44% to a 
median PFS of 13 months in the PD-0332991 plus letrozole treatment arm is clinically 
meaningful.  A total of 347 events are required in the 2 arms of the study based on a 
2:1 randomization to have 90% power to detect a difference assuming a true hazard ratio of 
0.69 in favor of the PD-0332991 plus letrozole arm using a one-sided log-rank test at a 
significance level of 0.025.  Assuming a 15% drop-out rate on either treatment arm, a 
non-uniform accrual accomplished over a 15-month period and follow-up that will continue 
for about 10 months after the last patient is enrolled, a total sample size of approximately 
650 patients (approximately 433 patients in the PD-0332991 plus letrozole arm and 
approximately 217 patients in the placebo plus letrozole arm) is required.
The sample size described above will also allow the assessment of differences in the 
secondary endpoint of overall survival (OS) with a high level of significance.  The OS 
outcome of a Phase 3 clinical trial in a similar patient population demonstrated a median OS 
of 34 months for the arm receiving letrozole.  Using this value as an assumption with a 
hypothesized 26% risk reduction (a hazard ratio of 0.74) or 35% improvement in median OS 
(from 34 months to 46 months) in patients randomized to receive PD-0332991 plus letrozole 
and a follow-up period of approximately 68 months, evaluation of 390 events using a 
one-sided log-rank test is required for a significance level of 0.025 and power of 80% to 
detect a difference. OS will be hierarchically tested for significance at its interim analysis, 
provided the primary endpoint, PFS, is statistically significant at the interim PFS analysis, or 
at the final PFS analysis. 
 


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Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration, investigational drug compliance, efficacy endpoints, safety parameters, and 
biomarkers.  Data will also be displayed graphically, where appropriate. 
The primary efficacy analyses will be based on the intent-to-treat (ITT) population, defined 
as all patients randomized to the study. Some efficacy analyses will also be performed on the 
as-treated (AT) population, defined as patients who receive at least 1 dose of study treatment 
(ie, PD-0332991/placebo or letrozole), with treatment assignments designated according to 
actual study treatment received. 
Time-to-event endpoints, including PFS, DR, and OS will be summarized using Kaplan-
Meier methods and displayed graphically.  The median event time and 2 sided 
95% confidence interval for the median will be provided for each endpoint.  Stratified log 
rank tests will be used to compare PFS and OS between the treatment arms.
The 1-year, 2-year, and 3-year survival probabilities will be estimated using the Kaplan-
Meier method and a 2 sided 95% confidence interval for the log [-log(1-year, 2-year or 
3-year survival probability)] will be calculated using a normal approximation using the 
Greenwood’s formula and then back transformed to give a confidence interval for the 1-year, 
2-year, and 3-year survival probability itself.
The objective response rate (ORR) will be summarized by treatment arm along with the 
corresponding exact 2 sided 95% confidence interval calculated using a method based on the 
F distribution.  Response rate comparisons between the 2 treatment arms as randomized will 
be assessed using Cochran-Mantel-Haenszel (CMH) test with the same stratification factors 
as for the PFS analysis.
The study is designed to have one interim analysis and the final analysis based on the 
primary endpoint of PFS. A formal efficacy stopping boundary (Haybittle-Peto) for rejecting 
the null hypothesis will be used for the interim analysis. The purposes for the interim 
analysis are to allow early stopping of the study for futility or efficacy, to assess safety of the 
combination regimen, and to potentially adjust the sample size. The interim analysis will be 
performed after approximately 226 patients have documented progressive disease or die 
(approximately 65% of the total events expected).  If the value of the test statistic exceeds the 
Haybittle-Peto efficacy boundary (z ≥4.2059, p ≤0.000013), the trial may be stopped for 
efficacy. Under exponential distribution assumption, this boundary equates to a hazard ratio 
of ~0.55 or smaller in favor of the palbociclib plus letrozole arm versus the letrozole alone 
arm.. Alternatively, as appropriate, the sample size of the study may be adjusted using the 
method outlined by Cui et al.  If the results of the interim analysis indicate serious safety 
concerns, the sponsor will communicate with the Health Authorities regarding stopping the 
clinical trial.
An interim analysis for efficacy is also planned for the secondary endpoint of OS.  The 
analysis will be performed at the time of the interim or final PFS analyses if the primary 
endpoint PFS analysis is positive. The nominal significance levels for the interim and final 
analyses for OS will be determined by using the Lan-DeMets procedure with an 
O’Brien-Fleming stopping rule.  The overall significance level for the efficacy analysis of OS 
will be preserved at 0.025 (one-sided test).
 


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OS will be hierarchically tested for significance at the time of PFS analyses, provided the 
primary endpoint, PFS, is statistically positive at the interim 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, OS will not be statistically 
evaluated. 
All patients treated with at least one dose of study treatment (ie, PD-0332991/placebo or 
letrozole) will be included in all safety analyses.  Summaries of AEs and other safety 
parameters will be provided as appropriate.  Frequencies of patients experiencing at least one 
AE will be displayed by body system and preferred term according to MedDRA terminology.  
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, severity, relationship to study drug, action taken, and clinical 
outcome.  Severity of the AEs will be graded according to the NCI CTCAE version 4.0.  
Summary tables of clinical laboratory results will be prepared to examine the worst toxicity 
grade on study and distribution of laboratory measures over time.  Shift tables will be 
provided to examine the distribution of laboratory abnormalities.
Breast cancer-specific quality of life mean scores at each assessment time point and change 
from baseline scores will be compared between the treatment arms at various time points 
using a mixed model repeated measures (MMRM) approach adjusting for specified 
covariates. In addition, analyses will be performed to determine if the change from baseline 
scores achieve the appropriate minimally important difference (MID) cut-off for the scale 
being examined. Patients from the ITT population who completed a baseline assessment and 
at least one post-baseline assessment prior to study treatment discontinuation will be 
considered evaluable for the patient-reported outcome (PRO) analysis.  In addition to the 
above analyses, an examination of the time to deterioration (TTD) also will be carried out 
using survival analysis methods. A composite definition for deterioration based on death, 
tumor progression, and MID will be used.
 


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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 (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol.
Please refer to Appendix 10 for the A5481008 Schedule of Activities for patients continuing to receive active treatment after 
IRB/IEC approval of Amendment 8.
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, v
Day 14
Day 1v
Time Window
±2d
±2d
±2d
±7d
Baseline Documentation
Informed Consent Processe
X
Medical/Oncological Historyf
X
Baseline Signs/Symptoms 
Xg
Retained Pharmacogenomic Blood 
Sampleh
X
Tumor Tissue for Biomarkeri
X
Xi
Physical Examination/Vital signsj
X
Xb
X
X
Ophthalmic Examinationk
X
X
X
ECOG Performance Status
X
X
X
X
Laboratory Studies
Hematologyl
X
Xb
X
X
X
Blood Chemistryl
X
Xb
X
X
X
12-Lead ECGm
Xm
Xb
Xm
Xn
X
Disease Assessment
Computed Tomography (CT)/Magnetic 
Resonance Imaging (MRI) Scans of 
Chest, Abdomen, Pelvis, any clinically 
indicated sites of disease, and of bone 
lesions; Clinical evaluation of 
superficial diseaseo
X
◄--►p,o
Performed every 12 weeks (±7 days) from the date
of randomization
X
Xo
 


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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, v
Day 14
Day 1v
Time Window
±2d
±2d
±2d
±7d
Radionuclide Bone Scan, Whole Bodyo
X
◄--►q,o
Performed every 24 weeks (±7 days) from the date 
of randomization
X
Xo
Other Clinical Assessments 
Drug Compliancer
◄--►
Averse Event Reportings
X
X
X
X
X
X
Review Concomitant 
Medications/Treatmentst
X
X
X
X
X
X
EuroQol; EQ-5Du
X
X
X
FACT - Breast Questionnaireu
Xu
X
X
Xy
Survival Follow-up
X
Study Treatment
Randomization 
X
Letrozole (both treatment arms)
Once Daily ◄--►w
PD-0332991 or Placebo
◄--►x
Once Daily on Day 1 to Day 21 of each cycle 
followed by 7 days off
Special Laboratory Studies 
Pharmacokineticsm
X
a.
Active Treatment Phase: All assessments should be performed prior to dosing with study medications on the visit day unless otherwise indicated.  
Acceptable time windows for performing each assessment are described in the column headers. For the purposes of this trial 1 cycle is 28 days. A cycle 
could be longer than 28 days if persistent toxicity delays the initiation of the subsequent cycle.
b.
Cycle 1/Day 1: Blood chemistry, hematology, 12-lead ECG and physical examination not required if acceptable screening assessment is performed within 
7 days prior to randomization.
c.
End of Treatment/Withdrawal: End of Treatment/Withdrawal evaluations will be performed as soon as possible but no later than 4 weeks (ie, 28 days) 
±7days from last dose of study treatment and prior to the initiation of any new anti-cancer therapy. Obtain these assessments if not completed during the 
previous 4 weeks on study (or within the previous 8 weeks for disease assessments).  
 


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d.
Post Treatment Follow-up: After discontinuation of study treatment, post-treatment follow-up information (ie, survival status, and post-study anti-cancer
therapy details [including regimen number, name of therapy, start/stop dates, and dates of disease progression on subsequent anti-cancer therapies]) will be 
collected every 6 months (±7 days) from the last dose of study treatment.  Telephone contact is acceptable.
e.
Informed Consent: Informed consent may be obtained greater than 28 days from randomization; however, must be obtained prior to any protocol required 
assessments being performed (with the exception of certain imaging assessments if meeting the criteria defined in Section 6.1).
f.
Medical/Oncological History: To include information on prior anti-cancer 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.
Retained Pharmacogenomic Blood Sample: A single 4 mL blood sample (Prep D1; K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected pre-dose at the Cycle 1 Day 1 visit from all patients, unless prohibited by local regulations, to be retained for possible analysis of genetic 
associations with pharmacokinetics, drug response or adverse drug reactions.  Examples of genes that may affect pharmacokinetics or drug response include, 
but may not be limited to, genes encoding drug metabolizing enzymes and transporters, and genes thought to be related to the mechanism of drug action.
i.
Mandatory Tumor Tissue For Confirmatory Testing and for Biomarker Assessments: Tumor tissue is required for patient participation.  Submission of 
formalin-fixed paraffin embedded (FFPE) tumor samples (blocks) of adequate size to allow for three 0.6 mm diameter x 5 mm deep core punches that will 
be used to generate a tissue microarray are needed.  If FFPE tissue block cannot be submitted, at least 12 glass slides, each containing an unstained 5-micron 
FFPE tissue section, will be required for patient participation. Tissue sample from a metastatic or recurrent tumor lesion must be provided whenever 
possible. If such tissue sample is unavailable, a de novo fresh biopsy is recommended when, in the investigator’s judgment, such biopsy is feasible and can 
be safely performed.  A sample of the original diagnostic tissue (ie, archival) will also be collected when available and sent to the sponsor-designated central 
laboratories for assessment of biomarkers associated with sensitivity and/or resistance to PD-0332991 (eg, Ki67, CDKN2A (p16), pRb).  Retrospective 
confirmation of ER status and prospective confirmation of HER2 status when required to be repeated for eligibility purpose will be performed using the most 
recent tumor sample.  Original diagnostic tumor tissue will be used for confirmation of ER and HER2 status in the event that a recurrent/metastatic tissue 
sample is not available and a fresh biopsy of the recurrent/metastatic lesion is not feasible.  An optional fresh tumor biopsy will be collected at the end of 
treatment visit, only for patients who discontinue treatment due to disease progression.  The tumor tissue will be used to determine possible mechanisms of 
resistance.  Tissue samples from all patients will be used for additional biomarker analyses.  Details on preparation of these samples including processing, 
storage, and shipment will be provided in the Study Manual.  
j.
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems (including general appearance, head, 
ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and 
pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, will be required at screening and, Day 1 of 
Cycles 1 and 2.  Symptom-directed physical examinations, blood pressure and pulse rate will be performed at subsequent visits.
k.
Ophthalmic Examinations: Once Amendment #3 is IRB approved, all newly enrolled patients will undergo an ophthalmic examination at baseline, and on 
study treatment after 3 months (Cycle 4 Day 1), 6 months (Cycle 7 Day 1), 12 months (Cycle 13 Day 1), every 12 months (Day 1 of Cycles 25, 37 etc…)
thereafter, and at the End of Treatment visit. Additional ophthalmic examinations may be performed during the study as clinically indicated (including for 
patients randomized prior to Amendment 3 approval). The ophthalmic examinations will include: best corrected distant visual acuity (Snellen), refractive 
error associated with best corrected distant visual acuity, intraocular pressure (IOP – one reading), slit lamp biomicroscopy of the anterior segment including 
cell count and flare grading, crystalline lens grading using the Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens Opacity Grading 
procedure, and fundoscopy. All ophthalmic examinations will be performed by an ophthalmologist. Refer to Section 7.2.3. Ocular Safety Assessments for 
further details on these procedures.
 


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l.
Hematology, and Blood Chemistry Panel: Hematology includes hemoglobin, WBC, absolute neutrophils, platelet count.  Blood chemistry includes 
AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, total calcium, total bilirubin, BUN (or urea), serum creatinine, and albumin.  Additional 
hematology/chemistries panels may be performed as clinically indicated. Additionally, hemoglobin A1c will be measured during the active treatment phase 
in all patients every 3 months from the date of randomization (ie, C4D1, C7D1, C10D1, etc), and at the end of treatment visit.
m. 12-Lead ECG/Pharmacokinetics: Refer to Pharmacokinetic and ECGs Schedule of Activities table for details and timing of procedures.
n.
12-Lead ECG: To be performed on Day 1 of Cycles 4, 7, and 10.  ECGs beyond Cycle 10 will be performed as clinically indicated.  Refer to 
Pharmacokinetic and ECGs Schedule of Activities table for further details and timing of procedures.
o.
Disease Assessments: Please refer to the tumor assessment requirement flowchart for details and timing of procedures.
p.
CT/MRI Scans of Chest, Abdomen, Pelvis, any clinically indicated sites of disease, and of bone lesions; clinical evaluation of superficial disease: Please 
refer to the tumor assessment requirement flowchart for details and timing of procedures.
q.
Radionuclide Bone Scan, Whole Body: Please refer to the tumor assessment requirement flowchart for details and timing of procedures.
r.
Drug Compliance: PD-0332991, placebo and letrozole bottle(s)/blisters including any unused capsules/tablets will be returned to the clinic for drug 
accountability.  Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.
s.
Adverse Events: For SAEs, the active reporting period begins from the time that the patient provides informed consent through and including 28 calendar 
days after the last administration of the investigational product.  Following the active safety reporting period, other SAEs of which the investigator becomes 
aware should be reported to Pfizer, unless the SAE is attributed by the investigator to complications of either the underlying malignancy or any subsequent 
anti-cancer therapy or to the patient’s participation in a subsequent clinical study.  AEs (serious and non serious) should be recorded on the CRF from the 
time the patient has taken at least one dose of study treatment through last patient visit.
t.
Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 28 days after the last dose of study treatment.
u.
EQ-5D, FACT-B Assessments: Patients will complete questionnaires prior to any study or medical procedure on Day 1 of Cycles 1, 2 and 3 and then 
Day 1 of every other cycle thereafter starting with Cycle 5 (ie, Cycle 5, 7, 9, etc), and at the end of treatment visit.  All self-assessment questionnaires must 
be completed by the patients while in the clinic and cannot be taken home.  Interviewer administration in clinic may be used under special circumstances.
v.
Cycle X, Day 1: In the event that the start of a new cycle is delayed due to treatment related toxicity, procedures required on Day 1 of the given cycle will be 
performed when PD-0332991/placebo is resumed.  New cycle Day 1 procedures (ie, physical examination, ECOG performance status, ECG, Quality of Life 
questionnaires, blood chemistry, hematology) that were performed prior to knowing the need to delay the start of the cycle do not need to be repeated (1) if 
not required to determine whether study drug may be resumed and (2) if performed within 7 days prior to study drug resumption.
w.
Letrozole (both treatment arms): To be taken orally, daily, and continuously.
x.
PD-0332991 or Placebo:To be taken orally, daily from Day 1 to Day 21 (21 days) of every 28-day cycle followed by 7 days off treatment. In the event the 
Day 1 clinic visit of the subsequent cycle is scheduled during the -2 day allowable visit time window (ie. Day 27, Day 28), patients must be instructed to 
complete their 7-day off treatment period of the current cycle prior to resuming blinded therapy even if criteria for treatment resumptions are met at the visit. 
Cycle off treatment periods of less than 7 days are considered protocol deviations. 
y.
FACT-B Assessments: After patients discontinue from the active treatment phase, FACT-B questionnaire will continue to be collected during the follow-up 
period every 6 months (±7 days) from the last dose of investigational product until patient permanent discontinuation from study or end of follow-up period 
whichever occurs first. During the follow-up period, all self-assessment questionnaires should preferably be completed by the patients during a scheduled 
clinic visit. However, if no clinic visits are being scheduled during the follow-up period interviewer administration via phone call may be used instead and 
documented accordingly in the patient source notes.
 


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Pharmacokinetic and ECGs, Schedule of Activities
Protocol Activity
Screening
Active Treatment Phase
End of 
Treatment
Within 28 days prior to randomization unless specified 
otherwise
Cycle 1
Cycle 2
Cycle
≥4
Day -27 
to
Day 0
Day 0 (day prior to Day 1)
Day 1
Day 14
Day 14
Day 1
ECGE* ECG1°
2 Hrs 
Post-ECG1
4 Hrs 
Post-ECG1
6 Hrs 
Post-ECG1
8 Hrs 
Post-ECG1
0 Hrs 
Pre-dose
0 Hrs 
Pre-dose
2 Hrs 
Post-dose
4 Hrs 
Post-dose
6 Hrs 
Post-dose
8 Hrs 
Post-dose
0 Hrs 
Pre-dose
0 Hrs 
Pre-Dose
Anytime
Group 1 (approx. 60 Patients) at selected sites
12 Lead ECGa
X
X
X
X
X
X
Xa
X
X
X
X
X
X
X
X
Pharmacokineticsb
X
X
X
X
X
X
Group 2 (All other patients)
12 Lead ECGa
X
Xa
X
X
X
X
Pharmacokineticsb
X
X
*ECGE = Triplicate ECGs performed to determine patient’s eligibility.
°ECG1 = First triplicate ECGs performed for patient in Group 1.
a.
12-lead ECG: A 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs. ECGs will be performed in triplicate approximately 2 minutes 
apart but within 10 minutes for all 3 ECGs.  It is preferable that the machine used has the 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.  Blinded manual interval measurements at a core ECG laboratory will be used for primary 
statistical analysis of ECG data in group 1 patients (as described below).  ECG measurements will include PR interval, QT interval, RR interval and QRS 
complex.  Additional ECGs may be performed as clinically indicated. 
Triplicate ECGs (also referred as ECGE) will be performed during the screening period for all patients to determine the mean QTc interval for eligibility 
purpose. 
Patients found to be eligible will be part of one of the two groups highlighted below depending on which site screened the patient.  ECG frequency for each 
group is described below:  
Group 1 (approximately 60 patients) at selected sites: 
•
On the day preceding treatment initiation (day 0), triplicate ECGs will be obtained at time 0 (first ECG also referred to as ECG1), and then 2, 4, 6, and 
8 hours after ECG1. 
•
At Cycle 1 Day 14, triplicate ECGs will be obtained at 0 hour (pre-dose) and then, 2, 4, 6, and 8 hours following PD-0332991/placebo dosing. Timing 
of ECGs performed on Day 14 MUST be time-matched (clock time ±35 minutes) with ECG assessments performed on Day 0 (eg, if ECG1 on Day 0 
was performed at 10:00 AM then the 0 hour triplicate ECGs on Day 14 must be performed within the 9:30AM-10:30AM timeframe but as close as 
possible to 10:00AM whenever feasible).  On day 14 of Cycle 1, study treatment should be administered immediately after the pre-dose PK draw has 
been collected. 
 


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All ECGs should be obtained after a fast of at least 1 hour.  ECGs should be performed immediately before PK blood draws at respective time points.  
Patients who cannot complete ECG measurements on Day 0 and/or PK-matched ECG measurements (both ECG and PK collected) on Day 14 will need to be 
replaced. 
•
Additionally, triplicate ECGs will be obtained for safety monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1*, Day 14 of Cycle 2, then on Day 1 of 
Cycles 4, 7, and 10.  ECGs beyond Cycle 10 will be performed as clinically indicated. 
Group 2 (all other patients): 
•
Triplicate ECGs will be obtained for safety monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1*, Day 14 of Cycles 1 and Cycle 2, then on Day 1 of 
Cycles 4, 7, and 10.  ECGs beyond Cycle 10 will be performed as clinically indicated. 
*NOTE: Triplicate ECGs do not need to be repeated on Day 1 of Cycle 1 if ECGE was performed within 7 days of the date of randomization. 
All triplicate ECG tracings will be sent electronically to a core ECG laboratory for blinded manual interval measurements.
If at any time the mean QTc is prolonged (≥501 msec on at least two separate ECGs, ie, CTCAE≥ Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including verification that the machine reading is accurate.  If manual reading 
confirms a QTc of ≥501 msec, immediate search for reversible causes (including electrolyte abnormalities, hypoxia and concomitant medications for drugs 
with the potential to prolong the QTc interval) should be performed.  In addition, repeat ECGs should be immediately performed hourly for at least 3 hours 
until the QTc interval falls below 501 msec. 
•
If QTc interval reverts to less than 501 msec, and in the judgment of investigator(s) in consultation with the sponsor the cause is determined to be due to 
cause(s) other than study drug, treatment may be continued with regular ECG monitoring under hospital supervision. 
•
If in that timeframe the QTc intervals remain above 501 msec the study drug will be held until the QTc interval decreases to <501 msec. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation by specialist.  If 
investigational product causality cannot be ruled out, Investigational product dose adjustment and/or discontinuation should be performed according to 
Section 5.3.4: Recommended Dose Modification. Additional triplicate ECGs may be performed as clinically indicated.
b.
Pharmacokinetics (collected right after ECG assessment): For patients in the ECG Group 1, plasma PK samples for PD-0332991 (including its active 
metabolites, if appropriate) determination will be obtained at the times indicated for ECGs. One additional plasma PK sample will be collected pre-dose on 
Day 14 of Cycle 2. 
For all other patients (ECG Group 2), plasma PK samples for PD-0332991 (including its active metabolites, if appropriate) determination will be collected 
prior to dosing (pre-dose) on Day 14 of Cycle 1 and Cycle 2. 
Additional blood samples may be requested from patients experiencing unexpected or serious adverse events, or adverse events that lead to discontinuation.
 


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TUMOR ASSESSMENT REQUIREMENTS FLOWCHART
Please refer to Appendix 10 for the A5481008 Schedule of Activities for patients continuing to receive active treatment after 
IRB/IEC approval of Amendment 8.
Screeninga
Treatment Periodb
End of Treatment Visitc
CTd or MRI of chest, abdomen, and 
pelvis (CAP)
Requirede
Required
Required
CTd or MRI of any other site of 
disease, as clinically indicated
Requirede, f
Required for sites of disease 
identified at screening
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere
Radionuclide bone scan (whole body)
and correlative bone imaging
Requiredg,h
Required for sites of disease 
identified at screening or if 
clinically indicatedi
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere
Photographs of all superficial lesions 
as applicablej
Required
Required for sites of disease 
identified at screening
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere
a.
Screening scans must occur within 4 weeks (ie, 28 days) prior to randomization unless otherwise specified. 
b.
Tumor assessment must be done during the treatment period, every 12 weeks (±7 days) and bone scans (as applicable) every 24 weeks (±7 days) from 
randomization until radiographically and/or clinically (ie, for photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment 
discontinuation (for patients continuing treatment beyond RECIST-defined disease progression), initiation of new anti-cancer therapy or discontinuation of 
patient from overall study participation (eg, death, patient's request, lost to follow up), whichever occurs first.  The schedule of assessments should be fixed 
according to the calendar, regardless of treatment delays/interruptions.  Imaging assessments are to be scheduled using the randomization date as the 
reference date for all time-points and are NOT to be scheduled based on the date of the previous imaging time-point.  Imaging assessment delay to conform 
to treatment delay is not permitted.  The same tumor assessment technique MUST be used throughout the study for a given lesion/patient. 
c.
Patients who have already demonstrated objective disease progression as per RECIST v.1.1 do not need to have scans repeated at the end of treatment visit 
or during the post-treatment follow-up.  For patients who do not have documented objective disease progression at time of study treatment discontinuation, 
tumor assessment will continue to be performed every 12 weeks (±7 days) and bone scans (as applicable) every 24 weeks (±7 days) until radiographically 
and/or clinically confirmed objective disease progression, initiation of new anti-cancer 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 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).
 


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e.
Radiographic assessments obtained per the patient’s standard of care prior to randomization into the study do not need to be repeated and are acceptable to 
use as baseline evaluations, if (1) obtained within 28 days before randomization, (2) they were performed using the method requirements outlined in 
RECIST v.1.1 (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, and (4) appropriate 
documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. 
f.
Baseline brain scans are only required if signs and symptoms suggest presence of metastatic brain disease. Brain scans performed before the signing of 
informed consent as routine procedures (but within 6 weeks before randomization) do not need to be repeated and may be used as baseline assessments as 
long as (1) tests were performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality can be used to follow identified 
lesions throughout the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor assessments were performed as 
standard of care is available in the patient’s source notes.  Post-baseline repeat brain scans will only be required only if metastases are suspected. 
g.
Bone scans will be carried out at baseline for all patients within 12 weeks prior to randomization in order to detect bony sites of disease. Bone scans 
performed before the signing of informed consent as routine procedures (but within 12 weeks before randomization) do not need to be repeated and may be 
used as baseline assessments as long as (1) tests were performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality 
can be used to follow identified lesions throughout the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor 
assessments were performed as standard of care is available in the patient’s source notes.
h.
Any suspicious abnormalities (ie, hotspots) identified on the bone scans at baseline and on subsequent bone scans MUST be confirmed by X-ray, CT scan 
with bone windows or MRI.  The same modality must be used throughout the trial for confirmation for a given lesion/patient.  Bone lesions identified at 
baseline will be followed up according to the same assessment schedule (ie, every 12 weeks ±7 days from randomization) as for all other lesions.  Areas that 
have received palliative radiotherapy cannot be used to assess response to study treatment.
i.
If bone lesions were identified at baseline bone scans will be repeated during the active treatment phase every 24 week (±7 days) from the date of 
randomization and at the time of confirmation of CR.  If no bone lesions were identified at baseline, bone scans will only be repeated during the active 
treatment phase when clinically indicated (ie, patient describes new or worsening bone pain, or has increasing alkaline phosphatase level, or other signs and 
symptoms of new/progressing bone metastases) but are required at the time of confirmation of CR. New Abnormalities found on subsequent bone scans 
must also be confirmed by X-ray, CT scan with bone windows or MRI. 
j.
Clinical assessment of superficial disease must be carried out on the same date as the imaging studies and will include photographs of all superficial 
metastatic lesions. All lesion measurements must be recorded in the case report form (CRF).
Notes: 
- Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression at the discretion of the investigator.  If progressive 
disease is confirmed per RECIST v.1.1, patients are expected to discontinue study therapy and begin the follow-up phase of the trial. However, patients may 
continue treatment as assigned at randomization beyond the time of RECIST-defined PD at the discretion of the investigator if that is considered to be in the best 
interest of the patient and as long as no new anti-cancer treatment is initiated.  
 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................32
APPENDICES .........................................................................................................................33
1. INTRODUCTION ...............................................................................................................34
1.1. Indication.................................................................................................................34
1.2. Background and Rationale ......................................................................................34
1.2.1. Role of Letrozole in the Treatment of Estrogen Receptor Positive 
Breast Cancer...................................................................................................34
1.2.2. Interaction of Estrogens and Cyclin-Dependent Kinases in Breast 
Cancer Cells.....................................................................................................35
1.2.3. Deregulation of Cell Cycle Related Genes and Proteins in Breast 
Cancer ..............................................................................................................36
1.2.4. ER and HER2 Status in Breast Cancer.......................................................36
1.2.5. Overview of PD-0332991...........................................................................37
1.2.5.1. Preclinical Data .........................................................................37
1.2.5.2. Human Pharmacokinetic (PK) Data..........................................37
1.2.5.3. QTc Evaluation Data.................................................................39
1.2.5.4. Preclinical Ocular Data .............................................................40
1.2.5.5. PD-0332991 Dose Rationale.....................................................42
1.2.5.6. Phase I/II Data in Combination with Letrozole in 
Advanced Breast Cancer ...................................................................42
1.2.6. Study Rationale...........................................................................................44
1.2.7. Amendment Rationale ................................................................................45
1.2.7.1. Rationale for Changes in Amendment 1, 01 October 2013 ......45
1.2.7.2. Rationale for Changes in Amendment 2, 03 January 2014.......45
1.2.7.3. Rationale for Changes in Amendment 3, 21 March 2014.........45
1.2.7.4. Rationale for Changes in Amendment 4, 18 September 
2014 ...................................................................................................46
1.2.7.5. Rationale for Changes in Amendment 5, 02 December 
2014 ...................................................................................................46
1.2.7.6. Rationale for Changes in Amendment 6, 07 April 2015...........47
1.2.7.7. Rationale for Changes in Amendment 7, 15 October 2015 ......47
1.2.7.8. Rationale for Changes in Amendment 8, 21 May 2018............47
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................49
 


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2.1. Objectives................................................................................................................49
2.2. Endpoints.................................................................................................................49
3. STUDY DESIGN.................................................................................................................50
4. PATIENT SELECTION......................................................................................................53
4.1. Inclusion Criteria.....................................................................................................53
4.2. Exclusion Criteria....................................................................................................54
4.3. Randomization Criteria ...........................................................................................56
4.4. Sponsor’s Qualified Medical Personnel..................................................................57
5. STUDY TREATMENTS.....................................................................................................57
5.1. Allocation to Treatment ..........................................................................................57
5.2. Breaking the Blind ..................................................................................................58
5.3. Drug Supplies..........................................................................................................58
5.3.1. Formulation and Packaging........................................................................58
5.3.1.1. PD-0332991 ..............................................................................58
5.3.1.2. Placebo ......................................................................................59
5.3.1.3. Letrozole....................................................................................59
5.3.2. Preparation and Dispensing........................................................................59
5.3.2.1. PD-0332991/Placebo.................................................................59
5.3.2.2. Letrozole....................................................................................59
5.3.3. Administration............................................................................................60
5.3.3.1. PD-0332991/Placebo.................................................................60
5.3.3.2. Letrozole....................................................................................60
5.3.3.3. General Rules ............................................................................60
5.3.4. Dose Modification ......................................................................................61
5.3.4.1. Letrozole....................................................................................61
5.3.4.2. PD-0332991/Placebo.................................................................61
5.3.5. Medication Errors and Overdose................................................................65
5.3.6. Compliance.................................................................................................66
5.4. Drug Storage and Drug Accountability...................................................................66
5.4.1. PD-0332991/Placebo..................................................................................66
5.4.2. Letrozole.....................................................................................................67
5.5. Concomitant Medications .......................................................................................67
 


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5.5.1. Prohibited Medications...............................................................................67
5.5.2. Medications Not Recommended.................................................................68
5.5.3. Permitted Medications................................................................................69
5.6. Concomitant Radiotherapy or Surgery....................................................................70
6. STUDY PROCEDURES .....................................................................................................70
6.1. Screening.................................................................................................................70
6.1.1. Screen Failure .............................................................................................72
6.2. Active Treatment Phase ..........................................................................................72
6.3. End of Treatment Visit............................................................................................72
6.4. Follow-up Visit .......................................................................................................73
6.5. Patient Withdrawal..................................................................................................73
6.5.1. Active Treatment Phase Discontinuation ...................................................73
6.5.2. Study Discontinuation ................................................................................74
7. ASSESSMENTS..................................................................................................................75
7.1. Efficacy Assessments..............................................................................................75
7.1.1. Independent Review of Disease Assessments............................................75
7.1.2. Tumor Assessments....................................................................................76
7.1.3. Overall Survival..........................................................................................79
7.2. Safety Assessments .................................................................................................79
7.2.1. Laboratory Safety Assessments..................................................................79
7.2.2. Electrocardiogram (ECG)...........................................................................80
7.2.3. Ocular Safety Assessments.........................................................................81
7.2.3.1. Snellen Best Corrected Visual Acuity and Refraction..............81
7.2.3.2. Intraocular Pressure Measurement............................................82
7.2.3.3. Slit-lamp Biomicroscopy...........................................................82
7.2.3.4. Lens Grading.............................................................................83
7.2.3.5. Funduscopy (Ophthalmoscopy) ................................................84
7.2.4. Other Safety Assessments...........................................................................84
7.3. Pharmacokinetic Assessments.................................................................................84
7.4. Patient Reported Outcomes.....................................................................................85
7.4.1. EuroQol Health Utilities Index EQ-5D (Appendix 5)................................86
 


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7.4.2. Functional Assessment of Cancer Therapy-Breast (FACT-B) 
[Version 4] (Appendix 6).................................................................................86
7.5. Biomarker Assessment............................................................................................86
7.5.1. Optional Tumor Tissue Biopsy for Molecular Profiling ............................87
7.6. Retained Pharmacogenomic Sample(s)...................................................................87
7.6.1. Pharmacogenomics of Drug Response .......................................................87
7.6.2. Additional Pharmacogenomic Research (Optional)...................................88
8. ADVERSE EVENT REPORTING......................................................................................88
8.1. Adverse Events........................................................................................................88
8.2. Reporting Period .....................................................................................................89
8.3. Definition of an Adverse Event...............................................................................89
8.4. Abnormal Test Findings..........................................................................................90
8.5. Serious Adverse Events...........................................................................................90
8.5.1. Protocol-Specified Serious Adverse Events...............................................91
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................91
8.6. Hospitalization ........................................................................................................92
8.7. Severity Assessment................................................................................................94
8.8. Causality Assessment..............................................................................................94
8.9. Exposure During Pregnancy....................................................................................95
8.10. Occupational Exposure .........................................................................................96
8.11. Withdrawal Due to Adverse Events (See Also Section on Patient 
Withdrawal)...............................................................................................................96
8.12. Eliciting Adverse Event Information ....................................................................96
8.13. Reporting Requirements........................................................................................96
8.13.1. Serious Adverse Event Reporting Requirements .....................................96
8.13.2. Non-Serious Adverse Event Reporting Requirements .............................97
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................98
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................98
9.1. Sample Size Determination.....................................................................................98
9.2. Analysis Population.................................................................................................99
9.2.1. Intent-to-Treat Population (ITT).................................................................99
9.2.2. As-Treated Population (AT).......................................................................99
 


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9.3. Efficacy Analysis ....................................................................................................99
9.3.1. Analysis of Primary Endpoint ..................................................................100
9.3.2. Analysis of Secondary Endpoints.............................................................100
9.4. Analysis of Other Endpoints .................................................................................104
9.5. Safety Analysis......................................................................................................104
9.6. Interim Analysis ....................................................................................................105
9.7. Data Monitoring Committees................................................................................106
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................107
11. DATA HANDLING AND RECORD KEEPING ...........................................................107
11.1. Case Report Forms/Electronic Data Record .......................................................107
11.2. Record Retention.................................................................................................108
12. ETHICS............................................................................................................................108
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........108
12.2. Ethical Conduct of the Study ..............................................................................108
12.3. Patient Information and Consent.........................................................................109
12.4. Patient Recruitment.............................................................................................109
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................109
13. DEFINITION OF END OF TRIAL.................................................................................110
13.1. End of Trial in a Member State...........................................................................110
13.2. End of Trial in all Participating Countries ..........................................................110
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................110
15. PUBLICATION OF STUDY RESULTS........................................................................110
15.1. Communication of Results by Pfizer ..................................................................110
15.2. Publications by Investigators ..............................................................................111
16. REFERENCES ................................................................................................................113
LIST OF TABLES
Table 1.
PD-0332991/Placebo Capsule Characteristics .....................................................58
Table 2.
Available Dose Levels..........................................................................................64
Table 3.
PD-0332991/Placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal 
Medical Treatment................................................................................................64
 


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Table 4.
PD-0332991/Placebo Dose Modifications in the Event of QTc 
Prolongation..........................................................................................................65
APPENDICES
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............120
Appendix 2. Sponsor Approved HER2 Assays .....................................................................121
Appendix 3. List of Drugs Known to Predispose to Torsade de Pointes...............................122
Appendix 4. Bone Marrow Reserve in Adult ........................................................................123
Appendix 5. EuroQol Health Utilities Index EQ-5D.............................................................125
Appendix 6. Functional Assessment of Cancer Therapy-Breast (FACT-B) [Version 4]......128
Appendix 7. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines...........................................................................................................131
Appendix 8. Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure ................................................................................136
Appendix 9. List of Abbreviation..........................................................................................138
Appendix 10. Schedule of Activities for Patients Continuing to Receive Active 
Treatment After IRB/IEC Approval of Amendment 8.......................................141
 


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1. INTRODUCTION
Breast cancer (BC) is the most common invasive cancer in women, with more than one 
million cases and over 411,000 deaths occurring worldwide annually.1  Although 
age-adjusted mortality from breast cancer has been decreasing since 1990, the median 
survival for patients with metastatic disease is still only approximately 18 to 24 months2 and 
the medical need for more active agents in this clinical setting remains very high.
The role of estrogens in breast cancer etiology and progression is well established.  
Modification of estrogen activity or synthesis represents the treatment of choice for 
postmenopausal women with hormonal receptor positive advanced breast cancer, particularly 
for those with slowly progressive disease and limited tumor-related symptoms. Letrozole 
(Femara®) is an oral nonsteroidal aromatase inhibitor and it is approved worldwide for the 
first-line treatment of postmenopausal women with hormone receptor-positive advanced 
breast cancer (ABC).
1.1. Indication
Estrogen receptor-positive (ER(+)), HER2 negative (HER2(-)) Advanced Breast Cancer 
(ABC)
1.2. Background and Rationale
1.2.1. Role of Letrozole in the Treatment of Estrogen Receptor Positive Breast Cancer
Approximately two-thirds of breast cancers express estrogen receptor (ER)3 and a role for 
estrogens in breast cancer etiology and progression is well established. Modification of 
estrogen activity or synthesis represents the treatment of choice for postmenopausal women 
with hormone receptor-positive ABC, particularly for those with slowly progressive disease 
and limited tumor-related symptoms.2
Conversion of androgens to estrogens via aromatase enzyme action represents the main 
source of estrogens in postmenopausal women.  Letrozole (Femara®) is an oral nonsteroidal 
aromatase inhibitor that is approved worldwide for the first-line treatment of postmenopausal 
women with hormone receptor-positive ABC.  In a multicenter Phase 3 trial,4 916 patients
with hormone receptor-positive or hormone receptor-unknown ABC were randomized to 
receive either letrozole or tamoxifen until disease progression. Most of the patients 
(91%) had received no prior treatment for their advanced disease. Letrozole was superior to 
tamoxifen for time to tumor progression (median, 9.4 vs 6.0 months, P<0 .0001), time to 
treatment failure (median, 9 vs 5.7 months, P<0.0001), overall objective response rate 
(32% vs 21%, P= 0.0002), and overall clinical benefit (50% vs 38%, P=0 .0004). Median 
overall survival (OS) was slightly prolonged for the letrozole arm (34 vs 30 months);
however, approximately 50% of the patients in the tamoxifen arm crossed over to letrozole at 
disease progression.
Letrozole is administered orally on a continuous 2.5 mg daily dosing regimen. Multiple 
clinical studies have shown that letrozole is well tolerated. 
 


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1.2.2. Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer Cells
Studies of ER-positive breast cancer cell lines indicate that estrogens5 and antiestrogens6 act 
on sensitive populations of cells in early to mid-G1 phase.  G1/S transition is under the 
control of CDKs activated by specific complex formation with regulatory cyclins.  
CDK4 and CDK6 are activated by binding to D-type cyclins and act early in G1 phase.7-10 A 
primary target of CDK action in G1 phase is the retinoblastoma susceptibility gene product 
(pRb), which mediates G1 arrest through sequestration of transcriptional factors of the 
E2F-DP family. Phosphorylation of pRb and other members of the pocket protein family 
(p107 and p130) by active cyclin-CDK complexes leads to release of E2F and DP 
transcription factors and transcription of requisite genes for S-phase entry.10
D-type cyclins play an essential role in recognition of extracellular growth stimuli and
initiation of G1 transit,11,12 and several lines of evidence have linked estrogen regulation of 
cellular proliferation to cyclin D1 expression. Estrogen-induced proliferation of normal 
uterine and breast epithelium in vivo is associated with increased expression of 
cyclin D1 mRNA and protein.13-16 Expression of cyclin D1 in breast tumor isolates 
correlates with ER-positive status.17-19 MCF-7 breast cancer cells treated with estrogen 
exhibit increased expression of cyclin D1 mRNA and protein, formation of active cyclin 
D1-CDK4 complexes, and phosphorylation of pRb leading to G1 /S transition.20-23
Estrogen-induced S-phase entry in these cells is inhibited by microinjection of antibodies to 
cyclin D1.24 Antiestrogen-induced growth arrest of ER-positive breast cancer cells is 
associated with decreased cyclin D1 expression.25 Collectively, these studies are consistent 
with a model of estrogen action in which receptor activation induces increased 
cyclin D1 expression, CDK4 activation, and cell cycle progression. An upstream role for 
cyclin D1 has been suggested by recent reports describing direct physical interactions 
between cyclin D1 and the ER, leading to recruitment of steroid receptor coactivators and 
activation of ER-dependent transcription.  This occurs in the absence of hormone and is 
independent of D-type cyclin association with CDK4.26-29
Constraint upon CDK activity and G1 progression is provided by the universal CDK 
inhibitors of the Cip-Kip family, including gp21Cip1 and p27Kip1, and the specific 
CDK4 and CDK6 inhibitors of the INK4 family, typified by p16INK4a.12,30-33 The CDKN2A 
gene product inhibits formation of active D-type cyclin-CDK complexes through specific 
binding interactions with CDK4 or CDK6 that prevent D-type cyclin-CDK association.34-36
Over expression of p16INK4a in cells with functional pRb results in inhibition of both 
CDK4-and CDK6-associated kinase activity and pRb phosphorylation, with subsequent cell 
cycle arrest.34,35 In addition, inhibition of D-type cyclin-CDK4 complex formation by 
p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, 
leading to suppression of cyclin E-CDK2 activity.37-39
Overexpression of p16INK4a through adenoviral transduction of CDKN2A into MCF-7 cells 
leads to G1 arrest associated with inhibited CDK activity.40,41 Cell cycle progression induced 
by estradiol requires action of the steroid through mid-G1, well beyond the point of cyclin 
D1-CDK4 activation.21 Functional association of cyclin D1-CDK4 is required for 
estrogen-induced CDK2 activation and G1/S transition and estrogen regulates expression of 
p21Cip1, p27Kip1, and Cdc25A independent of D-type cyclin-CDK4 function.42
 


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1.2.3. Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer
Cell cycle related genes and proteins are frequently deregulated in breast cancer.  
Approximately 15%–20% of human breast cancers exhibit amplification of the 
cyclin D1 (CCND1) gene,43-45 while the majority of human mammary carcinomas over
express cyclin D1 protein.46-48 Over expression of cyclin D1 is seen early in breast cancer, 
and it is maintained at all stages of breast cancer progression, including metastatic 
lesions.46,49 Amplification of the CDK4 gene, located at 12q13-q14, has been shown as an 
alternative genetic alteration to CDKN2A inactivation in various human tumor including 
breast cancer.50,51 There is a mounting body of evidence linking a specific 
CCND1 polymorphism (G/A870) to increased risk of cancer and outcome in a variety of 
tumor types including breast cancer.  This polymorphism results in a splice variant, altered 
protein structure and enhanced oncogenic activity in experimental models.52  The continued 
presence of CDK4-associated kinase activity is actually required to maintain breast 
tumorigenesis.53 Direct analyses of primary tumors have revealed loss of pRb expression in 
20–35% of tumors, and loss of heterozygosity or other alterations of the Rb locus in 
7-37% of tumors.54-57 In preclinical models, Rb depletion appears to be associated with 
resistance to antiestrogen therapy.58 Finally, virtually all ER-positive cell lines harbor loss of 
p16INK4a 59,60 expression, and low expression of CDK inhibitors p21 and p27 and high 
expression level of cyclin E and D1 have all been associated with resistance to anti-estrogen 
therapy.
1.2.4. ER and HER2 Status in Breast Cancer
The ER and HER2 status of breast metastatic disease are usually assumed to be the same as 
that of the primary tumor. However, mounting evidences from both prospective and 
retrospective studies have shown a discordant rate of approximately 25% in either ER or 
HER2 status between primary breast tumor and its metastatic lesions.61,62 The change can be 
from ER- positive primary tumor to ER-negative metastatic disease or vice versa. The
analytical variables of immunohistochemistry (IHC) testing such as antigen retrieval and 
subjectivity in observer analysis also contribute to the observed discordance.63 Another 
dilemma in ER testing accuracy has been primary institutional site testing versus high 
volume central laboratory testing. It has been stated in the recently published American 
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines 
for ER testing that the concordance rate between local and central laboratory testing for ER is 
about 80 to 90%.64 This variation may be due to the lack of rigorous assay optimization 
and/or reproducibility of IHC testing procedures at some of local testing laboratories
including methods of antigen retrieval and subjectivity in observer analysis. This highlights
the importance of confirmative testing of ER status using Food and Drug Administration 
(FDA)-cleared and/or approved kits and platform at a central CLIA/CAP certified laboratory 
to minimize, if not eliminate, these differences/variables for patients participating in clinical
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1.2.5. Overview of PD-0332991
PD-0332991 (Molecular Weight: 573.67) is an orally active potent and highly selective 
reversible inhibitor of CDK4 and CDK6.  The compound prevents cellular deoxyribonucleic 
acid (DNA) synthesis by prohibiting progression of the cell cycle from G1 into the S phase.
1.2.5.1. Preclinical Data
Treatment of cultured tumor cells with PD-0332991 causes growth arrest that is accompanied 
by the inhibition of specific pRb phosphorylation by CDK4 or CDK6 on residues serine
-780 and -795 of pRb.  The IC50 values for reduction of pRb phosphorylation at serine 
-780 and -795 in MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 μM, 
respectively.  The IC50 values for reduction of pRb phosphorylation are similar to the 
IC50 values of inhibition of thymidine incorporation across a range of cultured tumor and 
normal cells.
PD-0332991 was tested in vitro on molecularly characterized human breast cancer cell lines.  
Results from these experiments indicate that those cell lines that are more sensitive to 
PD-0332991 (IC50 <150 nM) have low levels of CDKN2A (p16) and high levels of 
Rb1, while resistant cell lines show the opposite characteristics. Sensitive cell lines in this 
panel represent mostly the luminal ER+ subtype.65 The combination of PD-0332991 and 
aromatase inhibitors has not been tested in preclinical models. However, the combination of 
PD-0332991 with tamoxifen has recently been tested in vitro in ER+ human breast cancer 
cell lines indicating a synergistic interaction65 and provides a biologic rationale for evaluating 
the combination of PD-0332991 with anti-hormonal therapy in the clinic.
1.2.5.2. Human Pharmacokinetic (PK) Data
To date, pharmacokinetic data have been collected in 4 clinical studies in cancer patients
(A5481001, A5481002, A5481003 and A5481004).  Pharmacokinetic parameters are 
available from all 74 patients enrolled in Study A5481001 following a single dose (Day 1 of 
Cycle 1), and from 51 patients following multiple-dose administration (Day 8 of Cycle 1) at
daily doses ranging from 25 to 225 mg of PD-0332991.  In addition, PK parameters are also 
available for nine patients on Day 14 of Cycle 1 (from patients on Schedule 2/1, ie, 2 weeks
on treatment followed by 1 week off treatment) and 4 patients on Day 21 of Cycle 1 (from 
patients on Schedule 3/1, ie, 3 weeks on treatment followed by 1 week off treatment).  The 
exposure (AUC(0-10) and Cmax) increased in a dose proportional manner over the dose range of 
25 to 225 mg once daily (QD) following PD-0332991 administration on Days 1 and 8 of 
Cycle 1, although some variability (low to moderate) around these doses was observed 
particularly at the 150 mg QD dose level.  Following repeated daily dosing to Day 14 and 
Day 21 (assumed to be steady state), PD-0332991 was absorbed with a median Tmax of 
~4 hours.  The mean PD-0332991 Vz/F was 3103 L, which is significantly greater than total 
body water (42 L), indicating that PD-0332991 extensively penetrates into peripheral tissues.  
PD-0332991 was eliminated slowly; the mean t½ was 26.5 hours (ranged 15.8 to 36.2 hours) 
and the mean CL/F was 86.1 L/hour.  PD-0332991 accumulated following repeated dosing 
with a median Rac of 2.4, which is consistent with a half life of ~27 hours.
 


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Preliminary results from the recently performed food effect study, A5481021, a Phase 1, 
open-label 4 sequence 4 period crossover study of palbociclib (PD-0332991) in healthy 
volunteers to estimate the effect of food on the bioavailability of palbociclib, suggest that the 
administration of palbociclib with food results in more consistent drug absorption and 
exposure than administration of palbociclib in a fasted state. As a result of these findings,
patients should be instructed to take palbociclib with food.  
Preliminary results from the recently performed antacid effect study, A5481018, a Phase 1, 
open-label fixed-sequence 2-period crossover study of palbociclib in healthy subjects to 
investigate the potential effect of antacid treatment on the pharmacokinetics of a single oral 
dose administered under fasted conditions, suggest that the administration of proton-pump 
inhibitors concomitantly with palbociclib treatment leads to a significant decrease in 
palbociclib exposure. Since proton-pump inhibitors affect the pH of the upper GI tract for an 
extended period the concomitant use of proton-pump inhibitors with PD-0332991 should be 
avoided. 
Study A5481038, a Phase 1 study was designed to investigate the effect of famotidine (an
histamine H2-receptor antagonist) given 10 hours before and 2 hours after palbociclib; 
rabeprazole sodium (a proton-pump inhibitor (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 
palbociclib 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 this data, under fed 
conditions, the use of H2-receptor antagonists or local antacids or PPIs is now permitted as 
defined in Section 5.5.3. 
Pharmacokinetic data from Study A5481002 indicate that PD-0332991 exposure at steady 
state in mantle cell lymphoma patients, is similar to that observed in solid tumors 
(Protocol A5481001).
Pharmacokinetic analysis of preliminary data from the Phase 1 portion of 
Study A5481003 (breast cancer, combination with letrozole) was conducted to evaluate the 
potential for drug-drug interaction between PD-0332991 and letrozole.  The results indicate 
lack of a potential for drug-drug interaction between PD-0332991 and letrozole when 
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PD-0332991 is metabolized to multiple metabolites in a qualitatively similar manner in rat, 
dog and human liver microsomes.  In vitro, PD-0332991 is primarily metabolized by 
CYP3A4 enzymes. An exploratory evaluation of the circulating metabolites for 
PD-0332991 was conducted in plasma samples obtained from patients treated with 
PD-0332991 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 
PD-0332991 and the lactam of PD-0332991 (PF-05089326) were the main metabolites 
present in plasma.  Other metabolites observed were the glucuronide conjugates of 
hydroxylated PD-0332991 and the glucuronide conjugate of reduced PD-0332991.  
PF-05089326 was also observed in the circulation of rats following repeated daily oral 
administration of PD-0332991 at the dose levels of 50 and 100 mg/kg/day.  Plasma protein 
binding of PD-0332991 and PF-05089326 is ~85% and 95%, respectively.
1.2.5.3. QTc Evaluation 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 (refer to the PD-0332991 investigator's brochure for additional 
details).
A preliminary pharmacokinetic/pharmacodynamic analysis has been conducted to explore 
the QT/QTc and plasma PD-032991 concentration relationship for Study A5481001 (FIH 
study) by using graphical methods and mixed effects linear modeling (NONMEM).  Data 
from 73 patients were used for the analysis, and an analysis of the QTcF and QTcB data 
demonstrated that QTcF was the more appropriate correction method based on plots of the 
QTc versus RR interval. No patient had a maximum on treatment QTcF value of ≥500 msec.  
The QTcF changes from the baseline at the mean Cmax calculated for 200 mg dose were 
simulated for 10000 patients.  The mean and upper 95% confidence interval of QTcF change 
from the baseline were 5.8 and 9.4 msec, respectively.
In order to achieve more extensive evaluation of the effect of PD-0332991 on QTc 
prolongation, time-matched electrocardiogram (ECG) and PK data will be collected in a 
subset of at least 60 patients participating to Study A5481008 (see Schedule of Activities
table and Section 7.2.2 for further details).
Results from Study A5481008 showed that in the QTc analysis population, no patients had a 
postbaseline absolute mean maximum QTcF or QTcS of ≥500 msec or a maximum increase 
from QTcF or QTcS baseline of ≥60 msec during the intensive QTc assessment period. A 
random effect analysis of the QTc data in the QTc analysis population demonstrated that the 
upper bounds of the 1-sided 95% CI for the mean change time-matched from baseline for 
QTcF, QTcS and QTcB were <10 msec at all time points in the QTc assessment period, 
indicating that palbociclib, when added to letrozole at the recommended dosing regimen, did 
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1.2.5.4. Preclinical Ocular Data
Preliminary results from an ongoing 27-week repeat-dose oral toxicity study with 
PD-0332991 in Sprague-Dawley rats identified a potential nonclinical safety finding related 
to the eye. Palbociclib was administered by oral gavage at doses of 0, 10, 30, and 
100 mg/kg/day in males and 0, 50, 100, and 300 mg/kg/day in females (20/sex/group; 
15/sex/group in main and 5/sex/group in recovery) on an intermittent dosing schedule 
(7 cycles of treatment where each cycle consisted of 3 weeks of continuous daily dosing 
followed by a 1-week non-dosing period) for 27 weeks. Animals were evaluated by indirect 
ophthalmoscopy and by slit lamp biomicroscopy predose and prior to termination (within 
7 days prior to scheduled necropsy). Indirect ophthalmoscopy results revealed a degraded 
view of the fundus and the presence of cataracts in males treated at high dose
(100 mg/kg/day) that had normal fundus examinations prior to the start of the study. 
Cataracts (anterior cortical, incomplete, and complete) were identified by slit lamp 
biomicroscopy in male rats at ≥30 mg/kg/day with dose-related severity (Table 1), but not in 
females at any dose tested (up to 300 mg/kg/day).
Lens degeneration was observed microscopically with dose-related incidence and with 
minimal to moderate severity in males at ≥30 mg/kg/day and minimal severity in males at 
10 mg/kg/day and females at ≤100 mg/kg/day (not identified in females at 300 mg/kg/day).  
Lens degeneration was identified in all animals that were noted with cataracts by slit lamp 
ophthalmoscopy.
The available data suggests that the cataracts and/or lens degeneration observed at the lowest 
doses in both male and female rats are palbociclib-related. Exposures in this non clinical 
study are comparable to clinical exposures at the recommended human dose of 125 mg QD 
(unbound AUC 301 ng•h/mL).
The mechanism for cataract formation in palbociclib-treated rats is unknown; however, 
emergent data from the 27-week rat toxicity study suggested its pathogenesis in rats may be 
related to altered glucose metabolism.  Ten of 11 male rats with lens degeneration were 
shown to have glycosuria (+2 or +3) and/or increased serum glucose (compared to the upper 
range of control values).  One of 3 female rats with lens degeneration also had glycosuria and 
hyperglycemia.  In addition to the correlation observed between altered glucose metabolism 
and lens degeneration, a correlation between altered glucose metabolism and pancreatic islet 
cell vacuolation was identified in all (10 of 10) male animals with the histological change.  In 
females, the one female with lens degeneration that correlated with glycosuria and 
hyperglycemia also had pancreatic islet cell vacuolation. No altered glucose levels, 
cataracts/lens degeneration, or pancreatic islet cell vacuolation have been observed in the 
39-week dog toxicity study.  
To date, approximately 1200 patients have enrolled in palbociclib trials. A review of the 
Pfizer safety database for cases received through 14 January 2014 identified no serious cases 
from clinical studies or other solicited sources including palbociclib or blinded therapy that 
included adverse events which code to the MedDRA (Version 16.1) High Level Group Term 
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the afore mentioned MedDRA term were reported to the safety database from any other 
sources during this period for patients who received palbociclib. Cataract has been reported 
as an adverse event in 2 patients (1 Grade 2 and 1 Grade 3) out of approximately 400 patients 
who have been treated with palbociclib in Pfizer-sponsored studies. Neither event was 
considered serious nor related to palbociclib and both patients had other identifiable risk 
factors for cataracts, such as age and long term corticosteroid use. Both patients continued 
on treatment for 16-18 months beyond the diagnosis of cataract. 
It is interesting to note that literature reports suggest that the incidence of cataract in women 
aged 35 and older with risk of breast cancer is approximately 2.3%.67 Cataract is also a 
known finding in patients treated with tamoxifen or letrozole.66,67
Given the observed nonclinical findings in rats, palbociclib clinical studies were also
carefully reviewed for adverse events relevant to a new diagnosis of diabetes or
hyperglycemia. Baseline and on-study glucose data were collected as part of the Palbociclib 
A5481001 first-in-human Phase 1 trial (N= 74). In this trial, 2 treatment schedules (3 weeks
on/1 week off [n= 39]; and 2 weeks on/1 week off [n= 33]) were evaluated at escalating
dosing levels (25-225mg) of single-agent palbociclib. In the 3/1 and 2/1 schedules,
16 (41.0%) and 12 (36.4%) subjects experienced a worsening of serum glucose to Grade 1
from their pre study baseline, respectively; 6 (15.4%) and 2 (6.1%) worsening to Grade 2 
from their baseline, respectively; and 1 (2.6%) and 2 (6.1%) worsening to Grade 3 from their 
baseline, respectively. No subjects experienced a worsening of serum glucose to Grade 4 
from their baseline on this study. Of the 4 cases of Grade 3 elevated serum glucose 
measurements observed on-study (independent of worsening from baseline), 3 occurred in 
patients known to be diabetic at time of study entry, and 1 case was observed in a patient 
being treated with short-term steroids for a gastrointestinal toxicity. Additionally, there were 
no report of newly diagnosed cases of diabetes mellitus on study. There was a median 
number of 2 treatment cycles received by patients in both treatment schedules and although 
no statement can be made about potential chronic effects of palbociclib in humans, the 
available data do not suggest any apparent effect of duration of exposure or dose on glucose 
levels. Additionally, the incidence of hyperglycemia seen in Study A5481001 may be
explained by the characteristics of this advanced cancer patient population.
Glucose laboratory tests were not collected in the PALOMA-1 (A5481003) randomized 
Phase 1/2 trial of Palbociclib in combination with letrozole in first line metastatic breast 
cancer patients (n= 172 received study treatment); however, clinical adverse event reports of
elevated glucose levels or diabetes mellitus terms were evaluated. On the palbociclib + 
letrozole arm, in patients known to be non-diabetic (n = 85) there was 1 report of Grade 2
diabetes mellitus in a patient who started to receive an anti-diabetic medication while on 
study. In patients known to be diabetic (n = 10), there was 1 report of Grade 2
hyperglycaemia. On the letrozole alone arm, in patients known to be non-diabetic (n =71) 
there was 1 report of Grade 2 diabetes mellitus in a patient who also started to receive an
anti-diabetic medication while on study, and 1 report of Grade 1 hyperglycaemia in another 
patient who did not initiate any anti-diabetic medication. In patients known to be diabetic 
(n = 6) there were no reports of hyperglycaemia. In summary, there was no apparent 
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Based on the review of the available clinical data, there does not appear to be a clinical
association of hyperglycemia and diabetes mellitus with palbociclib at this time.  However, 
the current clinical dataset is limited and therefore, in order to prospectively characterize 
whether or not there is an impact of palbociclib on glucose metabolism, monitoring of 
appropriate laboratory measurements is being implemented in ongoing and future palbociclib 
studies.
1.2.5.5. PD-0332991 Dose Rationale
PD-0332991 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 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 was reported in a 
patient with testicular cancer.  A total of 13/37 patients treated with Schedule 3/1 evaluable 
for efficacy experienced stable disease (SD), including 6 patients with SD lasting 40 weeks 
or longer.  One of these patients was a 
 with ER+ breast cancer who had previously
received 7 lines of treatment for 
 disease.  This patient remained on treatment for 
80 weeks (7 cycles at 50 mg/d and 13 cycles at 75 mg/d) and eventually discontinued 
treatment due to disease progression.  Based on the relatively improved safety profile of 
Schedule 3/1, and the efficacy results from this study, the Schedule 3/1 has been selected for 
further clinical development and the RP2D for this schedule was determined to be 125 mg/d.  
This schedule and associated RP2D was further explored in combination with letrozole in the 
Phase I/II study in patients with ABC described below. 
1.2.5.6. Phase I/II Data in Combination with Letrozole in Advanced Breast Cancer
Based on the preclinical evidence that PD-0332991 is highly active in ER(+) cell lines and 
the encouraging safety and PK profiles observed in the initial clinical studies, a randomized, 
multicenter active-controlled Phase 1/2 Study (A5481003) was designed to assess the 
efficacy, safety and pharmacokinetics of letrozole 2.5 mg QD (continuously) in combination 
with PD-0332991 125 mg QD (schedule 3/1) versus single agent letrozole 2.5 mg QD 
(continuously) for the first-line treatment of ER(+), HER2 (-) ABC in postmenopausal 
women. Letrozole was selected as the active control based on its worldwide approval and 
use as standard of care for the first-line hormonal treatment of postmenopausal women with 
ER(+) ABC.
 
33'
33'


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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 PD-0332991 when compared to letrozole alone in the first-line treatment of 
postmenopausal patients with ER(+), HER2(-) ABC.  The Phase 2 portion consisted of 
2 parts. In Part 1, patient selection was based only on ER/HER2 status.  In Part 2, patients 
were prospectively selected also taking into account tumor CCND1 amplification and/or 
p16 loss. As of 18 May 2012, 177 patients have been enrolled in this study and enrollment is 
closed. Twelve (12) were enrolled in the Phase 1 portion and 165 (66 and 99 in Part 1 and 
2, respectively) were enrolled in the Phase 2 portion.
Results from the Phase 1 portion,68 indicated no PK interaction between PD-0332991 and 
letrozole with mean AUC(0-24) of 2002 and 2043 ng•hr/mL (n=11) for PD-0332991 in the 
absence and presence of letrozole, respectively, and 1990 and 1730 ng•hr/mL (n=10) for 
letrozole in the absence and presence of PD-0332991, respectively. The RP2D was 
determined to be 125 mg QD on Schedule 3/1 (3 weeks continuous treatment followed by 
1 week off treatment) in combination with letrozole 2.5 mg QD continuously.  Partial 
responses were reported for 3 (33%) out of 9 patients with measurable disease (3 had 
bone-only disease). Another 5 patients (42%) had stable disease for ≥6 months and the 
clinical benefit rate (PR + SD ≥6 months) was 67%. Eight (8) patients discontinued from the 
study due to disease progression, including 2 patients with clinical progression, and 
4 patients are still ongoing. 
Preliminary results from Part 1 of the Phase 2 portion were presented at the 2012 IMPAKT 
Breast Cancer Conference69 and included a total of 66 postmenopausal women with 
ER(+)/HER2(-) locally recurrent or metastatic breast cancer randomized to either receive 
PD-0332991 in combination with letrozole (n=34 patients) or letrozole monotherapy 
(n=32 patients). 
The combination therapy was generally well tolerated when compared to letrozole alone with 
AEs similar to those seen with PD-0332991 and letrozole when administered alone.  
Uncomplicated neutropenia, leucopenia and fatigue were the most frequent adverse events
with neutropenia (54%), leucopenia (21%) being the most commonly reported 
Grade 2 events in patients treated with the combination therapy. Grade 4 events included 
neutropenia and fatigue, each reported in 6% of patients treated with 
PD-0332991 + letrozole. No Grade 4 events were reported in the letrozole alone arm.  
Treatment-related Grade 1/2 AEs reported more frequently in patients in the 
PD-0332991 + letrozole arm compared with the letrozole alone arm included: leukopenia, 
anemia, fatigue, alopecia, arthralgia, nausea, neutropenia, and thrombocytopenia.  Hot flush 
was the most common Grade 1/2 treatment-related AE reported in patients enrolled in the
letrozole alone arm.
Overall, 3 (9%) patients in the PD-0332991 + letrozole arm and 1 (3%) patient in the 
letrozole arm discontinued the Part 1 Phase 2 of Study A5481003 due to AEs including: 
1 patient with Grade 4 fatigue (not related to PD-0332991) and 2 patients with 
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the letrozole alone arm. The median duration of treatment was 13.7 months in the 
PD-0332991 + letrozole arm vs 5.4 months in the letrozole alone arm, with 
PD-0332991 dosing interruptions and dose reductions due to AEs reported in 61% and 
39% of patients enrolled in the PD-0332991 + letrozole arm, respectively. The median 
duration of dosing interruptions was 4.5 days and the median time to first dosing interruption 
was 55.5 days.  Despite the dosing interruptions and/or reductions, the median dose intensity 
for PD-0332991 was 87% across all cycles. 
Efficacy analyses were performed on the basis of radiologic assessment of disease status by
investigators to determine preliminary antitumor activity according to RECIST v.1.0. After a 
median follow-up of 16.5 months, median PFS was prolonged in patients who received 
combination therapy compared to letrozole alone (18.2 months vs 5.7 months).  Objective 
response and clinical benefit rates (52% vs 32% and 76% vs 47%, respectively) were also 
superior with the combination therapy. No complete responses were observed.  Data from 
the Part 2 are not yet mature.
These results indicate that the combination of PD-0332991 with letrozole is well tolerated 
with AEs similar to those seen with either PD-0332991 or letrozole when administered alone. 
Additionally, the combination demonstrated antitumor activity which was consistent with the 
sensitivity of ER(+) breast cancer observed in the preclinical models.  Results from Part 2 are 
not yet available. 
1.2.6. Study Rationale 
In the first-line treatment setting, letrozole is among the preferred anti-hormonal therapies for 
postmenopausal women with ER(+)/HER2(-) ABC.70  It is approved and commercially 
available globally with a well known and manageable safety profile. However, median 
progression-free survival in this patient population remains less than 1 year and median 
overall survival is approximately 3 years.4  Furthermore, aromatase inhibitor failure has been 
linked to increased proliferative index and cell cycle dysregulation, providing a strong 
rationale for combining letrozole with PD-0332991. Preliminary data from 
Phase 1/2 Study A5481003 suggest that the combination of PD-0332991 inhibition of
CDK 4/6 (blocking DNA synthesis by prohibiting progression of the cell cycle from G1 to 
S phase) with the antiproliferative effects of letrozole provides greater antitumor activity and 
prolongs PFS (ie, median 18.2 months vs 5.7 months) when compared to single agent 
letrozole. Additionally, the study shows that the combination is generally well tolerated with 
uncomplicated neutropenia as the most frequent adverse event.69
The current Phase 3 study provides the opportunity to confirm the clinical benefit of the 
combination of PD-0332991 with letrozole observed in Study A5481003. The study is 
designed to demonstrate that PD-0332991 in combination with letrozole provides superior
clinical benefit compared to letrozole in combination with placebo in postmenopausal 
women with ER(+)/HER2(-) locoregionally recurrent or metastatic breast cancer who have 
not received any prior systemic anti-cancer therapies for their advanced disease.
 


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Complete information for PD-0332991 may be found in the Single Reference Safety 
Document for the compound, which for this study is the Investigator's Brochure. The Single 
Reference Safety Document for the active comparator agent, letrozole, is the United 
Kingdom (UK) Summary of Product Characteristics (SPC) for Femara.66
1.2.7. Amendment Rationale 
1.2.7.1. Rationale for Changes in Amendment 1, 01 October 2013
Protocol was amended to address a specific request from the French Regulatory Agency to 
emphasize the importance of obtaining tumor tissue from a recurrence/metastatic disease at 
the time of study entry. The protocol language was revised accordingly and implemented for 
France only.  
1.2.7.2. Rationale for Changes in Amendment 2, 03 January 2014
Preliminary results from two clinical pharmacology studies A5481018 and A5481021 
suggested that palbociclib exposure may be decreased when administered in a minimally 
fasted state or concomitantly with proton-pump inhibitors. Therefore the protocol was
amended to revise the study drug administration instructions from administration in a 
minimally fasted state to administration with food and also to prohibit the concomitant use of 
proton-pump inhibitors. 
Additional changes included clarification to some protocol eligibility criteria to address the 
most frequently asked eligibility-related questions and minimize potential patient enrollment 
errors. 
1.2.7.3. Rationale for Changes in Amendment 3, 21 March 2014
Taking into account the preliminary results from studies A5481018 and A5481021, it was
assumed that drug exposures before and after implementation of Amendment 2 might be 
different in patients who took palbociclib in a minimally fasted state (ie, fast from 1 hour 
before to 2 hours after dosing) and/or concomitantly with proton-pump inhibitors compared 
to those patients who did not. This difference could potentially reduce the statistical power 
to detect the true treatment effect of palbociclib in the intent to treat (ITT) population under 
the current study design. As a result, the protocol is being amended prior to the interim 
analysis to increase the sample size from 450 patients to 650 patients to preserve the desired 
statistical power. 
Additionally, based on the limited pre-clinical and clinical data currently available, it is not 
known whether true clinical risk exists for developing palbociclib-associated cataracts. The 
protocol is therefore being amended to implement prospective ophthalmic assessments in all 
newly enrolled, lens grading patients at baseline and while on study treatment. The results of 
the ophthalmic assessments will provide a better understanding of the risk of ocular adverse 
events and will provide information to determine whether further actions are warranted.
 


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1.2.7.4. Rationale for Changes in Amendment 4, 18 September 2014
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. 
Additionally, the protocol was amended to reflect the Sponsor’s decision to no longer require 
safety review by the IOBU-SDMC for studies already monitored by an E-DMC.
Language related to cycle delay was also further defined to clearly state that any new cycle 
may only start if blinded study treatment can be resumed.
Lastly, 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.
1.2.7.5. Rationale for Changes in Amendment 5, 02 December 2014
In the current study design, an interim analysis will be performed after approximately 
266 PFS events occur (about 65% of total PFS events needed for final analysis) using 
O’Brien-Fleming efficacy boundary (Lan-DeMets procedure). Under these conditions, the 
study could be stopped for efficacy if z ≥2.5469 which would equate to a hazard ratio (HR)
≤0.6979, or about 4 months improvement in median PFS if the median PFS of the control 
arm is exactly 9 months as the study design assumed. In this instance, the interim efficacy 
boundary, while reaching statistical significance, may not represent a clinically meaningful 
improvement. 
The interim analysis is being revised in this protocol amendment to ensure that the study
would only be stopped at the interim analysis if the primary analysis (PFS) results are
statistically significant and clinically meaningful.
Language related to the analysis of the primary endpoint was updated to further define the
planned analysis. 
Additionally, the protocol is being amended to allow the concomitant use of strong/moderate 
CYP3A inducers/inhibitors and proton-pump inhibitors for patients who permanently 
discontinue blinded therapy but continue on study with letrozole monotherapy only. 
Finally, editorial changes were made to the drug destruction supply instruction to reflect 
current trial practices. 
 


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1.2.7.6. Rationale for Changes in Amendment 6, 07 April 2015
In order to assess the breast cancer specific quality of life of patients beyond progression in 
the follow- up period, patient reported outcomes using the FACT-B questionnaire will 
continue to be collected every 6 months.   
Additionally, editorial changes to the adverse event reporting section, the quality control and 
quality assurance section as well as the publication of study results section were done to 
reflect the current sponsor’s protocol template.  
1.2.7.7. Rationale for Changes in Amendment 7, 15 October 2015
In order to better understand the potential influence of palbociclib on response to subsequent 
anti-cancer treatments, the study is being amended to collect the date of disease progression 
while on subsequent anti-cancer therapy in addition to the follow-up anti-cancer therapy 
details already collected (ie, regimen number, name of therapy, and start/stop dates).
The protocol is also being amended to incorporate editorial changes plus remind participating 
investigators of the requirement for patients to complete their 7-day off treatment period in 
any given cycle prior to resuming blinded therapy. 
1.2.7.8. Rationale for Changes in Amendment 8, 21 May 2018
The present study met its primary objective of improving investigator-assessed PFS at the 
final analysis (data cutoff of 26 February 2016), demonstrating that in postmenopausal
women with ER-positive/HER2-negative ABC who had not received any prior systemic anti-
cancer therapies for their advanced/metastatic disease, the addition of palbociclib to letrozole 
resulted in statistically significant, robust, and clinically meaningful 10-month improvement 
in median PFS (42% risk reduction) as compared with placebo plus letrozole (24.8 months vs 
14.5 months, HR=0.576 [95% CI: 0.463, 0.718], 1 sided p<0.000001). Prolongation of PFS 
in the palbociclib plus letrozole arm was also demonstrated in multiple sensitivity analyses 
and, importantly, was consistently observed in individual patient subgroups defined by 
stratification factors and baseline demographics and disease characteristics, supporting the 
robustness and internal consistency of PFS benefit findings within the study. The blinded 
independent central review (BICR) showed no investigator bias in favor of the palbociclib 
plus letrozole arm and the analysis results of BICR corroborated the results of investigator-
assessed PFS.
Palbociclib plus letrozole was generally well tolerated with toxicities that were manageable 
by temporary discontinuations (including cycle delays) (335 [75.5%] patients), dose 
reduction (160 [36.0%] patients), and/or standard medical therapy.  The observed AEs were 
generally consistent with the known safety profile of palbociclib when administered with 
letrozole and when letrozole is administered as monotherapy; there were no unexpected 
major safety findings in this study population. The most common adverse events in the 
palbociclib plus letrozole group were neutropenia, leukopenia, fatigue, nausea, arthralgia, 
and alopecia. The majority of adverse events  were mild to moderate in severity with the 
exception of neutropenia and leukopenia.76  Additionally, palbociclib, when added to 
letrozole, did not prolong QT interval to a clinically meaningful extent.77
 


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Double-blinding of the present study will be maintained to allow ongoing collection of data 
for other pre-specified secondary endpoints including overall survival and patient reported 
outcomes.
Given that the completion of the primary objective and most of the secondary objectives of 
the study, the management of patients who are still receiving active treatment will be 
modified.  Upon IRB/IEC approval of Amendment 8, clinical assessments will be reduced in 
scope and the required schedule of activities is provided in Appendix 10. 
Guidance on management of these patients is summarized below.
Upon approval of Amendment 8, tumor assessments may be performed at a different 
schedule than the original protocol 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 institutional 
practice.  RECIST 1.1 may continue to be used to evaluate imaging assessments at the 
investigator’s discretion but will no longer be mandatory.  Assessments of tumor lesions [ie, 
target lesion(s), non-target lesion(s) and target lymph node(s)] will no longer be recorded in 
the CRF, nor will the RECIST assessments.  Only the date of progression of disease will be 
recorded.
Additionally, the retrospective review of radiographic images and clinical information 
collected on study to verify the protocol-defined endpoints of disease response and 
progression determinations as assessed by the investigator will be discontinued and thus, the
investigators will no longer be required to send the tumor scans to the independent core 
imaging laboratory.
Considering that the results from the safety analyses from this study have been consistent 
with the known safety profile of palbociclib and no new safety findings have been identified, 
upon IRB/IEC approval of Amendment 8, blood chemistry will only need to be monitored on 
Day 1 of every 3 cycles.  For patients who experienced a maximum of Grade 1 or 
2 neutropenia in the first 6 cycles, hematology for subsequent cycles will be monitored every 
3 months, at the beginning (Day 1) of a cycle. For patients who experienced a maximum of 
Grade 3 or 4 neutropenia during the first 6 cycles, hematology will continue to be assessed at 
the beginning (Day 1) of each cycle.  Additionally, hemoglobin A1c will no longer be 
required to be measured every 3 months from the date of randomization (ie, C4D1, C7D1, 
etc...) but is required to be collected at the end of treatment visit. Additional unscheduled 
hematology and blood chemistry panels may be collected as clinically indicated and results 
will be recorded on the appropriate CRF. 
Finally, PPIs and drugs known to prolong QT interval were removed from the “Prohibited
Medications” Section 5.5.1 and added under Permitted Medications Section 5.5.3 to reflect 
results from Study A5481038 showing that coadministration of PPI with palbociclib under 
fed conditions had no clinically relevant effect on the exposure of palbociclib and results 
from Study A5481008 showing that palbociclib, when added to letrozole, did not prolong QT 
interval to a clinically meaningful extent.77
 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives
Primary Objective(s)
•
To demonstrate that the combination of PD-0332991 with letrozole is superior to 
placebo plus letrozole in prolonging PFS in postmenopausal women with 
ER(+)/HER2 (-) advanced breast cancer who have not received any prior systemic 
anti-cancer therapies for their advanced/metastatic disease.
Secondary Objective(s)
•
To compare measures of tumor control duration and overall survival between the 
treatment arms;
•
To compare safety and tolerability between the treatment arms;
•
To compare health related quality of life between the treatment arms;
•
To characterize the effects of PD-0332991 at therapeutic doses in combination with 
letrozole on QTc interval in this patient population;
•
To determine trough PD-0332991 plasma concentration in this patient population and 
explore correlations between exposure and response and/or safety findings;
•
To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle 
(eg, CCND1 amplification, CDKN2A deletion), drug targets (eg, CDK 4/6), and 
tumor sensitivity and/or resistance (eg, Ki67, pRb) in tumor tissues.
2.2. Endpoints
Primary Endpoint(s)
•
Progression-Free Survival (PFS).
Secondary Endpoint(s)
•
Overall Survival (OS);
•
1-year, 2-year, and 3-year survival probabilities;
•
Objective Response (OR: Complete Response or Partial Response);
•
Duration of Response (DR);
•
Disease Control (DC: CR+PR+Stable disease ≥24 weeks);
 


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•
Corrected QT interval (QTc);
•
Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1, CDKN2A), 
proteins (eg, Ki67, pRb), and RNA expression (eg, cdk4, cdk6);
•
Trough plasma concentration of PD-0332991;
•
EuroQol (EQ-5D) Score (see Appendix 5);
•
Functional Assessment of Cancer Therapy - Breast (FACT-B) (See Appendix 6);
•
Type, incidence, severity (as graded by NCI CTCAE v4.0), seriousness and 
relationship to study medications of adverse events (AE) and any laboratory 
abnormalities.
3. STUDY DESIGN
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, Phase 3 clinical trial comparing the efficacy and safety of PD-0332991 in 
combination with letrozole versus placebo in combination with letrozole in postmenopausal 
women with ER(+)/HER2 (-) advanced breast cancer. Eligible patients will have 
histologically or cytologically proven diagnosis of adenocarcinoma of the breast with 
evidence of locoregionally recurrent or metastatic disease and will be candidates to receive
letrozole as first-line treatment for their advanced disease. In order to avoid inclusion of 
patients who are refractory or resistant to non-steroidal aromatase inhibitors, patients who 
received anastrozole or letrozole as a component of their (neo)adjuvant regimen may only 
enter the study if their disease did not progress while on or within 12 months from 
completion of their anastrozole/letrozole-containing (neo)adjuvant therapy. Patients will not 
have received any prior systemic anti-cancer therapies for their advanced disease and will not 
be candidates for curative therapies. Patients must have measurable disease as per 
RECIST v.1.1 or bone disease as their only site of disease.  Tumor tissue availability is 
required for patient participation.
At least 650 eligible patients will be randomized 2:1 to receive either PD-0332991 plus 
letrozole (Arm A: at least 433 patients) or placebo plus letrozole (Arm B: at least
217 patients). Patients will be stratified by site of disease (visceral* vs non-visceral**), by 
disease-free interval since completion of prior (neo)adjuvant therapy (de novo metastatic; 
≤12 months; >12 months), and by the nature of prior (neo)adjuvant anti-cancer treatment 
received (prior hormonal therapy; no prior hormonal therapy).
*"Visceral" refers to any lung (including pleura) and/or liver involvement. 
**"Non-visceral" refers to absence of lung (including pleura) and/or liver involvement.
 


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Patients randomized to Arm A (experimental arm) will receive: 
•
PD-0332991, 125 mg, orally once daily on Day 1 to Day 21 of every 28-day cycle 
followed by 7 days off treatment;
in combination with 
•
Letrozole, 2.5 mg, orally once daily (continuously). 
Patients randomized to Arm B (control arm) will receive: 
•
Placebo orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 
7 days off treatment;
in combination with 
•
Letrozole, 2.5 mg, orally once daily (continuously). 
Patients will continue to receive assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  However, patients may continue treatment as assigned at randomization beyond 
the time of 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 anti-cancer 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.
The importance of timely and complete disease assessments in this study cannot be 
overstated. Disease assessments will be performed every 12 weeks (±7 days) from the date 
of randomization. Patients with bone lesions identified at baseline will also have repeat bone 
scans performed every 24 weeks (±7 days) from the date of randomization.  Each assessment 
will be performed as scheduled according to the calendar regardless of any dosing delay to 
prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the 
required disease assessments will result in the inability to determine disease status for that 
time point.  Tumor assessments will be performed until radiographically and/or clinically 
(ie, for photographed or palpable lesions) documented PD as per RECIST v.1.1, study 
treatment discontinuation (for patients continuing treatment beyond RECIST-defined disease 
progression), initiation of new anti-cancer therapy or discontinuation of patient from overall 
study participation (eg, death, patient's request, lost to follow-up), whichever occurs first.  
A series of incomplete disease assessments will result in censoring of the primary endpoint 
of PFS back to the time of the last full assessment that did not show progression. 
Upon IRB/IEC approval of Amendment 8, tumor assessments may be performed at a 
different schedule than the original protocol 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 institutional 
practice.  RECIST 1.1 may continue to be used to evaluate imaging assessments at the 
 


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investigator’s discretion but will no longer be mandatory.  Assessments of tumor lesions [ie, 
target lesion(s), non-target lesion(s) and target lymph node(s)] will no longer be recorded in 
the CRF, nor will the RECIST assessments.  Only the date of progression of disease will be 
recorded. Please refer to Appendix 10 for tumor assessment requirements. 
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as primary data source. However, a blinded independent third-party core 
imaging laboratory will complete a retrospective review of radiographic images and clinical 
information collected on-study to verify the protocol-defined endpoints of disease response 
and progression as assessed by the investigator.  Upon IRB/IEC approval of Amendment 8, 
retrospective blinded independent central review of radiographic images and clinical 
information will be discontinued.
Patients discontinuing the active treatment phase will enter a follow-up period during which 
FACT-B questionnaire, survival and new anti-cancer therapy information (including regimen 
number, name of therapy, start/stop dates, and dates of disease progression on subsequent 
anti-cancer therapies) will be collected every 6 months from the last dose of investigational 
product. The follow-up period will conclude at the time of the final OS analysis. Crossover 
will not be allowed in the trial. 
Patients will undergo study-related safety, efficacy, and PK assessments as outlined in the
relevant Schedule of Activities located in the summary section. 
The study also includes:
•
QTc monitoring to evaluate the effect of PD-0332991 on QT interval via triplicate 
ECGs time-matched with select serial PK draws (subset study in at least 60 patients 
enrolled at selected sites);  
•
Quantification of trough PD-0332991 plasma concentration;
•
A molecular profiling component aimed at assessing the relationship between breast 
tumor sensitivity and resistance to PD-0332991 and the alteration of cell cycle 
pathway-related genes and proteins in tumor tissues.
A total of 347 PFS events is required to have a 90% power to detect an improvement 
assuming a true hazard ratio equivalent to 44% improvement in median PFS over benchmark 
(single-agent letrozole PFS = 9 months) if tested at one-sided significance level of 0.025. 
The trial is designed to have one interim analysis for futility, efficacy, or possible sample size 
re-estimation planned after 65% (approximately 226 events) of expected PFS events have 
been observed using an Haybittle-Peto stopping boundary (for efficacy). The study is also 
powered for the secondary endpoint of overall survival (OS). An interim OS analysis will be 
performed at the time of the interim or final PFS analyses if the primary PFS analysis is 
positive. 
 


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4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom the protocol treatment is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Adult women (≥18 years of age) with proven diagnosis of adenocarcinoma of the breast 
with evidence of locoregionally recurrent or metastatic disease not amenable to resection 
or radiation therapy with curative intent and for whom chemotherapy is not clinically 
indicated.
2. Documentation of histologically or cytologically confirmed diagnosis of 
estrogen-receptor positive (ER+) breast cancer based on local laboratory results. 
3. Previously untreated with any systemic anti-cancer therapy for their locoregionally 
recurrent or metastatic ER+ disease.
4. Postmenopausal women defined as women with: 
•
Prior bilateral surgical oophorectomy, or
•
Medically confirmed post-menopausal status defined as spontaneous cessation of 
regular menses for at least 12 consecutive months or follicle-stimulating hormone 
(FSH) and estradiol blood levels in their respective postmenopausal ranges with no 
alternative pathological or physiological cause.
5. Measurable disease as defined per RECIST v.1.1 (see Appendix 7) or bone-only disease
(with bone lesions confirmed by CT, MRI or bone X-ray).  Tumor lesions previously 
irradiated or subjected to other locoregional therapy will only be deemed measurable if 
disease progression at the treated site after completion of therapy is clearly documented.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 (see 
Appendix 1).
7. 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);
 


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•
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 (≤3.0 x ULN if Gilbert’s disease);
•
AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);
•
Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present). 
8. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to 
NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator's discretion).
9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures.
10. All patients must agree to provide tumor tissues for centralized retrospective 
confirmation of ER status and to evaluate correlation between genes, proteins, and RNAs 
relevant to the cell cycle pathways and sensitivity/resistance to the investigational agents.  
Freshly biopsied, recurrent/metastatic tumor samples must be provided whenever 
possible.  If such a biopsy is not feasible or cannot be safely performed, then an archived 
tumor sample may be accepted.  In either case a formalin fixed, paraffin embedded 
(FFPE) block or 12 unstained FFPE slides are required for patient participation.
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 
before any study-specific activity is performed.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. HER2-positive tumor as defined by documentation of erbB-2 gene amplification by FISH 
(as defined by a HER2/CEP17 ratio ≥2) or chromogenic in situ hybridization (CISH, as 
defined by the manufacturer’s kit instruction) or INFORM HER2 dual ISH (as defined by 
manufacturer’s kit instruction) or documentation of HER2-overexpression by IHC 
(defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory 
results utilizing one of the sponsor-approved assays (see Appendix 2). If HER2 status is 
unavailable or was determined using a test other than a sponsor-approved assay, then 
testing must be performed/repeated using one of these assays prior to randomization. If 
tissue sample from both primary and recurrent/metastatic tumors are available, HER2 
assessment from the most recent sample (ie, recurrent/metastatic sample) should be used 
to define eligibility whenever feasible.
 


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2. Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening 
complications in the short term (including patients with massive uncontrolled effusions 
[pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver 
involvement).
3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, 
or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or 
progressive growth.  Patients with a history of CNS metastases or cord compression are 
eligible if they have been definitively treated with local therapy (eg, radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 
4 weeks before randomization.
4. Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor 
(ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of 
completing treatment.
5. Prior treatment with any CDK4/6 inhibitor.
6. Patients treated within the last 7 days prior to randomization with:
•
Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, 
boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, 
fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice);
•
Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, 
nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and 
St. John’s wort);
•
Drugs that are known to prolong the QT interval (see Appendix 3).
7. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other 
anti-cancer therapy within 2 weeks before randomization. Patients who received prior 
radiotherapy to ≥25% of bone marrow are not eligible independent of when it was 
received (see Appendix 4).
8. Diagnosis of any other malignancy within 3 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.
9. QTc >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 (TdP).
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging 
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
 


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11. Any of the following within 6 months of randomization: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE
version 4.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident including transient 
ischemic attack, or symptomatic pulmonary embolism.
12. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any 
upper gastrointestinal surgery including gastric resection.
13. Known hypersensitivity to letrozole, or any of its excipients, or to any 
PD-0332991/placebo excipients.
14. Known human immunodeficiency virus infection.
15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
16. Patients who are investigational site staff members or relatives of those site staff 
members or patients who are Pfizer employees directly involved in the conduct of the 
trial.
17. Participation in other studies involving investigational drug (s) (Phases 1-4) within
2 weeks before randomization and/or during participation in the active treatment phase of 
the trial.
18. Recent or active suicidal ideation or behavior.
4.3. Randomization Criteria
•
Patients will be randomized into the study provided they have satisfied all patient 
selection criteria. 
•
The investigators or their pre-specified designee will randomize eligible patients by 
interactive randomization technology (IRT) as described in the Study Reference 
Manual. 
•
At the time of randomization, information about patient demographics and 
stratification factors [ie, site of disease (visceral vs non-visceral), disease-free interval 
since the end of the (neo)adjuvant treatment to disease recurrence (de novo metastatic 
vs ≤12 months vs >12 months), nature of prior (neo)adjuvant anti-cancer therapies 
(prior hormonal therapy vs no prior hormonal therapy)] will be requested. 
•
The central computerized system will provide the randomization number and 
treatment assignment. 
 


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4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a 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 
subject’s 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 
the study team for advice on medical questions or problems that may arise during the study.  
The help desk number is not intended for use by the subject directly, and if a subject calls 
that number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
If the patient is found to be eligible for the study, she should be randomized using a 
centralized internet/telephone registration system no more than 4 business days before 
administration of the first dose of investigational product. 
After a patient has provided written informed consent, has completed the necessary baseline
assessments, and is found to be eligible for the study, the clinical site must complete a Patient 
Pre-Randomization Form which includes key eligibility criteria (eg, breast cancer diagnosis, 
stage of disease at initial diagnosis and at screening, hormonal receptor and HER2 status as 
per local results, prior systemic therapy, disease free interval (DFI) from prior (neo)adjuvant 
letrozole or anastrozole (if applicable)) and send it to the sponsor for approval of 
randomization.  Upon receipt of the sponsor’s approval the site must contact a centralized 
internet/telephone registration system as described in the Study Reference Manual, to enroll 
the patient on study (see Section 4.3). 
Eligible patients will be randomly assigned in a 2:1 ratio to either Arm A (experimental arm: 
PD-0332991 plus letrozole) or Arm B (control arm: placebo plus letrozole) stratified 
according to site of disease, disease-free interval since completion of prior (neo)adjuvant 
therapy, and nature of prior (neo)adjuvant anti-cancer treatment received (see Section 4.3).
Clinical sites must complete the screening case report forms (CRFs) for all registered and 
randomized patients, even if the patient is not subsequently treated in this study.
 


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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 progressive disease (eg, in case of clinical deterioration, increase in 
tumor markers or any other evidence suggestive of disease progression but in the absence of 
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. 
5.3. Drug Supplies
The investigational drug used in the course of this trial is PD-0332991/placebo. In addition, 
all patients will receive letrozole.  All three medications will be supplied by the sponsor.
5.3.1. Formulation and Packaging
5.3.1.1. PD-0332991
PD-0332991 will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents 
of PD-0332991 free base. The sponsor will supply the oral drug formulation to sites in 
HDPE bottles containing 75 mg, 100 mg, or 125 mg capsules. The capsules can be 
differentiated by their size and color (see below).
Table 1.
PD-0332991/Placebo Capsule Characteristics
Dosage
Capsule color
Capsule size
75 mg
Sunset Yellow/Sunset Yellow
2
100 mg 
Caramel/Sunset Yellow
1
125 mg
Caramel/Caramel
0
 


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5.3.1.2. Placebo
Placebo will be indistinguishable from the PD-0332991 capsules and will be supplied as 
capsules matching in size and color the various PD-0332991 formulations (see Table 1). The 
sponsor will supply placebo to sites in HDPE bottles. 
5.3.1.3. Letrozole
Commercially available letrozole 2.5 mg film-coated tablets will be supplied to sites by the 
sponsor. Complete information about letrozole formulation can be found in the UK
Summary of Product Characteristics (SPC) for Femara.66
5.3.2. Preparation and Dispensing
5.3.2.1. PD-0332991/Placebo
PD-0332991 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 PD-0332991. 
The patient number should be recorded on the bottle label in the spaces provided by site 
personnel at the time of assignment to patient.  Site personnel must ensure that patients 
clearly understand the directions for self-medication.  Patients should be given a sufficient 
supply to last until their next study visit.  Unused drug and/or empty bottles should be 
returned to the site at the next study visit. Returned unused medication MUST NOT be 
re-dispensed to patient. 
PD-0332991/placebo is an agent that must be handled and administered with care.  Patients 
should be instructed to keep their medication in the bottles provided and not transfer it to any 
other container.  Due to possible unknown hazards associated with topical and environmental 
exposure to experimental agents, capsules must not be opened and/or emptied into any 
vehicle for oral ingestion; capsules must be swallowed intact.
Only one capsule strength will be dispensed to the patient at each dispensing visit. In the 
event of dose modification, request should be made of the patient to return all previously 
dispensed medication to the clinic and new capsules will be dispensed.
5.3.2.2. Letrozole
Letrozole tablets will be provided in blister packs or in bottles with a safety screw cap.
The patient number should be recorded on the bottle/blister pack label in the spaces provided 
by site personnel at time of assignment to patient.  Site personnel must ensure that patients 
clearly understand the directions for self-medication.  Patients should be given a sufficient 
supply to last until their next study visit.  Unused drug and/or empty bottles/blister packs 
should be returned to the site at the next study visit.
 


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5.3.3. Administration
5.3.3.1. PD-0332991/Placebo
Patients should be instructed to swallow PD-0332991/placebo capsules whole and not to 
chew them prior to swallowing.  No capsule should be ingested if it is broken, cracked, or 
otherwise not intact.  Patients should be encouraged to take their dose at approximately the 
same time each day.  Patients should be instructed to record daily administration of the study 
drugs in a patient diary.
PD-0332991/placebo will be administered together with letrozole. Patients should take 
PD-0332991/placebo with food. For patients enrolled in Group 1, patients should fast from 
1 hour before to 2 hours after dosing, during Cycle 1.  Cycle 2 and beyond, patients should 
take PD-0332991/placebo with food. 
PD-0332991/placebo will be administered orally once a day for 21 days of every 28-day 
cycle followed by 7 days off treatment. In the event the Day 1 clinic visit of the subsequent 
cycle is scheduled during the -2 day allowable visit time window (ie, Day 27, Day 28), 
patients must be instructed to complete their 7-day off treatment period of the current cycle 
prior to resuming blinded therapy even if criteria for treatment resumption are met at the 
visit. Cycle off treatment periods of less than 7 days are considered protocol deviations.
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section 5.3.4.
5.3.3.2. Letrozole
Letrozole will be administered orally once daily continuously together with 
PD-0332991/placebo or alone in the event of PD-0332991/placebo dosing interruption.
Refer to the UK Summary of Product Characteristics (SPC) for Femara66 for additional 
administration instructions.
5.3.3.3. General Rules
For both PD-0332991/placebo and letrozole: 
•
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the 
next day.
•
Patients who vomit anytime after taking a dose must be instructed NOT to “make it 
up,” and to resume treatment the next day as prescribed. 
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose. Also refer to Section 5.3.5 for further details on medication errors and overdose.
 


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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 study drugs 
(PD-0332991/placebo or letrozole) may need to be adjusted as described in the following 
sections. Depending on the nature of the toxicity observed, dosing adjustment may be 
required for just one or both study drugs in the combination.  In the event treatment 
interruption is deemed necessary for just one of the study drugs in the combination, treatment 
with the other study drug will continue as planned. 
5.3.4.1. Letrozole 
No dose adjustment for letrozole is permitted but dosing interruptions are allowed.  
Treatment interruption for letrozole-related toxicities will be performed as per the 
investigator’s best medical judgment.
Patients discontinuing letrozole treatment due to treatment-related toxicity will be 
discontinued from the active treatment phase of the study and enter the follow-up phase. 
5.3.4.2. PD-0332991/Placebo
In the event of significant treatment-related toxicity, PD-0332991/placebo dosing may be 
interrupted or delayed and/or reduced as described below.  In the event of multiple toxicities, 
dose modification should be based on the worst toxicity observed.  Patients are to be 
instructed to notify Investigators at the first occurrence of any adverse sign or symptom.
Dose modifications may occur in three ways:
•
Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle;
•
Between cycles: next cycle administration may be delayed due to persisting toxicity
when a new cycle is due to start;
•
In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
Patients discontinuing PD-0332991/placebo treatment due to treatment-related toxicity may 
continue on the active treatment phase of the study receiving letrozole monotherapy as per
the investigator’s discretion. 
5.3.4.2.1. Dosing Interruptions
Patients experiencing the following adverse events should have their treatment 
interrupted/delayed: 
•
Uncomplicated Grade 3 neutropenia (ANC<1000/mm3);
 


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•
Grade 3 neutropenia (ANC<1000/mm3) associated with a documented infection or 
fever ≥38.5°C;
•
Grade 4 neutropenia (ANC<500/mm3);
•
Grade 4 thrombocytopenia (Platelet count <25,000/mm3);
•
Grade ≥3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment);
•
Grade 3 QTc prolongation (QTc ≥501 msec on at least two separate ECGs).
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. Criteria required before treatment can resume are described in
Section 5.3.4.2.2.
Doses may be held as needed until toxicity resolution. Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the same 
cycle.  The need for a dose reduction at the time of treatment resumption should be based on 
the criteria defined in Section 5.3.4.2.3 Dose Reductions unless expressly agreed otherwise 
following discussion between the investigator and the sponsor. If a dose reduction is applied 
in the same cycle, the patient will need to return to the clinic to receive new drug supply.
In the event of a treatment interruption for reasons other than treatment-related toxicity
(eg, non-cancer related surgery) lasting >2 weeks, treatment resumption will be decided in 
consultation with the sponsor.
5.3.4.2.2. Dose Delay
Retreatment following treatment interruption for treatment-related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met:
•
Platelet count ≥50,000/mm3;
•
ANC ≥1000/mm3 and no fever;
•
Grade 3 or higher treatment-related non-hematologic AEs (including, nausea, 
vomiting, diarrhea, and hypertension only if persisting despite optimal medical 
treatment), with the exception of alopecia, have recovered to Grade ≤1 or baseline 
(or, at the investigator’s discretion, Grade ≤2 if not considered a safety risk for the 
patient).
 


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•
QTc <501 msec and potential reversible causes (eg, electrolyte imbalance, 
concomitant medications known to prolong QTc) corrected.  If QTc remains above 
480 msec, ECG should be monitored more frequently as per the investigator’s best 
medical judgement until QTc≤480 msec.
If a treatment delay results from decline in hematologic parameters, the frequency of blood 
count assessments should be increased as clinically indicated.
If these parameters are met within 2 weeks of treatment interruption or cycle delay, 
PD-0332991/placebo may be resumed. Please refer to Section 5.3.4.2.3 Dose Reductions for 
adverse events requiring dose reduction at the time of treatment resumption. 
If these parameters have not been met after 2 weeks of dosing interruption (including the 
scheduled 1 week off treatment) or 2 weeks of cycle delay, permanent discontinuation of 
PD-0332991/placebo treatment should be considered.  Treatment resumption for patients 
recovering from treatment-related toxicity after >2 weeks of treatment interruption or cycle 
delay but deemed to be deriving obvious clinical benefit per the investigator’s best medical 
judgment is left at the investigator’s discretion.
A new cycle only starts when the criteria listed above are met and blinded study treatment
may be administered, otherwise initiation of the new cycle must be delayed until such criteria 
are met. 
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 
PD-0332991/placebo is resumed. New cycle Day 1 procedures (ie, physical examination, 
ECOG performance status, ECG, Quality of Life questionnaires, blood chemistry, 
hematology) that were performed prior to knowing the need to delay the start of the cycle do 
not need to be repeated unless required to confirm that the parameters necessary for study 
drug to be resumed are met (see Section 5.3.4.2.2).
5.3.4.2.3. Dose Reductions
Following dosing interruption or cycle delay the PD-0332991/placebo dose may need to be 
reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Dose reduction of PD-0332991/placebo by 1 and, if needed, 2 dose levels (Table 2) will be 
allowed depending on the type and severity of toxicity encountered.  Patients requiring more 
than 2 dose reductions will be discontinued from the study and entered into the follow-up 
phase. All dose modifications/adjustments must be clearly documented in the patient's 
source notes and Investigational product administration CRF. 
 


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Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Dose re-escalation 
is not allowed.
Table 2.
Available Dose Levels
Dose Level
PD-0332991/Placebo for 3 out of 4 
weeks (3/1 schedule)
Letrozole on a continuous daily 
dosing regimen
Starting dose
125 mg/d
2.5 mg/d
-1
100 mg/d
2.5 mg/d
-2
75 mg/d*
2.5 mg/d
Discontinue Study Treatment
* PD-0332991/placebo dose de-escalation below 75 mg/d is not allowed.
PD-0332991/placebo recommended dose modifications for treatment related toxicities 
requiring treatment interruption/delay or persisting despite optimal medical treatment are 
described in Table 3.
Table 3.
PD-0332991/Placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal 
Medical Treatment.
Toxicity
Restart PD-0332991/Placebo Treatment 
at:
Uncomplicated Grade 3 neutropenia (ANC<1000/mm3)
Same dose level
Grade 3 neutropenia (ANC<1000/mm3) associated with a 
documented infection or fever ≥38.5°C
↓1 Dose Level
Grade 4 neutropenia (ANC<500/mm3)
↓1 Dose Level
Grade 4 thrombocytopenia (Platelet count <25,000/mm3)
↓1 Dose Level
Grade ≥3 non-hematologic toxicity (including, nausea, 
vomiting, diarrhea, and hypertension only if persisting despite 
optimal medical treatment)
↓1 Dose Level
QTc prolongation management
In the event of QTc prolongation of, possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong 
the QTc interval should be evaluated. 
If such reversible causes are identified, then they should be corrected accordingly
(ie, correction of electrolyte abnormalities with supplements to within normal limits and/or
discontinuation (if possible) of concomitant medications known to prolong the QT interval). 
Recommended dose modifications in the event of QTc prolongation are provided in Table 4. 
 


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Table 4.
PD-0332991/Placebo Dose Modifications in the Event of QTc Prolongation
Toxicity (NCI CTC Grade, Version 4.0)
Grade 2 QTc prolongation
Grade 3 QTc prolongation
Grade 4 QTc 
prolongation
Reversible 
cause 
identified 
Treat reversible cause
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc≤480 msec
Continue at the same dose level(1)
Treat reversible cause 
Withhold treatment until QTc<501 msec
Resume treatment at the same dose level.
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc≤480 msec.  
Permanently 
discontinue
No reversible 
cause 
identified
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc≤480 msec 
Continue at the same dose level(1)
Withhold treatment until QTc<501 msec 
Resume treatment at the next lower dose 
level(2)
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc≤480 msec.
Permanently 
discontinue
1.
If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence of other 
alternative causes or despite correction of alternative causes, dose adjustment and/or discontinuation should be 
considered in consultation with a cardiologist and the study medical monitor, taking into account the emerging safety 
data from PD-0332991 trials and the investigator’s best medical judgment.
2.
If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment and/or discontinuation 
should be discussed with study medical monitor in consultation with a cardiologist, taking into consideration the 
emerging safety data from PD-0332991 trials and the investigator’s best medical judgment.
5.3.5. Medication Errors and Overdose
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 case report form (CRF) which is a specific version of the adverse event (AE) page and 
on the serious adverse event (SAE) form when appropriate.  In the event of medication 
dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:
•
Medication errors involving patient exposure to the investigational product;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated adverse event(s) are captured on an 
adverse event (AE) CRF page.
 


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5.3.6. Compliance
Patients will be required to return all bottles of PD-0332991/placebo and all blisters/bottles 
of letrozole as well as the completed patient diary at the beginning of each cycle for drug 
accountability.  Drug accountability will be performed on Day 1 of every cycle prior to 
dispensing drug supply for the next cycle.  The number of remaining capsules/tablets will be 
documented and recorded.
To be considered compliant, each study patient must have received at least 80% of the 
planned number of doses of primary therapy based on the number of days of actual dose 
administration. Dose adjustments must follow instructions provided in the dose adjustment 
guidelines section. 
5.4. Drug Storage and Drug Accountability
Storage conditions stated in the Study Reference Safety Document (ie, Investigator’s
Brochure (IB), United States Package Insert (USPI), Summary of Product Characteristics 
(SPC), or Local Product Document (LPD)) may be superseded by the label storage.
Investigators and site staff are reminded to continuously monitor room storage temperatures 
and ensure that thermometers are working correctly as required for proper storage of 
investigational products (See Sections 5.4.1 & 5.4.2).  These include thermometers for both 
the room storage and refrigerator storage.  Any temperature excursions must be reported 
immediately to the sponsor and documented.  Once a deviation is identified, the 
investigational products (PD-0332991/placebo or letrozole) MUST be quarantined and not 
used until the sponsor provides documentation of permission to use the investigational 
product. 
At the end of the trial, or at the close-out of the site, the site will destroy any unused 
investigational product. 
If the destruction occurs 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.  Alternatively, investigational product may be shipped to a local depot for 
destruction.
5.4.1. PD-0332991/Placebo
PD-0332991/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.
 


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To ensure adequate records, PD-0332991/placebo capsules will be accounted for as 
instructed by the sponsor. Patients are requested to return previously dispensed containers as 
well as their completed patient diary to the clinic at each visit for accountability purposes 
even if they will not be issued with new medication at that visit. 
5.4.2. Letrozole
Letrozole tablets must be stored according to the instructions detailed in the local package 
insert. 
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication should be stored separately from 
medication that needs to be dispensed.
To ensure adequate records, letrozole tablets will be accounted for as instructed by the 
sponsor.  Patients are requested to return previously dispensed containers as well as their 
completed patient diary to the clinic at each visit for accountability purposes even if they will 
not be issued with new medication at that visit.
5.5. Concomitant Medications
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator.  Any medications
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior 
to the start of study treatment and up to 28 days following the last dose of investigational 
product and the reason for their administration must be recorded on the CRF. 
Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded.  Anesthetics used for any 
surgical procedures performed during the patient’s participation in the study can be recorded 
as “unspecified anesthesia” on the concomitant treatment records; it is not necessary to list 
the specific anesthetics.  Palliative and supportive care for cancer-related symptoms will be 
offered to all patients in this study.
5.5.1. Prohibited Medications
The following treatments are prohibited throughout the duration of the active treatment 
phase: 
•
Anti-cancer agents: No additional investigational or commercial anti-cancer agents 
such as chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy other than letrozole will be permitted during the 
active treatment phase.  In general, any drugs containing “for the treatment of breast 
cancer” on the product insert are not permitted on study.
 


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•
Strong/Moderate CYP3A inhibitors/inducers: PD-0332991 is metabolized to 
multiple metabolites in a qualitatively similar manner in rat, dog and human liver 
microsomes.  In vitro, PD-0332991 is primarily metabolized by CYP3A4 enzymes.  
Co-administration with drugs that are strong CYP3A inhibitors or inducers may 
change the plasma concentrations of PD-0332991 in humans.  The concurrent use of 
the compounds listed below is not allowed in the study: 
•
Strong CYP3A inhibitors, including boceprevir, clarithromycin, conivaptan, 
delavirdine, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
suboxone, telaprevir, telithromycin, voriconazole, and grapefruit, grapefruit juice
or any product containing grapefruit.
•
The following moderate CYP3A inhibitors: amprenavir, atazanavir, diltiazem, 
erythromycin, fosamprenavir, and verapamil.
•
Strong CYP3A inducers, including carbamazepine, phenytoin, primidone,
rifampin, rifapentin, and St. John’s wort.
•
The following moderate CYP3A inducers, felbamate, nevirapine, phenobarbital, 
and rifabutin.
•
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.
The strong/moderate CYP3A inhibitors/inducers listed above are permitted for any patients 
who permanently discontinue blinded therapy and continue on trial with letrozole 
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. If usage 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. 
 


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5.5.3. Permitted Medications
The following treatments are permitted throughout the duration of the active treatment phase: 
•
Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care 
(eg, analgesics, antidiarrheals, antidepressants) may also be used at the investigator’s 
discretion. All medications should be recorded. 
•
Bisphosphonates and receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitors for the treatment of osteoporosis or management of existing 
bone metastases may be continued for patients who have been receiving them at a 
stable dose for at least 2 weeks prior to randomization. However the need to initiate 
or increase the dose of these therapies during the study will be considered as 
indicative of disease progression leading to the discontinuation of patient from the 
active treatment phase unless disease progression can be completely ruled out and the 
exact reason for the use of these therapies clearly documented in the subject’s source 
documentation.
•
Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic 
use of granulocyte-colony stimulating factors is not permitted but they may be used to 
treat treatment-emergent neutropenia as indicated by the current American Society of 
Clinical Oncology (ASCO) guideline.71  If neutropenic complications are observed in 
a cycle in which primary prophylaxis with CSFs was not received, secondary 
prophylaxis may be given at the discretion of the investigator, but only if dose 
reduction or delay are not considered to be a reasonable alternative.
•
Erythropoietin may be used at the investigator's discretion for the supportive 
treatment of anemia. 
•
Local antacids may decrease PD-0332991 absorption and exposure; however, if 
needed, local antacid should be given at least 2 hours before or after 
PD-0332991/placebo administration.
•
H2-receptor antagonists (including, but not limited to, cimetidine, famotidine, 
nizatidine, ranitidine). The dosing of PD-0332991/placebo should occur at least 
10 hours after H2-receptor antagonist evening dose and 2 hours before H2-receptor 
antagonist morning dose.
•
Proton-pump inhibitors: (including, but not limited to, dexlansoprazole, 
esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) with 
PD-0332991/placebo is permitted upon IRB/IEC approval of Amendment 8.
•
Drugs known to cause QT interval prolongation are permitted upon IRB/IEC
approval of Amendment 8. Refer to Appendix 3 for a list of drugs known to 
predispose to TdP.
 


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5.6. Concomitant Radiotherapy or Surgery
Any concurrent radiotherapy (except palliative radiotherapy as specified below) or 
cancer-related surgery are prohibited throughout the duration of the active treatment phase of 
the study. Patients requiring any of these procedures will be discontinued from the active 
treatment phase and will enter the follow-up phase.
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 PD-0332991 with radiotherapy, 
PD-0332991/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 PD-0332991 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Based on the available 
pharmacokinetic data, stopping PD-0332991/placebo is recommended at least 7 days prior to 
elective surgery.  Postoperatively, the decision to reinitiate PD-0332991/placebo treatment 
should be based on a clinical assessment of satisfactory wound healing and recovery from 
surgery.
6. STUDY PROCEDURES
Prior to undergoing any study specific procedures (with the exception of certain imaging 
assessments if meeting the criteria defined in Section 6.1), patients must read and sign the 
consent form.  All study procedures and the timing when they must be performed are detailed 
in the Schedule of Activities tables. All data obtained for these assessments must be 
supported in the patients' source documentation.
For the purposes of this trial, 1 cycle is 28 days. A cycle could be longer than 28 days if 
persistent toxicity delays the initiation of the subsequent cycle. 
6.1. Screening
Voluntary, written, dated, and signed informed consent must be obtained before any study 
specific procedures are performed (with the exception of certain imaging assessments if 
meeting the criteria defined in this section); however, it may be obtained more than 28 days 
before randomization. 
 


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Radiographic tumor assessments (as documented on the Tumor Assessment Requirement 
Flowchart) that were performed before the signing of the informed consent form as routine 
procedures (but within 28 days prior to randomization) do not need to be repeated and may 
be used as baseline assessments, as long as:
•
The tests were performed per the method requirements outlined in the 
Tumor Assessment Requirement Flowchart, the Efficacy Assessments sections. 
•
Appropriate documentation indicating that these radiographic tumor assessments 
were performed as standard of care is available in the patient’s source notes.
Bone scans performed as routine procedures within 12 weeks prior to randomization may 
also be accepted as baseline assessment if they meet the same requirements listed above.
Brain scans performed as routine procedures within 6 weeks prior to randomization may also 
be accepted as baseline assessment if they meet the same requirements listed above.
Once Amendment 3 is IRB approved, all lens grading evaluable, newly enrolled patients will 
undergo the following ophthalmic procedures at baseline: 
•
Best corrected distant visual acuity (Snellen).
•
Refractive error associated with best corrected distant visual acuity.
•
Intraocular pressure (IOP - one reading).
•
Slit lamp biomicroscopy of the anterior segment including cell count and flare 
grading.
•
Lens grading with the Wisconsin Age-Related Eye Disease Study (AREDS) 2008 
Clinical Lens Opacity Grading Procedures using a laminated reference pocket card
(See Appendix 8) - (pupil dilated examination).
•
Funduscopy (Ophthalmoscopy - 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 7.2.3. Ocular Safety Assessments for further details on these procedures.
For details on baseline procedures, see the Schedule of Activities tables. 
 


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6.1.1. Screen Failure
Patients who completed the informed consent process but do NOT meet all eligibility criteria 
and therefore are NOT randomized to either treatment arm will be considered as screen 
failures. 
Clinical sites must provide for all screen failures the following information using the 
appropriate case report forms (CRFs): screening number, demographic data as well as the 
final subject summary including the reason for screening failure.
6.2. Active Treatment Phase
For details on procedures during the active treatment phase, see the Schedule of Activities
tables. Please refer to Appendix 10 for the Schedule of Activities for patients continuing to 
receive active treatment after IRB/IEC approval of Amendment 8.
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 
PD-0332991/placebo is resumed. New cycle Day 1 procedures (ie, physical examination, 
ECOG performance status, ECG, Quality of Life questionnaires, blood chemistry, 
hematology) that were performed prior to knowing the need to delay the start of the cycle do 
not need to be repeated unless required to confirm that the parameters necessary for study 
drug to be resumed are met (see Section 5.3.4.2.2).
All lens-grading evaluable patients randomized under Amendment 3 will repeat screening
ophthalmic procedures also during the active treatment phase after 3 months (Cycle 4 Day 1), 
6 months (Cycle 7 Day 1), 12 months (Cycle 13 Day 1) then every 12 months (Day 1 of 
Cycles 25, 37, etc…) thereafter. Additional ophthalmic examinations may be repeated 
during the study as clinically indicated (including for patients randomized prior to 
Amendment 3 approval). 
6.3. End of Treatment Visit
The end of treatment visit will be performed as soon as possible but no later than 4 weeks 
(ie, 28 days) ±7 days from last dose of investigational product and prior to the initiation of 
any new anti-cancer therapy.
All lens-grading evaluable patients randomized under Amendment 3 will repeat screening
ophthalmic procedures also at the End of Treatment visit. 
For details on procedures to be performed at the End of Treatment visit, see the Schedule of 
Activities tables. 
 


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6.4. Follow-up Visit
After discontinuation of study treatment, the following follow-up activities will be required: 
•
Post-study survival status and information related to post-study anti-cancer therapies
(including regimen number/name of post-study anti-cancer therapy, start/stop dates,
and dates of disease progression on subsequent anti-cancer therapies) will be 
collected approximately every 6 months (±7 days) from the last dose of 
investigational product until patient permanent discontinuation from study or end of 
follow-up period whichever occurs first. Telephone contact is acceptable.
•
In addition, post-study breast cancer specific quality of life questionnaire (FACT-B) 
will also be collected every 6 months (±7 days) from the last dose of investigational 
product until patient permanent discontinuation from study or end of follow-up period 
whichever occurs first.  During the follow-up period, all self-assessment 
questionnaires should preferably be completed by the patients during a scheduled 
clinic visit. However, if no clinic visits are being scheduled during the follow-up 
period interviewer administration via phone call may be used instead and documented 
accordingly in the patient source notes.
For details on follow-up visit procedures, see the Schedule of Activities tables. 
The follow-up period will conclude at the time of the final OS analysis.
6.5. Patient Withdrawal
6.5.1. Active Treatment Phase Discontinuation
The term "interruption" refers to a patient stopping the investigational product during the 
course of the study, but then re-starting it at a later time in the study.  The reason for dosing 
interruption will be collected on the appropriate CRF. 
The term "discontinuation" refers to a patient's withdrawal from the active treatment phase.  
The reason for discontinuation from treatment will be collected on the appropriate CRF. 
Patients may be withdrawn from the active treatment phase in case of:
•
Disease progression;
•
Symptomatic deterioration (ie, global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression);
•
Need for additional anti-cancer therapy not specified in the protocol;
•
Unacceptable toxicities;
•
Investigator conclusion that it is in the patient’s best interest to discontinue therapy 
(eg, poor compliance with either protocol monitoring or with taking the study 
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•
Lost to follow-up*;
•
Patient choice to withdraw from treatment (follow-up permitted by patient);
•
Withdrawal of patient consent (cessation of follow-up);
•
Death.
*If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. If after 3 unsuccessful attempts to contact the patient, one of which is by registered 
letter, the patient should be considered “lost to follow-up”. Steps taken to contact the patient 
(eg, dates of telephone calls, registered letters, etc) must be clearly documented in the source 
documents.
Patient who discontinue from the active treatment phase must have end of 
treatment/withdrawal evaluations performed as soon as possible but no later than 4 weeks 
from the last dose of investigational product and prior to initiation of any new anti-cancer
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. 
6.5.2. Study Discontinuation
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol required schedule of study 
visits or procedures at a given study site.
Patients will be withdrawn from study in the case of:
•
Withdrawal of consent (ie, refuses tumor assessments or survival status after end of 
treatment);
•
Lost to follow-up;*
•
Death.
*If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  If after three unsuccessful attempts to contact the patient, one of which is by 
registered letter, the patient should be considered “lost to follow-up”.  Steps taken to contact 
the patient (eg, dates of telephone calls, registered letters, etc) must be clearly documented in 
the source documents.  In any circumstance, every effort should be made to document patient
 


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outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request the patient to return all unused investigational product(s), request the patient to return 
for a final visit, if applicable, and follow-up with the patient regarding any unresolved 
adverse events (AEs).
Data to be collected for the end of study treatment/withdrawal are described in the Schedule 
of Activities tables. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
All study procedures are described in the Schedule of Activities tables footnotes.
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well being of the patient. When a protocol-required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
7.1.1. Independent Review of Disease Assessments
A blinded independent third-party core imaging laboratory will perform a retrospective
review of radiographic images and clinical information collected on-study to verify the 
protocol defined endpoints of disease response and progression as assessed by the 
investigator. 
It is important to the integrity of the study that all imaging studies and clinical information 
(including photographs) are forwarded to the independent core imaging laboratory as each 
patient enrolls and progresses through the study. 
Upon IRB/IEC approval of Amendment 8, the following materials no longer need to be 
forwarded for independent review:
•
All imaging studies performed on study;
•
Photographs of sites of disease assessed using clinical methods.
 


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7.1.2. Tumor Assessments
The importance of timely and complete disease assessments in this study cannot be
understated. Disease assessments must be performed as scheduled according to the calendar, 
regardless of treatment delays resulting from toxicity, to prevent the introduction of bias into 
the assessment of efficacy.  Failure to perform any of the required disease assessments will
result in the inability to determine disease status for that time point. A series of incomplete
disease assessments will result in censoring of the primary endpoint of PFS back to the time
of the last full assessment that did not show progression. Frequent off schedule or
incomplete disease assessments have the potential to weaken the conclusion of this clinical
trial.
Please refer to Appendix 10, for tumor assessment requirements for patients continuing to 
receive active treatment after IRB/IEC approval of Amendment 8. 
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 (CAP).
•
CT or MRI scan of any other sites of disease as clinically indicated. 
•
Clinical assessment of superficial disease which will include photographs of all 
superficial metastatic lesions.  All lesion measurements must be recorded in the 
CRF. 
•
Bone scans in order to detect bony sites of disease.  Any suspicious abnormalities 
(ie, hotspots) identified on the bone scans at baseline must be confirmed by X-ray, 
CT scan with bone windows or MRI.  Bone lesions identified at baseline will 
follow the same assessment schedule as for measurable lesions.  Baseline brain 
CT or MRI are only required in case signs and symptoms suggest the presence of 
metastatic brain disease.  Refer to Section 6.1 for further details on timing 
allowance for baseline brain and bone scans. 
Post-baseline tumor assessments:
For patients continuing to receive active treatment after IRB/IEC approval of Amendment 8, 
please refer to Appendix 10, for tumor assessment requirements. 
Disease assessments will be performed every 12 weeks (±7 days) and bone scans (as 
applicable) every 24 weeks (±7 days) from randomization until radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented PD as per RECIST v.1.1, 
study treatment discontinuation (for patients continuing treatment beyond RECIST-defined 
disease progression), initiation of new anti-cancer therapy, or discontinuation of patient from 
overall study participation (eg, death, patient's request, lost to follow-up). Imaging 
 


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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.
Post-baseline tumor assessments will include:
•
CT or MRI scan of the chest, abdomen, and pelvis (CAP).
•
CT or MRI scan of any other sites of disease identified at baseline.
•
Clinical assessment of sites of superficial disease identified at baseline. Clinical 
assessment of superficial disease must coincide with the imaging studies and will 
include photographs of all superficial metastatic lesions. All lesion measurements 
must be recorded in the CRF. 
•
Bone lesions imaging:
•
If bone lesions were identified at baseline the following assessment must be 
performed:
•
X-ray/CT scan/MRI every 12 weeks (±7 days) from the date of randomization
using the same modality used to confirm the bone lesions at baseline. Areas 
that have received palliative radiotherapy on study cannot be used to assess 
response to study treatment.
•
Bone scans every 24 weeks (±7 days) from the date of randomization and to 
confirm complete response. Abnormalities found on subsequent bone scans 
must also be confirmed by X-ray, CT scan, or MRI.
•
If no bone lesions were identified at baseline, bone scans should be performed as 
clinically indicated (ie, patient describes new or worsening bone pain, or has 
increasing alkaline phosphatase level, or other signs and symptoms of 
new/progressing bone metastases) but are required to confirm complete response.  
Abnormalities found on subsequent bone scans must also be confirmed by X-ray, 
CT scan, or MRI.
•
Repeat brain scans will be required only if metastases are suspected.
The CT scans, including brain CT scan if applicable, should be performed with contrast 
agents unless contraindicated for medical reasons. If IV contrast is medically 
contraindicated, the imaging modality to be used to follow the disease (either CT without 
contrast or MRI) should be the modality which best evaluates the disease, and the choice 
should be determined by the investigator in conjunction with the local radiologist. MRI of 
the abdomen and pelvis can be substituted for CT if MRI adequately depicts the disease.
 


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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).73
The same method and technique should be used to characterize each lesion identified and 
reported at baseline, during the study treatment period and during follow-up.  The use of 
plain-film X-rays (with the exception of bone X-rays as detailed above) is discouraged. The 
use of positron emission tomography (PET) imaging as the only imaging modality is not 
permitted.
For patients having effusions or ascites, cases having cytological proof of malignancy should 
be recorded as non-target lesions on the tumor assessment CRFs.  Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be recorded on 
the non-target lesion CRF.
Objective tumor response will be measured using the Response Evaluation Criteria in Solid 
Tumors (RECIST Version 1.1, see http://www.eortc.be/recist/default.htm). Also please refer 
to Appendix 7. All measurements should be recorded in metric notation using a ruler or 
calipers. For patients with bone-only disease:
•
Treatment outcome will be recorded in the CRF as complete response (CR), stable 
disease (SD) or progression (PD). 
Interpretation will be PD if:
•
The malignant nature of one or more new lesions identified with bone scan is
confirmed with X-ray, or CT, or MRI scan;
•
Flare observed in bone scan is followed by confirmation of progression with other
imaging modalities;
•
Clinical worsening of the disease is assessed by bone scan and disease progression
(ie, new lesion(s)) is confirmed with other imaging modalities;
•
Unequivocal progression of existing bone lesions.
Interpretation will be SD if:
•
The malignant nature of all the new lesions identified with bone scan is not
confirmed.
In the following cases the patient will be censored at the date of prior tumor assessment with 
no PD: 1) on-study fracture; 2) on-study management of pain (palliative radiation therapy, 
palliative surgery), 3) clinical worsening not objectively confirmed; 4) on-study change of 
therapy. In all the censored cases (no objectively documented PD) tumor assessment will be 
performed until PD. Also, it will be at the discretion of the investigator to discontinue the 
study treatment.
 


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It is suggested to institute palliative radiotherapy (eg, lesions at risk for spontaneous 
micro-fractures or painful lesions) before study initiation as well as palliative surgery if 
possible and clinically appropriate.
7.1.3. Overall Survival
Following the End of Treatment visit, survival status will be collected in all patients 
(telephone contact is acceptable) every 6 months (±7 days) from the last dose of study 
treatment. Information on subsequent anti-cancer therapy will also be collected (See
Section 6.4).
7.2. Safety Assessments
Safety assessment will consist of monitoring of all adverse events (AEs), including serious 
adverse events (SAEs), regular monitoring of hematology, serum chemistry, and routine 
monitoring of ECGs, physical examinations, vital signs, and ECOG performance status. 
Adverse event assessment will include type, incidence, severity (graded by the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], 
Version 4.0, see Severity Assessment section), timing, seriousness, and relatedness.
Baseline tumor-related signs and symptoms will be recorded at the Cycle 1 Day 1 visit and 
then reported as adverse events during the trial if they worsen in severity or increase in 
frequency.
7.2.1. Laboratory Safety Assessments
Blood tests will include the following:
Hematology Panel
Blood Chemistry Panel
1
Hemoglobin
1
ALT
2
Platelets
2
AST
3
WBC
3
Alkaline Phosphatase
4
Absolute Neutrophils
4
Sodium
5
Potassium
6
Total Calcium
7
Magnesium
8
Total Bilirubin
9
BUN or Urea
10
Serum Creatinine
11
Albumin
12
Hemoglobin A1c 
Blood tests will be drawn at the time points described in the Schedule of Activities table, and 
analyzed at local laboratories.  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. 
 


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7.2.2. Electrocardiogram (ECG)
All 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. 
Triplicate ECGs (referred as ECGE) will be performed for all patients to determine the mean 
QTc interval for eligibility purpose. 
Patients found to be eligible will be part of one of the two groups highlighted below 
depending on which site screened the patient.  ECG frequency for each group is described 
below:  
•
Patients in Group 1 (approximately 60 patients) will be enrolled at selected sites and
will have their QTc monitored to evaluate the effect of PD-0332991 on QT interval 
via serial triplicate ECGs time-matched with PK draws.  ECGs will be obtained on 
the day preceding treatment initiation (Day 0) at time 0 (time of first ECG also 
referred to as ECG1) and then 2, 4, 6, and 8 Hrs after ECG1, and on Day 14 of
Cycle 1 pre-dose (0 Hrs) and 2, 4, 6, and 8 Hrs following PD-0332991 administration.  
Timing of ECGs performed on Day 14 MUST be time-matched (clock 
time ± 35 minutes) with ECG assessments performed on Day 0 (eg, if the ECG1 on 
Day 0 was performed at 10:00 AM then the 0 hour triplicate ECGs on Day 14 must 
be performed within the 9:30 AM - 10:30 AM timeframe but as close as possible to 
10:00 AM whenever feasible).  On Day 14 of Cycle 1, study treatment should be 
administered immediately after the pre-dose PK draw has been collected.  All ECGs 
should be obtained after a fast of at least 1 hour.  ECGs should be performed 
immediately before PK blood draws at respective time points.  Patients who cannot 
complete ECG measurements on Day 0 and/or PK-matched ECG measurements (both 
ECG and PK collected) on Day 14 will need to be replaced.  Additionally, triplicate 
ECGs will be obtained for safety monitoring at 0 hour (pre-dose) on Day 1 of 
Cycle 1*, Day 14 of Cycle 2, then on Day 1 of Cycles 4, 7, and 10.  ECGs beyond 
Cycle 10 will be performed as clinically indicated.
•
Patients in Group 2 (all other patients) will have triplicate ECGs performed for safety 
monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1*, Day 14 of Cycles 1 and 2, then 
on Day 1 of Cycles 4, 7, and 10. ECGs beyond Cycle 10 will be performed as 
clinically indicated. All ECGs should be obtained after a fast of at least 1 hour.
*Note: Triplicate ECGs do not need to be repeated on Day 1 of Cycle 1 if ECGE was 
performed within 7 days of the date of randomization. 
 


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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 but within 10 minutes for all 3 ECGs at the 
protocol specified timepoints (see Schedule of Activities table for details) to determine the 
mean QTc interval. All triplicate ECG tracings will be sent electronically to a core ECG 
laboratory for blinded manual interval measurements. The blinded manual interval 
measurements from the core ECG laboratory will be used for primary statistical analysis of 
ECG data in Group 1 patients. 
If at any time during the course of treatment, the mean QTc is prolonged (≥501 msec on at 
least two separate ECGs, ie, CTCAE Grade ≥3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate. If manual reading confirms a QTc of 
≥501 msec, immediate search for reversible causes (including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the QTc 
interval) should be performed. In addition, repeat ECGs should be immediately performed 
hourly for at least 3 hours until the QTc interval falls below 501 msec.
•
If QTc interval reverts to less than 501 msec, and in the judgment of investigator(s) in 
consultation with the sponsor the cause is determined to be other than study drug, 
treatment may be continued with regular ECG monitoring under hospital supervision.
•
If in that timeframe the QTc intervals remain above 501 msec the study drug will be 
held until the QTc interval decreases to <501 msec. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (eg, change in 
patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If investigational product causality cannot be ruled out, Investigational product dose 
adjustment and/or discontinuation should be performed according to instructions provided in 
Section 5.3.4: Dose Modification.  Additional triplicate ECGs may be performed as clinically 
indicated.
When matched with PK sampling, ECG must be carried out before PK sample drawing such 
that the PK samples are collected at the nominal time (ie, the timing of the PK collections 
over rides the timing of the ECG collections). 
7.2.3. Ocular Safety Assessments
7.2.3.1. Snellen Best Corrected Visual Acuity and Refraction
Snellen visual acuity will be assessed by using a standard wall or projection chart before 
implementing any procedures that can affect vision (eg, pupil dilation, tonometry, and 
gonioscopy).  The same optotype will be used throughout the study for a specific patient, and 
 


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the right eye should be tested first.  The refractive error will be determined at the Screening 
visit.  The examiner should ensure that patients are seated comfortably and that they do not 
move their head forward or backward during testing.  Patients will be told that the chart 
contains only letters.
The line read with 2 or fewer errors will be recorded.  If 3 of the 5 letters on a line are read 
correctly, the patient will be given credit for that line.  For example, if the patient reads 
20/25 +3, 20/20 will be recorded.  
A decrease in best-corrected visual acuity of 3 lines or more from the Screening visit will be 
reported as an adverse event.  An adverse event of visual acuity will be counted from the 
following lines: 20/20 or better, 20/25, 20/30, 20/40, 20/50, 20/60, 20/70, 20/80, 20/100, 
20/125, 20/150, and 20/200.  If the acuity at screening is better than 20/20, the decrease will 
be calculated from 20/20.  
In the event of a decrease in visual acuity of 3 lines or more from screening, refraction will 
be rechecked at all subsequent study visits.  A change in refraction power (spherical or 
cylindrical) of ±1.25 diopters compared with the screening examination will be reported as 
an adverse event.
7.2.3.2. Intraocular Pressure Measurement
Intraocular pressure (IOP) will be measured using a calibrated Goldmann applanation 
tonometer.  Both eyes will be tested, with the right eye preceding the left eye.  The operator 
will initially set the dial at 10 mm Hg, then look through the slit lamp and adjust the dial to 
take the reading, and then record the results, including the time assessment is made. 
Any IOP increase of greater than 10 mmHg above baseline or any IOP that increases above 
25 mm Hg will be reported as an adverse event (AE).
7.2.3.3. Slit-lamp Biomicroscopy
Slit-lamp biomicroscopy with fluorescein will be performed.  At each scheduled visit, 
deposition of pigment on the corneal endothelial layer or the lens capsule or any 
abnormalities of the lids, conjunctivae, cornea, anterior chamber, iris, or lens (see Lens 
Grading) will be graded as mild, moderate, or severe.  Slit-lamp biomicroscopy should 
precede IOP measurement and the administration of any pupil-dilating agent for 
ophthalmoscopy.
Cells and flare in the anterior chamber should be noted during the slit-lamp examination.
 


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Intraocular Inflammation Grading Scale for Biomicroscopy:
Grade
0
1
2
3
4
Grading of aqueous 
flarea
Completely 
Absent
Barely 
Detectable
Moderate (iris and 
lens details clear)
Marked (iris and 
lens details hazy)
Intense (formed 
fibrin in aqueous)
Grading of cells in the 
aqueousa,b
No cells
1 to 5 cells
6 to 10 cells
11 to 20 cells
>20 cells
a.
Evaluation of Anterior Chamber Inflammation:
1.
Examination of the anterior chamber for cells must be performed before either dilation or applanation tonometry.
2.
The light intensity of the slit lamp is turned to the maximum tolerated by the patient.
3.
High magnification and 1 x 2 mm slit are used.
4.
The ray of light as directed at an angle of approximately 45ο to the plane of the iris.
b.
Modified from Hogan et al. 1959.74  
During the study, any new finding or deterioration from baseline findings should be reported 
as an adverse event.
7.2.3.4. 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.72  Once the pupils are dilated to at least 5 mm, use slit lamp with 
~10X magnification and brightest beam intensity.
•
Nuclear opacity.
•
Orient beam at 45° to viewing axis.
•
Adjust slit beam to standard parameters: 8 mm height and 0.3 mm width.
•
Compare opalescence of nucleus with those on the provided pocket card of 
standard photos.
•
Cortical and Posterior Subcapsular Cataract (PSC) opacities.
•
Select wide slit beam setting optimum for retro-illumination of lens.
•
Visualize lens opacities against red fundus reflex background.
•
Count only opacities definitely visible against red reflex.
•
Mentally combine all cortical opacities into one contiguous area.
 


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•
Compare total opacity area with those on the provided pocket card of standard 
photos.
•
Grade each type of opacity in half steps from <1 to >3 (1=mild, 2=moderate and 
3=severe) using the scale defined on the provided pocket card of standard photos.
7.2.3.5. Funduscopy (Ophthalmoscopy)
Funduscopy (Ophthalmoscopy) will be performed after dilation of the pupils to examine the 
vitreous body, retina, and optic nerve head.  At screening, any abnormalities and pathologic 
findings will be graded as mild, moderate, or severe.  
Any new findings or deterioration from baseline findings will be reported as an adverse 
event.
7.2.4. Other Safety Assessments
A full physical examination including an examination of all major body systems (including 
general appearance, head, ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, 
abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and pulse 
rate which may be performed by a physician, registered nurse or other qualified health care 
provider, will be required at screening, and Day 1 of Cycles 1 and 2. 
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits.
Performance Status: The Eastern Cooperative Oncology Group (ECOG) performance status 
scale will be used (see Appendix 1). 
7.3. Pharmacokinetic Assessments
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing. However, samples obtained within 10 min or 10% of the nominal time 
AND collected prior to administration of the investigational product on that day (with the 
exception of the planned post-dose samples that will be collected on Day 14 of Cycle 1) 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 assessments 
(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.
One 3 mL sample of venous blood will be collected in appropriately labeled K2 EDTA 
collection tubes for assessment of PD-0332991 (including its active metabolites, if
appropriate) levels at the protocol-specified times.  Samples will be analyzed using validated 
analytical methods in compliance with Pfizer standard operating procedures. 
 


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Blood samples will be collected from all participating patients for PK assessments of 
PD-0332991 on Day 14 of Cycles 1 and Cycle 2 before administration of investigational 
product on that day. In the event a pre-dose sample cannot be/is not collected on Day 14 of 
Cycle 1 or Cycle 2 as scheduled, every effort should be made to collect a makeup pre-dose 
sample between Day 15 and Day 21 of the same cycle or between Day 14 and Day 21 of any 
subsequent cycles beyond Cycle 2 following the same rules described above. 
For patients participating in the dedicated QTc portion of the trial (Group 1), all PK draws at 
Day 14 of Cycles 1 and 2 will be done immediately after triplicate ECGs have been 
performed so that the PK samples are collected at the nominal time. 
Additional blood samples may be requested from patients experiencing unexpected or serious 
adverse events, or adverse events that lead to discontinuation.
As part of understanding the pharmacokinetics of the PD-0332991, blood samples may be 
used for metabolite identification and/or evaluation of the bioanalytical method.  These data 
will be used for internal exploratory purposes and will not be included in the Clinical Study 
Report.
Refer to the Study Manual for detailed collection, processing and shipping procedures. 
7.4. Patient Reported Outcomes
Patient reported outcomes of health-related quality of life and health status will be assessed 
using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol-5D 
(EQ-5D) instruments. 
The FACT-B and EQ-5D will be given to the patient in the appropriate language for the site.
Patients will complete each instrument pre-dose on Day 1 of Cycle 1 through 3, then on 
Day 1 of every other subsequent cycles starting with Cycle 5 (eg, Cycles 5, 7, 9, etc), and 
then at the end of study treatment visit. After patients discontinuation from the active study 
treatment phase, FACT-B questionnaire will continue to be collected during the follow-up 
period every 6 months (+/- 7 days) from the last dose of investigational product until patient 
permanent discontinuation from study or end of follow-up period whichever occurs first.  
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). Completion of FACT-B during the follow-up period
should also be completed by the patients during a scheduled clinic visit whenever possible. 
However, if no clinic visits are being scheduled during that time interviewer administration 
via phone call may be used instead and documented accordingly in the patient source notes.
 


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7.4.1. EuroQol Health Utilities Index EQ-5D (Appendix 5)
The EuroQol-5D (EQ-5D) is a 6 item instrument designed to assess health status in terms of 
a single index value or utility score.  It consists of 5 descriptors of current health state 
(mobility, self care, usual activities, pain/discomfort, and anxiety/depression); a patient is 
asked to rate each state on a three level scale (1=no problem, 2=some problem, and 
3=extreme problem) with higher levels indicating greater severity/impairment.  It also 
includes a visual analogue scale: the EQ VAS.  The EQ VAS records the patient’s self rated 
health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).  
Published weights are available that allow for the creation of a single summary score.  
Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction 
and 1 as perfect health.
7.4.2. Functional Assessment of Cancer Therapy-Breast (FACT-B) [Version 4]
(Appendix 6)
The Functional Assessment of Cancer Therapy (FACT) is a modular approach to assess 
patient health-related quality of life using a ‘core’ set of questions (FACT-G) as well as a 
cancer site-specific module. 
The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical 
Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. 
The FACT-B consists of the FACT-G (27-items) and a breast-specific module: a 10-item 
instrument designed to assess patient concerns relating to breast cancer.  Patients are asked to 
respond to a likert scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 
4=very much.
7.5. Biomarker Assessment
Tumor tissues are required from all patients for study participation. 
Retrospective confirmatory testing of tumor tissue samples for ER status will be performed 
in a central laboratory designated by the sponsor using a validated test.  Results from this 
testing will be used for sensitivity analyses and will not be made available to the sites. 
In addition, tumor tissue biomarkers, including DNA, RNA and protein analytes, will be 
analyzed to investigate possible associations with resistance/sensitivity to treatment with 
study drugs.  Biomarkers that will be analyzed will be selected based on their known 
relevance to mechanisms involved in cell cycle regulation.  Examples of such biomarkers 
include CCND1 and CDKN2A gene copy number, cdk4 and cdk6 RNA expression, and 
Ki67, pRb and p16 protein expression.
Submission of formalin-fixed paraffin embedded (FFPE) tumor samples (blocks) of adequate 
size to allow for three 0.6 mm diameter x 5 mm deep cores that will be used to generate a 
tissue microarray are needed. If FFPE tissue block cannot be provided, a minimum of 
12 glass slides each containing an unstained 5-micron FFPE tissue section, will be required 
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Tissue sample from a metastatic or recurrent tumor lesion must be provided whenever 
possible.  If such tissue sample is unavailable, a de novo fresh biopsy is recommended when, 
in the investigator’s judgment, such biopsy is feasible and can be safely performed.  A 
sample of the original diagnostic tissue (ie, archival) will also be collected when available 
and sent to the sponsor-designated central laboratories for assessment of biomarkers 
associated with sensitivity and/or resistance to PD-0332991 (eg, Ki67, CDKN2A (p16), 
pRb).  Retrospective confirmation of ER status and HER2 status when needing to be repeated 
for eligibility purpose will be performed using the most recent tumor sample. Original 
diagnostic tumor tissue will be used for confirmation of ER and HER-2 status in the event 
that a recurrent/metastatic tissue sample is not available and a fresh biopsy of the 
recurrent/metastatic lesion is not feasible. 
Note: Tissue sample collected after neoadjuvant treatment is not acceptable for eligibility 
purposes as the molecular characteristics of the sample may be different from the original 
diagnostic tissue sample. 
Tissue samples from all patients will be used for additional biomarker analyses.  Detailed 
information about biomarker sample collection, preparation, storage, labeling, and shipment 
is indicated in the Study Reference Manual.
7.5.1. Optional Tumor Tissue Biopsy for Molecular Profiling
An optional fresh metastatic/recurrent tumor biopsy sample should be collected at the end of 
treatment visit for patients who discontinue treatment due to disease progression. The tumor 
tissue will be used to determine possible mechanisms of resistance to study treatment.
7.6. Retained Pharmacogenomic Sample(s)
7.6.1. Pharmacogenomics of Drug Response
Genomic and metabonomic variation may help to explain some of the variability in response 
seen with some drugs among different individuals.  This is referred to as pharmacogenomics.  
Comparing the DNA, RNA, protein, and metabolite variation patterns of patients who 
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment.  Collecting samples for 
pharmacogenomic analyses and retaining them in the Pfizer BioBank makes it possible to 
seek explanations for differences in, for example, exposure, efficacy, tolerability, or safety 
not anticipated prior to the beginning of the study. 
A single 4 mL blood sample (Prep D1; K2 edetic acid (ethylenediaminetetraacetic acid) 
(EDTA) whole blood collection optimized for DNA analysis) will be collected pre-dose at 
the Cycle 1 Day 1 to be retained for potential pharmacogenomic analyses related to drug 
response or adverse drug reactions.  For example, putative safety biomarkers, drug 
metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to 
the mechanism of drug action may be examined. 
 


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The Retained Pharmacogenomic Sample(s) will be collected from all patients unless 
prohibited by local regulations.  Detailed collection, processing, storage and shipment 
instructions are provided in the central laboratory manual. 
7.6.2. Additional Pharmacogenomic Research (Optional)
Unless prohibited by local regulations, patients will be asked to indicate on the consent form 
whether they will allow the Retained Pharmacogenomic Sample to also be used for the 
following research:
•
Investigations of the disease under study in the clinical trial, and related conditions.
•
Samples may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics. 
Patients need not provide additional samples for the uses described in Section 7.6.1; the 
samples specified in Section 7.6.1 will be used.  Patients may still participate in the clinical 
trial if they elect not to allow their Retained Pharmacogenomic Samples to be used for the 
additional purposes described in Section 7.6.2.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
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.
 


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8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the 
time the patient has taken at least one dose of investigational product through the patient’s 
last visit.
If a patient begins a new anti-cancer 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;
•
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;
 


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•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy (EDP);
•
Exposure via breast feeding;
•
Medication error;
•
Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
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.
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
A Serious Adverse Event is any untoward medical occurrence at any dose that:
•
Results in death;
•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
 


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•
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 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 subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
8.5.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section on Serious Adverse Event Reporting Requirements). 
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 values ≥3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value ≥2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 X ULN or not available.
 


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•
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 values ≥2 times the baseline values and ≥3 X ULN, or 
≥8 X ULN (whichever is smaller).
Concurrent with:
•
For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level 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, and 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 
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.
 


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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 examination);
•
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);
•
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);
•
Hospitalization for observation without a medical AE;
•
Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient.
•
Admission exclusively for the administration of blood products.
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.
 


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8.7. Severity Assessment
As required on the AE CRFs, the investigator will report adverse events using concise 
medical terminology (verbatim) as well as collect on the CRF the appropriate Common 
Terminology Criteria for Adverse Events (CTCAE) (version 4.0, Publish Date:
May 28, 2009, http://ctep.cancer.gov/reporting/ctc.html) and will use the following 
definitions of severity to describe the maximum intensity of the adverse event.
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING Consequences; Urgent Intervention Indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
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 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 an SAE Report 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 EIU reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EIU Form.  In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth.  In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 
•
Spontaneous abortion includes miscarriage and missed abortion;
 


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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 the 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 Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
 


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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.
In addition to recording observed or volunteered adverse events, certain additional data will 
be solicited from the patients in this study to more fully characterize the clinical 
pharmacology of PD-0332991/placebo in combination with letrozole. These additional 
measurements are contained under Section 7.4 and include Patient Reported Outcomes.
Patient reported outcomes are collected and evaluated in a different manner than the 
observed or volunteered adverse events.  Given these differences, no attempt will be made to 
resolve any apparent discrepancies between observed or volunteered adverse events and the 
additional data collected from patients to more fully characterize the clinical pharmacology 
of PD-0332991/placebo in combination with letrozole. These additional data will be 
presented in separate tables, figures, and data listings, and will be reviewed in the final study 
report.  Adverse event incidence rates will not be calculated from these solicited data but 
rather from the information recorded on the Adverse Event pages on the Case Report Form 
(CRF).
 


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8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the sponsor.  This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment.  The planned data analysis in this section was performed 
when this study met its primary endpoint at the final primary analysis performed with the
data cutoff date of 26 February 2016.  With the ongoing data collection of survival
information, the planned final OS analysis will be performed based on the detailed plan 
described in the SAP.  
9.1. Sample Size Determination
The primary purpose of this study is to demonstrate that the combination of 
PD-0332991 with letrozole is superior to placebo plus letrozole in prolonging PFS in 
postmenopausal women with ER (+), HER2 (-) ABC who have not received any prior 
systemic anti-cancer treatment for advanced disease.  The study is designed to test the null 
hypothesis that the true PFS distributions for both PD-0332991 plus letrozole and placebo 
plus letrozole arms are the same with a median PFS 9 months versus the alternative 
hypothesis that the true PFS distribution has a median that is longer than 9 months4 for the 
PD-0332991 plus letrozole arm. 
Under the original study design, 450 patients were to be enrolled using a 2:1 randomization 
schema. A total of 239 PFS events would be required to have 90% power to detect a hazard 
ratio of 0.64. On 03 January 2014, the protocol was amended to revise the study drug 
administration instructions from a recommended fasting state to administration with food and
to prohibit the concomitant use of proton-pump inhibitors, as both conditions were found to 
negatively impact PD-0332991 plasma exposures. To mitigate the impact on efficacy results 
of potentially lower PD-0332991 exposures in some patients, an adjustment is now being 
made to the alternative hypothesis and an additional 200 patients will be enrolled into the 
study, and required number of PFS events for final analysis will be increased to 347. This 
will allow the trial to maintain a 90% power to detect significant treatment difference 
assuming a true hazard ratio of 0.69 in favor of the PD-0332991 plus letrozole arm using a 
one sided log rank test at a significance level of 0.025. 
The sample size for this study is determined based on the assumptions that the median PFS 
for patients receiving placebo plus letrozole in the first-line treatment setting is 9 months and 
a risk reduction by 31% (hazard ratio of 0.69) or an improvement by 44% to median PFS of 
13 months in the PD-0332991 plus letrozole treatment is clinically significant.  A total of 
347 events are required in the 2 arms of the study based on a 2:1 randomization to have 
90% power to detect a difference assuming a true hazard ratio of 0.69 in favor of the 
 


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PD-0332991 plus letrozole arm using a one-sided, log-rank test at a significance level of 
0.025. Assuming a 15% drop-out rate on either treatment arm, a non-uniform accrual 
accomplished over a 15-month period and follow-up for about 10 months after the last 
patient is enrolled, a total sample size of approximately 650 patients (approximately 433 in 
the PD-0332991 plus letrozole arm and approximately 217 in the placebo plus letrozole arm) 
is required.
The sample size described above will also allow the assessment of differences in the 
secondary endpoint of overall survival (OS) with a high level of significance.  The OS 
outcome of a reported Phase 3 clinical trial in a similar patient population demonstrated a 
median of 34 months for the arm receiving letrozole.4  Using this value as an assumption 
with a hypothesized 26% risk reduction (hazard ratio of 0.74) or 35% improvement in 
median OS (from 34 months to 46 months) in patients randomized to receive PD-0332991 
plus letrozole and follow-up period of approximately 68 months, evaluation of 390 events 
using a one-sided log-rank test is required for a significance level of 0.025 and power of 80% 
to detect the difference.
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, 
PD-0332991/placebo or letrozole/placebo), 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. 
9.3. Efficacy Analysis
All efficacy analyses will be based on intent-to-treat (ITT) population.  Some efficacy 
analyses will also be performed on the AT population.  All 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, DC) will be derived using the 
local radiologist’s/investigator’s assessment.  Radiographic images 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 
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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 a duration of 1 day. Additionally, patients who start a new 
anti-cancer therapy prior to documented PD will be censored at the date of the last tumor 
assessment prior to the start of the new therapy. 
The primary analyses of PFS will be performed in the ITT population. A stratified log-rank 
test (one-sided) will be used to compare PFS time between the 2 treatment arms at the 
interim and/or final analyses with the overall significance level preserved at 
0.025 (one-sided).  The stratification factor(s) are specified in Section 3.  PFS time associated 
with each treatment arm will be summarized for the ITT population using the Kaplan-Meier 
method and displayed graphically where appropriate. Confidence intervals (CIs) for the 
25th, 50th and 75th percentiles of the event-free time will be reported. The Cox Proportional 
hazards model will be fitted to compute the treatment hazard ratio and the corresponding 
95% CI.
PFS will also be evaluated in the AT Population and the stratified long-rank test (one-sided, 
α=0.025) will be used. In addition, to assess the impact of proton-pump inhibitors and 
fasting condition, PFS will also be evaluated in the population excluding patients who took 
proton-pump inhibitors and/or any other antacid medications concomitantly with study drug 
under fasting conditions during the active treatment phase. 
9.3.2. Analysis of Secondary Endpoints
The secondary efficacy endpoints are:
Survival
Overall Survival (OS) is defined as the time from date of randomization to date of death due 
to any cause. In the absence of confirmation of death, survival time will be censored to last 
date the patient is known to be alive. 
All patients randomized will be considered evaluable for OS.  OS will be hierarchically 
tested for significance at the time of PFS analyses, provided the primary endpoint, PFS, is 
statistically significant at the PFS interim 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 arms will be assessed using Kaplan-Meier methods and 
displayed graphically where appropriate. The median event times and 95% CIs will be 
estimated. Cox regression models will be used to estimate the treatment hazard ratio and its 
95% confidence interval.
 


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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)
Objective response is defined as a complete response (CR) or partial response (PR) according 
to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1; Appendix 7) 
recorded from randomization until disease progression or death due to any cause. 
A patient will be considered to have achieved an OR if the patient has a sustained complete 
response (CR) or partial response (PR) according to RECIST v.1.1 definitions. Otherwise, 
the patient will be considered as non-responders in the OR rate analysis.  Additionally, 
patients with inadequate data for tumor assessment (eg, no baseline assessment or no 
follow-up assessments) will be considered as non-responders in the OR rate analysis. 
The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the 
number of patients with objective response (CR or PR) by the number of patients randomized 
to the respective treatment arm (“response rate”). A 95% CI for the response rates will be 
provided.  Response rate comparisons between the 2 treatment arms as randomized will be 
assessed using Cochran-Mantel-Haenszel (CMH) test with the same stratification factors as 
for the PFS analysis. 
Analyses for ORR will be performed on the ITT population based on the investigator’s 
assessment as well and also on the review of the blinded independent third-party core 
imaging laboratory. 
In addition, the best overall response for each patient will be summarized by treatment arm.
Disease Control (DC)
Disease control (DC) is defined as complete response (CR), partial response (PR), or stable 
disease (SD) ≥24 weeks according to the RECIST version 1.1(Appendix 7) recorded in the 
time period between randomization and disease progression or death to any cause. 
The DC rate (DCR) on each randomized treatment arm will be estimated by dividing the 
number of patients with CR, PR, or SD ≥24 weeks by the number of patients randomized to 
the treatment arm. A 95% CI for the DC rates will be provided.  DC rate comparison 
between the two treatment arms as randomized will be assessed using CMH test with the 
same stratification factors as for the PFS analysis.
Analyses for DCR will be performed on the ITT population based on the investigator’s 
assessment as well and also on the review of the blinded independent third-party core 
imaging laboratory. 
 


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Duration of Response (DR)
Duration of response (DR) is defined as the time from the first documentation of objective 
tumor response (CR or PR) to the first documentation of objective tumor progression or to 
death due to any cause, whichever occurs first. DR data will be censored on the date of the 
last tumor assessment on study for patients who do not have objective tumor progression and 
who do not die due to any cause while on study. 
DR will only be calculated for the subgroup of patients with an objective response. 
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.
All of these secondary analyses will be conducted at a one-sided 0.025 level of significance.  
Additional sensitivity analyses will be outlined in the SAP. 
Additional secondary endpoints include:
Patient Reported Outcomes (PRO)
Breast cancer-specific quality of life scores and change from baseline scores will be 
compared between the treatment arms at various time points using a mixed model repeated 
measures (MMRM) approach adjusting for specified covariates. In addition, analyses will be 
performed to determine if the change from baseline scores achieve the appropriate minimally 
important difference (MID) cut-off for the scale being examined. Patients from the ITT
population who completed a baseline assessment and at least one post-baseline assessment 
prior to study treatment discontinuation will be considered evaluable for the patient reported 
outcome analysis.
In addition to the above analyses, an examination of the time to deterioration (TTD) also will 
be carried out using survival analysis methods. A composite definition for deterioration 
based on death, tumor progression, and MID will be used.
Electrocardiogram (ECG) Analysis 
QT measurements corrected by heart rate (QTc) will be used for the data analysis and 
interpretation.  In addition to commonly used techniques including Bazett’s (QTcB) and 
Fridericia’s (QTcF) methods, a study-specific correction method will be evaluated (QTcS) 
for the ECG sub-group of Arm A. QTcF will be used for the primary analysis. 
The QTc analysis will be based on a non-inferiority hypothesis testing framework.  
Approximately 40 PD-0332991 plus letrozole treated patients are needed to establish 
non-inferiority (no unacceptable QTc prolongation from the PD-0332991 plus letrozole 
combination) between post-dose baseline and baseline (∆QTc) at all 5 QTc sampling time 
points on Cycle 1 Day 14 with 90% power.  The test is based on a one-sided difference in 
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between ∆QTc under the alternative hypothesis is 10 msec, assuming a non-inferiority 
margin of 20 msec and the standard deviation of the paired differences equals 16 msec (based 
on Study A5481003). If the upper bounds of one-sided 95% confidence intervals of ∆QTc
for all 5 QTc sampling time points are below 20 msec, the post-baseline dose QTc interval is 
considered to be “non-inferior” to the baseline; the QTc effect of PD-0332991 in 
combination with letrozole is concluded to not be unacceptable. 
Since this is a double-blind study with a 2:1 randomization, approximately 60 patients will be 
needed for QTc evaluation to ensure approximately 40 patients from the experimental arm 
(ie, PD-0332991 plus letrozole). 
Changes in QTc (QTcB, QTcF, and/or QTcS) from baseline will be summarized using 
descriptive statistics and categorical analysis by nominal time point. A random effect model 
with the nominal time point as a fixed effect and the patients as a random effect will be used 
to estimate the mean change in QTc (QTcF, QTcS optional) from baseline at each 
post-baseline nominal time point.  The 90% confidence intervals for the changes from 
baseline in QTc will be provided at each post-baseline nominal time point.
Pharmacokinetic/Pharmacodynamic Analysis of QTc
Concentration data of PD-0332991 will be listed by patient and by actual collection time and 
day. 
Concentration-QTc analysis will be conducted using the PK and ECG data from this study.  
Linear, log-linear, and/or saturable models will be examined for the concentration-QTc
relationship. Exploratory analyses (via graphical displays and/or model fitting) include 
accounting for a delayed effect and the justification for the choice of pharmacodynamic 
model.  Diagnostic evaluation will be included to explore the adequacy of the model.  Refer 
to SAP for details of the analysis.  The results of these modeling analyses may be reported 
separately from the clinical study report.
Pharmacokinetic Analysis 
Average trough concentrations will be listed by patient. Summary statistics will be provided 
for trough concentrations by study cycle and for average trough concentrations by patient.  
The relationship between trough concentration and potential covariates will be evaluated. 
All patients treated with PD-0332991 and for whom drug plasma concentration results (from 
at least 1 visit) are available will be included in the analysis. 
Exposure/Response Analysis 
In addition, the relationship between exposure and efficacy and 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. 
 


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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 PD-0332991 plus letrozole anti-tumor efficacy.
9.4. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed
graphically, where appropriate.
9.5. Safety Analysis
The AT population will be the primary population for safety evaluation.  Summaries of AEs 
and other safety parameters will be provided as appropriate.
Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.0 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html). 
Adverse events will be summarized by treatment and by the frequency of patients 
experiencing treatment emergent adverse events corresponding to body systems and 
MedDRA preferred term. Adverse events will be graded by worst NCI CTCAE v4.0 Grade.  
Adverse events will be summarized by cycle and by relatedness to trial treatment.  Detailed 
information collected for each AE will include a description of the event, duration, whether 
the AE was serious, intensity, relationship to study drug, action taken, and clinical outcome.  
Emphasis in the analysis will be placed on AEs classified as treatment emergent.
Adverse events leading to death or discontinuation of trial treatment, events classified as NCI 
CTCAE v4.0 Grade 3 or higher, trial drug-related events, and serious adverse events will be 
considered with special attention. 
Laboratory Abnormalities 
Hematology and chemistry laboratory data will be summarized by treatment and by cycle.  
The laboratory results will be graded according to the NCI CTCAE v4.0 severity grade.  The 
frequencies of the worst severity grade observed will be displayed by study treatment.  Shift 
tables will be provided to examine the distribution of laboratory toxicities. For parameters 
for which an NCI CTCAE v4.0 scale does not exist, the frequency of patients with values 
below, within, and above the normal ranges will be summarized by treatment. 
 


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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.  
Summary and Categorical Electrocardiogram (ECG) Analysis 
All ECGs obtained during the study will be evaluated for safety.  The triplicate data will be 
averaged and all summary statistics and data presentations will use the triplicate averaged 
data.  Any data obtained from ECGs repeated for safety reasons after the nominal time-points 
will not be averaged along with the preceding triplicates. 
For all patients in the safety analysis population, individual change in QTc (QTcF, QTcB, 
QTc S) will be calculated for each nominal post-baseline time point. These individual 
changes will be summarized using descriptive statistics. 
For all patients in the safety analysis population, categorical analysis of the 
QTcF/QTcB/QTcS data will be conducted and summarized as follows: 
1. The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB/QTcS (<30, 30- 60, and ≥60 msec).
2. The number of and percentage patients with maximum post-dose QTcF/QTcB/QTcS
(<450, 450-<480, 480- <500, and >500 msec).
3. PR changes from baseline ≥50% if absolute baseline value was <200 msec, and 
≥25% if absolute baseline value was >200 msec. 
4. QRS changes from baseline ≥50% if absolute baseline value was <100 msec, and 
≥25% if absolute baseline value was >100 msec.
The analyses described above for all patients will be repeated separately for the ECG
sub-population in group 1 for QTcF/QTcB/QTcS.
9.6. Interim Analysis
The study is designed to have one interim analysis and the final analysis based on the 
primary PFS endpoint.  A formal efficacy boundary (Haybittle-Peto) for rejecting the null 
hypothesis will be used for the interim analysis.  To protect the integrity of the study and to 
preserve the type-1 error rate, a fraction of alpha (0.000013) for efficacy will be spent at the 
interim analysis and accounted for in the overall type I error rate. The overall significance 
level for the efficacy analysis of PFS will be preserved at 0.025 (1-sided test).
 


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The purposes of the interim analysis are to allow early stopping of the study for futility and
efficacy, to assess safety of the combination regimen, and to potentially adjust the sample
size. The interim analysis will be performed after approximately 226 patients have 
documented progressive disease or die (approximately 65% of the total events expected).  If 
the value of the test-statistic exceeds the Haybittle-Peto efficacy boundary (z ≥4.2059, p 
≤0.000013) the trial may be stopped for efficacy. Under exponential distribution assumption, 
this boundary equates to a hazard ratio of ~0.55 or smaller in favor of the palbociclib plus 
letrozole arm versus the letrozole alone arm.  Alternatively, as appropriate, the sample size of 
the study may be adjusted using the method outlined by Cui et al.75  If the results of the 
interim analysis indicate serious safety concerns, the sponsor will communicate with the 
Health Authorities regarding stopping the clinical trial. 
An interim analysis of efficacy is also planned for the secondary OS endpoint.  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 using the Lan-DeMets procedure with an O’Brien-Fleming stopping rule. 
The overall significance level for the efficacy analysis of OS will be preserved at 
0.025 (one-sided test).  Details of the analysis will be provided in the SAP. 
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, OS will not be 
statistically evaluated. 
9.7. Data Monitoring Committees
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 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 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. 
 


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


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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 or its designated 
agents, 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.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (ICH 1996), and the Declaration of 
Helsinki (World Medical Association 1996 & 2008). 
 


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on harmonization guideline for GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient. In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent form(s) used during the informed consent process must be reviewed by 
the sponsor, approved by the IRB/IEC, 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.
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.
 


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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 Participating Countries
End of Trial in all 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 PD-0332991 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 this study on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical 
Trials Database (EudraCT) and/or www.pfizer.com, and other public registries in accordance 
with applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
 


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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.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of Confidential Information or unprotected 
Inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the Study is part of a multi-centre study, Investigators agree that the first publication is to 
be a joint publication covering all study sites and that any subsequent publications by the  
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
Study at all participating sites, Investigators are free to publish separately, subject to the other 
requirements of this Section.
 


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


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


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Appendix 2. Sponsor Approved HER2 Assays
HER2 results based on 1 of the following commercial kit assays are acceptable (for the 
purposes of study entry)
IHC Approved 
Assay
FISH Approved 
Assay
CISH Approved Assay
Other Approved Assay
HercepTest™
Pathvysion HER2 
DNA Probe Kit
SPOT-Light® HER2 
CISH™Kit
INFORM HER2 Dual 
ISH DNA Probe 
Cocktail Assay
PATHWAY™
Her2a
INFORM HER2/neu 
Probe Kit
HER2 CISH PharmDx™
Kit
-
Bond™Oracle™
HER2 IHC System
HER2 FISH 
PharmDx™Kit
-
-
PATHWAY HER-
2/neub
-
-
-
Footnote: 
a.
PATHWAY™Her2 (clone CB11) is a mouse monoclonal antibody intended for laboratory use for the semi-
quantitative detection of c-erbB-2 antigen in sections of formalin fixed, paraffin embedded normal and 
neoplastic tissue on a Ventana automated immunohistochemistry slide staining device.
b.
PATHWAY HER-2/neu (clone 4B5) is rabbit monoclonal antibody intended for the semi-quantitative 
detection of HER2 antigen in sections of formalin-fixed, paraffin-embedded normal and neoplastic tissue. 
Created to run on a Ventana automated immunohistochemistry slide staining device, it is indicated as an aid 
in the assessment of breast cancer patients for whom Herceptin treatment is considered.
 


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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®
Ondansetron*
Zofran®
Pentamidine
Pentam®, NebuPent®
Pimozide
Orap®
Probucol
Lorelco®
Procainamide
Pronestyl®, Procan®
Quinidine
Cardioquin®, Quinaglute®
Sotalol
Betapace®
Sparfloxacin
Zagam®
Terfenadine
Seldane®
Thioridazine
Mellaril®
Vandetanib
Caprelsa®
*when administered intravenously at high dose (32 mg).
Adapted from the University of Arizona Cancer Center for Education and Research on 
Therapeutics: "Torsades List: Drugs with a Risk of Torsades de Pointes," drugs that are 
generally accepted by the QTdrugs.org Advisory Board to carry a risk of Torsades de Pointes 
on the University of Arizona CERT website: http://www.crediblemeds.org/.  This list is not 
meant to be considered all inclusive.  See website for current list. 
 


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


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


P D -0 3 3 2 9 9 1
A 5 4 8 1 0 0 8
Fi nal Pr ot oc ol A me n d me nt 8 , 2 1 Ma y 2 0 1 8
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 5
A p pe n di x 5. E ur o Q ol He alt h Utilities I n de x E Q -5 D 
 
 
C O P Y RI G H T E D M A T E RI A L


P D -0 3 3 2 9 9 1
A 5 4 8 1 0 0 8
Fi nal Pr ot oc ol A me n d me nt 8 , 2 1 Ma y 2 0 1 8
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 6
 
 
C O P Y RI G H T E D M A T E RI A L


P D -0 3 3 2 9 9 1
A 5 4 8 1 0 0 8
Fi nal Pr ot oc ol A me n d me nt 8 , 2 1 Ma y 2 0 1 8
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 7
 
 
C O P Y RI G H T E D M A T E RI A L


P D -0 3 3 2 9 9 1
A 5 4 8 1 0 0 8
Fi nal Pr ot oc ol A me n d me nt 8 , 2 1 Ma y 2 0 1 8
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 8
A p pe n di x 6. F u ncti o n al Assess me nt of C a ncer T her a p y- Bre ast ( F A C T -B) [ Versi o n 4] 
 
 
C O P Y RI G H T E D M A T E RI A L


P D -0 3 3 2 9 9 1
A 5 4 8 1 0 0 8
Fi nal Pr ot oc ol A me n d me nt 8 , 2 1 Ma y 2 0 1 8
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 9
 
 
C O P Y RI G H T E D M A T E RI A L


P D -0 3 3 2 9 9 1
A 5 4 8 1 0 0 8
Fi nal Pr ot oc ol A me n d me nt 8 , 2 1 Ma y 2 0 1 8
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3 0
 
 
C O P Y RI G H T E D M A T E RI A L


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Appendix 7. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247.
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions  
•
Lesions that can be accurately measured in at least one dimension.
•
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).
•
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.  
•
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.
•
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical examination 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 treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
•
If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.
•
Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.
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. 
 


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•
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.
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
 


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


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


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


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EDTA
Ethylenediaminetetraacetic acid
EIU
Exposure In Utero
EQ-5D
Dimension Health State EuroQoL Score
ER
Estrogen Receptor
FACT
Functional Assessment of Cancer Therapy
FACT-B
Functional Assessment of Cancer Therapy - Breast
FACT-G
Functional Assessment of Cancer Therapy - General
FDA
US Food and Drug Administration 
FFPE
Formalin Fixed Paraffin Embedded
FIH
First in Human
FISH
Fluorescent In Situ hybridization
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
Hb
Hemoglobin
HDPE
High Density Polyethylene
HER
Human Epidermal Growth Factor Receptor
hERG
Human Ether-à-Go-Go
HR
Heart Rate
IB
Investigator’s Brochure
IC50
Concentration of 50% Inhibition 
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International Normalized Ratio
IOP
Intraocular Pressure
IMPAKT
Improving Care and Knowledge through Translational Research
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
ISH
In Situ Hybridization
ITT
Intent-to-Treat 
LFT
Liver Function Test
LPD
Local Product Document
LSLV
Last Subject Last Visit
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
 


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PCD
Primary Outcome Completion Date
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival
PK
Pharmacokinetic 
PPI
Proton Pump Inhibitor
PR
Partial Response or Progesterone Receptor (depending on context)
PR
The PR interval is measured from the beginning of the P wave to 
the beginning of the QRS complex.
PS
Performance Status
PSC
Posterior Subcapsular Cataract
PRO
Patient Reported Outcome
PT
Prothrombin Time
QD
Quaque Die (once daily)
QRS
The QRS complex is a name for the combination of three of the 
graphical deflections seen on a typical electrocardiogram.
The QRS complex reflects the rapid depolarization of the right and 
left ventricles.
QT
Time between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett's formula
QTcF
QT interval corrected for heart rate using Fridericia's formula
QTcS
QT interval corrected for heart rate using study-specific factor
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 or Standard Deviation (depending on context)
SPC
Summary of Product Characteristic
t½
Terminal Elimination Half-life
TdP
Torsade de Pointes
Tmax
Time for Cmax
UK
United Kingdom
ULN
Upper Limit of Normal
USPI
United States Package Insert
Vz/F
Apparent Volume of Distribution
WBC
White Blood Cell
 


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Appendix 10. Schedule of Activities for Patients Continuing to Receive Active 
Treatment After IRB/IEC Approval of Amendment 8. 
Upon IRB/IEC approval of Amendment 8, clinical assessments will be reduced in scope and 
the required schedule of activities is revised as shown in this appendix.
The following reduced Schedule of Activities describes the timing of procedures to be 
performed during treatment for patients receiving study drug after IRB/IEC approval of 
Amendment 8. 
A5481008 Schedule of Activities:
Protocol Activity
Active Treatment Phasea - One 
Cycle = 28 days
End of 
Treatment/ 
Withdrawalb
Post-Treatment 
Follow-Upc
All Cycles
Study Day
Day 1d
Time Window
±2d
±7d
Tumor Tissue for Biomarker
Xe
Physical Examination/Vital signsf
X
X
Ophthalmic Examinationg
X
X
ECOG Performance Statush
X
X
Hematologyi
Xi
X
Blood Chemistryi
Assessed every 3 cycles and as 
clinically indicated
X
Hemoglobin A1c
Xj
12-Lead ECG
Xk
X
Tumor imagingl
◄--► 
Performed as per local institutional practice
Drug Compliancem
◄--►
Averse Event Reportingn
X
X
X
Review Concomitant 
Medications/Treatmentso
X
X
X
EuroQol; EQ-5Dp
X
X
FACT - Breast Questionnaireq
X
X
Xq
Survival Follow-up
X
Study Treatment
Letrozole (both treatment arms)
Once Daily ◄--►r
PD-0332991 or Placebo
◄--►s
Once Daily on Day 1 to Day 21 of 
each cycle followed by 7 days off
a.
Active Treatment Phase: All assessments should be performed prior to dosing with study medications on 
the visit day unless otherwise indicated.  Acceptable time windows for performing each assessment are 
described in the column headers.  For the purposes of this trial 1 cycle is 28 days.  A cycle could be longer 
than 28 days if persistent toxicity delays the initiation of the subsequent cycle.
b.
End of Treatment/Withdrawal: End of Treatment/Withdrawal evaluations will be performed as soon as 
possible but no later than 4 weeks (ie, 28 days) ±7days from last dose of study treatment and prior to the 
initiation of any new anti-cancer therapy. Obtain these assessments if not completed during the previous 
4 weeks on study.  
 


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c.
Post Treatment Follow-up:  After discontinuation of study treatment, post-treatment follow-up 
information (ie, survival status, and post-study anti-cancer therapy details [including regimen number, 
name of therapy, start/stop dates, and dates of disease progression on subsequent anti-cancer therapies]) 
will be collected every 6 months (±7 days) from the last dose of study treatment.  Telephone contact is
acceptable.  The follow-up period will conclude at the time of the final OS analysis.
d.
Cycle X, Day 1: In the event that the start of a new cycle is delayed due to treatment related toxicity, 
procedures required on Day 1 of the given cycle will be performed when PD-0332991/placebo is resumed.  
New cycle Day 1 procedures (ie, physical examination, ECOG performance status, ECG, Quality of Life 
questionnaires, blood chemistry, hematology) that were performed prior to knowing the need to delay the 
start of the cycle do not need to be repeated unless required to confirm that the parameters necessary for 
study drug to be resumed are met (see Section 5.3.4.2.2). 
e.
Mandatory Tumor Tissue For Confirmatory Testing and for Biomarker Assessments: An optional
fresh tumor biopsy will be collected at the end of treatment visit, only for patients who discontinue 
treatment due to disease progression.  The tumor tissue will be used to determine possible mechanisms of 
resistance.  Tissue samples from all patients will be used for additional biomarker analyses.  Details on 
preparation of these samples including processing, storage, and shipment will be provided in the Study 
Manual.  
f.
Physical Examination/Vital signs: Symptom-directed physical examinations, blood pressure and pulse 
rate will be performed.
g.
Ophthalmic Examinations: Once Amendment #3 is IRB approved, all newly enrolled patients will 
undergo an ophthalmic examination at baseline, and on study treatment after 3 months (Cycle 4 Day 1), 
6 months (Cycle 7 Day 1), 12 months (Cycle 13 Day 1), every 12 months (Day 1 of Cycles 25, 37 etc…) 
thereafter, and at the End of Treatment visit.  Additional ophthalmic examinations may be performed 
during the study as clinically indicated (including for patients randomized prior to Amendment 3 approval).  
The ophthalmic examinations will include: best corrected distant visual acuity (Snellen), refractive error 
associated with best corrected distant visual acuity, intraocular pressure (IOP – one reading), slit lamp 
biomicroscopy of the anterior segment including cell count and flare grading, crystalline lens grading using 
the Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens Opacity Grading procedure, 
and fundoscopy.  All ophthalmic examinations will be performed by an ophthalmologist.  Refer to 
Section 7.2.3.  Ocular Safety Assessments for further details on these procedures.
h.
ECOG Performance Status: To be performed on Day 1 of every other cycle thereafter starting with 
Cycle 5 (ie, Cycle 5, 7, 9, etc), and at the end of treatment visit.
i.
Hematology, and Blood Chemistry Panel: Hematology includes hemoglobin, WBC, absolute neutrophils, 
platelet count.  Blood chemistry includes AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, 
total calcium, total bilirubin, BUN (or urea), serum creatinine, and albumin.  Upon IRB/IEC approval of 
Amendment 8, blood chemistry will only need to be monitored every 3 cycles from the date of 
randomization (eg. C4D1, D7D1, C10D1, etc).  Also, for patients who experienced a maximum of Grade 1 
or 2 neutropenia in the first 6 cycles, hematology for subsequent cycles may also be be monitored every 
3 cycles from the date of randomization, at the beginning (Day 1) of a cycle (eg, C4D1, C7D1, C10D1, 
etc). For patients who experienced a maximum of Grade 3 or 4 neutropenia during the first 6 cycles, 
hematology will continue to be assessed at the beginning (Day 1) of each cycle. Additional  unscheduled 
hematology and blood chemistry panels may be collected as clinically indicated and results will be 
recorded on the appropriate CRF. 
j.
Hemoglobin A1c: Hemoglobin A1c will no longer be required to be measured every 3 months from the 
date of randomization (ie., C4D1, C7D1, etc...) but is required to be collected at the end of treatment visit.
Additional unscheduled hemoglobin A1 may be collected as clinically indicated and results will be 
recorded on the appropriate CRF.
 


PD-0332991
A5481008
Final Protocol Amendment 8, 21 May 2018
PFIZER CONFIDENTIAL
Page 143
k.
12-Lead ECG: ECGs beyond Cycle 10 will be performed as clinically indicated.  Refer to 
Pharmacokinetic and ECGs Schedule of Activities table for further details and timing of procedures.
l.
Disease Assessments: Upon approval of Amendment 8, tumor assessments may be performed at a different 
schedule than the original protocol 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.  RECIST 1.1 may continue to be used to evaluate imaging 
assessments at the investigator’s discretion but will no longer be mandatory.  Assessments of tumor lesions 
[ie, target lesion(s), non-target lesion(s) and target lymph node(s)] will no longer be recorded in the CRF, 
nor will the RECIST assessments.  Only the date of progression of disease will be recorded.
m. Drug Compliance: PD-0332991, placebo and letrozole bottle(s)/blisters including any unused 
capsules/tablets will be returned to the clinic for drug accountability.  Drug accountability will be 
performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.
n.
Adverse Events: For SAEs, the active reporting period begins from the time that the patient provides 
informed consent through and including 28 calendar days after the last administration of the investigational 
product.  Following the active safety reporting period, other SAEs of which the investigator becomes aware 
should be reported to Pfizer, unless the SAE is attributed by the investigator to complications of either the 
underlying malignancy or any subsequent anti-cancer therapy or to the patient’s participation in a 
subsequent clinical study.  AEs (serious and non serious) should be recorded on the CRF from the time the 
patient has taken at least one dose of study treatment through last patient visit.
o.
Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 
28 days prior to the start of study treatment and up to 28 days after the last dose of study treatment.
p.
EQ-5D, FACT-B Assessments: Patients will complete questionnaires prior to any study or medical 
procedure on Day 1 of Cycles 1, 2 and 3 and then Day 1 of every other cycle thereafter starting with 
Cycle 5 (ie, Cycle 5, 7, 9, etc), and at the end of treatment visit.  All self-assessment questionnaires must be 
completed by the patients while in the clinic and cannot be taken home.  Interviewer administration in 
clinic may be used under special circumstances.
q.
FACT-B Assessments: After patients discontinue from the active treatment phase, FACT-B questionnaire 
will continue to be collected during the follow-up period every 6 months (+/- 7 days)  from the last dose of 
investigational product until patient permanent discontinuation from study or end of follow-up period 
whichever occurs first.  During the follow-up period, all self-assessment questionnaires should preferably 
be completed by the patients during a scheduled clinic visit.  However, if no clinic visits are being 
scheduled during the follow-up period interviewer administration via phone call may be used instead and 
documented accordingly in the patient source notes.
r.
Letrozole (both treatment arms): To be taken orally, daily, and continuously.
s.
PD-0332991 or Placebo:To be taken orally, daily from Day 1 to Day 21 (21 days) of every 28-day cycle 
followed by 7 days off treatment. In the event the Day 1 clinic visit of the subsequent cycle is scheduled 
during the -2 day allowable visit time window (ie, Day 27, Day 28), patients must be instructed to complete 
their 7-day off treatment period of the current cycle prior to resuming blinded therapy even if criteria for 
treatment resumptions are met at the visit. Cycle off treatment periods of less than 7 days are considered 
protocol deviations. 
 

SAP_001.pdf: 
Protocol A5481008  
Statistical Analysis Plan 
 
 
 
 
Protocol  A5481008 
 
A Randomized, Multicenter, Double-Blind Phase 3 Study Of PD-0332991 (Oral 
CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole For The 
Treatment Of Postmenopausal Women With ER (+), HER2 (-) Breast Cancer 
Who Have Not Received Any Prior Systemic Anti-Cancer Treatment For 
Advanced Disease 
 
 
Statistical Analysis Plan  
(SAP) 
 
 
 
Version: 
3.1 
Author:  
 
Date:  
January 30, 2017 
 
 
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. 
PFIZER CONFIDENTIAL 
Page 1 
 
33'


Protocol A5481008  
Statistical Analysis Plan 
 
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................6 
2. INTRODUCTION .......................................................................................................................8 
2.1. Study Design ...................................................................................................................9 
2.2. Study Objectives ...........................................................................................................11 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ......................................11 
4. HYPOTHESES AND DECISION RULES ...............................................................................13 
4.1. Statistical Hypotheses ...................................................................................................13 
4.2. Sample Size Determination and Statistical Decision Rules ..........................................14 
4.2.1. Sample Size for PFS .........................................................................................14 
4.2.2. Sample Size for OS ...........................................................................................14 
4.2.3. Sample Size for QTc .........................................................................................15 
5. ANALYSIS SETS .....................................................................................................................15 
5.1. Intent-to-Treat Population (Full Analysis Set) ..............................................................15 
5.2. Modified Intent-to-Treat (MITT) Population ................................................................15 
5.3. As-Treated (AT) Population (Safety Analysis Set) .......................................................15 
5.4. Other Analysis Sets .......................................................................................................16 
5.4.1. QTc Analysis Set ..............................................................................................16 
5.4.2. Ocular Analysis Set ..........................................................................................16 
5.4.3. Pharmacokinetic Analysis Set ..........................................................................16 
5.4.4. Biomarker Analysis Set ....................................................................................16 
5.4.5. Patient Reported Outcome (PRO) Analysis Set ...............................................16 
5.5. Treatment Misallocations ..............................................................................................16 
5.6. Protocol Deviations .......................................................................................................16 
5.6.1. Protocol Deviations Assessed Prior to Randomization ....................................16 
5.6.2. Protocol Deviations Assessed Post Randomization .........................................17 
6. ENDPOINTS AND COVARIATES .........................................................................................17 
6.1. Efficacy Endpoints ........................................................................................................17 
6.1.1. Primary Endpoint ..............................................................................................17 
6.1.2. Secondary Endpoints ........................................................................................18 
6.2. Safety Data ....................................................................................................................19 
6.2.1. Treatment Emergent Adverse Event .................................................................20 
6.2.2. Treatment Related Adverse Event ....................................................................20 
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Protocol A5481008  
Statistical Analysis Plan 
 
6.2.3. Laboratory Safety Assessments ........................................................................20 
6.2.4. Electrocardiogram (ECG) .................................................................................21 
6.2.5. Ocular Safety Assessment ................................................................................22 
6.2.6. Other Safety Assessment ..................................................................................22 
6.3. Other Endpoints .............................................................................................................22 
6.3.1. Pharmacokinetic and Pharmacodynamic Data .................................................22 
6.3.2. Biomarkers ........................................................................................................23 
6.3.3. Patient Reported Outcome Endpoints ...............................................................23 
6.3.3.1. Functional Assessment of Cancer Therapy-Breast (FACT-
B) [Version 4] ................................................................................23 
6.3.3.2. EuroQol Health Utilities Index EQ-5D ...........................................24 
6.4. Covariates and Stratification Factors ............................................................................24 
6.4.1. Covariates .........................................................................................................24 
6.4.2. Stratification Factors .........................................................................................24 
7. HANDLING OF MISSING VALUES ......................................................................................25 
7.1. Missing Dates ................................................................................................................25 
7.2. Missing Tumor Assessments .........................................................................................25 
7.3. Missing Data in PFS Derivation ....................................................................................26 
7.4. Missing QTc Data .........................................................................................................26 
7.5. Missing Patient Reported Outcome Data ......................................................................26 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................27 
8.1. Statistical Methods ........................................................................................................27 
8.1.1. Gate-keeping procedure for primary endpoint PFS ..........................................27 
8.1.2. Hierarchical Group Sequential Testing for PFS and OS ..................................27 
8.1.3. Analyses for Time-to-Event Data .....................................................................28 
8.1.4. Analyses for Binary Data ..................................................................................29 
8.1.5. Analyses of Continuous Data ...........................................................................29 
8.1.6. Analyses for Categorical Data ..........................................................................30 
8.1.7. Evaluation of the Discordance Rate between Investigator and 
Independent Core Imaging Laboratory on Assessing PFS data ...................30 
8.1.8. Analyses for QTc Data .....................................................................................31 
8.1.8.1. Derived Analysis Variables .............................................................31 
8.1.8.2. Derivation of Study Specific QT Correction Factor .......................31 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.1.8.3. Assessment of QT Correction Methods ..........................................32 
8.1.8.4. Baseline Values for ECG Parameters ..............................................32 
8.1.8.5. Change from Baseline Definition ....................................................32 
8.1.8.6. Change from Baseline Analysis ......................................................33 
8.1.8.7. Summary of Categorical Analysis ...................................................33 
8.1.9. Analyses for Ocular Assessment Data ..............................................................34 
8.1.9.1. Snellen Best Corrected Visual Acuity and Refraction ....................34 
8.1.9.2. Intraocular Pressure Measurement ..................................................35 
8.1.9.3. Slit-lamp Biomicroscopy, Funduscopy 
(Ophthalmoscopy), and Lens Grading ...........................................36 
8.1.10. Analyses for Patient Reported Outcomes Data ..............................................36 
8.2. Statistical Analyses .......................................................................................................36 
8.2.1. Primary Efficacy Analysis ................................................................................37 
8.2.2. Sensitivity Analyses for the Primary PFS Endpoint .........................................37 
8.2.3. Secondary Analyses ..........................................................................................39 
8.2.4. Supportive Efficacy Analyses...........................................................................39 
8.2.5. Standard Analyses ............................................................................................40 
8.2.6. Safety Analyses ................................................................................................41 
8.2.6.1. Adverse Events ................................................................................41 
8.2.6.2. Laboratory abnormalities ................................................................43 
8.2.7. QTc Analyses ....................................................................................................44 
8.2.8. Ocular Assessment Data Analyses ...................................................................45 
Any new finding or deterioration from baseline findings in Slit-lamp 
biomicroscopy, Lens Grading, and Funduscopy will be reported 
by treatment groups in data listing. ..............................................................45 
8.2.9. Pharmacokinetic and Pharmacodynamic Analyses ..........................................45 
8.2.10. Biomarkers Analyses ......................................................................................45 
8.2.11. Patient Reported Outcomes Analyses .............................................................46 
FACT-G .......................................................................................................46 
8.2.11.1. FACT-G Subscales ........................................................................46 
8.2.11.2. Breast Cancer Subscale (BCS) ......................................................46 
8.2.11.3. FACT-B .........................................................................................46 
8.2.11.4. Trial Outcome Index (TOI) ...........................................................47 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.2.11.5. EQ-5D Index .................................................................................47 
8.2.11.6. EQ-VAS ........................................................................................47 
8.2.11.7. Time to Deterioration ....................................................................47 
8.3. Summary of Key Efficacy Analyses .............................................................................48 
9. REFERENCES ..........................................................................................................................49 
10. APPENDICES .........................................................................................................................51 
10.1. Schedule of Activities .................................................................................................51 
10.2. Tumor Assessment Requirements Flowchart ..............................................................56 
10.3. RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 
Guidelines ...................................................................................................................59 
10.4. Rules for Determining PFS Status and Date ...............................................................63 
10.5. Data Derivation Details ...............................................................................................64 
10.6. Study Treatment Modification and Compliance .........................................................65 
10.6.1. Dose Modification ..........................................................................................65 
10.6.2. Summarizing Relative Dose (RD) and Relative Dose Intensity 
(RDI) ............................................................................................................65 
10.7. Functional Assessment of Cancer Therapy - Breast (FACT-B) (Version 4) ..............71 
10.8. EuroQol Health Utilities Index EQ-5D .......................................................................74 
10.9. Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens 
Opacity Grading Procedure ........................................................................................76 
10.10. List of Abbreviation ..................................................................................................77 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
The SAP is being amended to reflect the changes in Protocol Amendments 1 (October 1, 
2013), 2 (January 3, 2014), 3 (March 21, 2014), 4 (September 18, 2014), 5 (December 2 
2014), 6 (April 17, 2015), and 7 (October 15, 2015). 
1.1 Amendment 1  
1.1.1 Sample size adjustment to address potential impact of antacid concomitant medication 
and fed condition (Protocol Amendment 3). 
PD-0332991 was initially administered as a free base capsule formulation under minimal 
fasting conditions (fasting 1 hour before and two hours after PD-0332991 dosing).  Data 
from clinical pharmacology studies that emerged after the initiation of Study A5481008 
showed that administration of free base capsule formulations under fasting conditions 
resulted in high variability in PD-0332991 exposure due to low PD-0332991 exposure of in a 
subgroup of PK profiles (referred to as “low-liers”).   Data from the Food Effect study in 
healthy subjects (Study 1021) demonstrated that low-liers were not observed when the PD-
0332991 free base capsules were administered with food or in-between meals (moderate-fat 
meal 1 hour before and 2 hours after dosing).  In addition, preliminary results from clinical 
pharmacology study A5481018 showed that proton pump inhibitors (PPI) administered 
concomitantly with PD-0332991 free base capsule under overnight fasting conditions 
substantially decreased the exposure of PD-0332991.  The combination of these observations 
resulted in Protocol Amendment 2, to revise the dosing instructions from drug taken in a 
fasted state to drug taken with food.  The protocol was also revised to prohibit the 
concomitant use of proton pump inhibitors. 
Given the fact that patients who took PD-0332991 concomitantly with PPIs/other antacids or 
under fasted conditions prior to the implementation of Protocol Amendment 2 may have 
experienced lower PD-0332991 exposure the treatment effect in the ITT population could 
have been diluted, potentially resulting in a study with lower power than originally designed 
(90%). To mitigate this potential risk, an adjustment for the alternative hypothesis was made 
in Protocol Amendment 3 from HR=0.64 to HR=0.69. It resulted an increase of PFS events 
by 108 and additional 200 patients, which is approximately the number of patients enrolled 
prior to the initiation of Amendment 2.  The study still maintains 90% power to detect a 
hazard ratio of 0.69 or better in favor of PD-0332991 plus letrozole combination in the larger 
ITT population.  
In addition, considering that patients who may have been affected by the use of PPI or dosing 
under fasting conditions would have been enrolled in the early part of the study (prior to the 
Protocol Amendment 2), the interim analysis is being conducted after 226 events or 65% of 
total PFS events (instead of 55% in the original plan). As a result of the sample size revision, 
the final analysis will occur at 347 events). 
1.1.2 Modification of efficacy boundary of primary endpoint PFS for interim analysis 
(Protocol Amendment 5). 
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Protocol A5481008  
Statistical Analysis Plan 
 
A modification for interim analysis was proposed to, and agreed with FDA to increase the 
stringency of the efficacy stopping boundary in the interim analysis to ensure that the results 
are not only statistically significant but also clinically meaningful. Specifically, the efficacy 
stopping boundary is changed from O’Brien-Fleming to the Haybittle-Peto approach. A p-
value of 0.000013 will be used as the efficacy boundary for interim analysis. The overall 
significance level for the efficacy analysis of PFS will be preserved at 0.025 for 1-sided test 
(section 3). 
1.1.3 Gate-keeping procedure for primary PFS hypothesis testing in ITT population and a 
sub-population in the final analysis. 
The treatment effect on PFS for all patients randomized in the study (ITT population) and a 
sub-group population who were not impacted by PPI, and/or other antacids concomitant 
medication will be assessed. A gate-keeping procedure is added in this SAP amendment as a 
prospectively planned analysis to test the treatment effect of PFS of PD-0332991 plus 
letrozole in this optimal sub-population (section 8.1.1). 
1.1.4 Prospective ophthalmic assessments (Protocol Amendment 3). 
Based on available limited pre-clinical and clinical data, it was not evident that a clinical risk 
exists for developing PD-0332991-associated cataracts, however it was viewed to be 
important to increase the level of clinical information in this area.  The protocol was 
therefore amended to implement prospective ophthalmic assessments and lens grading in all 
newly enrolled patients at baseline and while on study treatment.   
The results of the ophthalmic assessments will provide a better understanding of any 
potential risk of ocular adverse events. The analysis plan for the ocular assessment data is 
added in the amendment. 
Additionally, the following changes were made in this SAP amendment:  
1) A detailed sequence of hierarchical tests of PFS and OS to preserve the family wise 
error rate at the level of 0.025 is provided in section 8.1.2;  
2) Sensitivity analyses in section 8.2 are modified to provide clarity to each analysis. 
3) Clarification is added in the PRO data analysis section.  
 
1.2 Amendment 1 Revision  
After the SAP amendment, additional data with regard to the effect of acid reducing agents 
(ARAs) including PPI, H2RA and local antacid on PD-0332991 exposure under fed 
condition became available. The results showed that co-administration of ARAs with PD-
0332991 under fed conditions did not have clinically relevant effect on PD-0332991 
exposure. This led to the revision of SAP Amendment 1 and the subgroup definition is 
modified in section 8.1.1.  
 
 
 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
1.3 Amendment 2  
Protocol Amendment 7 expanded data collection of disease progression date for the 
subsequent anti-cancer therapy in post treatment follow up phase.  The SAP is modified to 
reflect the protocol changes. Corresponding analysis may be performed if appropriate.  
 
Other editorial modifications include:  
x Section 5.4.4 modified definition of biomarker analysis set. 
x Section 8.2.4 a kappa test is added to the summary of concordance between 
investigator and BICR assessments.  
x Section 10.6.2 clarified the calculation of Relative Dose Intensity. 
 
Per FDA request, a formal interim analysis on data cutoff of November 24, 2016 is added for 
OS analysis. To preserve the type-1 error rate, a fraction of alpha (0.0001) will be spent for 
this analysis (section 3). 
2. INTRODUCTION 
This document describes the planned statistical analyses for original Protocol A5481008 
dated on October 30, 2012. The changes in Protocol Amendment 1 (October 1, 2013), 2 
(January 3, 2014), 3 (March 21, 2014), 4 (September 18, 2014), and 5 (December 2 2014) 
were also incorporated. This analysis plan is meant to supplement the study protocol.  Any 
deviations from this analysis plan will be described in the Clinical Study Report.  
 
In the first-line setting, letrozole is among the preferred anti-hormonal therapies for 
postmenopausal women with ER(+)/HER2(-) advanced breast cancer (ABC). It is approved 
and commercially available globally with a well known and manageable safety profile. 
However, median progression-free survival (PFS) in this patient population remains less than 
1 year and median overall survival (OS) is approximately 3 years.  Furthermore, aromatase 
inhibitor failure has been linked to increased proliferative index and cell cycle dysregulation, 
providing a strong rationale for combining letrozole to PD-0332991. Preliminary data from 
Phase 1/2 Study A5481003 suggests that the combination of PD-0332991 inhibition of CDK 
4/6 (blocking DNA synthesis by prohibiting progression of the cell cycle from G1 to S 
phase) with the anti-proliferative effects of letrozole provides greater antitumor activity and 
prolongs PFS (i.e. median 26.1 months vs. 7.5 months) when compared to single agent 
letrozole. Additionally, the study showed that the combination is generally well tolerated 
with uncomplicated neutropenia as the most frequent adverse event.  
 
This randomized Phase 3 study (A5481008) provides the opportunity to confirm the clinical 
benefit of the combination of PD-0332991 with letrozole observed in Study A5481003.  The 
study is designed to demonstrate that PD-0332991 in combination with letrozole provides 
superior clinical benefit compared to letrozole in combination with placebo in 
postmenopausal women with ER(+)/HER2(-) locoregionally recurrent or metastatic breast 
cancer who have not received any prior systemic anti-cancer therapies for their advanced 
disease. 
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Protocol A5481008  
Statistical Analysis Plan 
 
2.1. Study Design 
This is an international, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, Phase 3 clinical trial comparing the efficacy and safety of PD-0332991 in combination 
with letrozole versus placebo in combination with letrozole in postmenopausal women with 
ER(+)/HER2 (-) advanced breast cancer. Eligible patients will have histologically or 
cytologically proven diagnosis of adenocarcinoma of the breast with evidence of 
locoregionally recurrent or metastatic disease and will be candidates to receive letrozole as 
first-line treatment for their advanced disease. To further ensure that the study will enroll 
only those women for whom letrozole is the most appropriate treatment, patients with 
advanced, symptomatic, visceral spread, that are at risk of life threatening complications in 
the short term will be excluded from this study. In order to avoid inclusion of patients who 
are refractory or resistant to non-steroidal aromatase inhibitors, patients who received 
anastrozole or letrozole as a component of their (neo)adjuvant regimen may only enter the 
study if their disease did not progress while on or within 12 months from completion of their 
anastrozole/letrozole-containing (neo)adjuvant therapy. Patients will not have received any 
prior systemic anti-cancer therapies for their advanced disease and will not be candidates for 
curative therapies. Patients must have measurable disease as per RECIST v.1.1 or bone 
disease as their only site of disease. Tumor tissue availability is required for patient 
participation.    
Approximately 650 eligible patients will be randomized 2:1 to receive either PD-0332911 
plus OHWUR]ROH$UP$§433 patients) or placebo plus OHWUR]ROH$UP%§217 patients).   
 
Patients will be stratified by site of disease (visceral vs. non-visceral), by disease free interval 
since completion of prior (neo)DGMXYDQWWKHUDS\GHQRYRPHWDVWDWLFPRQWKV!
months), and by the nature of prior (neo)adjuvant anticancer treatment received (prior 
hormonal therapy vs. no prior hormonal therapy).   
 
Patients randomized to Arm A (experimental arm) will receive:  
x PD-0332991, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle 
followed by 7 days off treatment;  
in combination with   
x Letrozole, 2.5mg, orally once daily (continuously). 
 
Patients randomized to Arm B (control arm) will receive:  
x Placebo orally once daily from Day 1 to Day 21 of every 28-day cycle followed by 7 
days off treatment; 
in combination with   
x Letrozole, 2.5mg, orally once a daily (continuously). 
 
Patients will continue to receive assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first. However, patients may continue treatment as assigned at randomization beyond 
the time of RECIST-defined progression disease (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 
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Protocol A5481008  
Statistical Analysis Plan 
 
treatment is initiated. In this case, the patient would continue with routine safety assessments 
as per the Schedule of Activities for the active treatment period. 
The importance of timely and complete disease assessments in this study cannot be 
overstated. Disease assessments will be performed every 12 weeks (± 7 days) from the date 
of randomization. Patients with bone lesions identified at baseline will also have repeat bone 
scans performed every 24 weeks (± 7 days) from the date of randomization. Each assessment 
will be performed as scheduled according to the calendar regardless of any dosing delay to 
prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the 
required disease assessments will result in the inability to determine disease status for that 
time point. Tumor assessments will be performed until radiographically and/or clinically (for 
photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment 
discontinuation (for patients continuing treatment beyond RECIST-defined disease 
progression), initiation of new anticancer therapy or discontinuation of patient from overall 
study participation (e.g., death, patient's request, lost to follow-up), whichever occurs first. A 
series of incomplete disease assessments will result in censoring of the primary endpoint of 
PFS back to the time of the last full assessment that did not show progression. Frequently off 
schedule or incomplete disease assessments have the potential to weaken the conclusion of 
this clinical trial.  
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (for photographed or palpable lesions) documented PD as per RECIST v.1.1 will 
continue to have tumor assessments performed during the follow-up visits every 12 weeks (± 
7 days) and bone scans (if applicable) every 24 weeks (± 7 days) until RECIST-defined 
disease progression, initiation of new anticancer therapy or discontinuation of patient from 
overall study participation (e.g., death, patient's request, lost to follow-up), whichever occurs 
first.  
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as primary data source. However, a blinded independent third-party core 
imaging laboratory will complete a retrospective review of radiographic images and clinical 
information collected on-study to verify the protocol defined endpoints of disease response 
and progression as assessed by the investigator. 
Patients discontinuing the active treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every 6 months from the 
last dose of investigational product. The follow-up period will conclude at the time of the 
final OS analysis. Crossover will not be allowed in the trial.   
Patients will undergo study-related safety, efficacy, and PK assessments as outlined in the 
relevant Schedule of Activities located in the Appendix section. 
The study also includes:    
x QTc monitoring to evaluate the effect of PD-0332991 on QT interval via triplicate ECGs 
time-matched with select serial PK draws (subset study in at least 60 patients enrolled at 
selected sites);   
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Protocol A5481008  
Statistical Analysis Plan 
 
x Ocular safety assessments. Corresponding to protocol amendment 3, ophthalmic 
procedures are added to assess a potential risk of PD-0332991-associated crystalline lens 
changes. 
x Quantification of trough PD-0332991 plasma concentration.   
x A molecular profiling component aimed at assessing the relationship between breast 
tumor sensitivity and resistance to PD-0332991 and the alteration of cell cycle pathway-
related genes and proteins in tumor tissues.    
 
2.2. Study Objectives 
Primary Objective: 
x To demonstrate that the combination of PD-0332991 with letrozole is superior to 
placebo plus letrozole in prolonging PFS in postmenopausal women with 
ER(+)/HER2 (-) advanced breast cancer who have not received any prior systemic 
anti-cancer therapies for their advanced/metastatic disease.   
 
Secondary Objectives: 
x To compare measures of tumor control duration and overall survival  between the 
treatment arms; 
x To compare safety and tolerability between the treatment arms; 
x To compare health related quality of life between the treatment arms; 
x To characterize the effects of PD-0332991 at therapeutic doses in combination with 
letrozole on QTc interval in this patient population; 
x To determine trough PD-0332991 plasma concentration in this patient population and 
explore the correlations between exposure and response and/or safety findings; 
x To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle 
(e.g., CCND1 amplification, CDKN2A deletion), drug targets (e.g. CDK 4/6), and 
tumor sensitivity and/or resistance (e.g., Ki67, pRb) in tumor tissues. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
The study is designed to have one interim analysis and the final analysis at 347 events based 
on the primary PFS endpoint with the investigator assessment. The Haybittle-Peto efficacy 
boundary (Haybittle 1971; Peto et al. 1976) for rejecting the null hypothesis will be used at 
the time of the interim analysis.  To protect the integrity of the study and to preserve the 
type-1 error rate, a fraction of alpha (0.000013) for efficacy will be spent at the interim 
analysis and accounted for in the overall type I error rate. The overall significance level for 
the efficacy analysis of PFS will be preserved at 0.025 (1-sided test). 
 
The purposes of the interim analysis are to allow early stopping of the study for futility and 
efficacy, to assess the safety of the combination regimen, and to potentially adjust the sample 
size. The analysis will be performed after approximately 226 PFS events (documented 
progressive disease or death; approximately 65% of the total events expected).  
 
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Protocol A5481008  
Statistical Analysis Plan 
 
x If the value of the test-VWDWLVWLFH[FHHGVWKHHIILFDF\ERXQGDU\]4.2059S
0.000013) the trial may be stopped for efficacy. It is assumed that a hazard ratio less 
than 1.0 is in favor of the PD-0332991 plus letrozole arm. 
x If the hazard ratio between the PD-0332991 plus letrozole arm and the placebo plus 
letrozole arm equates 1.0 or greater, the trial will be stopped for futility.  
x Alternatively, as appropriate, the sample size of the study may be adjusted using the 
method outlined by Cui et al. The detailed information about the sample size re-
estimation will be described in a separate document for confidentiality reasons. 
x If the results of the interim analysis indicate serious safety concerns, the sponsor will 
communicate with the Health Authorities regarding stopping the clinical trial. 
x The final analysis of PFS will be performed after approximately 347 PFS events have 
been observed if the Interim Analysis is not significant and the sample size is not 
adjusted after the interim analysis. 
 
If the study is determined to be stopped due to efficacy, the interim analysis will become the 
final and all the subsequent efficacy and safety analyses specified in this SAP will be 
performed.  
 
Efficacy Stopping Boundary for Rejecting Null Hypothesis Expressed as  
Z Scales and p-values 
Analysis 
Number of Event (%) 
Z Scale 
p-value 
Interim 
226 (65%) 
4.2059 
0.000013 
Final 
347 (100%) 
1.96 
0.025 
Interim analyses of efficacy are also planned for the secondary OS endpoint and OS will be 
tested in a hierarchical 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 also be determined by using the Lan-
DeMets procedure with an O’Brien-Fleming stopping rule. The overall significance level for 
the efficacy analysis of OS will be preserved at 0.025 (one-sided test). 
 
x The first possible time for OS interim analysis will be at the time of the PFS interim 
analysis. If improvement in PFS is significant at its interim, the OS interim analysis 
can be performed at this time. However, the number of deaths could be relatively low. 
The reasonable time for OS interim analysis will be at approximately 131 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 390 deaths have been 
observed. 
x If PFS is not significant at the time of the interim analysis of PFS, a final analysis for 
PFS will be performed. If PFS is significant at its final analysis, the OS interim 
analysis will also be performed at this time. If OS is not significant at its interim, the 
final analysis for OS will be performed when a total of 390 deaths have been 
recorded. 
x If PFS is not significant at its final analysis or did not meet the futility stopping 
boundary, OS will not be statistically evaluated. 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
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 recommendations made by the 
E-DMC to alter the conduct of the study will be forwarded to the Sponsor for final decision. 
The Sponsor will forward such decisions, which may include summaries of aggregate 
analyses of endpoint and 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 in the data preparation. Clinical sites will be 
restricted from access to study results until the conclusion of the study. 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 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 (e.g., 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. 
During sNDA reviewing, US FDA requested a formal OS analysis on data cutoff of 
November 24, 2016. This interim analysis does not have intention to change the course of 
planned final OS analysis at 390 deaths. To protect the integrity of the study and to preserve 
the type-1 error rate, a fraction of alpha (0.0001) will be spent for this interim analysis and 
accounted for in the overall type I error rate. 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
The primary purpose of this study is to demonstrate that the combination of PD-0332991 
with letrozole is superior to placebo plus letrozole in prolonging PFS in post-menopausal 
women with ER (+), HER2 (-) ABC who have not received any prior systemic anti-cancer 
treatment for advanced disease.  All primary and secondary endpoints based on radiological 
(and photographical when applicable) assessments of tumor burden (i.e. PFS, OR, DR, and 
DC) will be derived using the local radiologist’s/investigator’s assessment. Tumor 
assessments will also be performed by a blinded independent third-party core imaging 
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Protocol A5481008  
Statistical Analysis Plan 
 
laboratory and the data will be used for secondary supportive analyses. The study is designed 
to test the null hypothesis that the true PFS distributions for both letrozole plus PD-0332991 
and letrozole plus placebo arms are the same with a median PFS 9 months versus the 
alternative hypothesis that the true PFS distribution has a median that is longer than 9 months 
for the letrozole plus PD-0332991 arm. 
4.2. Sample Size Determination and Statistical Decision Rules 
4.2.1. Sample Size for PFS 
The sample size for this study is determined based on the assumptions that the median PFS 
for patients receiving placebo plus letrozole in the first-line treatment setting is 9 months and 
a risk reduction by 31% (a hazard ratio of 0.69) or an improvement by 44% to median PFS of 
13 months in the PD-0332991 plus letrozole treatment is clinically significant.  With one 
interim analysis performing at 65% of total PFS events, a total of 347 events are required in 
the two arms of the study based on a 2:1 randomization to have 90% power to detect a hazard 
ratio of 0.69 in favor of PD-0332991 plus letrozole arm using a 1-sided, unstratified log-rank 
test at a significance level of 0.025. Assuming a 15% drop-out rate on either treatment arm, a 
non-uniform accrual accomplished over a 15-month period and follow-up for about 10 
months after the last patient is enrolled, a total sample size of approximately 650 patients 
(~433 in PD-0332991 plus letrozole arm and ~217 in placebo plus letrozole arm) is required. 
This study will be considered a positive trial if the 1-sided, stratified log-rank test for PFS 
based on randomization stratification factors is significant at the significance level of 
0.000013 at the time of the interim or 0.025 at the final analysis in favor of PD-0332991 plus 
letrozole combination. 
4.2.2. Sample Size for OS 
The sample size described above will also allow the assessment of differences in the 
secondary endpoint of OS. No crossover to experimental therapy is permitted in the control 
group within the current study design. The OS outcome of a reported phase 3 clinical trial 
with a similar patient population was 34 months for the arm receiving letrozole.  Using this 
value as an assumption with a hypothesized 26% reduction risk (a hazard ratio of 0.74) or 
35% improvement in median OS (from 34 months to 46 months) in patients randomized to 
receive PD-0332991 plus letrozole and follow-up period of approximately 68 months, 
evaluation of 390 events using a 1-sided, unstratified log-rank test is required for a 
significance level of 0.025 and power of 80% to detect the difference. 
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, OS will not be 
statistically evaluated.    
Other 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 those secondary 
and supportive hypothesis tests. 
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Protocol A5481008  
Statistical Analysis Plan 
 
4.2.3. Sample Size for QTc 
The QTc analysis will be based on a non-inferiority hypothesis testing framework.  
Approximately 40 PD-0332991 plus letrozole treated patients are needed to establish non-
inferiority (no unacceptable QTc prolongation from the PD-0332991 plus letrozole 
FRPELQDWLRQEHWZHHQSRVWGRVHEDVHOLQHDQGEDVHOLQH¨47FDWDOO47FVDPSOLQJWLPH
points on Cycle 1 Day 14 with 90% power. The test is based on a 1-sided difference in means 
t-teVWIRUSDLUHG¨47FZLWKVLJQLILFDQFHOHYHO7KHGLIIHUHQFHLQPHDQVEHWZHHQ¨47F
under the alternative hypothesis is 10 mSec, assuming a non-inferiority margin of 20 mSec 
and the standard deviation of the paired differences equal 16 mSec based on Study 
A5481003). If the upper bounds of one-VLGHGFRQILGHQFHLQWHUYDOVRI¨47FIRUDOO
QTc sampling time points are below 20 mSec, the post-baseline dose QTc interval is 
considered to be “non-inferior” to the baseline; the QTc effect of the PD-0332991 in 
combination with letrozole is concluded to be not unacceptable.   
 
Since this is a double-blind study with a 2:1 randomization, approximately 60 patients will be 
needed for QTc evaluation to ensure approximately 40 patients from the PD-0332991 plus 
letrozole arm. 
5. ANALYSIS SETS 
5.1. Intent-to-Treat Population (Full Analysis Set) 
The intent-to-treat (ITT) population 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. Modified Intent-to-Treat (MITT) Population 
The MITT population will include all patients who are randomized, with the Sponsor-
designated central laboratories confirmed ER (+) status, 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. This will be the 
secondary population for evaluating all efficacy endpoints as well as patient characteristics.  
5.3. 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. 
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Protocol A5481008  
Statistical Analysis Plan 
 
5.4. Other Analysis Sets 
5.4.1. QTc Analysis Set 
A subset of AT patients, who are enrolled at selected sites (considered as Group 1) and have 
their QTc monitored to evaluate the effect of PD-0332991 on QT interval via serial triplicate 
ECGs time-matched with PK draws,  must have at least one pair of time-matched baseline 
(Day 0) and post-PD-0332991 dose (Day 14 of Cycle 1) ECG measurements. 
5.4.2. Ocular Analysis Set 
A subset of AT patients, whose ocular safety assessments are collected. 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 as they do not undergo these ophthalmic procedures. The analysis of ocular 
assessment data will be performed in ocular analysis set.  
5.4.3. Pharmacokinetic Analysis Set 
A subset of AT patients, who are treated with PD-0332991 and have at least one measured 
plasma concentration. 
5.4.4. Biomarker Analysis Set 
A subset of AT patients, who have baseline values for at least one biomarker. 
5.4.5. Patient Reported Outcome (PRO) Analysis Set 
A subset of ITT patients, who have both baseline and at least one follow-up PRO assessment 
5.5. Treatment Misallocations  
x 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. 
x 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 for all safety analyses.  
5.6. Protocol Deviations 
All deviations will be described when they appear and relate to the statistical analyses or 
populations. 
5.6.1. Protocol Deviations Assessed Prior to Randomization 
 
Deviations prior to randomization are typically not allowed. Major deviations that do occur 
will be tabulated. 
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Protocol A5481008  
Statistical Analysis Plan 
 
5.6.2. Protocol Deviations Assessed Post Randomization  
 
Major deviation is defined as having been treated according to the other treatment arm.  
Patients not treated with one of the protocol treatments are excluded from safety analyses. 
Otherwise patients are not excluded from analyses due to post-randomization deviations. 
 
6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoints 
6.1.1. Primary Endpoint  
x Progression Free Survival (PFS) is defined as the time from the date of randomization 
to the date of the first documentation of objective tumor progression as per RECIST v.1.1 
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.  PFS (in 
months) will EHFDOFXODWHGDVILUVWHYHQWGDWHíUDQGRPL]DWLRQGDWH 
Tumor assessments will be performed every 12 weeks (± 7 days) and bone scans (as 
applicable) every 24 weeks (±7 days) from randomization until radiographically and/or 
clinically (for photographed or palpable lesions) documented PD as per RECIST v.1.1, 
study treatment discontinuation (for patients continuing treatment beyond RECIST-
defined disease progression), initiation of new anticancer therapy, or discontinuation of 
patient from overall study participation (e.g., death, patient's request, lost to follow-up). 
Imaging assessments are to be scheduled using the randomization date as the reference 
date for all time-points and are NOT to be scheduled based on the date of the previous 
imaging time-point. Patients who discontinue study treatment for reasons other than 
radiographically and/or clinically (for photographed or palpable lesions) documented 
disease progression as per RECIST definitions will continue to have tumor assessment 
performed during the follow-up visits every 12 weeks (± 7 days) and bone scans (as 
applicable) every 24 weeks (±7 days) until documented disease progression, initiation of 
new anticancer therapy or discontinuation of patient from overall study participation 
(e.g., death, patient's request, lost to follow-up), whichever occurs first. Every effort 
should be made to perform a last tumor assessment before starting a new anticancer 
therapy. Additional unscheduled tumor assessments may be performed as clinically 
indicated at any time. 
Patients last known to be 1) alive and 2) progression-free, are censored at the date of the 
last objective disease assessment that verified lack of disease progression (see Appendix 
10.4 for determining the date in details). In addition, 
 
x Patients with inadequate baseline disease assessment are censored at the 
randomization date. 
x Patients with no on-study disease assessments are censored at the randomization 
date unless death occurred prior to the first planned assessment (in which case the 
death is an event).  
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Protocol A5481008  
Statistical Analysis Plan 
 
x If a new anti-cancer treatment is started prior to progression and death, then 
censorship is at the date of the last objective disease assessment that verified lack 
of disease progression prior to the new treatment. 
x 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. 
x Patients with documentation of progression or death after an unacceptably long 
LQWHUYDO!consecutive assessments) since the last tumor assessment will be 
censored at the time of last objective assessment documenting no progression. 
 
6.1.2. Secondary Endpoints  
x Overall Survival (OS) is defined as the time from the date of randomization to the date 
RIGHDWKGXHWRDQ\FDXVH26LQPRQWKVLVFDOFXODWHGDVGDWHRIGHDWKíUDQGRPL]DWLRQ
date +1)/30.4.  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.   
Following the End of Treatment visit, survival status will be collected in all patients 
(telephone contact is acceptable) every 6 months (± 7 days) from the last dose of study 
treatment. Information on subsequent anticancer therapy will also be collected. 
x 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. 
x 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; Appendix 10.3.).  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 
SD requires the criteria to be met at least 12 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 for any reason prior to reaching a CR or PR will be counted as non-responders 
in the assessment of ORR. 
Tumor response will be determined from tumor assessment data (where data meet the 
criteria for CR or PR as described in Appendix 10.3.).   
x Disease Control (DC)/Clinical Benefit Response (CBR) is defined as the overall 
FRPSOHWHUHVSRQVH&5SDUWLDOUHVSRQVH35RUVWDEOHGLVHDVH6'ZHHNV
according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1; 
Appendix 1). Disease Control Rate (DCR)/ Clinical Benefit Response Rate (CBRR)  
is defined as the proportion of patients with CR, PR, or SD ZHHNVUHODWLYHWR(1) all 
randomized patients and randomized patients with measurable disease at baseline. 
Designation of best response of SD 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 
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Protocol A5481008  
Statistical Analysis Plan 
 
reaching a CR or PR, a best response of SD 24 weeks, or who die, progress, or drop out 
for any reason prior to achieving reaching a CR or PR and a best response of SD 
weeks will be counted as non-responders in the assessment of DCR/CBRR. 
Tumor response will be determined from tumor assessment data (where data meet the 
criteria for CR or PR and best response of SD as described in Appendix 10.3.).   
x 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 
(i.e. 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. 
Patients last known to be 1) alive and 2) progression-free, are censored at the date of the 
last objective disease assessment that verified lack of disease progression. In addition, 
 
x If a new anti-cancer treatment is started prior to progression and prior to 28 days 
after discontinuation of treatment, then censorship is at the date of the last 
objective disease assessment that verified lack of disease progression prior to the 
new treatment.  
x 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. 
x Patients with documentation of progression or death after an unacceptably long 
LQWHUYDO!consecutive assessments) since the last tumor assessment will be 
censored at the time of last objective assessment documenting no progression. 
 
6.2. Safety Data 
Overall safety profile as characterized by type, frequency, severity of adverse events as 
graded by NCI Common Toxicity Criteria for Adverse Events version 4 (NCI CTCAE v.4.0), 
timing and relationship to treatment on each arm, and laboratory abnormalities observed. 
Adverse events (AEs), hematology, blood chemistry will be assessed as described in the 
Schedule of Activities of the protocol. 
Adverse events will be classified using the MedDRA classification system. The severity of 
the toxicities will be graded according to the NCI CTCAE version 4. For labs without 
CTCAE grade definitions, results are summarized as normal, 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 death or 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. 
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Protocol A5481008  
Statistical Analysis Plan 
 
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. 
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).  
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 
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. 
6.2.1. Treatment Emergent Adverse Event 
An adverse event is considered treatment emergent if: 
x The event occurs for the first time after the start of study treatment and before 28 days 
after final dose of study treatment and was not seen prior to the start of treatment or 
x The event was seen prior to the start of treatment but increased in NCI CTCAE v.4.0 
grade during study treatment. 
x Disease progression is not considered a treatment emergent adverse event unless the 
patient dies of disease prior to 28 days after discontinuation of treatment. 
6.2.2. Treatment Related Adverse Event 
Adverse events defined as treatment emergent adverse events with cause possibly, probably 
or definitely related to treatment as judged by the investigator are defined as treatment related 
adverse events. Events that are continuation of baseline abnormalities are not considered 
treatment related unless there is an increase in grade, or if there is an increase following a 
decrease, and the increase is judged by the investigator to be caused by the treatment. 
6.2.3. Laboratory Safety Assessments 
Laboratory assessment will be assigned to cycles based on the collection date of the sample 
relative to the start dates of cycles from the study drug administration as described in the 
Schedule of Activities table in Appendix 10.1. 
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Protocol A5481008  
Statistical Analysis Plan 
 
Baseline evaluations for laboratory are those collected 
x Within 28 days prior to or on first day of study drug and 
x If there is more than one baseline evaluation, closest to but any time prior to the 1st 
dosing on the first day of study treatment. 
 
6.2.4. Electrocardiogram (ECG) 
ECG measurements will include PR interval, QT interval, RR interval, and QRS complex. 
Triplicate ECGs will be performed for all patients to determine the mean QTc interval for 
eligibility purpose. 
 
Patients found to be eligible will be part of one of the two groups highlighted below 
depending on which site screened the patient. ECG frequency for each group is described 
below:   
x Patients in Group 1 (approximately 60 patients) will be enrolled at selected sites and 
will have their QTc monitored to evaluate the effect of PD-0332991 on QT interval 
via serial triplicate ECGs time-matched with PK draws. ECGs will be obtained on the 
day preceding treatment initiation (Day 0) at time 0 (time of first ECG also referred to 
as ECG1) and then 2, 4, 6, and 8 Hrs after ECG1, and on Day 14 of Cycle 1 pre-dose 
(0 Hrs) and 2, 4, 6, and 8 Hrs following PD-0332991 administration. Timing of ECGs 
performed on Day 14 MUST be time-matched (clock time +35 minutes) with ECG 
assessments performed on Day 0 (e.g, if the ECG1 on Day 0 was performed at 10:00 
AM then the 0 hour triplicate ECGs on Day 14 must be performed within the 9:30 
AM - 10:30 AM timeframe but as close as possible to 10:00 AM whenever feasible). 
On Day 14 of Cycle 1, study treatment should be administered immediately after the 
pre-dose PK draw has been collected. All ECGs should be obtained after a fast of at 
least 1 hour. ECGs should be performed immediately before PK blood draws at 
respective time points. Patients who cannot complete ECG measurements on Day 0 
and/or PK-matched ECG measurements (both ECG and PK collected) on Day 14 will 
need to be replaced. Additionally, triplicate ECGs will be obtained for safety 
monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1, Day 14 of Cycle 2, then on Day 
1 of Cycles 4, 7, and 10. ECGs beyond Cycle 10 will be performed as clinically 
indicated. 
x Patients in Group 2 (all other patients) will have triplicate ECGs performed for safety 
monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1, Day 14 of Cycles 1 and 2, then 
on Day 1 of Cycles 4, 7, and 10. ECGs beyond Cycle 10 will be performed as 
clinically indicated. All ECGs should be obtained after a fast of at least 1 hour. 
 
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. All triplicate ECG 
tracings will be sent electronically to a core ECG laboratory for blinded manual interval 
measurements.  The blinded manual interval measurements from the core ECG laboratory 
will be used for primary statistical analysis of ECG data in Group 1 patients. 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
QT measurements corrected by heart rate (QTc) will be used for the data analysis and 
interpretation.  In addition to commonly used techniques including Bazett’s (QTcB) and 
Fridericia’s (QTcF) methods, a study-specific correction method will be evaluated (QTcS) 
for the ECG Group 1.  QTcF will be used for the primary analysis. 
 
6.2.5. Ocular Safety Assessment 
Corresponding to protocol amendment 3, ocular safety assessments will be applied to all the 
newly enrolled, lens grading evaluable, patients in the study. Ocular assessments include 
Snellen best corrected visual acuity, intraocular pressure measurements, slit-lamp 
biomicroscopy, funduscopy, and lens grading. The ocular assessments will be performed at 
baseline (screening), every 3 months in the first year, and every 12 months thereafter during 
study treatments.  
 
6.2.6. Other Safety Assessment 
A full physical examination including an examination of all major body systems, height (at 
screening only), weight, blood pressure and pulse rate which may be performed by a 
physician, registered nurse or other qualified health care provider, will be required at 
screening, and Day 1 of Cycle 1 and Cycle 2. 
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits. Performance Status: The Eastern Cooperative Oncology Group (ECOG) 
performance status scale will be used. 
6.3. Other Endpoints 
6.3.1. Pharmacokinetic and Pharmacodynamic Data  
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10 min or 10% of the nominal time 
and collected prior to administration of the investigational product on that day (with the 
exception of the planned post-dose samples that will be collected on Day 14 of Cycle 1) will 
be considered protocol compliant.   
One 3 mL sample of venous blood will be collected in appropriately labeled K2 EDTA 
collection tube for assessment of PD-0332991 (including its active metabolites, if 
appropriate) levels at the protocol-specified times.  Samples will be analyzed using validated 
analytical methods in compliance with Pfizer standard operating procedures.   
Blood samples will be collected from all participating patients for PK assessments of 
PD-0332991 on Day 14 of Cycle 1 and Cycle 2 before administration of investigational 
product on that day.  In the event a pre-dose sample cannot be/is not collected on Day 14 of 
Cycle 1 or Cycle 2 as scheduled, every effort should be made to collect a makeup pre-dose 
sample between Day 15 and Day 21 of the same cycle or between Day 14 and Day 21 of any 
subsequent cycles beyond Cycle 2 following the same rules described above.   
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Protocol A5481008  
Statistical Analysis Plan 
 
For patients participating in the dedicated QTc portion of the trial (Group 1), all PK draws at 
Day 14 of Cycles 1 and 2 will be done immediately after triplicate ECGs have been 
performed so that the PK samples are collected at the nominal time.  
As part of understanding the pharmacokinetics of the PD-0332991, plasma samples may be 
used for metabolite identification and/or evaluation of the bioanalytical method.  These data 
will be used for internal exploratory purposes and will not be included in the Clinical Study 
Report. 
6.3.2. Biomarkers 
Retrospective confirmatory testing of tumor tissue samples for ER status will be performed 
in a central laboratory designated by the sponsor using a validated test. Results from this 
testing will be used for sensitivity analyses and will not be made available to the sites.  In 
addition, tumor tissue biomarkers, including DNA, RNA and protein analytes, will be 
analyzed to investigate possible associations with resistance / sensitivity to treatment with 
study drugs. Biomarkers that will be analyzed will be selected based on their known 
relevance to mechanisms involved in cell cycle regulation. Examples of such biomarkers 
include CCND1 and CDKN2A gene copy number, cdk4 and cdk6 RNA expression, and 
Ki67, pRb and p16 protein expression. 
Genomic and metabonomic variations may help to explain some of the variability in response 
seen with some drugs among different individuals. This is referred to as pharmacogenomics. 
Comparing the DNA, RNA, protein, and metabolite variation patterns of patients who 
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment.  
Collecting samples for pharmacogenomic analyses and retaining them in the Pfizer BioBank 
makes it possible to seek explanations for differences in, for example, exposure, efficacy, 
tolerability, or safety not anticipated prior to the beginning of the study. 
6.3.3. Patient Reported Outcome Endpoints  
Patient reported outcomes of health-related quality of life and health status will be assessed 
using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol-5D (EQ-
5D) instruments.   
Patients will complete each instrument pre-dose on Day 1 of Cycle 1 through 3, then on Day 
1 of every other subsequent cycles starting with Cycle 5 (e.g., cycles 5, 7, 9, etc),  and at the 
end of treatment.  
6.3.3.1. Functional Assessment of Cancer Therapy-Breast (FACT-B) [Version 4]  
The Functional Assessment of Cancer Therapy (FACT) is a modular approach to assess 
patient health-related quality of life using a ‘core’ set of questions (FACT-G) as well as a 
cancer site-specific module (see Appendix 10.7 for details).  
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Protocol A5481008  
Statistical Analysis Plan 
 
The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical 
Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being.   
The FACT-B consists of the FACT-G (27-item) and a breast-specific module: a 10-item 
instrument designed to assess patient concerns relating to breast cancer.  
For all questions, patients are asked to respond to a five-level scale where 0=not at all, 1=a 
little bit, 2=somewhat, 3=quite a bit, and 4=very much. 
6.3.3.2. EuroQol Health Utilities Index EQ-5D 
The EuroQol EQ-5D is a brief self-administered health status instrument consisting of two 
parts.  In the first part patients are asked to describe their health state on 5 dimensions 
(mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each 
dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme 
problem). The scores on the 5 dimensions are summarized to create a single summary score. 
Because the questions may be answered differently in different countries / regions due to 
different local customs and social perspectives, published weights from the EuroQol group 
are used in determining the country appropriate summary scores (EQ-5D User’s Guide). The 
summary score is called the summary index or the health utility value (Shaw et al. 2005). 
This study will use the UK summary score which ranges from -0.594 to 1 with lower scores 
corresponding to higher levels of dysfunction (see Appendix 10.8 for details). 
The second part of EuroQoL EQ-5D is a visual analogue scale (VAS) in which the patients 
rate their overall health status using values from 0 (worst imaginable) to 100 (best 
imaginable).  
6.4. Covariates and Stratification Factors 
6.4.1. 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. 
6.4.2. Stratification Factors  
x Site of disease (visceral1 vs. non-visceral2) 
x Disease free interval since completion of prior (neo)adjuvant therapy (de novo 
PHWDVWDWLFPRQWKV!PRQWKV 
x The nature of prior (neo)adjuvant anticancer treatment received (prior hormonal 
therapy vs. no prior hormonal therapy) 
 
1"Visceral" refers to lung and/or liver involvement.  
2"Non-visceral" refers to absence lung and/or liver involvement.   
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Protocol A5481008  
Statistical Analysis Plan 
 
7. HANDLING OF MISSING VALUES 
7.1. Missing Dates 
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (e.g., date of onset cannot be prior to day one 
date).  In this case, the date resulting in 1 day duration will be used. If the day of the month 
and the month is missing for any date used in a calculation, January 1 will be used to replace 
the missing date. 
Missing dates for adverse events will be imputed based on the similar principle. 
x For the start date, if the day of the month is missing, the 1st day of the month will be 
used to replace the missing date. If both day and month are missing, January 1 of the 
non-missing year will be used to replace the missing date. If the first dose date is later 
than this imputed date, then impute the start date again to the first dose date. 
x For the stop date, if the day of the month is missing, the last day of the month will be 
used to replace the missing date. If both day and month are missing, December 31 of 
the non-missing year will be used to replace the missing date. 
 
If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date. 
 
7.2. Missing Tumor Assessments 
If baseline tumor assessment is inadequate the patient cannot be assessed for response. 
Inadequate baseline assessment may include  
x Not all required baseline assessments were done 
x Assessments were done outside the required window  
x Measurements were not provided for one or more target lesions 
x 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. 
PFIZER CONFIDENTIAL 
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Pr ot oc ol A 5 4 8 1 0 0 8   
Statistic al A nal ysis Pla n  
 
 
7. 3.  Missi n g D at a i n P F S De ri v ati o n 
P F S ca n n ot be assess e d i n patie nts wit h i na de q uat e baseli ne t u m or ass ess me nt.  P F S ca n n ot 
be assesse d i n patie nts w h o ha ve n o o n-st u d y assess me nts u nless deat h occ urs pri or t o t he 
first pla n ne d assess me nt ti me.  
If a s u bsta ntial n u m ber of patie nts ha ve q u esti o na ble fail ure or ce ns ors hi p dates f or eit her 
P F S defi niti o n (s uc h as pr o gressi o n or deat h n ot d oc u me nte d u ntil after m ulti ple missi n g 
assess me nts) sce n ari os s uc h as best case (fail ure at ti me of d oc u me ntati o n) a n d w orst case 
( pr o gressi o n at earliest p ossi ble pla n ne d assess me nt date) will be i n vesti gate d.   
F or P F S  a n al ysis, n o val ues will be i m p ute d f or missi n g data.  F or ti me t o e ve nt e n d p oi nts, 
n o n-e ve nt o bser vati o ns will be ce ns ore d as defi n e d i n Secti o n 6 .   
 
7. 4.  Missi n g Q Tc D at a  
F or Q T c a nal ysi s, n o val ues will be i m p ute d f or missi n g data e x ce pt f or a vera gi n g of 
tri plicate meas ur e me nts. If o ne or t w o of t he tri plicate meas ure me nts f or a n E C G para meter 
are misse d, t he a v er a ge of t he re mai ni n g t w o meas ure me nts or t he si n gle m eas ure m e nt ca n 
be use d  i n t he a nal ys es. If all tri plicate meas ure me nts are missi n g at a ti me p oi nt f or a n E C G 
para meter, n o val ues will be i m p ute d f or t his ti me p oi nt a n d n o a nal ys es rel ate d t o t his ti me 
p oi nt will be perf or me d.  If t he tri plicate is n o t g o o d beca use of a n arti fact, t he n if t he 
tri plicate is re peate d wit hi n a b o ut ±  1 5 mi n utes ca n be use d at t hat n o mi nal ti me. Patie nts 
w h o ha ve dat a o n ot her d a ys or u nsc he d ul e d E C Gs b ut n ot at t he ti mes of t he f or mal 
statistical a nal ysis will be i ncl u de d i n t he cate g ori cal ta bles b ut n ot t he statistical a nal yses.  
7. 5.  Missi n g P atie nt R e p ort e d O utc o me D at a  
F or t he F A C T - B a n d E Q- 5 D a n a m bi g u o us a ns w er t o a q uesti o n will be assi g ne d t he w orst 
sc ore of t he a ns wers cir cle d. F or t h e i n di vi d ual d o mai ns of F A C T- B, a pr orate d s u bscale 
sc ore will be calc ulate d as l o n g as m ore t ha n 5 0 % of t he ite ms are a ns were d. F or t he t otal 
sc ores F A C T-B, F A C T - G, T OI, a pr orate d s c ore will be calc ulate d if m ore t ha n 8 0 % of t he 
o verall ite ms are a ns were d (e g, f or F A C T -G at least 2 2 of t he 2 7 ite ms) a n d all t he 
c om p o ne nt s u bscales ha v e vali d sc ores. Pr orate d s c ores ma y b e o btai ne d usi n g t he f or m ula 
bel o w:  
Pr orate d s u bscal e sc or e = [ S u m of ite m sc ores] x [ N of ite ms i n s u bscale]
 ÷ 
 
      [ N of ite ms a ns were d]   
 
F or t he E Q- 5 D, si nce eac h di me nsi o n has a si n gle ite m , res p o nses t o all 5 ite ms are n ee de d t o 
calc ulate a n i n de x -base d s u m mar y s c ore.  
P FI Z E R C O N FI D E N TI A L  
P a ge 2 6  
 
 


Protocol A5481008  
Statistical Analysis Plan 
 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1. Gate-keeping procedure for primary endpoint PFS  
At the final analysis of the primary endpoint PFS, the treatment effect of letrozole plus PD 
0332991 versus letrozole plus placebo will be assessed in two ways. 
 
(1) The treatment effect on PFS for all patients randomized in the study (ITT 
population). 
(2) The treatment effect on PFS in a sub-group patients who administered PD-332991 
with food.  
 
The sub-group is defined as all patients who were randomized after January 21, 2014 when 
both the guidance of administration of PD-332991 with food and prohibition of PPI had been 
communicated to study sites. This is the patient population who administered PD-332991 
with food.   
A Gate-keeping procedure will be used for hypotheses testing in a hierarchical approach to 
control the family-wise error rate for the analyses of primary endpoint PFS. The significance 
level Dfor the test will be adjusted for interim analyses. The testing begins with comparing 
letrozole plus PD 0332991 treatment to letrozole plus placebo treatment in all patients 
randomized. This testing serves as a gatekeeper in the sense that the null hypothesis of “no 
treatment effect” must be rejected prior to proceeding to the next level of comparisons which 
will be the hypotheses testing for the sub-group population. 
If the null hypothesis in ITT population can be rejected, then the study is claimed positive 
and the same hypotheses will be tested for the sub-group population with the same significant 
level as used for ITT population.  
 
8.1.2. Hierarchical Group Sequential Testing for PFS and OS 
To protect the family-wise error rate (FWER) at level of 0.025, the hierarchical group 
sequential testing with separate error spending functions at level 0.025 for PFS and OS 
hypotheses is proposed in this study. To preserve the FWER at 0.025, it is only necessary 
that the secondary hypothesis for OS is tested whenever the primary null hypothesis for PFS 
is rejected. That is, if the primary null hypothesis has been rejected (positive PFS) at an 
interim analysis, the secondary hypothesis can be tested on partial data at the interim 
analyses as well and again at the final analysis, if it was not significant before.  
x Let H0p and H0o denote the null hypotheses for testing PFS and OS, respectively. 
x /HWĮpWDQGĮo(t) denote the alpha-spending functions for PFS and OS, respectively, 
at information fraction t. 
x Let TΌ <T΍* < TΎ denote the time points for: 
          TΌ: Interim analysis (driven by PFS events), 
PFIZER CONFIDENTIAL 
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Protocol A5481008  
Statistical Analysis Plan 
 
          T΍: Planned final analysis of PFS* when targeted number of PFS events is 
expected to be observed, 
          TΎ: Planned final analysis of OS. 
x Let tp(TΌ), tp(T΍) represent information fractions for PFS at time points TΌ, T΍, 
respectively. 
x Let to(TΌ), to(T΍), to(TΎ) represent information fractions for OS at time points TΌ, T΍*, 
TΎ, respectively. 
x up(t) and uo(t) are the efficacy stopping boundaries for PFS and OS, respectively, at 
information fraction t. 
 
Note: *In a special case when PFS is statistically significant at TΌ and OS is not significant at 
TΌ, the timing of T΍ 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 T΍ can change but the information fraction to(T΍) should remain 
approximately the same. 
 
Using the following testing algorithm or strategy, the overall type-I error rate can be 
controlled in a strong sense.  
     
1. Interim Analysis of PFS at TΌ7HVW3)6DWĮp(tp(TΌ)) 
       If up(tp(TΌ)) is crossed, H0p is rejected. 
          Interim Analysis of OS at TΌ7HVW26DWĮo(to(TΌ)). 
             If uo(to(TΌ)) is crossed, H0o is rejected. 
             If uo(to(TΌ)) is not crossed, go to 2. 
       If up(tp(TΌ)) is not crossed, go to 2. 
     
2. Final Analysis of PFS at T΍7HVW3)6DWĮp(tp(T΍DGMXVWLQJIRUĮp(tp(TΌ)) 
       If up(tp(T΍)) is crossed, H0p is rejected. 
          Interim Analysis of OS at T΍7HVW26DWĮo(to(T΍DGMXVWLQJIRUĮo(to(TΌ))†. 
             If uo(to(T΍)) is crossed, H0o is rejected. 
             If uo(to(T΍)) is not crossed, go to 3. 
       If up(tp(T΍)) is not crossed, PFS not met, study failed and no testing for OS. 
     
3. Final Analysis of OS at TΎ7HVW26DWĮo(to(TΎDGMXVWLQJIRUĮo(to(T΍)). 
       If uo(to(TΎ)) is crossed, H0o is rejected. 
       If uo(to(TΎ)) is not crossed, OS not met. 
 
1RWHĮo(to(T΍QHHGVWREHDGMXVWHGIRUĮo(to(TΌ)) even under the scenario when OS was 
not tested at TΌ. 
 
8.1.3. 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 Site of disease (one of the baseline stratification factors 
as listed in Section 6.4.2) and/or a 1-sided unstratified log-rank test at the D=0.025 overall 
PFIZER CONFIDENTIAL 
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Protocol A5481008  
Statistical Analysis Plan 
 
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 6.4.2) 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 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 will be applied to the overall survival 
analysis. 
8.1.4. Analyses for Binary Data 
The rates of binary endpoints for the two treatments will be tested with a 1-sided significance 
level of 0.025 using a Cochran Mantel Haenszel (CMH) test stratified by Site of disease (one 
of the baseline stratification factors as listed in Section 6.4.2) and an exact test. The odds 
ratio and its 95% confidence interval will be calculated. 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, while 
the point estimate of the difference of the rates between treatment arm will be provided along 
with corresponding approximate 2-sided 95% confidence intervals based on normal 
distribution.  
 
8.1.5. Analyses of Continuous Data 
Descriptive statistics, including the mean, standard deviation, median, minimum, and 
maximum values, will be provided for continuous endpoints.  
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Protocol A5481008  
Statistical Analysis Plan 
 
 
8.1.6. Analyses for Categorical Data  
The number and percentage of patients in each category will be provided for categorical 
variables.   
8.1.7. Evaluation of the Discordance Rate between Investigator and Independent Core 
Imaging Laboratory on Assessing PFS data  
Potential evaluation bias between the investigator and independent core imaging laboratory 
assessments with respect to either the progression status of the patient or the timing at which 
progression occurs will be evaluated using two measures, the early discrepancy rate and late 
discrepancy rate. The agreement between the investigator and independent core imaging 
laboratory within a treatment arm is represented in a tabular form below 
 
Independent Core Imaging Laboratory 
Investigator 
PD 
No PD 
PD 
a=a1+a2+a3 
b 
No PD 
c 
d 
Note: In practice an investigator PD occurring later than an independent core imaging laboratory PD (a2) 
would be observed rarely. 
a1: number of agreements on timing and occurrence of PD. 
a2: number of times investigator declares PD later than independent core imaging laboratory. 
a3: number of times investigator declares PD earlier than independent core imaging laboratory. 
 
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 independent 
core imaging laboratory 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 
independent core imaging laboratory 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. 
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Protocol A5481008  
Statistical Analysis Plan 
 
The EDR and LDR can be calculated for each treatment arm and the differential discordance 
around each measure can be defined 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. 
8.1.8. Analyses for QTc Data  
 
8.1.8.1. Derived Analysis Variables 
All ECGs will be recorded in triplicate i.e. three ECGs taken approximately 2 minutes apart. 
Only the scheduled ECGs will be used for the formal analysis. ECGs obtained only for safety 
will not be included in the formal statistical analysis.  
 
The data will be centrally read by Biomedical Systems (BMS) and will include the following 
parameters: 
 
ECG Parameter 
Units 
Abbreviation 
QTc, Fridericia’s correction 
msec 
QTcF 
QTc, Bazett’s correction 
msec 
QTcB 
QT Interval 
msec 
QT 
Heart Rate 
bpm 
HR 
PR Interval 
msec 
PR 
RR Interval 
msec 
RR 
QRS Complex 
msec 
QRS 
 
The following variables will be derived as follows: 
ECG Parameter 
Units 
Abbrev. Derivation 
QTc, study specific 
correction 
msec 
QTcS 
= QT/(RR) S  (derivation of S is 
given in section ) 
 
Averaging of triplicate measurements:  
After the above variables have been derived within each patient and scheduled time-point, 
each ECG parameter (including QTcF, QTcB, QTcS, QT, HR, PR, RR, QRS) should each be 
averaged as follows:  (1st measurement + 2nd measurement + 3rd measurement) / 3.  All 
summary statistics, analyses and figures will be based on the triplicate averaged data. 
8.1.8.2. Derivation of Study Specific QT Correction Factor 
The study specific QT correction factor (ICH E14 Step 4, May 12, 2005) will be derived.  
The dataset will consist of Day 0 all three measurements of QT and RR observed at the 0, 2, 
4, 6 and 8 hour time points for all Group 1 patients. 
Prior to estimating the regression, QT and RR will be transformed by the natural logarithm to 
Ln(QT) and Ln(RR), respectively.  Ln (RR) will be treated in the regression as the 
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Protocol A5481008  
Statistical Analysis Plan 
 
explanatory variable with Ln (QT) as the response variable.  The regression equation will be 
as follows: 
Ln(QT) = Intercept + S u Ln(RR) + Error 
Where  S = slope of the regression line. 
Once (S) is estimated, it will be used to derive the study specific QT correction, QTcS. 
8.1.8.3. Assessment of QT Correction Methods   
The relationship between QT/QTc and RR and the adequacy of each of the 3 QT correction 
methods will be assessed by the following scatterplots (see Figure 1): 
x QT, QTcF, QTcB, and QTcS vs. RR  
Interpretation of the scatterplots should give the following information: 
x Variability of the QT/QTc relative to changing RR 
x Slope or lack of slope and pattern to assess adequacy of QT correction method 
x Apparent patterns in the data 
Figure 1. A Sample scatterplot of relationship between QT/QTc and RR 
8.1.8.4. Baseline Values for ECG Parameters 
Time-matched baseline:  Day 0 series of 5 QTc (QTcF, QTcB or QTcS as appropriate) 
measurements will be used as time-matched baseline values for the corresponding time-
points (Hour 0 through Hour 8) on Day 14.  This is matched within time-point and within 
patient. 
 
8.1.8.5. Change from Baseline Definition 
The change from baseline calculations for ECG measurements (abbreviated as “change”) is 
derived from the triplicate averaged measurements.  Change from baseline is defined as a 
RR (ms)
QTcF (ms)
0.6
0.8
1.0
1.2
1.4
340
360
380
400
420
440
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Protocol A5481008  
Statistical Analysis Plan 
 
patient’s parameter value at a particular time-point minus the appropriately matched baseline 
value (value - baseline value). Change from baseline calculations should only use post-dose 
ECG measurements. 
8.1.8.6. Change from Baseline Analysis 
For Group 1, Cycle 1 Day 14 ECG assessment, a linear mixed effects modeling approach 
will be used to quantify the relationship between study drug plasma concentrations  and 
ǻ47FWLPH-matched, baseline-adjusted).  Based upon this relationship, the predicted 
SRSXODWLRQDYHUDJHǻ47FDQGLWVFRUUHVSRQGLQg upper 95% 1-sided confidence interval 
bound may be computed at appropriate concentrations, e.g., the mean maximum plasma 
concentrations under therapeutic doses.  This analysis will be reported separately as a 
population modeling analysis report (PMAR).    
As part of the CSR, for Groups 1 and 2, the following summaries by time-point will be 
presented by treatment group: 
x the mean absolute QTc (QTcF, QTcB and QTcS) RR, PR and QRS, with two-sided 
95% confidence intervals; 
x the baseline-adjusted mean QTc (ǻQTcF, ǻQTcB and ǻQTcS) RR, PR and QRS, 
with two-sided 90% confidence intervals (Baseline is defined as the mean of triplicate 
measurements closest to the first palbociclib dose but prior to dosing. For group 1, 
baseline is time-matched, see protocol design for further details); 
x Group 1 only: The point estimates of mean of change from baseline (time-matched) at 
all 5 time points and their 2-sided 90% confidence interval as error bars will be 
displayed graphically 
 
8.1.8.7.  Summary of Categorical Analysis 
Shift summaries of QT/QTc values will be summarized and tabulated by the following 
CTCAE grade v.4.0 according to Day 0 or Day 14 with summary statistics as a supplement to 
the primary analysis.  
Grade 
1 
2 
3 
4 
5 
Prolonged 
QTc 
interval 
QTc  450 – 
480 msec 
QTc 481 – 
500 msec 
QTc t501 
msec on at 
least two 
separate 
ECGs 
QTc t501 RU!msec 
change from baseline 
and Torsade de pointes 
or polymorphic 
ventricular tachycardia 
or signs/symptoms of 
serious arrhythmia 
Death 
 
The change from baseline will summarize occurrences of shift by t 1 grade by CTC. 
Individual QT and QTc values t501 msec from each ECG within a triplicate will be flagged 
in data listings. 
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Protocol A5481008  
Statistical Analysis Plan 
 
In addition, the maximum QTc value for each patient can be categorized and summarized in 
the following cut-offs.  All post dose QTc interval data should be used in determining the 
maximum for a patient, including all scheduled and unscheduled ECG’s.  
 Absolute QTc interval 
prolongation 
QTc < 450 msec 
450 msec  47Fmsec 
481 msec  47Fmsec 
QTc t501 msec 
 
The maximum increase from baseline QTc value for each patient by treatment will be 
categorized and summarized as well.  For reporting the maximum increase QTc value the 
following categories: <30 msec, 30-59 msec DQGmsec will be used. 
8.1.9. Analyses for Ocular Assessment Data  
8.1.9.1. Snellen Best Corrected Visual Acuity and Refraction 
Snellen visual acuity charts are commonly used for safety evaluations.  In the most familiar 
acuity test, a Snellen chart is placed at a standard distance, twenty feet in countries where that 
is the customary unit of measure.  This line, designated 20/20, is the smallest line that a 
person with normal acuity can read at a distance of twenty feet.  Three lines above, the letters 
have twice the dimensions of those on the 20/20 line. The chart is at a distance of twenty feet, 
but a person with normal acuity could be expected to read these letters at a distance of forty 
feet. This line is designated by the ratio 20/40. If this is the smallest line a person can read, 
the person's acuity is "20/40," meaning, in a very rough kind of way, that this person needs to 
approach to a distance of twenty feet to read letters that a person with normal acuity could 
read at forty feet.  
In countries using the metric system, the standard chart distance is six meters, normal acuity 
is designated 6/6, and other acuities are expressed as ratios with a numerator of 6. 
Besides Snellen fraction (such as 20/20, 20/40), visual acuity can also be specified with 
several other scales, for example the decimal visual acuity and the logarithm of the minimal 
angle of resolution (LogMar).  Decimal visual acuity is obtained by dividing the numerator 
of the Snellen fraction by the denominator.  The logarithm of the reciprocal of this decimal 
visual acuity approximates the logarithm of the minimal angle of resolution. The table below 
displays equivalent visual acuity measurements. 
Equivalent Visual Acuity Measurements 
Snellen Visual Acuities 
Decimal 
Fraction 
LogMar 
4 Meters 
6 Meters 
20 Feet 
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Protocol A5481008  
Statistical Analysis Plan 
 
4/40 
6/60 
20/200 
0.10 
+1.0 
4/32 
6/48 
20/160 
0.125 
+0.9 
4/25 
6/38 
20/125 
0.16 
+0.8 
4/20 
6/30 
20/100 
0.20 
+0.7 
4/16 
6/24 
20/80 
0.25 
+0.6 
4/12.6 
6/20 
20/63 
0.32 
+0.5 
4/10 
6/15 
20/50 
0.40 
+0.4 
4/8 
6/12 
20/40 
0.50 
+0.3 
4/6.3 
6/10 
20/32 
0.63 
+0.2 
4/5 
6/7.5 
20/25 
0.80 
+0.1 
4/4 
6/6 
20/20 
1.00 
0.0 
4/3.2 
6/5 
20/16 
1.25 
-0.1 
4/2.5 
6/3.75 
20/12.5 
1.60 
-0.2 
4/2 
6/3 
20/10 
2.00 
-0.3 
 
In summary tables, proportion of subjects with visual acuity of improvement, no change, 
GHFUHDVHE\OLQHOLQHDQG!OLQHVZLOOEHGLVSOD\HGE\WUHDWPHQWJUoups.  If different 
visual acuity scales are used by different investigators, all visual acuity scores will be 
converted to LogMAR scale according the table above before data summarization. The 
change of 0.1 in LogMAR is equivalent to 1 line change Snellen chart. 
 
LogMAR = - log10(Decimal Fraction) 
In the event of a decrease in visual acuity of 3 lines or more from baseline, refraction will be 
rechecked at all subsequent study visits.  A change in refraction power (spherical or 
cylindrical) of +/– 1.25 diopters compared with the baseline examination will be reported in 
data listing by treatment groups. 
8.1.9.2. 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.  
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Protocol A5481008  
Statistical Analysis Plan 
 
 
Any IOP increase of greater than 10 mmHg above baseline or any IOP that increases above 
25 mm Hg will be reported by treatment groups. 
8.1.9.3. Slit-lamp Biomicroscopy, Funduscopy (Ophthalmoscopy), and Lens Grading 
 
Slit-lamp biomicroscopy results will be graded according to Intraocular Inflammation 
Grading Scale for Biomicroscopy criteria.  
For lens grading, The Wisconsin AREDS 2008 Clinical Lens Opacity Grading Procedure 
will be used.  
8.1.10. Analyses for Patient Reported Outcomes Data  
The FACT-B produces five subscale scores: physical well-being (PWB), social/family well-
being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast 
cancer subscale (BCS).  These subscale scores are used to derive three assessment outcomes: 
FACT-B total score, FACT-G score, and Trial Outcome Index (TOI), which are calculated as 
follows: 
FACT-B total score = PWB+SWB+EWB+FWB+BCS 
FACT-G total score = PWB+SWB+EWB+FWB 
TOI score = PWB+FWB+BCS 
 
The EQ-5D index is derived by combining one level from each of the 5 dimensions and 
converting it to a single summary index or health utility value (Shaw, et al, 2005). 
 
8.2. Statistical Analyses  
All efficacy analyses will be conducted on intent-to-treat (ITT) population and the sub-group 
population who were not impacted by antacids. Some efficacy analyses will also be 
performed on the MITT and AT populations, if appropriate. All analyses will be performed 
by using SAS® Version 9.1.3 or higher.  
The primary and secondary analyses of endpoints dependent on disease assessments (PFS, 
OR, DR, and DC) will be based on investigator assessments of disease response and 
progression. However, a blinded independent third-party core imaging laboratory will 
complete a retrospective review of radiographic images and clinical information collected 
on-study to verify the protocol defined endpoints of disease response and progression 
determinations as assessed by the investigator. Analyses based on the independent third-party 
core imaging laboratory assessments are considered as secondary and supportive. Evaluation 
of the Discordance Rate between Investigator and Independent Core Imaging Laboratory on 
Assessing PFS data will be provided. Summary of concordance between Investigator and 
Independent Core Imaging Laboratory Assessments of tumor response will be provided as 
well. 
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Protocol A5481008  
Statistical Analysis Plan 
 
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, D=0.025) 
stratified by Site of disease 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 on the day 
following the date of the last tumor assessment documenting absence of progressive disease 
and death. In addition, several sensitivity analyses on the primary PFS endpoint will be 
performed in determining whether the primary PFS analysis is robust.  The stratified log-rank 
test (1-sided, D=0.025) will be used to evaluate the primary efficacy endpoint, PFS in the ITT 
population. 
Influence of additional anti-cancer therapy prior to disease progression or death -A 
sensitivity analysis will be performed by following patients until PD after discontinuation of 
the study treatment regardless the initiation of additional anti-cancer therapies. PFS data will 
be censored on the day of the last tumor assessment documenting absence of progressive 
disease or death for patients who  
x Are removed from the study prior to documentation of objective tumor progression; 
or  
x Remaining on study without PD or death at the time of the analysis.  
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. 
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 Unable to Evaluate (UE) 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 UEs) instead of 
the date of the next Time Point (X+1) as the primary analysis. 
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Protocol A5481008  
Statistical Analysis Plan 
 
Influence of Censoring for Patients Who Discontinued from Study due to Adverse 
Event or Systemic Deterioration – A sensitivity analysis will be performed to investigate 
whether the censoring for patients discontinued without PD due to adverse event or systemic 
deterioration of health. In this analysis, the patients who are censored in primary analysis will 
be counted as events.  
Influence of Patients With Major Protocol Deviation – A sensitivity analysis to 
investigate whether the patients with major protocol deviation from inclusion and exclusion 
criteria affect the outcome of the primary PFS analysis by excluding those patients in the 
analysis. 
Influence of Antacid Concomitant Medication (e.g. PPI) and /or Food Effect - Sensitivity 
analyses will be performed to investigate the impact of PPI, other antacids, and fasting 
condition on the treatment effect of the combination of PD-332991 with letrozole. PFS will 
be evaluated in the sub-populations excluding patients who took PPI, other antacids, and/or 
in fasting condition during the active treatment phase, if appropriate.  
Influence of Bone-only Disease Patients - Sensitivity analyses will be performed to 
investigate whether addition of bone-only disease patients influenced the outcome of the 
primary endpoint PFS, if appropriate. 
(1) For patients with bone-only disease, progression is defined as the appearance of t1 
new lesion(s) 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 at Section 6.1.1:  
x On-study fracture; or 
x On-study management of pain (palliative radiation therapy, palliative 
surgery); or 
x Clinical worsening not objectively confirmed (ECOG performance status 
increase from baseline by at least 2 points in 2 assessments); or 
x On-study change of therapy 
(2) For patients with bone-only disease, progression is defined as the appearance of t1 
new lesion(s) after the first on-study bone scan. The following cases the patient will 
also be considered as PD:  
x On-study fracture; or 
x On-study management of pain (palliative radiation therapy, palliative 
surgery); or  
x Clinical worsening not objectively confirmed (ECOG performance status 
increase from baseline by at least 2 points in 2 assessments); or 
x On-study change of therapy 
(3) Excluding bone-only disease patients from the analysis of the primary PFS endpoint. 
(4) Time to disease progression due to existing bone lesion progression, and/or new bone 
lesion. 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.2.3. Secondary Analyses 
An unstratified log-rank test (1-sided, D=0.025) and Cox regression model will be used on 
the primary PFS endpoint as supportive analyses. In addition, the potential influences of the 
stratification factors (as listed in Section 6.4.2) and baseline patient characteristics such as 
age, ethnic origin, ECOG performance status, geographical region/country, and selected 
biomarkers on the primary PFS endpoint will be evaluated. 
The stratified (by Site of disease) log-rank test (1-sided, D=0.025) may be used to evaluate 
the primary efficacy endpoint, PFS, in the AT and MITT Populations.   
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 Site of disease) 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, OS will not be 
statistically evaluated.  
The 1-year, 2-year and 3-year survival probabilities will be provided with their 95% 
confidence intervals. 
 
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.  CMH test stratified by Site of disease  
and exact test will be used to compare ORR between two treatment arms. 
The number and proportion of patients achieving disease control/clinical benefit response  
(CR or PR DQG6'ZHHNVZLOOEHVXPPDUL]HG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.  A 
stratified (by Site of disease) CMH test and exact test will be used to compare DCR/CBRR 
between two treatment arms.  
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  
Supportive analyses for the time-to event endpoints such as PFS and DR will be performed in 
the ITT population based on the independent third-party core imaging laboratory assessment 
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Protocol A5481008  
Statistical Analysis Plan 
 
as described as 8.2.1. and 8.2.3. In addition, analyses will be performed for OR and DC in the 
ITT population based on the independent third-party core imaging laboratory assessment as 
described as 8.2.3.  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 with kappa statistics by treatment arms as well. 
 
A supportive analysis will be performed by combining the OS data from this study and from 
the randomized phase 2 Study A5481003 with similar approaches described above. The 
Study as a stratification factor (A5481003 vs. A5481008) will also be included in the 
analysis. Since the median OS time for the studied patient population is relatively long and it 
is anticipated a small fraction of OS events would be available at the time of OS interim 
analysis, this analysis will certainly increase the power of detecting the OS difference 
between two treatment arms, given both randomized studies have similar patient populations 
and OS follow up processes.   
 
8.2.5. Standard Analyses  
Descriptive statistics will be used to summarize study conduct and patient disposition, 
baseline characteristics, and treatment administration/compliance.   
 
x 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. 
x Baseline Characteristics - patient characteristics such as patient age, height, weight, 
race, ethnicity, ECOG performance status, primary diagnosis, ER 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.  
x Treatment Administration and Compliance  
x Extent of Treatment 
The extent of treatment will be summarized as follows: 
 
x The number and % of patients on treatment and off for each reason 
x Treatment assigned vs. actual received  
x The number and percent of patients beginning 1, 2, 3, 4, 5+ cycles of either study 
drug  
x The number of cycles started (median, minimum, maximum) will be reported 
(overall and by study treatment).    
x Duration of treatment (weeks) (overall and by study treatment) 
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Protocol A5481008  
Statistical Analysis Plan 
 
x Cumulative dose and relative dose intensity (see Appendix 10.6 for details) 
(overall and by cycle; by study treatment)  
 
x Treatment Delays and Dose Modifications 
Dose reductions are not allowed for letrozole. Treatment delays and dose 
modifications of study treatments will be summarized as follows including number 
and percent (see Appendix 10.6 for details): 
 
x The number of patients with at least one PD 0332991 dose reduction and the 
number of patients with at least one PD 0332991 or letrozole dose omission at any 
time during drug administration will be reported. 
x The number of patients with at least one PD 0332991 dose reduction due to an 
adverse event will be reported. 
x The number of patients with at least one PD 0332991 dose delay (i.e. start of 
following cycle is delayed) and percentage due to each reason for the delay will 
be reported  
 
x 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 (i.e. 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. 
 
x Follow-Up Therapy  
Follow-up cancer therapy will be summarized by treatment as patients with number 
of regimens (0, 1, 2, t3), and patients with particular agents. Disease progression on 
follow up therapies will be collected according to protocol amendment 7. Disease 
progression on new anti-cancer therapies may be explored if sufficient data is 
collected and the analyses is appropriate.  
 
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 (i.e. PD-0332991/Placebo or 
letrozole) will be included in all the safety analyses.  
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v.4.0 whenever possible (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
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Protocol A5481008  
Statistical Analysis Plan 
 
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. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this exploratory analysis. 
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 death or 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. 
x 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. 
x 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. 
x Tier-3 events will be presented by observed event proportions. The following will be 
provided: 
o Incidence and grades of treatment emergent (all causality, preferred term, and 
by System Organ Class) AEs for all cycles combined. 
o Incidence and grades of treatment emergent (all causality, preferred term) AEs 
for all cycles combined in descending frequency order. 
o Incidence and grades of treatment emergent (treatment related, preferred term 
and by System Organ Class) AEs for all cycles combined. 
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Protocol A5481008  
Statistical Analysis Plan 
 
o Incidence and grades of treatment emergent (treatment related, preferred term) 
AEs for all cycles combined in descending frequency order. 
x Disease progression will not be included 
x There will be no adjustment for multiplicity 
The following summaries of treatment emergent adverse events will also be provided by arm: 
x Discontinuations Due to Adverse Events including causality: all cause, treatment 
related, including relationship to specific study treatment of letrozole, PD-0332991, 
and placebo 
x Temporary Discontinuations or Dose Reductions Due to Adverse Events including 
causality and relationship to specific study treatment of letrozole, PD-0332991, and 
placebo 
x Treatment-Emergent Adverse Events (All Causality, and Treatment Related) 
including the number of patients evaluable for adverse events, total number of 
adverse events (counting each unique preferred term across all patients), number of 
patients with serious adverse events, number of patients with Grades 3 and 4 adverse 
events, number of patients with Grade 5 adverse events, and number with dose 
reductions or temporary discontinuations due to adverse events 
x Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Maximum NCI CTCAE v.4.0 Grade (All Causality, and Treatment related) 
x Treatment-Emergent Adverse Events by MedDRA Preferred Term sorted by 
Descending Order of AE Frequency (All Causality, and Treatment related) 
x 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. 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.2.7. QTc Analyses 
All ECGs obtained during the study will be evaluated for safety. The triplicate data will be 
averaged and all summary statistics and data presentations will use the triplicate averaged 
data. Any data obtained from ECGs repeated for safety reasons after the nominal time-points 
will not be averaged along with the preceding triplicates. 
For all patients in the safety analysis population, individual change in QTc (QTcF, QTcB, 
QTc S) will be calculated for each nominal post-baseline time point. These individual 
changes will be summarized using descriptive statistics. 
For all patients in the safety analysis population, categorical analysis of the 
QTcF/QTcB/QTcS data will be conducted and summarized as follows:  
Shift summaries of QT/QTc values will be summarized and tabulated by the following 
CTCAE grade v.4.0 according to 8.1.6.7. 
1. The change from baseline will summarize occurrences of shift by t 1 grade by CTC. 
2.  Individual QT and QTc values t501 msec from each ECG within a triplicate will be 
flagged in data listings. 
3. The number and percentage of patients with maximum post-dose QTcF/QTcB/QTcS  
(<450, 450-480, 481-DQGPV, including all scheduled and unscheduled ECG’s.   
4. The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB/QTcS (<30, 30- 60, and ! 60 ms), including all scheduled and unscheduled 
ECG’s.   
5. PR changes frRPEDVHOLQHLIDEVROXWHEDVHOLQHYDOXHZDVPVDQGLI
DEVROXWHEDVHOLQHYDOXHZDV!PV 
6. 456FKDQJHVIURPEDVHOLQHLIDEVROXWHEDVHOLQHYDOXHZDVPVDQGLI
DEVROXWHEDVHOLQHYDOXHZDV!PV 
The analyses described above for all patients will be repeated separately for the ECG 
sub-population in Group 1 for QTcF/QTcB/QTcS. 
For safety analysis population, the following summaries by time-point will be presented by 
treatment group: 
x the mean absolute QTc (QTcF, QTcB and QTcS) RR, PR and QRS, with two-sided 
95% confidence intervals; 
x the baseline-adjusted mean QTc (ǻQTcF, ǻQTcB and ǻQTcS) RR, PR and QRS, 
with two-sided 90% confidence intervals; 
x Group 1 only: The point estimates of mean of change from baseline at all 5 time 
points and their 2-sided 90% confidence interval as error bars will be displayed 
graphically 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.2.8. Ocular Assessment Data Analyses 
Snellen Visual Acuity data will be analyzed by using LogMAR value, reporting the 
maximum changes from baseline of LogMAR. 
Any IOP increase of greater than 10 mmHg above baseline or any IOP that increases above 
25 mm Hg will be reported by treatment groups in data listing. 
Any new finding or deterioration from baseline findings in Slit-lamp biomicroscopy, Lens 
Grading, and Funduscopy will be reported by treatment groups in data listing.  
8.2.9. Pharmacokinetic and Pharmacodynamic Analyses 
Concentration data of PD-0332991 will be listed by patient and by actual collection time and 
day.  
Average trough concentrations will be listed by patient. Summary statistics will be provided 
for trough concentrations by study cycle and for average trough concentrations by patient. 
PK parameters will be calculated for Group 1 patients on Day 14 of Cycle 1 using the 
predose PK value as the 24 hrs value (assuming steady state conditions).  Summary statistics 
of the PK parameters will be provided.  All patients treated with PD-0332991 and for whom 
drug plasma concentration results (from at least 1 visit) are available will be included in the 
analysis.   
Concentration-QTc modeling analysis will be conducted using the ECG data from this study 
Linear, log-linear, and/or saturable models will be examined for the concentration-QTc 
relationship.  Exploratory analyses (via graphical displays and/or model fitting) include 
accounting for a delayed effect and the justification for the choice of pharmacodynamic 
model.  Diagnostic evaluation will be included to explore the adequacy of the model.   
In addition, the relationship between exposure and PD, efficacy and safety endpoints will be 
explored, as necessary, based on emerging PD, efficacy/safety data.   
The results of these modeling analyses may be reported separately from the clinical study 
report. 
8.2.10. Biomarkers Analyses 
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 letrozole plus PD-0332991 anti-tumor efficacy. 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.2.11. Patient Reported Outcomes Analyses 
The analysis for PRO endpoints will be in PRO analyses set as appropriate.  
The PRO endpoints will be FACT-G total score, FACT-G subscales, breast cancer subscale 
(BCS), FACT-B total score, trial outcome index (TOI), EQ-5D, EQ-VAS, and time to 
deterioration. 
For each questionnaire (FACT-B and EQ-5D) a completion status table will be provided 
showing the numbers and percentages of patients at each visit and the numbers and 
percentages of patients at that visit who completed, at least one item within the questionnaire. 
FACT-G 
FACT-G is the sum of the scores from the 27 questions from the FACT-G domains. FACT-G 
will be summarized using means, medians, standard deviations, and 95% confidence 
intervals at each assessment point, based on the observed values as well as changes from 
baseline both within group and between groups.  Comparisons between groups will be based 
on a repeated measures analysis using a mixed effects model.  The variables in the model 
will be treatment, time, treatment-by-time, with baseline as covariate.  The minimally 
important difference (MID) for FACT-G is 5-6 points. In fitting the mixed model, time will 
be used as a continuous variable and the method of restricted maximum likelihood will be 
used assuming an unstructured covariance matrix. No adjustments for multiple comparisons 
will be made.  The dropout rates of the two treatment groups will be compared and, if 
warranted, a pattern mixture analysis will be performed. This will augment the other analyses 
and may be available after the completion of the study report. 
In addition to the analysis described above, a graphical display of mean FACT-G over time 
for each treatment group will also be provided. 
8.2.11.1.  FACT-G Subscales 
The 4 FACT-G subscales, called domains, are Physical, Social/Family, Emotional, and 
Functional well-being (PWB, SWB, EWB, FWB, respectively).  Analysis of the FACT-G 
subscales will follow the same methodology as for FACT-G.  The MID for the FACT-G 
subscales is 2-3 points. 
8.2.11.2. Breast Cancer Subscale (BCS) 
This subscale consists 10 items associated with breast cancer. Analysis of BCS will follow 
the same methodology as for FACT-G. The MID for BCS is 2-3 points 
8.2.11.3. FACT-B 
This is the overall FACT-B questionnaire consisting of the 27 items from FACT-G and the 
10 items from BCS making it 37 items altogether.  Analysis of  FACT-B will follow the 
same methodology as for FACT-G.  The MID for FACT-B is 7-8 points. 
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Protocol A5481008  
Statistical Analysis Plan 
 
8.2.11.4. Trial Outcome Index (TOI) 
The trial outcome index is defined to be the sum of (PWB+FWB+BCS) making it 24 items 
altogether.  Analysis of TOI will follow the same methodology as for FACT-G.  The MID for 
TOI is 5-6 points.  
8.2.11.5. EQ-5D Index 
Analysis of EQ-5D will follow the same methodology as for FACT-B.  In addition, an EQ-
5D health state profile, which consists of a display of the numbers and percentages of 
patients in each of the 3 response levels for each of the 5 dimensions, will also be provided. 
8.2.11.6. EQ-VAS 
Analysis of EQ-VAS will follow the same methodology as for FACT-B. 
8.2.11.7. Time to Deterioration 
In addition to the above analyses, an examination of the time to deterioration (TTD) will be 
carried out using survival analysis methods including Kaplan Meier plots and log-rank tests 
to compare the two treatment groups.  Deterioration will be defined as a decrease of a pre-
specified number of points based on MID.  This analysis will be carried out for the variables 
BCS, FACT-B, FACT-G, and TOI, and the pre-specified decrease are 2, 7, 5, and 5, 
respectively.  
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Protocol A5481008  
Statistical Analysis Plan 
 
8.3. Summary of Key Efficacy Analyses  
Type of 
Analysis 
Endp
oint 
Analysis Set 
Statistical Method  
Primary  
PFS 
ITT 
Investigator assessment 
(See 8.2.1) 
Stratified log-rank test (stratified by disease site), 
K-M method (median and 95% CI) 
HR and 95% CI from the stratified Cox model 
Secondary 
PFS 
ITT 
BICR 
Stratified log-rank test (stratified by disease site), 
K-M method (median and 95% CI) 
HR and 95% CI from the stratified Cox model 
Secondary 
Sensitivity 
analysis1- 5 
PFS 
ITT 
Investigator assessment 
and BICR 
(See 8.2.2) 
Stratified log-rank test (stratified by disease site) 
K-M method (median and 95% CI) 
HR and 95% CI from the stratified Cox model 
Secondary 
Sensitivity analysis 
6 - 7 
PFS 
ITT 
Investigator assessment 
and BICR 
(See 8.2.2) 
Unstratified log-rank test  
K-M method (median and 95% CI) 
HR and 95% CI from the unstratified Cox model 
Secondary 
 
PFS 
ITT 
Investigator assessment 
And BICR  
Unstratified log-rank test  
K-M method (median and 95% CI) 
HR and 95% CI from the unstratified Cox model 
MITT 
Investigator assessment 
and BICR 
Stratified log-rank test (stratified by disease site) 
K-M method (median and 95% CI) 
HR and 95% CI from the stratified Cox model 
AT  
Investigator assessment 
and BICR 
(See 8.2.3) 
Stratified log-rank test (stratified by disease site) 
K-M method (median and 95% CI) 
HR and 95% CI from the stratified Cox model 
Secondary 
OS 
ITT 
(See 8.2.3) 
Stratified log-rank test (1-sided, D=0.025), 
Cox model, 
K-M method (median and 95% CI) 
Wilcoxon test 
RPSFT method 
Survival probability at 1, 2, and 3 years 
Secondary  
 
OR  
ITT  
Investigator assessment 
and BICR 
(See 8.2.3) 
stratified exact tests (stratified by disease site,) 
Exact CI based on Clopper-Pearson method (95% 
CI),   
Secondary 
 
DC/C
BR 
ITT  
Investigator assessment 
and BICR 
(See 8.2.3) 
stratified exact tests (stratified by disease site) 
Exact CI based on Clopper-Pearson method (95% 
CI),   
Secondary 
 
DR 
ITT patients with a CR 
or PR  
Investigator 
assessments and BICR 
(See 8.2.3) 
K-M method (median and 95% CI) 
Abbreviations: 
ITT: intent-to-treat; At: as-treated; MITT: modified intent-to-treat; 
DCR: disease control rate; DR: duration of response; ORR: objective response rate; OS: overall survival; PFS: 
progression-free survival.
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Protocol A5481008  
Statistical Analysis Plan 
 
9. REFERENCES  
1. Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  Biometrics 
1982; 38:29-41. 
2. Cox DR. Regression models and life-tables (with discussion). Journal of the Royal Statistical 
Society, Series B 1972; 34:187-220.  
3. DeMets D, Lan KKG. Interim analysis: the Alpha Spending function approach. Statistics in 
Medicine 1994; 13:1341-1352. 
4. 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. 
5. Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc 
1958; 53:457-481. 
6. 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. 
7. Cui L, Hung HMJ, Wang S, et al. Modification of sample size in group-sequential clinical trials. 
Biometrics. 1999; 55: 853-7. 
8. Dmitrienko A, Tamhane AC, Bretz F (2010). Multiple Testing Problems in Pharmaceutical 
Statistics. Chapman and Hall/CRC, Boca Raton.  
9. Pampallona S and Tsiatis AA, Group sequential designs for one-sided and two-sided hypothesis 
testing with provision for early stopping in favor of the null hypothesis. J. Statistical Planning and 
Inference, 1994; 42:19-35. 
10. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Brit. J. 
Radiology 1971; 44:793-797. 
11. 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. 
12. 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. 
13. ICH Harmonised Tripartite Guideline. The Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. E 14. May 12, 2005. 
14. National Cancer Institute (NCI). Common Terminology Criteria For Adverse Events (CTCAE). 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
15. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and 
testing of the D1 valuation model. Medical Care 2005; 43:203-220. 
16. The EuroQol Group. EQ-5D: A measure of health-related quality of life developed by the 
EuroQol Group: User Guide. V 2.0. 2009. The EuroQol Group, Rotterdam. 
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Protocol A5481008  
Statistical Analysis Plan 
 
17. Sprangers MAG, Groenvold M, Arraras JL, et. Al. The European Organization for Research and 
Treatment of Cancer Breast Cancer-Specific Quality-of-Life Questionnaire Module: First Results 
From a Three-Country Field Study. J Clin Oncol 1996; 14(10): 2756-2768. 
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Protocol A5481008  
Statistical Analysis Plan 
 
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 for detailed information on each procedure and assessment required for compliance with the protocol. 
A5481008 Schedule of Activities 
Protocol Activity 
Screening 
Active Treatment Phasea - One Cycle = 28 days End of Treatment / 
Withdrawalc 
Post-Treatment 
Follow-Upd 
Cycles 1 and 2 
Cycles t3 
Study Day 
Within 28 days prior 
to randomization 
unless specified 
otherwise 
Day 1b, v 
Day 14 
Day 1v 
Time Window 
r2d 
r2d 
r2d 
 
r7d 
 Baseline Documentation 
Informed Consent Processe 
X 
 
 
 
 
 
Medical / Oncological Historyf 
X 
 
 
 
 
 
Baseline Signs / Symptoms  
 
Xg 
 
 
 
 
Retained Pharmacogenomic Blood 
Sampleh 
 
X 
 
 
 
 
Tumor Tissue for Biomarkeri 
X 
 
 
 
Xi 
 
Physical Examination/Vital signsj 
X 
Xb 
 
X 
X 
 
Ophthalmic Examinationk 
X 
 
 
X 
X 
 
ECOG Performance Status 
X 
X 
 
X 
X 
 
 Laboratory Studies 
Hematologyl 
X 
Xb 
X 
X 
X 
 
Blood Chemistryl 
X 
Xb 
X 
X 
X 
 
12-Lead ECGm 
Xm 
Xb 
Xm 
Xn 
X 
 
 Disease Assessment  
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Protocol A5481008  
Statistical Analysis Plan 
 
Protocol Activity 
Screening 
Active Treatment Phasea - One Cycle = 28 days End of Treatment / 
Withdrawalc 
Post-Treatment 
Follow-Upd 
Cycles 1 and 2 
Cycles t3 
Study Day 
Within 28 days prior 
to randomization 
unless specified 
otherwise 
Day 1b, v 
Day 14 
Day 1v 
Time Window 
r2d 
r2d 
r2d 
 
r7d 
Computed Tomograhy (CT)/ Magnetic 
Resonance Imaging (MRI) Scans of 
Chest, Abdomen, Pelvis, any clinically 
indicated sites of disease, and of bone 
lesions; Clinical evaluation of 
superficial diseaseo 
X 
Ż--Źp,o 
Performed every 12 weeks (±7 days) from the date 
of randomization 
X 
Xo 
Radionuclide Bone Scan, Whole Bodyo 
X 
Ż--Źq,o 
Performed every 24 weeks (±7 days) from the date 
of randomization 
X 
Xo 
 Other Clinical Assessments  
Drug Compliancer 
 
Ż--Ź 
 
Averse Event Reportings 
X 
X 
X 
X 
X 
X 
Review Concomitant 
Medications/Treatmentst 
X 
X 
X 
X 
X 
X 
EuroQol; EQ-5Du 
 
X 
 
X 
X 
 
FACT - Breast Questionnaireu 
 
Xu 
 
X 
X 
Xy 
Survival Follow-up 
 
 
 
 
 
X 
 Study Treatment 
Randomization  
X 
 
 
 
 
 
Letrozole (both treatment arms) 
 
Once Daily Ż--Źw 
 
 
PD-0332991 or Placebo 
 
Ż--Źx 
Once Daily on Day 1 to Day 21 of each cycle 
followed by 7 days off 
 
 
 Special Laboratory Studies  
Pharmacokineticsm 
 
 
X 
 
 
 
a. 
Active Treatment Phase: All assessments should be performed prior to dosing with study medications on the visit day unless otherwise indicated.  
Acceptable time windows for performing each assessment are described in the column headers.  For the purposes of this trial 1 cycle is 28 days.  A cycle 
could be longer than 28 days if persistent toxicity delays the initiation of the subsequent cycle. 
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Protocol A5481008  
Statistical Analysis Plan 
 
b. Cycle 1/Day 1: Blood chemistry, hematology, 12-lead ECG and physical examination not required if acceptable screening assessment is performed within 
7 days prior to randomization. 
c. 
End of Treatment/Withdrawal: Obtain these assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks for 
disease assessments).  End of Treatment/Withdrawal visit will be performed as soon as possible but no later than 4 weeks (ie, 28 days) ±7days from last dose 
of study treatment and prior to the initiation of any new anticancer therapy. 
d. Post Treatment Follow-up:  After discontinuation of study treatment, post-treatment follow-up (including survival status and post-study anticancer therapy 
evaluation) will be collected every 6 months (±7 days) from the last dose of study treatment.  Telephone contact is acceptable. 
e. 
Informed Consent: Informed consent may be obtained greater than 28 days from randomization; however, must be obtained prior to any protocol required 
assessments being performed (with the exception of certain imaging assessments if meeting the criteria defined in Section 6.1). 
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. Retained Pharmacogenomic Blood Sample: A single 4 mL blood sample (Prep D1; K2 EDTA whole blood collection optimized for DNA analysis) will be 
collected pre-dose at the Cycle 1 Day 1 visit from all patients, unless prohibited by local regulations, to be retained for possible analysis of genetic 
associations with pharmacokinetics, drug response or adverse drug reactions.  Examples of genes that may affect pharmacokinetics or drug response include, 
but may not be limited to, genes encoding drug metabolizing enzymes and transporters, and genes thought to be related to the mechanism of drug action. 
i. 
Mandatory Tumor Tissue For Confirmatory Testing and for Biomarker Assessments: Tumor tissue is required for patient participation.  Submission of 
formalin-fixed paraffin embedded (FFPE) tumor samples (blocks) of adequate size to allow for three 0.6 mm diameter x 5 mm deep core punches that will 
be used to generate a tissue microarray are needed.  If FFPE tissue block cannot be submitted, at least 12 glass slides, each containing an unstained 5-micron 
FFPE tissue section, will be required for patient participation. Tissue sample from a metastatic or recurrent tumor lesion must be provided whenever 
possible.  If such tissue sample is unavailable, a de novo fresh biopsy is recommended when, in the investigator’s judgment, such biopsy is feasible and can 
be safely performed.  A sample of the original diagnostic tissue (ie, archival) will also be collected when available and sent to the sponsor-designated central 
laboratories for assessment of biomarkers associated with sensitivity and/or resistance to PD-0332991 (eg, Ki67, CDKN2A (p16), pRb).  Retrospective 
confirmation of ER status and prospective confirmation of HER2 status when required to be repeated for eligibility purpose will be performed using the most 
recent tumor sample.  Original diagnostic tumor tissue will be used for confirmation of ER and HER2 status in the event that a recurrent/metastatic tissue 
sample is not available and a fresh biopsy of the recurrent/metastatic lesion is not feasible.  An optional fresh tumor biopsy will be collected at the end of 
treatment visit,only for patients who discontinue treatment due to disease progression.  The tumor tissue will be used to determine possible mechanisms of 
resistance.  Tissue samples from all patients will be used for additional biomarker analyses.  Details on preparation of these samples including processing, 
storage, and shipment will be provided in the Study Manual.   
j. 
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems (including general appearance, head, 
ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and 
pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, will be required at screening and, Day 1 of 
Cycles 1 and 2.  Symptom-directed physical examinations, blood pressure and pulse rate will be performed at subsequent visits. 
k. Ophthalmic Examinations: Once Amendment #3 is IRB approved, all newly enrolled patients will undergo an ophthalmic examination at baseline, and on 
study treatment after 3 months (Cycle 4 Day 1), 6 months (Cycle 7 Day 1), 12 months (Cycle 13 Day 1), every 12 months (Day 1 of Cycles 25, 37 etc…) 
thereafter, and at the End of Treatment visit.  Additional ophthalmic examinations may be performed during the study as clinically indicated (including for 
patients randomized prior to Amendment 3 approval).  The ophthalmic examinations will include: best corrected distant visual acuity (Snellen), refractive 
error associated with best corrected distant visual acuity, intraocular pressure (IOP – one reading), slit lamp biomicroscopy of the anterior segment including 
cell count and flare grading, crystalline lens grading using the Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens Opacity Grading 
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Protocol A5481008  
Statistical Analysis Plan 
 
procedure, and fundoscopy.  All ophthalmic examinations will be performed by an ophthalmologist.  Refer to protocol Section 7.2.3.  Ocular Safety 
Assessments for further details on these procedures. 
l. 
Hematology, and Blood Chemistry Panel: Hematology includes hemoglobin, WBC, absolute neutrophils, platelet count.  Blood chemistry includes 
AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, total calcium, total bilirubin, BUN (or urea), serum creatinine, and albumin.  Additional 
hematology/chemistries panels may be performed as clinically indicated.  Additionally, hemoglobin A1c will be measured during the active treatment phase 
in all patients every 3 months from the date of randomization (ie, C4D1, C7D1, C10D1, etc), and at the end of treatment visit. 
m. 12-Lead ECG/Pharmacokinetics: Refer to Pharmacokinetic and ECGs Schedule of Activities table for details and timing of procedures. 
n. 12-Lead ECG: To be performed on Day 1 of Cycles 4, 7, and 10.  ECGs beyond Cycle 10 will be performed as clinically indicated.  Refer to 
Pharmacokinetic and ECGs Schedule of Activities table for further details and timing of procedures. 
o. Disease Assessments: Please refer to the tumor assessment requirement flowchart for details and timing of procedures. 
p. CT/MRI Scans of Chest, Abdomen, Pelvis, any clinically indicated sites of disease, and of bone lesions; clinical evaluation of superficial disease: Please 
refer to the tumor assessment requirement flowchart for details and timing of procedures. 
q. Radionuclide Bone Scan, Whole Body: Please refer to the tumor assessment requirement flowchart for details and timing of procedures. 
r. 
Drug Compliance: PD-0332991, placebo and letrozole bottle(s)/blisters including any unused capsules/tablets will be returned to the clinic for drug 
accountability.  Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle. 
s. 
Adverse Events: For SAEs, the active reporting period begins from the time that the patient provides informed consent through and including 28 calendar 
days after the last administration of the investigational product.  Following the active safety reporting period, other SAEs of which the investigator becomes 
aware should be reported to Pfizer, unless the SAE is attributed by the investigator to complications of either the underlying malignancy or any subsequent 
anti-cancer therapy or to the patient’s participation in a subsequent clinical study.  AEs (serious and non serious) should be recorded on the CRF from the 
time the patient has taken at least one dose of study treatment through last patient visit. 
t. 
Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 28 days after the last dose of study treatment. 
u. EQ-5D, FACT-B Assessments: Patients will complete questionnaires prior to any study or medical procedure on Day 1 of Cycles 1, 2 and 3 and then 
Day 1 of every other cycle thereafter starting with Cycle 5 (ie, Cycle 5, 7, 9, etc), and at the end of treatment visit.  All self-assessment questionnaires must 
be completed by the patients while in the clinic and cannot be taken home.  Interviewer administration in clinic may be used under special circumstances. 
v. Cycle X, Day 1: In the event that the start of a new cycle is delayed due to treatment related toxicity, procedures required on Day 1 of the given cycle will be 
performed when PD-0332991/placebo is resumed.  New cycle Day 1 procedures (ie, physical examination, ECOG performance status, ECG, Quality of Life 
questionnaires, blood chemistry, hematology) that were performed prior to knowing the need to delay the start of the cycle do not need to be repeated (1) if 
not required to determine whether study drug may be resumed and (2) if performed within 7 days prior to study drug resumption. 
w. Letrozole (both treatment arms): To be taken orally, daily, and continuously. 
x. PD-0332991 or Placebo:To be taken orally, daily from Day 1 to Day 21 (21 days) of every 28-day cycle followed by 7 days off treatment. 
y. FACT-B Assessments: After patients discontinue from the active treatment phase, FACT-B questionnaire will continue to be collected during the follow-up 
period every 6 months (+/- 7 days)  from the last dose of investigational product until patient permanent discontinuation from study or end of follow-up 
period whichever occurs first.  During the follow-up period, all self-assessment questionnaires should preferably be completed by the patients during a 
scheduled clinic visit.  However, if no clinic visits are being scheduled during the follow-up period interviewer administration via phone call may be used 
instead and documented accordingly in the patient source notes. 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
Pharmacokinetic and ECGs, Schedule of Activities 
Protocol Activity 
Screening 
Active Treatment Phase 
End of 
Treatment 
Within 28 days prior to randomization unless specified 
otherwise 
Cycle 1 
Cycle 2 
Cycle 
 
 
Day -27
to 
Day 0 
Day 0 (day prior to Day 1) 
Day 1 
Day 14 
Day 14 
Day 1 
 
ECGE* ECG1° 
2 Hrs 
Post-ECG1 
4 Hrs 
Post-ECG1 
6 Hrs 
Post-ECG1 
8 Hrs 
Post-ECG1 
0 Hrs 
Pre-dose 
0 Hrs 
Pre-dose 
2 Hrs 
Post-dose 
4 Hrs 
Post-dose 
6 Hrs 
Post-dose 
8 Hrs 
Post-dose 
0 Hrs 
Pre-dose 
0 Hrs 
Pre-Dose 
Anytime 
Group 1 (approx. 60 Patients) at selected sites 
12 Lead ECGa 
X 
X 
X 
X 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokineticsb 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Group 2 (All other patients)  
12 Lead ECGa 
X 
 
 
 
 
 
Xa 
X 
 
 
 
 
X 
X 
X 
Pharmacokineticsb 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
*ECGE = Triplicate ECGs performed to determine patient’s eligibility. 
°ECG1 = First triplicate ECGs performed for patient in Group 1. 
a. 
12-lead ECG: A 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  ECGs will be performed in triplicate approximately 2 minutes 
apart but within 10 minutes for all 3 ECGs.  It is preferable that the machine used has the 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.  Blinded manual interval measurements at a core ECG laboratory will be used for primary 
statistical analysis of ECG data in group 1 patients (as described below).  ECG measurements will include PR interval, QT interval, RR interval and QRS 
complex.  Additional ECGs may be performed as clinically indicated.  
Triplicate ECGs (also referred as ECGE) will be performed during the screening period for all patients to determine the mean QTc interval for eligibility purpose.  
Patients found to be eligible will be part of one of the two groups highlighted below depending on which site screened the patient.  ECG frequency for each 
group is described below:   
Group 1 (approximately 60 patients) at selected sites:  
x 
On the day preceding treatment initiation (day 0), triplicate ECGs will be obtained at time 0 (first ECG also referred to as ECG1), and then 2, 4, 6, 
and 8 hours after ECG1.  
x 
At Cycle 1 Day 14, triplicate ECGs will be obtained at 0 hour (pre-dose) and then, 2, 4, 6, and 8 hours following PD-0332991/placebo dosing. 
 Timing of ECGs performed on Day 14 MUST be time-matched (clock time +/- 35 minutes) with ECG assessments performed on Day 0 (eg, if 
ECG1 on Day 0 was performed at 10:00 AM then the 0 hour triplicate ECGs on Day 14 must be performed within the 9:30AM-10:30AM 
timeframe but as close as possible to 10:00AM whenever feasible).  On day 14 of Cycle 1, study treatment should be administered immediately 
after the pre-dose PK draw has been collected.  
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Protocol A5481008  
Statistical Analysis Plan 
 
All ECGs should be obtained after a fast of at least 1 hour.  ECGs should be performed immediately before PK blood draws at respective time points.  
Patients who cannot complete ECG measurements on Day 0 and/or PK-matched ECG measurements (both ECG and PK collected) on Day 14 will need to be 
replaced.  
x 
Additionally, triplicate ECGs will be obtained for safety monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1*, Day 14 of Cycle 2, then on Day 1 of 
Cycles 4, 7, and 10.  ECGs beyond Cycle 10 will be performed as clinically indicated.  
Group 2 (all other patients):  
x 
Triplicate ECGs will be obtained for safety monitoring at 0 hour (pre-dose) on Day 1 of Cycle 1*, Day 14 of Cycles 1 and Cycle 2, then on Day 1 
of Cycles 4, 7, and 10.  ECGs beyond Cycle 10 will be performed as clinically indicated.  
*NOTE: Triplicate ECGs do not need to be repeated on Day 1 of Cycle 1 if ECGE was performed within 7 days of the date of randomization.  
All triplicate ECG tracings will be sent electronically to a core ECG laboratory for blinded manual interval measurements. 
If at any time thHPHDQ47FLVSURORQJHGPVHFRQDWOHDVWWZRVHSDUDWH(&*VLH&7&$(*UDGHWKHQWKH(&*VVKRXOGEHUH-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including verification that the machine reading is accurate.  If manual reading 
FRQILUPVD47FRIPVHFLPPHGLDWHVHDUFKIRUUHYHUVLEOHFDXVHVLQFOXGLQJHOHFWURO\WHDEQRUPDOLWLHVK\SR[LDDQGFRQFRPLtant medications for drugs 
with the potential to prolong the QTc interval) should be performed.  In addition, repeat ECGs should be immediately performed hourly for at least 3 hours 
until the QTc interval falls below 501 msec.  
x 
If QTc interval reverts to less than 501 msec, and in the judgment of investigator(s) in consultation with the sponsor the cause is determined to be 
due to cause(s) other than study drug, treatment may be continued with regular ECG monitoring under hospital supervision.  
x 
If in that timeframe the QTc intervals remain above 501 msec the study drug will be held until the QTc interval decreases to <501 msec.  
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation by specialist.  If 
investigational product causality cannot be ruled out, Investigational product dose adjustment and/or discontinuation should be performed according to 
protocol Section 5.3.4: Recommended Dose Modification.  Additional triplicate ECGs may be performed as clinically indicated. 
b. Pharmacokinetics (collected right after ECG assessment): For patients in the ECG Group 1, plasma PK samples for PD-0332991 (including its active 
metabolites, if appropriate) determination will be obtained at the times indicated for ECGs.  One additional plasma PK sample will be collected pre-dose on 
Day 14 of Cycle 2.  
For all other patients (ECG Group 2), plasma PK samples for PD-0332991 (including its active metabolites, if appropriate) determination will be collected 
prior to dosing (pre-dose) on Day 14 of Cycle 1 and Cycle 2.  
Additional blood samples may be requested from patients experiencing unexpected or serious adverse events, or adverse events that lead to discontinuation. 
10.2. Tumor Assessment Requirements Flowchart 
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Protocol A5481008  
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Screeninga 
Treatment Periodb 
End of Treatment Visitc 
CT d or MRI of chest, abdomen, and 
pelvis (CAP) 
Requirede 
Required 
Required 
CT d or MRI of any other site of 
disease, as clinically indicated 
Requirede, f 
Required for sites of disease 
identified at screening 
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere 
Radionuclide bone scan (whole body) 
and correlative bone imaging 
Requiredg, h 
Required for sites of disease 
identified at screening or if 
clinically indicatedi 
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere 
Photographs of all superficial lesions 
as applicablej 
Required 
Required for sites of disease 
identified at screening 
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere 
a. 
Screening scans must occur within 4 weeks (ie, 28 days) prior to randomization unless otherwise specified.  
b. Tumor assessment must be done during the treatment period, every 12 weeks (r7 days) and bone scans (as applicable) every 24 weeks (r7 days) from 
randomization until radiographically and/or clinically (ie,for photographed or palpable lesions) documented PD as per RECIST v.1.1, study treatment 
discontinuation (for patients continuing treatment beyond RECIST-defined disease progression), initiation of new anticancer therapy or discontinuation of 
patient from overall study participation (eg, death, patient's request, lost to follow up), whichever occurs first.  The schedule of assessments should be fixed 
according to the calendar, regardless of treatment delays/interruptions.  Imaging assessments are to be scheduled using the randomization date as the 
reference date for all time-points and are NOT to be scheduled based on the date of the previous imaging time-point.  Imaging assessment delay to conform 
to treatment delay is not permitted.  The same tumor assessment technique MUST be used throughout the study for a given lesion/patient.  
c. 
Patients who have already demonstrated objective disease progression as per RECIST v.1.1 do not need to have scans repeated at the end of treatment visit 
or during the post-treatment follow-up.  For patients who do not have documented objective disease progression at time of study treatment discontinuation, 
tumor assessment will continue to be performed every 12 weeks (r7 days) and bone scans (as applicable) every 24 weeks (r7 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 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) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, and (4) appropriate 
documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes.  
f. 
Baseline brain scans are only required if signs and symptoms suggest presence of metastatic brain disease.  Brain scans performed before the signing of 
informed consent as routine procedures (but within 6 weeks before randomization) do not need to be repeated and may be used as baseline assessments as 
long as (1) tests were performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality can be used to follow identified 
lesions throughout the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor assessments were performed as 
standard of care is available in the patient’s source notes.  Post-baseline repeat brain scans will only be required only if metastases are suspected.  
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Protocol A5481008  
Statistical Analysis Plan 
 
g. Bone scans will be carried out at baseline for all patients within 12 weeks prior to randomization in order to detect bony sites of disease.  Bone scans 
performed before the signing of informed consent as routine procedures (but within 12 weeks before randomization) do not need to be repeated and may be 
used as baseline assessments as long as (1) tests were performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality 
can be used to follow identified lesions throughout the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor 
assessments were performed as standard of care is available in the patient’s source notes. 
h. Any suspicious abnormalities (ie, hotspots) identified on the bone scans at baseline and on subsequent bone scans MUST be confirmed by X-ray, CT scan 
with bone windows or MRI.  The same modality must be used throughout the trial for confirmation for a given lesion/patient.  Bone lesions identified at 
baseline will be followed up according to the same assessment schedule (ie, every 12 weeks r7 days from randomization) as for all other lesions.  Areas that 
have received palliative radiotherapy cannot be used to assess response to study treatment.  
i. 
If bone lesions were identified at baseline bone scans will be repeated during the active treatment phase every 24 week (r7 days) from the date of 
randomization and at the time of confirmation of CR.  If no bone lesions were identified at baseline, bone scans will only be repeated during the active 
treatment phase when clinically indicated (ie, patient describes new or worsening bone pain, or has increasing alkaline phosphatase level, or other signs and 
symptoms of new/progressing bone metastases) but are required at the time of confirmation of CR.  New Abnormalities found on subsequent bone scans 
must also be confirmed by X-ray, CT scan with bone windows or MRI.  
j. 
Clinical assessment of superficial disease must be carried out on the same date as the imaging studies and will include photographs of all superficial 
metastatic lesions.  All lesion measurements must be recorded in the case report form (CRF). 
Notes:  
- Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression at the discretion of the investigator.  If progressive 
disease is confirmed per RECIST v.1.1, patients are expected to discontinue study therapy and begin the follow-up phase of the trial.  However, patients may 
continue treatment as assigned at randomization beyond the time of RECIST-defined PD at the discretion of the investigator if that is considered to be in the best 
interest of the patient and as long as no new anticancer treatment is initiated.   
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10.3. 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. 
x 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) 
x Lesions with longest diameter at  least 20 mm when assessed by Chest X-ray   
x Superficial lesions with longest diameter 10 mm or greater when assessed by caliper   
x 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 examination that are not measurable 
by reproducible imaging techniques. 
x 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.   
x 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 
x 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. 
x Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS  
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start. For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
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Protocol A5481008  
Statistical Analysis Plan 
 
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.  
x  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. 
x 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 (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION. 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.   
Target disease 
x 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. 
x 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.   
x 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 
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Protocol A5481008  
Statistical Analysis Plan 
 
the nadir, but enough that a previously documented 30% decrease no longer holds.   
x 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.   
x Indeterminate. Progression has not been documented, and  
x one or more target measurable lesions have not been assessed  
x or assessment methods used were inconsistent with those used at baseline 
x or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure) 
x or one or more target lesions were excised or irradiated and have not reappeared or 
increased.   
Non-target disease 
x 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). 
x Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits.  
x 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.   
x 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. 
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 
x 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. 
x 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 
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Protocol A5481008  
Statistical Analysis Plan 
 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.   
 
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used: 
 
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 
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease 
Only 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Indeterminate 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 
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Protocol A5481008  
Statistical Analysis Plan 
 
10.4. 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 (e.g., superficial lesions one 
day, scans another), the last date is used as the assessment date. 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
10.5. 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.  
Baseline triplicate ECGs 
For Group 1, the day preceding treatment initiation 
(Day 0) 
For Group 2, Cycle 1 Day 1 dose or from date closest 
to, but prior to, start of study treatment if C1D1 is not 
available.  
Tumor assessment baseline values 
From date closest but prior to first dose.   
Design subsets 
ECG Group 1 (approximately 60 patients) 
ECG Group 2 (all other patients) 
Measurable disease 
Defined by RECIST 
Adequate baseline tumor 
assessment 
Within 35 (28 + 7) days prior to first dose. 
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.  
 
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Protocol A5481008  
Statistical Analysis Plan 
 
10.6. Study Treatment Modification and Compliance  
10.6.1. Dose Modification 
No dose adjustment for letrozole is permitted but dosing interruptions are allowed. Treatment 
interruption for letrozole-related toxicities will be performed as per the investigator’s best 
medical judgment. 
In the event of significant treatment-related toxicity, PD-0332991/placebo dosing may be 
interrupted or delayed and/or reduced as described below. 
x 
A treatment delay is defined as any delay of the cycle start date, based on the 
previous cycle’s start date. Since letrozole is administered daily continuously, a 
treatment delay is not applied to letrozole. 
 
x 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. 
 
x A dose interruptions/missed dose is defined as a planned dosing day with 0 mg 
administered. 
 
10.6.2. Summarizing Relative Dose (RD) and Relative Dose Intensity (RDI)  
The following types of summaries are proposed for administration of PD-0332991 (PD991) 
and letrozole. 
 
x When PD991 is administered in combination with letrozole (orally once daily 
continuously), on an orally once a day for 21 days of every 28-day cycle followed by 
7 days off treatment (cyclical dosing), the following summaries can be presented:RDI 
for PD991: by Cycle and Overall  
x RDI for letrozole: by Cycle and Overall 
 
Note: the denominator for tables summarizing “letrozole” will be all patients who took at 
least a dose of letrozole and for tables summarizing “PD991” will be all patients who took at 
least a dose of PD991 
 
Examples for the summaries described in above are included in the tables below. 
Conventions: 
x 
Regular Cycle or Complete Cycle: There is another cycle after the current one. 
x 
Last Cycle: The treatment is permanently discontinued after the current cycle.  
x 
Intended Total Dose Per Cycle is the same (2.5mg [once daily continuous] x 28 days 
for letrozole and 125mg [once a day for 21 days followed by 7 days break in a 28 days 
treatment cycle] x 21 days for PD991) for all regular cycles. The daily dose is fixed at 
the start of treatment rather than start of a cycle.  
x 
Intended Dosed Days Per Cycle for PD991 
o 21 days for a regular cycle, or 
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Protocol A5481008  
Statistical Analysis Plan 
 
o Minimum of (21 days, actual treatment duration) for the last cycle 
x 
Intended Treatment Duration is the same for the entire dosing period, except for the 
last cycle which is the actual duration of treatment up to 4 weeks. (e.g. for a 3/1 dosing 
schedule, all cycles have an intended duration of 4 weeks) 
o 28 days for a regular cycle, or 
o Minimum of (28 days, actual treatment duration) for the last cycle. 
 
x 
Actual Total Dose Per Cycle is the total dose a patient actually took in a cycle.  
x 
Actual Treatment Duration is the treatment duration for a cycle per CRF.  
 
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Protocol A5481008  
Statistical Analysis Plan 
 
Table 1 
Treatment / 
Summary 
Type  
Calculation of RD/RDI 
Example 
Cyclical 
PD991 / 
Overall  
 
 
 
                                       
                                   
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 
x PD991 is to be dosed at 125 
mg QD on a 3/1 Schedule  
x Actual PD991 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 of overall 
actual total dose) / (Sum of overall actual treatment 
duration)  
 
Intended Overall Dose Intensity = (Sum of overall 
Intended Total Dose during the study) /(Sum of 
overall Intended Treatment Duration) 
  
 
x PD991 is to be dosed at 125 
mg QD on a 3/1 Schedule  
x Actual PD991 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) /7 * (4 + 
5 + 3) = 83.3 mg/day 
                                                         
Intended Overall Dose 
Intensity=125 * (3 + 3 + 3)*7 /[4 
+ 4 + 3)*7] = 102.3 mg/day  
 
RDI = (83.3 / 102.3) *100% = 
81.5% 
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Protocol A5481008  
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Table 2 
Treatment / 
Summary 
Type  
Calculation of RD/RDI 
Example 
Cyclical 
PD991 / By 
Cycle  
 
 
 
 
                                 
100
*
 
 
 
 
Intensity
Dose
Intended
Intensity
Dose
Actual
RDI  
% 
 
Actual Dose Intensity (per day) = (Actual Total 
Dose per cycle) / (Actual treatment duration for the 
cycle) 
 
For a regular cycle 
Actual treatment duration for the Cycle = (Start 
date of next cycle – Start date of current cycle).   
 
For last cycle 
Actual treatment duration for the Cycle = (Last 
dose date – Start date of the cycle + 1).   
 
Intended Dose Intensity (per day) = (Intended Total 
Dose per cycle) / (Intended treatment duration for 
the cycle) 
  
For a regular cycle 
Intended Total Dose per cycle is always 125 * 21 = 
2625 mg;  
Intended treatment duration is always 28 days 
 
For the last cycle 
Intended Total Dose in last cycle = 125 * [Min(21, 
actual treatment duration)] 
Intended treatment duration in last cycle = Min[(28, 
actual treatment duration] 
x PD991 is to be dosed at 125 mg 
QD on a 3/1 Schedule  
x Actual PD991 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 in cycle 1, 
2 = (125*7*3) / (4*7) = 93.75 
mg/day 
 
Intended Dose Intensity in cycle 3 
(last cycle) = (125*7*3) / (3*7) = 
125 mg/day 
 
 
Cycle 1:  
Actual Dose Intensity = (125*7*3) / 
(4*7) = 93.75 mg/day 
RDI = (93.75/93.75) * 100% = 
100% 
 
Cycle 2:  
Actual Dose Intensity = (125*7*3) / 
(5*7) = 75 mg/day 
RDI = (75/93.75) * 100% = 80% 
 
Cycle 3 (Last Cycle):  
Actual Dose Intensity = (125*7*2) / 
(3*7) = 83.3 mg/day 
RDI = (83.3/125) * 100% = 66.7% 
 
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Protocol A5481008  
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Table 3 
Treatment / 
Summary 
Type  
Calculation of RD/RDI 
Example 
letrozole By 
Cycle & 
Overall 
 
 
 
  
                                 
100
*
 
 
 
 
Intensity
Dose
Intended
Intensity
Dose
Actual
RDI  
% 
 
Actual Dose Intensity (per day) = (Actual Total 
Dose per cycle) / (Actual treatment duration for 
the cycle) 
 
Actual Number of Days in Cycle = (Start date of 
next cycle – Start date of current cycle).   
 
Intended Dose Intensity (per day) = (Intended 
Total Dose per cycle) / (Intended treatment 
duration for the cycle) 
 
             
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 treatment 
duration for the cycle” ) 
 
Intended Overall Dose Intensity = Intended 
Dose Intensity (per day)  
x letrozole is to be dosed at 2.5 
mg daily continuously 
x Actual letrozole dosing: D1 to 
D28 on Cycle 1; D1 to D14 
and D22 to D28 in Cycle 2 (i.e. 
7 days interruption) 
 
x Actual Dose is 2.5*28 = 70mg 
in Cycle 1 
x Actual Dose is 2.5* 21 = 52.5 
mg in Cycle 2 
x Actual Total Dose level is 
70mg in Cycle 1 and 52.5 mg 
in Cycle 2 
 
Cycle 1: 
Actual Dose 
Intensity=70/(4*7)=2.5 mg/day 
 
Intended Dose Intensity = 
70/(4*7) = 2.5 mg/day 
 
RDI= (2.5 / 2.5) * 100% =100% 
 
Cycle 2: 
Actual Dose Intensity = 
52.5/(4*7) = 1.875 mg/day 
 
Intended Dose Intensity = 
70/(4*7) = 2.5 mg/day 
 
RDI= (1.875 / 2.5) * 100% =75% 
 
Overall: 
Actual Overall Dose Intensity =  
(70 + 52.5) / [(4 + 4)*7]  = 2.1875 
mg/day 
 
Intended Overall Dose Intensity = 
(70 + 70) / [(4 + 4)*7] = 2.5 
mg/day 
 
RDI= (2.1875/2.5)*100% = 
87.5% 
 
  
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Pr ot oc ol A 5 4 8 1 0 0 8   
Statistic al A nal ysis Pla n  
 
1 0. 7.  F u ncti o n al Assess me nt of C a ncer T her a p y - Bre ast ( F A C T -B) ( Versi o n 4)  
P FI Z E R C O N FI D E N TI A L  
P a ge 7 1  
 
 
Pa ge 7 0
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol A 5 4 8 1 0 0 8   
Statistic al A nal ysis Pla n  
 
P FI Z E R C O N FI D E N TI A L  
P a ge 7 2  
 
 
Pa ge 7 1
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol A 5 4 8 1 0 0 8   
Statistic al A nal ysis Pla n  
 
P FI Z E R C O N FI D E N TI A L  
P a ge 7 3  
 
 
Pa ge 7 2
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol A 5 4 8 1 0 0 8   
Statistic al A nal ysis Pla n  
 
1 0. 8.  E ur o Q ol He alt h Utilities I n de x E Q - 5 D 
P FI Z E R C O N FI D E N TI A L  
P a ge 7 4  
 
 
Pa ge 7 3
C O P Y RI G H T E D M A T E RI A L


Pr ot oc ol A 5 4 8 1 0 0 8   
Statistic al A nal ysis Pla n  
 
P FI Z E R C O N FI D E N TI A L  
P a ge 7 5  
 
 
Pa ge 7 4
C O P Y RI G H T E D M A T E RI A L


Protocol A5481008  
Statistical Analysis Plan 
 
10.9.  Wisconsin Age-Related Eye Disease Study (AREDS) 2008 Clinical Lens Opacity 
Grading Procedure 
x Dilate pupils to at least 5 mm diameter 
x Use slit lamp with ~10X magnification 
x Use brightest beam intensity 
x Nuclear opacity  
o Orient beam at 45° to viewing axis 
o Adjust slit beam to standard parameters: 8 mm height and 0.3 mm width 
o Compare opalescence of nucleus with that in standard photos 
x Cortical and PSC opacities 
o Select wide slit beam setting optimum for retro-illumination of lens 
o Visualize lens opacities against red fundus reflex background 
o Count only opacities definitely visible against red reflex 
o Mentally combine all cortical opacities into one contiguous area 
o Compare total opacity area with that in standard photos 
x Classify each opacity with scale defined by 3 standard photos 
x Select nearest half-step 
o Similar to standard or between two standards 
o Obviously less than mildest standard or greater than most severe 
 
 
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Protocol A5481008  
Statistical Analysis Plan 
 
10.10. List of Abbreviation 
ABC 
Advanced Breast Cancer 
ASCO 
American Society of Clinical Oncology 
AE 
Adverse Event 
ALT 
Alanine Aminotransferases  
AI 
Aromatase Inhibitor 
ANC 
Absolute Neutrophil Count 
AREDS 
Age-Related Eye Disease Study 
AST 
Aspartate Aminotransferases  
AT 
As Treated  
AUC 
Area Under the Curve 
BC 
Breast Cancer 
BUN 
Blood Urea Nitrogen 
CAP 
Chest, Abdomen, Pelvis OR College of American Pathologists 
depending on context. 
CBR 
Clinical Benefit Response 
CBRR 
Clinical Benefit Response Rate 
CCND1 
Cyclin D1 
CDK 
Cyclin-Dependent Kinase 
CDKN2A, p16Ink4A 
Cyclin-Dependent Kinase Inhibitor 2A 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridization 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Plasma Concentration 
CMH 
Cochran Mantel Haenszel 
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 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
DC 
Disease Control 
DCR 
Disease Control Rate 
DFI 
Disease Free Interval 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DR 
Duration of Response 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
E-DMC 
External Data Monitoring Committee 
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Protocol A5481008  
Statistical Analysis Plan 
 
EDR 
The early discrepancy rate 
EDTA 
Ethylenediaminetetraacetic acid 
EIU 
Exposure In Utero 
EQ-5D 
Dimension Health State EuroQoL Score 
ER 
Estrogen Receptor 
FACT 
Functional Assessment of Cancer Therapy 
FACT-B 
Functional Assessment of Cancer Therapy - Breast 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FDA 
US Food and Drug Administration  
FFPE 
Formalin Fixed Paraffin Embedded 
FIH 
First in Human 
FISH 
Fluorescent In Situ hybridization 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
Hb 
Hemoglobin 
HDPE 
High Density Polyethylene 
HER 
Human Epidermal Growth Factor Receptor 
hERG 
Human Ether-à-Go-Go 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
IC50 
Concentration of 50% Inhibition  
ICH 
 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IOBU-SDMC 
Internal Oncology Business Unit – Safety Data Monitoring 
Committee 
IOP 
Intraocular pressure 
IMPAKT 
Improving Care and Knowledge through Translational Research 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
ITT 
Intent-to-treat  
LDR 
The late discrepancy rate 
LFT 
Liver Function Test 
LPD 
Local Product Document 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measures 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
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Protocol A5481008  
Statistical Analysis Plan 
 
OBU 
Oncology Business Unit 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCD 
Primary Outcome Completion Date 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic  
PR 
Partial Response or Progesterone Receptor (depending on 
context) 
PR 
The PR interval is measured from the beginning of the P wave to 
the beginning of the QRS complex. 
PS 
Performance Status 
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 
QTcS 
Study specific QTc: QT interval corrected for heart rate using the 
study 
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 
RPSFTM 
Rank-Preserving Structural Failure Time Model 
RR 
The interval between an R wave and the next R wave 
Rac 
Accumulation Ratio 
SAE 
Serious Adverse Event 
SD 
Stable Disease or Standard Deviation (depending on context) 
SPC 
Summary of Product Characteristic 
t½ 
Terminal Elimination Half-life 
TdP 
Torsade de Pointes 
Tmax 
Time for Cmax 
ULN 
Upper Limit of Normal 
USPI 
United States Package Insert 
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Protocol A5481008  
Statistical Analysis Plan 
 
Vz/F 
Apparent Volume of Distribution 
WBC 
White Blood Cell 
 
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