A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer, Breast Carcinoma, Breast Tumors
Sponsor: NSABP Foundation Inc

 
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NSABP PROTOCOL FB-11 
 
 
A Phase II Randomized Study Evaluating the 
Biological and Clinical Effects of the Combination of 
Palbociclib with Letrozole as Neoadjuvant Therapy in Post-Menopausal 
Women with Estrogen-Receptor Positive Primary Breast Cancer 
 
 
 
 
 
NSABP Foundation, Inc. 
 
 
 
 
TELEPHONE: 
 
E-MAIL: 
 
CLINICAL QUESTIONS: 
 
 
 
NSABP DSSM KEY STUDY PERSONNEL 
NSABP Chair: 
 
Protocol Chair: 
 
Protocol Officer: 
 
Protocol Statistician: 
 
 
THE INSTITUTE OF CANCER RESEARCH AND THE  
ROYAL MARSDEN NHS FOUNDATION TRUST (UK) KEY STUDY PERSONNEL 
UK Protocol Chair: 
 
Translational Research Chair: 
 
Lead Statistician: 
 
 
 
Protocol FB-11 IND #123239 (palbociclib), 
sponsored by the NSABP 
 
 
 
 
Version Date: July 18, 2017 
 

 
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PROTOCOL REVISION RECORD 
 
Original Version: 
August 12, 2014 
Amendment #1: 
October 30, 2014 
NSABP FB-11 Protocol and Consent amended prior to activation of study. 
Amendment #2 : 
April 21, 2015 
Sections Changed/Added: 
Cover Page 
Protocol Revision Record 
Information Resources Page 
Section 1.0: 
1.0 (Schema) 
Section 3.0:  
3.2.4 added (subsequent sections renumbered) 
Section 4.0:  
4.1 
Section 5.0: 
5.1 (Table 2) 
Section 6.0: 
6.1 (Table 3), 6.2, 6.3, 6.4.1 
Section 7.0: 
7.1 (Tables 5, 6, and 7), 7.3.6 
Section 8.0: 
8.1, 8.2, 8.2.1 
Section 9.0: 
9.2.3, 9.2.4 
Section 10.0: 10.5 
Section 12.0: 12.2 
Section 14.0: 14.4.2, 14.5 
Section 16.0: References have been updated; where references were deleted subsequent references were 
 
renumbered 
Appendix C 
Corresponding FB-11 consents are not a part of the protocol document. 
 
The study consent has been revised in the Cover page, pages, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 
12, 13, 14, 16, 17, and Addendum #1 has been added. 
 
The Optional Tumor and Blood Sample Collection consent has been revised in the Cover 
page, pages 1, 2, 3, 5, and 6. 
 
Amendment #3: 
July 18, 2017 
Sections Changed/Added: 
Cover Page 
Protocol Revision Record 
Section 4.0: 
4.1.13 
Section 5.0 
Table 1 
Corresponding FB-11 consents have been revised and Addendum #2 has been added. 
 
 

 
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TABLE OF CONTENTS 
Protocol Revision Record ............................................................................................................................. 2 
Glossary of Abbreviations and Acronyms .................................................................................................... 6 
 
1.0 
OVERVIEW OF STUDY DESIGN ................................................................................................ 8 
2.0 
BACKGROUND ........................................................................................................................... 11 
2.1 
Overview of Palbociclib ................................................................................................... 11 
2.2 
Known Risks and Benefits of Palbociclib ........................................................................ 12 
2.3 
Study Rationale ................................................................................................................. 12 
3.0 
STUDY AIMS AND ENDPOINTS .............................................................................................. 13 
3.1 
Primary aims and endpoints .............................................................................................. 13 
3.2 
Secondary aims and endpoints .......................................................................................... 13 
4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY ........................................................................ 15 
4.1 
Conditions for patient eligibility ....................................................................................... 15 
4.2 
Conditions for patient ineligibility .................................................................................... 16 
5.0 
REQUIREMENTS FOR STUDY ENTRY, DURING TREATMENT, AND FOLLOW-UP ...... 18 
6.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES ...................................................... 20 
6.1 
Overview of requirements................................................................................................. 20 
6.2 
Use of specimens .............................................................................................................. 21 
6.3 
Tumor and blood sample submission procedures ............................................................. 21 
6.4 
Rationale for correlative science studies ........................................................................... 21 
7.0 
STUDY TREATMENT ................................................................................................................. 23 
7.1 
Treatment regimen ............................................................................................................ 23 
7.2 
Supportive therapy ............................................................................................................ 25 
7.3 
Prohibited therapies .......................................................................................................... 25 
7.4 
Participation in other clinical trials ................................................................................... 25 
8.0 
TREATMENT MANAGEMENT ................................................................................................. 26 
8.1 
General instructions .......................................................................................................... 26 
8.2 
Treatment management for palbociclib and letrozole ....................................................... 26 
8.3 
Study therapy following tumor progression...................................................................... 26 
8.4 
Dose modifications ........................................................................................................... 26 
8.5 
Liver dysfunction (Hy's Law) ........................................................................................... 30 
9.0 
DRUG INFORMATION ............................................................................................................... 31 
9.1 
Letrozole ........................................................................................................................... 31 
9.2 
Palbociclib (PD-0332991) ................................................................................................ 31 
10.0 
ADVERSE EVENT REPORTING ................................................................................................ 34 
10.1 
Definition of an AE ........................................................................................................... 34 
10.2 
Adverse Events and relationship to study therapy ............................................................ 34 
10.3 
Definition of an SAE ........................................................................................................ 35 
10.4 
Events requiring expedited reporting ................................................................................ 36 
10.5 
Grading the severity of the AE ......................................................................................... 37 
10.6 
Expedited reporting instructions ....................................................................................... 37 
10.7 
Time period and frequency for routine reporting of AEs ................................................. 38 
10.8 
Documentation requested following death ....................................................................... 38 
 
 

 
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11.0 
ASSESSMENT OF EFFECT ........................................................................................................ 39 
11.1 
Timing of clinical response assessments .......................................................................... 39 
11.2 
Pathologic assessment of effect ........................................................................................ 39 
12.0 
PATIENT ENTRY PROCEDURES .............................................................................................. 40 
12.1 
Patient consent form ......................................................................................................... 40 
12.2 
Study entry ........................................................................................................................ 40 
12.3 
Patient study number and treatment assignment ............................................................... 40 
12.4 
Investigator-initiated discontinuation of study therapy .................................................... 40 
12.5 
Patient-initiated discontinuation of study therapy ............................................................ 40 
12.6 
Patient-initiated withdrawal from the study ...................................................................... 40 
13.0 
DATA HANDLING AND RECORDKEEPING .......................................................................... 41 
14.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 42 
14.1 
Statistical design and sample size justification ................................................................. 42 
14.2 
Treatment allocation ......................................................................................................... 42 
14.3 
Endpoint definition ........................................................................................................... 43 
14.4 
Statistical Analysis Plan .................................................................................................... 43 
14.5 
Interim analyses and stopping rules .................................................................................. 44 
14.6 
Monitoring ........................................................................................................................ 45 
15.0 
PUBLICATION INFORMATION ................................................................................................ 46 
16.0 
REFERENCES .............................................................................................................................. 47 
 
Figure 1 
NSABP FB-11 Schema ....................................................................................................... 3 
 
Table 1 
Tests, exams, and other requirements prior to study entry ............................................... 11 
Table 2 
Tests, exams, and other requirements after study entry .................................................... 12 
Table 3 
Summary of FB-11 patient sample submission requirements .......................................... 13 
Table 4 
Treatment regimen – Arm A ............................................................................................. 16 
Table 5 
Treatment regimen –Arm B .............................................................................................. 16 
Table 6 
Treatment regimen –Arm C .............................................................................................. 17 
Table 7 
Treatment regimen –Arm D .............................................................................................. 17 
Table 8 
Dose levels for palbociclib................................................................................................ 19 
Table 9 
Dose modifications and treatment for letrozole and palbociclib ...................................... 20 
Appendix A 
Assessment of performance status and activities of daily living ...................................... 42 
Appendix B 
Concomitant medications and other substances prohibited during study therapy ............ 43 
Appendix C 
FB-11 treatment schedule ................................................................................................. 44 
Appendix D 
ECOG response criteria .................................................................................................... 45 
 
 

 
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INFORMATION RESOURCES 
NSABP Department of Site and Study Management 
 
 
 
 
For questions regarding: 
 
IRB review & informed consent 
 
Submission of IRB approval 
 
Study entry information 
 
Eligibility 
 
Treatment regimen 
 
Dose modifications/delays 
 
Other clinical aspects of the trial 
 
Adverse event reporting including SAE 
reporting 
 
eCRF completion 
 
Palbociclib shipments 
Department of Site and Study 
Management 
(DSSM) 
 
 
For questions regarding data 
management 
DSSM 
 
 
Submission of data forms 
(including expedited AE reports) 
DSSM 
 
Requests for study drug (palbociclib) 
DSSM 
 
Questions and submission of tumor and 
blood samples for correlative science 
studies 
NSABP Division of Pathology 
 
 
 
 
 
 
Refer to FB-11 Pathology and Correlative 
Science Instructions 
 
 
 

 
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GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
ACOSOG 
American College of Surgeons Oncology Group 
ADCC 
antibody dependent cytotoxicity 
AE 
adverse event 
AI 
aromatase inhibitor 
ALT (SGPT) 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the curve 
BCIRG 
Breast Cancer International Research Group 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA 
Canada 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CCND1 
cyclin D1 
CDK4,6 
cyclin-dependent kinase 4,6 
CHF 
congestive heart failure 
CI 
confidence interval 
CISH 
chromogenic in situ hybridization 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE v4.0 
Common Terminology Criteria for Adverse Events Version 4.0 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
dose-limiting toxicity 
DSMB 
Data safety Monitoring Board 
DSSM 
Department of Site and Study Management 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment Center 
ER 
estrogen receptor 
ErbB 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FISH 
fluorescence in situ hybridization 
FNA 
fine needle aspiration 
G-CSF 
granulocyte colony stimulating factor 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
H&P 
history and physical 
HER2 
human epidermal growth factor receptor 2 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
IB 
Investigator's Brochure 

 
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GLOSSARY OF ABBREVIATIONS AND ACRONYMS (Continued) 
ICR 
Institute of Cancer Research 
ICR-CTSU 
Institute of Cancer Research Clinical Trials Statistics Unit 
IDDI 
International Drug Development Institute 
IDMC 
Independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
LD 
longest diameter 
LFT 
liver function test 
LLN 
lower limit of normal 
MDT 
Multi-disciplinary Team 
Mg 
milligram 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSABP 
NSABP Foundation, Inc. 
ORR 
overall response rate 
OTC 
over-the-counter 
p 
probability 
pCR 
pathologic complete response 
PEPI 
preoperative endocrine prognostic index 
PD 
progressive disease 
PFS 
progression-free survival 
PgR 
progesterone receptor 
PO 
by mouth 
PPI 
proton pump inhibitor 
PR 
partial response 
PT 
prothrombin time 
q 
every 
RT 
radiation therapy 
SAE 
serious adverse event 
SD 
stable disease 
SN 
sentinel node 
TDM 
therapeutic drug monitoring 
TdP 
Torsade de Pointes 
TUNEL 
Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States of America 
WOCBP 
women of childbearing potential 
 
 

 
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1.0 
OVERVIEW OF STUDY DESIGN 
FB-11 is a phase II, randomized, open label, four arm study to examine the biological and clinical 
effect of neoadjuvant letrozole with or without palbociclib in the first-line treatment of estrogen-
receptor (ER) positive, HER2-negative early invasive breast cancer.  The co-primary aims of this 
study are to to compare the changes in the proliferation marker Ki67, and to compare clinical 
response after 14 weeks of therapy with letrozole with or without palbociclib.  
The FB-11 study initiative is a joint partnership between the NSABP Foundation, Inc. (NSABP) 
Department of Site and Study Management (DSSM) and United Kingdom (UK) co-investigators 
at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research (ICR).  Parallel 
protocols will be conducted in the US, Canada (FB-11), and the UK (PALLET) with joint 
analysis of interim and final data. 
Postmenopausal women, newly diagnosed with ER-positive/HER2-negative early breast cancer, 
who are suitable candidates for neoadjuvant endocrine therapy will be invited to join the  
FB-11 trial. Approximately 306 patients will be accrued to this study.  Each collaborative group 
will recruit at least 1/3 and no more than 2/3 of the target accrual. 
Patients will be randomized to one of four treatment arms (3:2:2:2 ratio). 
Treatment in the first 14 weeks of neoadjuvant therapy will be: 
Arm A   
Letrozole alone 
Arm B   
Letrozole for 2 weeks followed by letrozole + palbociclib to week 14  
Arm C   
Palbociclib for 2 weeks followed by letrozole + palbociclib to week 14 
Arm D   
Letrozole + palbociclib to week 14. 
Letrozole will be administered orally as a 2.5mg daily tablet.  Palbociclib will be administered 
orally as 125mg capsules, daily on a schedule of 3 weeks (21 days) on, 1 week (7 days) off of a  
4 week [28 day] cycle. 
The end of study therapy for patients in Arm A will be completion of week 14.  Patients in Arms 
B, C, and D will complete study therapy following 14 days of palbociclib in the final treatment 
cycle past 14 weeks if treatment delays have occurred. 
Note: After week 14 (end of study therapy) all patients should continue letrozole until surgery.  
Letrozole is not considered study therapy beyond completion of week 14 for Arm A or after  
14 days of palbociclib in the final treatment cycle for patients in Arms B, C, and D. 
Following completion of study therapy, surgery will be scheduled for 15-18 weeks  
post-randomization.  Post-surgical treatment will be at discretion of treating clinician, following 
local protocols, and not influenced by allocation of treatment within the FB-11 study. 
A minimum of 2 and a maximum of 4 core-cut biopsies will be collected from each patient at 
baseline, after 2 weeks of study therapy and upon completion of study therapy at 14 weeks.  If 
gross residual disease  1.0 cm remains, tumor samples will be collected at the time of definitive 
surgery. 

 
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Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0). 
All patients will have a 12 months post-randomization follow-up, including those who 
prematurely withdrew from trial treatment (unless patient withdraws consent). 
Pre-treatment samples and post-surgical samples (if residual disease  1.0 cm) will be collected 
and analysed to identify subgroups of patients who may derive the most clinical benefit.  The 
results of the biological analyses may allow a target sensitive population to be selected for future 
trials. If the clinical response rate reported is clinically meaningful, then a definitive trial of 
palbociclib combined with letrozole as neoadjuvant or adjuvant treatment in certain subgroups of 
ER-positive breast cancer may be warranted to see if an improved standard of care can be 
established.  Thus, the tissue collected in FB-11 will form an integral part of the primary 
analyses; so all core biopsies in this trial will be mandated for patients.   
Collection of blood samples to be used in biomarker research is an essential part of FB-11 so 
these will be mandatory for all participants.   Research blood samples will be collected at the time 
of each biopsy for germline DNA analyses and plasma estradiol analysis for confirmation of 
compliance with letrozole therapy and to study possible interaction of letrozole and palbociclib. 
Patients who stop therapy prior to 14 weeks, who have received at least 1 cycle (4 weeks) of 
study therapy, will be asked permission for core biopsies and blood samples at that time.  These 
tissue and blood samples will be optional (see optional tumor and blood sample collection 
consent). 
 
 

 
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Figure 1 
NSABP FB-11 SCHEMA 
Postmenopausal women with estrogen-receptor 
positive, HER2-negative, invasive breast cancer 
suitable for neoadjuvant therapy with letrozole 
Stratification 

Country (UK; USA/Canada) 
RANDOMIZATION 
ARM A 
 
Letrozole* alone 
for 14 weeks 
ARM B 
 
Letrozole* alone 
for 2 weeks 
followed by 
ARM C 
 
Palbociclib alone 
for 2 weeks 
followed by 
ARM D 
 
Letrozole* +Palbociclib** 
for 14 weeks 
Letrozole* + Palbociclib** 
for 12 weeks 
SURGERY 
Drug doses: 
 
*letrozole:  2.5 mg QD (for a minimum of 14 weeks;) 
Note: After 14 weeks (end of study therapy) all patients should continue letrozole 
until surgery.  Letrozole is not considered study therapy beyond completion of week 
14 for Arm A or after 14 days of palbociclib in the final treatment cycle for Arms B, 
C, and D. 
 
**palbociclib 125 mg QD (See Section 7.0.) 
Post-surgical treatment: 
 
Post-surgical treatment (e.g. letrozole) will be at discretion of treating physician 
and will not be considered study therapy 
 
 
 

 
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2.0 
BACKGROUND 
2.1 
Overview of Palbociclib 
In 2010 there were 49,564 new cases and 11,633 deaths related to breast cancer in the UK; 
209,005 new cases and 41,435 deaths related to breast cancer in the US.1,2  Of all breast cancer 
diagnoses between 2008 and 2010, 80% occurred in women aged 50 and over.3  Approximately 
80% of incident breast cancers express the estrogen receptor (ER)4 and are characterized by 
responsiveness to endocrine therapies. 
Aromatase inhibitors (AIs) are the most effective endocrine treatment for ER-positive breast 
cancer in postmenopausal women.  However, as with other treatments their effectiveness is 
limited in time as a result of escape pathways that are only partially defined.  Letrozole, along 
with other third generation AIs, is standard of care for the first-line hormonal treatment of 
postmenopausal women with ER-positive breast cancer. 
Palbociclib is an orally active potent and highly selective reversible inhibitor of CDK4 and 
CDK6. The compound prevents cellular DNA synthesis by prohibiting progression of the cell 
cycle from G1 into the S phase.  Palbociclib has recently been used in conjunction with letrozole 
in first-line treatment of ER-positive/HER2-negative advanced breast cancer patients.  Preclinical 
evidence that palbociclib is highly active in ER-positive cell lines and encouraging early safety 
and PK results led to a randomized phase II study evaluating the efficacy and safety of letrozole 
in combination with palbociclib when compared with letrozole alone in the first-line treatment of 
postmenopausal patients with ER-positive/HER2-negative advanced breast cancer 
(NCT00721409).  A phase II dose of 125mg QD on a schedule of 3/1 (i.e. 21 days continuous 
treatment followed by 7 days off treatment) was used in combination with letrozole 2.5mg QD 
continuously.  Later patients in the study were prospectively selected taking into account tumor 
CCND1 amplification and/or p16 loss.  One hundred sixty-five patients were enrolled and the 
study demonstrated an improved clinical benefit rate (CR+PR+SD) of 59% v 36% and a 
prolongation of PFS from 7.5 to 26.1 months (HR 0.37 95%CI: 0.21, 0.63 P<0.001).5  The shape 
of the survival curves suggests that patients who progress particularly quickly on letrozole alone 
may benefit markedly from the added palbociclib.  
Palbociclib appears to act primarily as an anti-proliferative agent although there are some data 
that indicate this may be accompanied by a pro-apoptotic effect.  Preclinical models have shown 
that lack of functional Rb precluded an anti-proliferative effect by palbociclib.6  No biomarkers 
have yet been identified as indicating populations with greater or lesser response to the additional 
palbociclib.  The response of tumors with gain of CCND1 and/or loss of p16 appears to be no 
different from that of tumors without these characteristics despite encouraging preclinical 
evidence.7  Thus, identifying populations that are more or less responsive to palbociclib when 
added to letrozole is a priority for the drug’s rational clinical application.  
A phase III (NCT01864746) study evaluating palbociclib in patients with hormone  
receptor-positive/HER2-negative primary breast cancer with high relapse risk after neoadjuvant 
chemotherapy is currently being launched internationally by the German Breast Group under the 
auspices of the Breast International Group with possible future UK participation.  Other phase III 
studies in advanced metastatic breast cancer with palbociclib are also in planning or underway: a 
phase III study with letrozole ± palbociclib in post menopausal women with  
ER-positive/HER2-negative disease (NCT017404271); a study with fulvestrant ± palbociclib in 
HR-positive/HER2-negative breast cancer (NCT01942135); and a study of  
exemestane + palbociclib vs. capecitabine (NCT02028507). 
This proposed neoadjuvant study FB-11 will be important in identifying hypothesis generating 
potential biomarkers of sensitivity which could be validated in phase III metastatic trials.  

 
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2.2 
Known Risks and Benefits of Palbociclib 
Clinical studies to date suggest that toxicity associated with palbociclib is largely limited to 
uncomplicated neutropenia, fatigue, diarrhea, anemia, and nausea.  The observed neutrophil nadir 
of 3 weeks will be managed by a 3 weeks on/1 week off schedule.  The combination of 
palbociclib with letrozole has been shown to be well tolerated with adverse events (AEs) similar 
to those seen with either palbociclib or letrozole alone (NCT00721409). 
Data from in vitro and in vivo non-clinical studies indicated that palbociclib has the potential to 
delay cardiac repolarization as measured by prolongation of the QT interval on ECG.  
 
 
  
 
  
No significant changes in blood pressure, pulse rate, and body weight have been observed in the 
two completed phase I clinical studies in advanced cancers (A5481001 and A5481002).  It is 
recommended that the monitoring of patients enrolled in clinical studies of palbociclib include 
clinical examinations, vital sign measurements, routine ECGs and AE monitoring.9 
2.3 
Study Rationale  
The use of AI therapy in the neoadjuvant treatment of women with ER-positive breast cancer has 
been established as a safe and effective treatment option allowing down-staging of tumors to 
enable less extensive surgery. The neoadjuvant setting is being increasingly used to provide early 
evidence of the clinical activity of novel agents and particularly to identify candidate markers of 
responsive populations and markers of resistance in residual disease. In ER-positive disease, 
change in the proliferation marker Ki67 has been validated as a marker of treatment benefit and 2 
week residual levels as an indicator of risk of recurrence.10 
Given the predominantly anti-proliferative effects of palbociclib, Ki67 is a rational end-point for 
estimating the added effectiveness of palbociclib in the neoadjuvant setting. The neoadjuvant 
design also allows a limited number of sequential biopsies to be taken for assessment of the 
effectiveness of single agents and subsequently the effect of a combination. FB-11 is a 
randomized trial to examine the biological and clinical effect of neoadjuvant letrozole with or 
without palbociclib for 14 weeks as a first-line treatment of ER-positive/HER2-negative early 
invasive breast cancer. 
 
 

 
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3.0 
STUDY AIMS AND ENDPOINTS 
3.1 
Primary aims and endpoints 
3.1.1 
Ki67 comparisons 
Aim: To compare the changes in the proliferation marker Ki67 (% positive tumor cells) as 
tested by immunohistochemistry (IHC) from baseline and following 14 weeks of 
treatment with letrozole with or without palbociclib.  
Endpoint: Ki67 changes as tested by IHC 
3.1.2 
Clinical Complete Response (cCR) 
Aim: To determine the clinical response by ultrasound according to ECOG criteria after 
14 weeks of therapy with letrozole with or without palbociclib. 
Endpoint: Clinical response of breast and axillary lesions as measured by ultrasound after 
14 weeks of study therapy. 
3.2 
Secondary aims and endpoints 
3.2.1 
Comparison of early and late drug effects on Ki67 
Aim: To compare Ki67 results after 2 weeks and 14 weeks of study therapy 
Endpoint: 
 
Ki67 results after 2 weeks of palbociclib and subsequent therapy with letrozole from 
weeks 2 to 14; and 
 
Ki67 results after 2 weeks of letrozole and subsequent therapy with palbociclib from 
weeks 2 to 14. 
3.2.2 
Pathological complete response (PCR) 
Aim: To compare the pCR rate after letrozole with or without 14 weeks of palbociclib. 
Endpoint: pCR, breast 
Endpoint: pCR, breast and axillary lymph nodes. 
3.2.3 
Preoperative endocrine prognostic index (PEPI) 
Aim: To compare the PEPI score after letrozole with or without 14 weeks of palbociclib. 
Endpoint: PEPI scores at 14 weeks of study therapy. 
3.2.4 
Comparison of surgical intent (mastectomy; breast conservation) 
Aim:  To compare changes between surgical intent at baseline; surgical intent after  
14 weeks; and actual surgery received after treatment with letrozole with or without 
palbociclib. 
Endpoint: Actual surgical procedure received after treatment. 
 
 

 
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3.2.5 
Toxicity 
Aim: To evaluate the overall safety and tolerability for the combination of letrozole and 
palbociclib 
Endpoint: Frequency and severity of adverse events categorized using the NCI Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). 
3.2.6 
Correlative science 
Aim: To explore whether subgroups with greater or lesser Ki67 response or clinical 
response to added palbociclib can be identified in molecular and genetic profiles 
conducted on breast biopsies performed before initiating study therapy. 
Aim: To examine the characterization of the molecular effects of palbociclib with and 
without letrozole and assess whether these vary according to assessment of breast tumor 
samples obtained before the initiation of study therapy. 
 

 
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4.0 
PATIENT ELIGIBILITY AND INELIGIBILITY 
Investigators should consider all other relevant factors (medical and non-medical), as well as the 
risks and benefits of the study therapy, when deciding if a patient is an appropriate candidate for 
the FB-11 trial. 
4.1 
Conditions for patient eligibility 
A patient cannot be considered eligible for this study unless all of the following conditions are 
met: 
4.1.1 
The patient must have consented to participate and, prior to study entry, must have signed 
and dated an appropriate IRB-approved consent form that conforms to federal and 
institutional guidelines (see FB-11 study therapy consent). 
4.1.2 
Patients must be female. 
4.1.3 
Patients must be  18 years old. 
4.1.4 
Patients must be postmenopausal women defined as:  
 
Age 56 or older with no spontaneous menses for at least 12 months prior to study 
entry; or 
 
Age 55 or younger with no menses for at least 12 months prior to study entry  
(e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol 
level in the postmenopausal range according to local institutional/laboratory  
standard; or 
 
Age  18 with documented bilateral oophorectomy. 
4.1.5 
Operable ER-positive/HER2- negative, invasive early breast cancer, suitable for 
neoadjuvant AI treatment.  HER2-negative as determined by ASCO-CAP guidelines. 
4.1.6 
No known severe hypersensitivity reactions to compounds similar to palbociclib or 
palbociclib excipients or to endocrine treatments. 
4.1.7 
A breast tumor with an ultrasound size of at least 2.0 cm. 
4.1.8 
Patients must have the ability to swallow oral medication.  
4.1.9 
ECOG performance status of 0 or 1. 
4.1.10 At the time of randomization, blood counts performed within 4 weeks prior to 
randomization must meet the following criteria: 
 
ANC must be  1500/mm3 
 
Platelet count must be  100,000/mm3 
 
Hemoglobin must be  10 g/dL. 
4.1.11 INR must be within normal limits of the local laboratory ranges. 
 
 

 
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4.1.12 The following criteria for evidence of adequate hepatic function performed within  
4 weeks prior to study entry must be met: 
 
total bilirubin must be  ULN for the lab unless the patient has a bilirubin elevation  
> ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow 
conjugation of bilirubin; and 
 
alkaline phosphatase must be must be  1.5 x ULN for the lab; and 
 
AST and ALT must be  1.5 x ULN for the lab. 
4.1.13 Serum creatinine performed within 4 weeks prior to study entry must be  1.25 x ULN or 
estimated creatinine clearance ≥ 60 mL/min (as calculated using the method standard for 
the institutions). 
4.2 
Conditions for patient ineligibility 
Any patient with one or more of the following conditions will be ineligible for this study: 
4.2.1 
Active hepatitis B or hepatitis C with abnormal liver function tests. 
4.2.2 
HIV positive patients receiving antivirals. 
4.2.3 
Premenopausal or peri-menopausal women. 
4.2.4 
Inflammatory/inoperable breast cancer. 
4.2.5 
HER2-positive as determined using ASCO-CAP Guidelines. 
4.2.6 
Concurrent use (defined as use within 4 weeks prior to baseline tissue sample being 
taken) of hormone replacement therapy (HRT) or any other estrogen-containing 
medication (including vaginal estrogens)  
4.2.7 
Prior endocrine therapy for breast cancer. 
4.2.8 
Any invasive malignancy within previous 5 years (other than basal cell carcinoma or 
cervical carcinoma in situ). 
4.2.9 
Other nonmalignant systemic disease that would preclude the patient from receiving 
study treatment or would prevent required follow up such as: 
 
Active infection or chronic infection requiring chronic suppressive antibiotics; 
 
Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of 
the stomach or small bowel, or other disease or condition significantly affecting 
gastrointestinal function; 
 
Chronic daily treatment with corticosteroids with a dose of  10 mg/day 
methylprednisolone equivalent (excluding inhaled steroids); 
 
Seizure disorders requiring medication. 
4.2.10 Diagnosis by fine needle aspiration (FNA) alone or excisional biopsy or lumpectomy 
performed prior to study entry. 
4.2.11 Surgical axillary staging procedure prior to study procedure (with exception of FNA or 
core biopsy). 

 
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4.2.12 Definitive clinical or radiologic evidence of metastatic disease. 
4.2.13 History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS 
treated with radiotherapy or contralateral invasive breast cancer at any time. 
4.2.14 Any treatment, including radiotherapy, chemotherapy, and/or targeted therapy, 
administered for the currently diagnosed breast cancer prior to study entry. 
4.2.15 Use of any medication or substances that are strong inhibitors or inducers of CYP3A 
isoenzymes (see Section 7.3.5). 
4.2.16 Class III or Class IV myocardial disease as described by the New York Heart 
Association11; a recent history (within 6 months) of myocardial infarction, or 
symptomatic arrhythmia at the time of randomization. 
Class III: 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  Such patients are comfortable at rest.  Less than 
ordinary physical activity that causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Class IV: 
Patients with cardiac disease resulting in inability to perform any 
physical activity without discomfort.  Symptoms of cardiac 
insufficiency or anginal syndrome may be present even at rest. 
4.2.17 QTc  480 msec or a family or personal history of long or short QT syndrome, Brugada 
syndrome or know history of QTc prolongation, or Torsade de Pointes (TdP). 
4.2.18 The investigator should assess the patient to determine if she has any psychiatric or 
addictive disorder or other condition that, in the opinion of the investigator, would 
preclude her from meeting the study requirements. 
 
 

 
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5.0 
REQUIREMENTS FOR STUDY ENTRY, DURING TREATMENT, AND FOLLOW-UP 
Tests, exams and other studies required prior to study entry are listed on Table 1.  Requirements 
following study entry are outlined on Table 2. 
TABLE 1.  Tests, exams, and other requirements prior to study entry 
Required Assessments 
Prior to study entry 
Consent form signed by the patient 
X 
Determination of hormone receptor status (Section 4.1.5) 
X 
Determination of HER2 status (Section 4.1.5) 
X 
History & physical exama 
X 
Within 4 weeks 
Performance status (Appendix A) 
X 
Height & weight 
X 
Assessment of concurrent therapies 
(Section 9.2.3 and Appendix B) 
X 
Determination of measurable diseaseb 
X 
CBC/differential/platelet count 
X 
Total bilirubin/alk phos/AST/ALT/albumin/ total protein/ 
INR 
X 
Serum chemistries: 
calcium/potassium/magnesium/sodium/chloride/bicarbonate 
or carbon dioxide/BUN or urea/glucose/ serum creatinine 
X 
ECG 
X 
After consent is signed 
and eligibility screening 
completed 
Submission of blood samplec 
X 
Core biopsy to procure tumor samples for submission  
to the NSABP Division of Pathologyc 
X 
a Complete H&P by physician or other healthcare professional; including assessment of primary 
breast tumor and palpable regional lymph nodes (axilla, and supra- and infra-clavicular 
region). 
b Radiologic tumor assessment by ultrasound. 
c 
Submission of tumor and blood samples is a study requirement for all patients (see  
Section 6.1) See FB-11 Pathology and Correlative Science Instructions. 

 
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TABLE 2.  Test, exams, and other requirements after study entrya 
Required studies 
(see footnote a) 
Week  
1 
Week  
2 
Week  
3 
Week  
4 
Week  
6 
Week  
8 
Week  
10 
Week  
12 
Week  
14 
End of study 
therapy 
(30 [+/-7] days 
after last dose of 
study therapy) 
Follow up  
(12 months 
following study 
randomization) 
History & physical examb 
 
 
 
 
 
 
 
X 
X 
X 
 
Performance status 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vital signs: including heart 
rate and blood pressure 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Assessment of concurrent 
therapiesc 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse event assessmentd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Xd 
  Xd 
Confirmation of study therapy 
compliancee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CBC/differential/platelets 
X 
X 
X 
X 
  Xf 
  Xf 
  Xf 
X 
X 
Xf 
X 
Sodium, potassium, calcium, 
magnesium, glucose, ALT, 
AST,  total bilirubin,  alkaline 
phosphatase, serum creatinine 
 
 
 
X 
 
X 
 
X 
 
X 
 
INR 
 
X 
 
 
 
 
 
 
X 
 
 
Tumor assessment by physical 
examg 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Radiologic tumor assessment 
by ultrasound 
 
 
 
 
 
 
 
 
Xh 
 
 
ECG, 
 
 
 
 
X 
 
 
 
X 
 
 
Blood samples, i,k 
 
X 
 
 
 
 
 
 
X 
 
 
Core breast biopsy samplesj,k 
 
X 
 
 
 
 
 
 
X 
  Xl 
 
Vital status 
 
 
 
 
 
 
 
 
 
 
X 
a 
At the discretion of the investigator, additional exams, bloodwork, x-rays, scans, and other testing may be performed as clinically indicated. 
b 
Updated H&P with exams (by physician or other healthcare professional on 1572) appropriate for assessments during therapy and follow-up. 
c 
See section 7.3 and 9.2.3. 
d 
Should the patient stop study therapy (e.g., due to disease/recurrence or second primary) and begin a new treatment prior to the 30 day assessment or following the 30 day assessment to  
12 months, AE assessments should be collected only up to the date the new therapy begins. 
e 
Verify assigned study therapy compliance with capsule/tablet count  
f 
CBC/Diff required for Groups B, C, and D only. 
g 
Assessment of the primary breast tumor and palpable regional lymph nodes.  Required tumor assessment to determine the presence or absence of cCR. 
h 
Should the patient stop study therapy after 1 cycle (4 weeks) and prior to Week 14, obtain ultrasound. 
 
Perform surgery as soon as possible after final clinical tumor assessment and recovery from therapy. 
i      See Section 6.0 for required correlative study blood collection instructions. 
j 
See Section 6.0 for core biopsy procurement study Week 2 and Week 14. 
k 
Should patients stop study therapy prior to study completion (Week 14), see Section 6.0 and optional tumor and blood sample collection consent. 
l 
If gross residual disease  1.0 cm remains, submission of tumor samples is required following definitive surgery. 
(Refer to the FB-11 Pathology and Correlative Science Instructions for tumor and blood sample submission instructions.) 

 
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6.0 
PATHOLOGY AND CORRELATIVE SCIENCE STUDIES 
6.1 
Overview of requirements 
Collection and submission of all patient samples are listed below.  By signing the FB-11 consent 
form, the patient has agreed to all required tumor and blood sample collections and submissions.  
(See Table 3, and FB-11 study treatment consent and optional tumor and blood sample collection 
consents.)  Non-submission of required patient samples will be a protocol violation. 
TABLE 3.  Summary of FB-11 patient sample submission requirements 
Study Requirements for 
ALL Patients 
(unless indicated 
otherwise) 
Prior to Study 
Therapy 
Week 2 
Week 14 
Time of Surgery 
Required collection & 
submission of blood 
samples 
Yes 
Yesa 
Yesa 
N/A 
Required collection and 
submission of biopsy 
tumor samples 
Yesa,b 
Samples should 
be submitted on 
the same day as 
procurement 
Yes 
Samples should be 
submitted on the 
same day as 
procurementa,b 
Yes 
Samples should be 
submitted on the 
same day as 
procurementb 
Yes 
Samples should be 
submitted on the 
same day as 
procurementc 
Optional collection and 
submission of biopsy 
tumor and blood 
samplesd 
N/A 
Samples should be submitted on the same 
day as procurementd 
N/A 
a See FB-11 Pathology and Correlative Science Instructions. 
b Procurement of core biopsy specimens (2 to 4 cores) from an accessible tumor site prior to study entry, Week 
2 and Week 14.  (Patients must have at least 14 days of consecutive study therapy prior to the procurement of 
the Week 14 biopsy.  See Section 8.2)  Note:  The final biopsy (week 14) should be performed within 48 
hours after the last dose of study therapy. 
c If gross residual disease  1.0 cm remains, collection and submission of tumor samples is required following 
definitive surgery. 
d Optional biopsy and blood samples: If the patient decides to stop study therapy prior to completion of  
14 weeks of therapy, procurement of optional core biopsy specimens from an accessible tumor site and blood 
samples should be requested and collected from consenting patients.  (See the Optional Tumor and Blood 
Sample Collection consent.)   
Note:  Blood and biopsy samples should be collected within 48 hours from the last dose of study therapy. 
NOTE: Refer to the FB-11 Pathology and Correlative Science Instructions for tumor and blood sample 
submission instructions. 
 
 
 

 
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6.2 
Use of specimens 
The blood and tumor samples collected in this study will be used for FB-11 studies as described 
in Section 6.0 and for analyses to be conducted in the future related to the purposes of the FB-11 
study but not currently described in the protocol document.  Additionally, the specimens procured 
may be used for future studies involving genes and protein conferring susceptibility to cancer or 
other diseases.  If hereditary genetic studies (germline involving traits that are passed on or 
inherited) are conducted, an anonymization process will be used.  Results of the correlative 
science studies, including raw sequencing data, will not be reported directly to the patient or the 
physician and will not have any bearing on patient treatment. 
6.3 
Tumor and blood sample submission procedures 
The required blood samples are submitted to the NSABP Division of Pathology (see Information 
Resources on page iii) where the samples will be logged into the database and assigned a unique 
code number.  The samples will be stripped of any remaining patient identifiers (except the 
NSABP FB-11 Patient ID numbers), processed, and stored.  A portion of the samples may be 
shipped to collaborating laboratories.  Refer to the FB-11 Pathology and Correlative Science 
Instructions for blood specimen collection and submission instructions. 
The required tumor tissue samples are to be submitted to the NSABP Division of Pathology 
(see Information Resources on page iii) where the samples will be logged into the database and 
assigned a unique code number.  The samples will be identified by the unique code number, 
processed, and stored.  A portion of the samples may be shipped to collaborating laboratories.  
Refer to the FB-11 Pathology and Correlative Science Instructions for tumor tissue specimen 
collection and submission instructions. 
6.4 
Rationale for correlative science studies 
6.4.1 
Tumor samples  
 
Core biopsies 
A minimum of two and a maximum of four core-cut biopsies will be collected from 
each patient at baseline, 2 weeks of study therapy, and 14 weeks of study therapy.  
The final biopsy should be performed within 48 hours of the last dose of study 
therapy. 
 
Surgical specimen 
Representative cores of gross residual disease  1.0 cm must be submitted to NSABP 
following definitive surgery.  These samples are required. 
Biomarker end-points and potential predictive biomarker analyses performed on these 
samples may include: 
 
Ki67, ER (H-score), PgR, apoptosis markers; 
 
senescence marker, p16INKa, Cyclin D1 amplification and expression, pRb, extended 
panel of cell cycle markers; and 
 
PIK3CA mutations (exon9 and 20). 
Additional exploratory work is expected to include: 
 
targeted or whole exome sequencing, whole genome gene expression, to include 
evaluation of PI3K activation signature and E2F signature; 
 
extended mutational profile; and 
 
reverse phase protein arrays. 

 
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The tissue collected in FB-11 will form an integral part of the primary analyses so all 
core biopsies in this trial will be mandated for patients. 
A prioritization list will be drawn up to ensure that the most important markers are 
evaluable of the maximum number of samples. 
6.4.2 
Blood samples 
Collection of blood samples to be used in biomarker research is an essential part of  
FB-11 so these will be mandatory for all participants. 
Research blood samples will be collected at the time of each biopsy for germline DNA 
analyses and plasma estradiol analysis for confirmation of compliance with letrozole 
therapy and to study possible interaction of letrozole and palbociclib. 
 

 
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7.0 
STUDY TREATMENT 
7.1 
Treatment regimen 
Study therapy should begin within 2 weeks following study entry.  Patients will be assigned one 
of four study therapy Arms.  (See Tables 4, 5, 6, 7, and Appendix C.) 
TABLE 4.  Treatment regimen – ARM A 
Drug 
Arm A 
Dosing Interval 
Planned Duration 
Letrozole 
2.5 mg PO 
Daily  
Study therapy duration:  
14 weeks total 
 
Use of a patient diary, calendar, or other tool for the patient to record letrozole doses should be 
strongly encouraged. 
TABLE 5.  Treatment regimen – ARM B 
Drug 
Arm B 
Dosing Interval 
Planned Duration 
Letrozole 
2.5 mg PO 
Daily 
Study therapy duration 
14 weeks total 
Palbociclib 
125 mg PO 
For Cycle 1 only 
Beginning two weeks after 
starting letrozole: palbociclib 
daily x 7 days (Days 14-21) 
of the 28 day cycle  
(Days 22-28 off) 
Cycles 2, 3, and 4: 
Daily for 3 weeks (21 days) of 
a 4 week (28 day) cycle  
(i.e., 3 weeks [21 days]  
on/1 week [7 days] off) 
Other  instructions: 
 
Instruct patients to take palbociclib capsules at the same time each day (preferably in the morning 
before noon), with food and a full glass of water.  Patients should swallow capsules whole and 
not chew them.  Instruct patients not to take capsules that are cracked or broken.  Capsules which 
are cracked or broken should be returned to the study team. 
 
Patients should be instructed not to eat grapefruit or drink grapefruit juice while taking palbociclib. 
 
If a palbociclib dose is missed at the usual time, it should be taken as soon as possible within  
12 hours following the time the dose should have been taken.  If 12 hours, the dose will be missed 
for that day. 
 
If a patient vomits after taking study therapy, the patient should be instructed to not take another 
dose that day.  The patient should resume taking study therapy at the next scheduled dose.  If 
vomiting persists, the patient should be instructed to notify the investigator. 
Use of a patient diary, calendar, or other tool for the patient to record palbociclib doses should be 
strongly encouraged. 
 
 
 

 
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TABLE 6.  Treatment regimen – ARM C 
Drug 
Arm C 
Dosing Interval 
Planned Duration 
Palbociclib 
125 mg PO 
Daily for 3 weeks (21 days) of a  
4 week (28 day) cycle  
i.e.,3 weeks [21 days] on/1 week 
[7 days] off) 
Study therapy 
duration: 14 weeks 
total  
Letrozole 
2.5 mg PO 
For Cycle 1 only 
Begin two weeks after 
starting palbociclib  
daily x 12 weeks  
Other instructions: 
 
Instruct patients to take palbociclib capsules at the same time each day (preferably in the morning 
before noon), with food and a full glass of water.  Patients should swallow capsules whole and 
not chew them.  Instruct patients not to take capsules that are cracked or broken.  Capsules which 
are cracked or broken should be returned to the study team. 
 
Patients should be instructed not to eat grapefruit or drink grapefruit juice while taking palbociclib. 
 
If a palbociclib dose is missed at the usual time, it should be taken as soon as possible within  
12 hours following the time the dose should have been taken.  If 12 hours, the dose will be missed 
for that day. 
 
If a patient vomits after taking study therapy, the patient should be instructed to not take another 
dose that day.  The patient should resume taking study therapy at the next scheduled dose.  If 
vomiting persists, the patient should be instructed to notify the investigator. 
Use of a patient diary, calendar, or other tool for the patient to record palbociclib doses should be 
strongly encouraged. 
TABLE 7.  Treatment regimen – Arm D 
Drug 
Arm D 
Dosing Interval 
Planned Duration 
Letrozole 
2.5 mg PO 
Daily 
Study therapy 
duration: 14 weeks 
total 
Palbociclib 
125 mg PO 
Daily for 3 weeks (21 days) of a  
4 week (28 day) cycle 
(i.e., 3 weeks [21 days] on/1 week 
[7 days] off) 
Other  instructions: 
 
Instruct patients to take palbociclib capsules at the same time each day (preferably in the morning 
before noon), with food and a full glass of water.  Patients should swallow capsules whole and 
not chew them.  Instruct patients not to take capsules that are cracked or broken.  Capsules which 
are cracked or broken should be returned to the study team. 
 
Patients should be instructed not to eat grapefruit or drink grapefruit juice while taking palbociclib. 
 
If a palbociclib dose is missed at the usual time, it should be taken as soon as possible within 12 
hours following the time the dose should have been taken.  If 12 hours, the dose will be missed 
for that day. 
 
If a patient vomits after taking study therapy, the patient should be instructed to not take another 
dose that day.  The patient should resume taking study therapy at the next scheduled dose.  If 
vomiting persists, the patient should be instructed to notify the investigator. 
Use of a patient diary, calendar, or other tool for the patient to record palbociclib doses should be 
strongly encouraged. 
 
 

 
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7.2 
Supportive therapy 
7.2.1 
G-CSF 
Use of growth factors, e.g., G-CSF, GM-CSF, is not permitted. 
7.2.2 
Erythropoietin 
Use of an erythropoiesis-stimulating agent is not permitted.   
7.3 
Prohibited therapies 
The following types of treatment, in addition to any cancer therapy other than the therapy 
specified in this protocol, are prohibited while on study therapy. 
7.3.1 
Chemotherapy 
Administration of chemotherapy other than the chemotherapy specified in this protocol is 
prohibited. 
7.3.2 
Targeted therapy 
Administration of targeted therapy for malignancy (other than the assigned targeted 
therapy regimen) is prohibited. 
7.3.3 
Radiation therapy 
Radiation therapy (RT) to target lesions is prohibited. 
7.3.4 
Hormone replacement therapy (HRT) 
Hormone replacement therapy (HRT), topical estrogens (including any intra-vaginal 
preparations, megestrol acetate and selective estrogen-receptor modulators  
(e.g., raloxifene) are prohibited. 
7.3.5 
Concomitant CYP3A4/5 inhibitors or inducers 
Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A isoenzymes are ineligible.  Lists including medications and substances known or 
with the potential to interact with the CYP3A isoenzymes are provided in Appendix B.  
Because the lists of these agents are constantly changing, it is important to regularly consult 
a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; 
medical reference texts such as the Physicians' Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new medications 
need to be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product. 
7.3.6 
Potential QTc prolongation 
Medications which are known to cause QTc interval prolongation should be avoided.  
Use of these medications is at the investigator's discretion.  QTc monitoring is 
recommended. 
7.4 
Participation in other clinical trials 
If a patient participating in FB-11 considers participation in another clinical trial (including 
supportive therapy trials), contact DSSM (see Information Resources on page iii).

 
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8.0 
TREATMENT MANAGEMENT 
8.1 
General instructions 
 
The NCI CTCAE v4.0 must be used to report the term and grade the severity of AEs. 
 
All treatment decisions must be based on the AE requiring the greatest modification. 
 
Drug doses that have been reduced may not be escalated. 
8.2 
Treatment management for palbociclib and letrozole 
The duration of the FB-11 study therapy is 14 weeks.  Every effort should be taken to maintain 
study therapy schedule (14 weeks). 
 
The end of study therapy for patients in Arm A will be at the completion of week 14. 
 
Patients in Arms B, C, and D will complete study therapy following 14 days of palbociclib in 
the final treatment cycle (past 14 weeks if treatment delays have occurred in the final cycle). 
 
Withholding study therapy doses until an AE resolves may lead to the patient missing some 
or all subsequent doses within that same cycle or delaying the initiation of the subsequent 
cycle. 
 
After week 14 (or end of study therapy) all patients should continue letrozole until surgery.  
(Note: Letrozole will not be considered study therapy beyond completion of study therapy as 
noted above, for all patients [Arms A, B, C, and D].) 
8.2.1 
Treatment decisions when therapy must be held 
 
See Section 7.0 (Tables 5, 6, and 7) and Section 8.4 (Table 8) for palbociclib doses. 
 
See Table 9 for treatment management. 
 
If study therapy must be held for  3 weeks of continuous delay, study therapy must 
be discontinued (see Section 8.2.2). 
8.2.2 
Treatment decisions when therapy must be discontinued 
 
If letrozole or palbociclib is discontinued, study therapy must be discontinued. 
 
If alternative (non-protocol) therapy is given at any time, study therapy must be 
discontinued. 
 
If study therapy is discontinued, further therapy is at the investigator's discretion; 
however, continuance with letrozole is recommended but will not be considered 
study therapy. 
 
Patients who prematurely discontinue study therapy should wait at least 2 weeks 
before undergoing surgery to allow normalization of neutrophil counts. 
See Section 6.0 for required and optional correlative science sample collection. 
8.3 
Study therapy following tumor progression 
If tumor progression occurs during study therapy, study therapy must be discontinued.  Further 
therapy is at the investigator's discretion. 
8.4 
Dose modifications  
There are no dose level changes or modifications for letrozole.  Dose modifications for 
palbociclib are based on dose level changes outlined in Table 8. 
8.4.1 
Dose modifications for palbociclib 
TABLE 8.  Dose levels for palbociclib 
 
Dose Level 0 
Starting Dose 
Dose Level −1 
Dose Level −2 
Dose Level −3 
Palbociclib 
125mg 
100mg 
75mg 
Discontinue 

 
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8.4.2 
Management of toxicities during letrozole and palbociclib study therapy 
The instructions for management of toxicities during letrozole and palbociclib are outlined in Table 9. 
TABLE 9.  Dose Modifications and Treatment management for letrozole and palbociclib 
CTCAE v.4.0  
Adverse Event 
CTCAE v.4.0 Grade 
Action to be Taken 
Letrozole 
Palbociclib (991) 
Blood and lymphatic system disorders 
Neutropenic fever 
3 
Maintain dose 
Hold until clinically stable, then resume: 
1st appearance: ↓one dose 
2nd appearance: ↓ one dose 
3rd appearance: Discontinue 
4 
Discontinue (see Section 8.2.2) 
Infections and infestations 
Infection (By site with normal ANC or 
grade 1 or 2 decrease in neutrophils) 
2 
Maintain dose 
Hold until clinically stable, then resume: 
Maintain dose 
3 
1st appearance: Maintain dose 
2nd appearance: Maintain dose  
3rd appearance Discontinue 
Hold until clinically stable, then resume: 
1st appearance: Maintain dose 
2nd appearance: ↓ one dose  
3rd appearance: Discontinue 
4 
Discontinue (see Section 8.2.2) 
Investigations 
Alanine aminotransferase (ALT) 
 increased 
Alkaline phosphatase increased 
Aspartate aminotransferase (AST) 
 increased 
Blood bilirubin increased 
(See Section 8.5 and 10.6.2 for 
information and reporting requirements 
related to Hy's Law cases.) 
2 
Hold until  Grade 1 
1st appearance: Maintain dose 
2nd appearance: Discontinue 
Hold until  Grade 1 
1st appearance:  dose level 
2nd appearance: Discontinue 
3, 4 
Discontinue (see Section 8.2.2) 
Table 9 continued on next page. 

 
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TABLE 9.  Dose Modifications and Treatment management for letrozole and palbociclib (continued) 
CTCAE v.4.0 
Adverse Event 
CTCAE v.4.0 Grade 
Action to be Taken 
Letrozole 
Palbociclib (991) 
Electrocardiogram QT 
corrected interval prolonged 
2 
Maintain dose 
Reversible cause identified: 
Maintain dose level 
1. Treat reversible cause 
2. Initiate more frequent ECG monitoring per 
investigator's discretion  until QTc ≤ 480msec 
No reversible cause identified: 
Maintain dose level 
3. Consult cardiologist 
4. Initiate more frequent ECG monitoring until QTc  
≤ 480msec 
Note: 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 with the 
investigator’s best medical judgment. 
3 
Maintain dose 
Reversible cause identified: 
Hold until QTc ≤ 500msec; resume at same dose level 
− Treat reversible cause 
− Monitor ECG more frequently per investigator's 
discretion until QTc ≤ 480msec 
No reversible cause identified: 
Hold until QTc ≤ 500msec; then resume at ↓ dose level 
− Consult cardiologist 
− Monitor ECG more frequently per investigator's 
discretion until QTc ≤ 480msec 
Note: If the Grade 3 QTc prolongation occurs again after 
one dose reduction, further dose adjustment and/or 
discontinuation should be considered in 
consultation with a cardiologist and with the 
investigator’s best medical judgment. 
Table 9 continued on next page. 

 
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TABLE 9.  Dose Modifications and Treatment management for letrozole and palbociclib (continued) 
CTCAE v.4.0 
Adverse Event 
CTCAE v.4.0 Grade 
Action to be Taken 
Letrozole 
Palbociclib (991) 
Neutrophil count decreased 
(Note: The use of growth factors is 
prohibited, see Section 7.2.1) 
3 
Maintain dose 
Hold until  1000/mm3.  
1st appearance, if recovery takes: 
 14 days – Resume at same dose level 
> 14 days and  21 days –  dose level 
2nd appearance: Hold until  1000/mm3 
If recovery takes  14 days:  dose level 
> 14 days: Discontinue 
4 
Maintain dose 
Hold until  1000/mm3 
1st appearance, if recovery takes: 
 21 days:  dose level 
2nd appearance, if recovery takes; 
 14 days:  additional dose level 
> 14 days: Discontinue 
Platelet count decreased 
2 
Hold until  75000/mm3 
1st appearance: Maintain dose 
2nd appearance: Maintain dose 
3rd appearance: Discontinue 
Hold until  75000/mm3 
1st appearance: Maintain dose 
2nd appearance: Maintain dose 
3rd appearance: Discontinue 
3 
Hold until  75000/mm3 
1st appearance:  Maintain dose 
2nd appearance: Discontinue 
Hold until  75000/mm3 
1st appearance:  dose level 
2nd appearance: Discontinue 
4 
Discontinue (see Section 8.2.2) 
Other 
1. Other AEs requiring dose 
modification per investigator 
(Note: Investigator must determine 
attribution of AE and only follow dose 
modifications for the causal agent.) 
2 
Maintain dose 
If lasting  3 weeks: 
Hold until ≤ Grade 1 and maintain dose. 
If recurrent ↓  one dose 
3, 4 
Discontinue (see Section 8.2.2) 

 
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8.5 
Liver dysfunction (Hy's Law) 
Hy’s Law is based on the observation that pure hepatocellular injury sufficient to cause 
hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver 
injury.  A diagnosis of potential drug-induced liver injury caused by a study drug can only be 
determined/inferred by excluding other potential causes of liver injury (e.g., other drugs or viral 
hepatitis) and by ruling out an obstructive cause for the elevated bilirubin (e.g., alkaline 
phosphatase should not be substantially elevated).12,13 
8.5.1 
Definition of cases potentially meeting Hy's Law criteria 
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 baseline values within the normal range who subsequently 
present with AST or ALT  3 times the ULN concurrent with a total bilirubin  2 
times the ULN with no evidence of hemolysis and an alkaline phosphatase  2 times 
the ULN or not available. 
 
Patients with pre-existing AST or ALT baseline values above the normal range who 
subsequently present with AST or ALT  2 times the baseline values and  3 times 
the ULN, or  8 times the ULN (whichever is smaller) concurrent with a total 
bilirubin of  2 times the ULN and increased by one ULN over baseline or > 3 times   
the ULN (whichever is smaller) with no evidence of hemolysis and an alkaline 
phosphatase  2 times the ULN or not available. 
8.5.2 
Evaluation of potential Hy's Law cases 
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.  In addition to 
repeating AST and ALT, laboratory tests should include albumin, creatine kinase, total 
bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), international 
normalized ratio (INR) and alkaline phosphatase. A detailed history, including relevant 
information, such as review of ethanol, recreational drug and supplement consumption, 
family history, sexual history, travel history, history of contact with a jaundiced patient, 
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 
(e.g. biliary tract) may be warranted. The possibility of progressive disease should be 
considered. 
Potential Hy's Law cases should be reported as serious adverse events (see Sections 
10.4.3 and 10.6.2). 
 
 

 
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9.0 
DRUG INFORMATION 
9.1 
Letrozole 
Letrozole is available as commercial supply, and will be administered orally as a 2.5 mg tablet. 
For further details regarding the study drug, see the letrozole U.S. Package Insert as well as local 
prescribing information. 
(Note: Postsurgical treatment (e.g. letrozole) will be at the discretion of the treating physician, 
and will not be considered study therapy.) 
9.2 
Palbociclib (PD-0332991) 
9.2.1 
Description 
Palbociclib is an orally administered highly selective reversible inhibitor of  
cycline-dependent kinases (CDK) 4 and 6. 
Palbociclib 125 mg capsules will be provided for the FB-11 study. Palbociclib will be 
available in 100mg and 75mg doses as study therapy where a dose reduction is required 
(see Section 8.4 and Table 8).  The open label palbociclib will be packaged with  
23 capsules per bottle. 
9.2.2 
Toxicity 
Refer to the current palbociclib IB for toxicity information. 
9.2.3 
Concomitant medications and other substances 
 
Patients should be instructed to avoid agents known to be strong cytochrome P450 
(CYP) 3A4 inducers or inhibitors (e.g., ketoconazole) for the duration of the study 
therapy.  Patients should also avoid grapefruit and herbal remedies, including St 
John's Wort.  Refer to Appendix B for a list of selected inhibitors and inducers of the 
cytochrome P450 CYP3A4, 5, 7 isoenzymes. 
 
Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids.  Steroids given for physiological replacement, as premedication for 
palbociclib, as anti-emetics or inhaled as well as short course of oral/topical steroids 
given for allergic reactions or asthma flares are allowed. 
 
Patients taking concomitant anticoagulant therapy (e.g., warfarin or its derivatives, 
low molecular weight heparin, unfractionated heparin) should be monitored regularly 
for changes in relevant coagulation parameters as clinically indicated, as well as for 
any clinical bleeding episodes.  The dose of anticoagulant should be adjusted as 
needed. 
 
Patients taking concomitant digoxin should have digoxin levels monitored closely 
and their digoxin dose adjusted as needed. 
 
 

 
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9.2.4 
Administration 
 
Palbociclib doses are found in Section 7.0 and Section 8.4. 
 
Refer to Section 7.1 (Tables 5, 6, and 7) for palbociclib administration instructions.  
Patients must be carefully instructed by study staff as to how to take palbociclib.  
Note: Studies suggest that the administration of palbociclib with food results in a 
more consistent drug uptake and exposure than administration of palbociclib in a 
fasted state.  Therefore, patients should be instructed to take palbociclib with food.14 
 
Patients should be strongly encouraged to use a patient diary, treatment calendar, or 
other tool to record palbociclib and letrozole doses. 
 
Instruct patients to bring all unused palbociclib and empty bottles to the treating site.  
Local site personnel must count and record the number of palbociclib capsules at the 
first study visit for each of the treatment cycles.  Drug accountability records must be 
maintained. 
9.2.5 
Procurement of palbociclib 
Palbociclib will be supplied free of charge by Pfizer, and distributed via an external 
vendor.  Palbociclib must be requested by the principal investigator (or his/her authorized 
designee) at each participating institution (see Information Resources on page iii for the 
e-mail address to be used for ordering study drug).  The initial supply of palbociclib may 
be requested at the time the first patient signs the FB-11 consent form.  Palbociclib will 
be shipped directly to the investigator whose sites are participating in FB-11. 
9.2.6 
Shipping 
Bottles of palbociclib are shipped at room temperature by overnight express delivery 
Monday through Thursday excluding holidays. 
9.2.7 
Storage/stability 
Palbociclib should be stored at room temperature (15-30°C [59-86°F]) in the study 
therapy containers.  Unopened bottles of palbociclib are stable until the date indicated on 
the package label when stored at room temperature (up to 30°C [86°F]). 
9.2.8 
Transfer of palbociclib 
Palbociclib may not be used outside the scope of FB-11, nor can palbociclib be 
transferred or licensed to any party not participating in this clinical trial. 
9.2.9 
Destruction of palbociclib 
 
All unopened, partially used, or empty bottles of palbociclib shall be destroyed by 
study sites in accordance with the local institution standard operating procedures after 
the approval of DSSM. 
 
Written documentation of destruction must contain the following: 
 
identity (batch numbers) of palbociclib destroyed; 
 
quantity of palbociclib  destroyed; 
 
date of destruction (date discarded in designated hazardous container for 
destruction); and 
 
name and signature of the person who discarded the palbociclib in a hazardous 
container for destruction. 

 
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9.2.10 Drug accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, disposition, and return of all drug received through the  
FB-11 study using an investigational agent accountability record form. 
 

 
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10.0 
ADVERSE EVENT REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an adverse event (AE) or a serious adverse event (SAE), as provided in this 
protocol.  Routine and expedited adverse event report forms and their supporting documentation 
must be submitted to DSSM according to the instructions in Section 10.0. 
10.1 
Definition of an AE 
An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, 
laboratory findings, or other physiologic observations occurring in a patient participating in  
FB-11.  The event does not need to be causally related to study therapy or other requirements of 
the FB-11 trial to be considered an AE. 
 
Examples of an AE include, but are not limited to, the following: 
 
Any toxicity related to study therapy. 
 
Any clinically significant worsening of a pre-existing condition. 
 
An AE occurring from a symptomatic overdose of any study therapy, whether accidental 
or intentional.  Overdose is a dose greater than that specified in the protocol. 
 
An AE occurring from abuse (e.g., use for non-clinical reasons) of any of the agents 
included in the study. 
 
An AE that has been associated with the discontinuation of the use of any of the agents 
included in the study therapy. 
 
An AE occurring during a clinical study that is not related to the study therapy, but is 
considered by the investigator or sponsor to be related to the study requirements, for 
example, an AE may be an untoward event related to a medical procedure required by the 
protocol. 
 
Examples of clinical events that should not be considered AEs: 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy).  Note, the condition that 
leads to the procedure may be an AE, but the procedure itself is not. 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.2 
Adverse Events and relationship to study therapy 
The clinician’s assessment of an AE's relationship to study therapy is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. All AEs must 
have their relationship to study therapy assessed using the terms ‘related’ or ‘not related’. To help 
assess, the following guidelines are used: 
Related 
 
Definitely – There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out.  The clinical event, including an abnormal laboratory 
test result, occurs in a plausible time relationship to study drug administration and cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to withdrawal of 
the study therapy should be clinically plausible. 
 
Probably – There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely.  The clinical event, including an abnormal laboratory test result, occurs 
within a reasonable time sequence to administration of the study drug, is unlikely to be 

 
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attributed to concurrent disease or other drugs or chemicals and follows a clinically 
reasonable response on withdrawal. 
 
Possibly – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the study therapy).  However, the influence 
of other factors may have contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). 
Not Related 
 
Unlikely- A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the study drug) and in which other 
drugs or chemicals or underlying disease provides plausible explanations.  
 
Not related –The AE is completely independent of study therapy administration, and/or 
evidence exists that the event is definitely related to another etiology. 
10.3 
Definition of an SAE 
An SAE is any untoward medical occurrence that, at any dose causes one of the following: 
 
Results in death 
 
Is life-threatening 
 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event.  It does not refer to an event, which might have 
caused death, if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is any inpatient admission to a health care facility even if for less than  
24 hours.  Hospitalization or prolongation of a hospitalization constitutes a criterion for an 
AE to be serious; however, it is not in itself considered an SAE.  In the absence of an AE, a 
hospitalization or prolongation of a hospitalization should not be reported as an SAE.  For 
example, the following hospitalizations would not require expedited reporting for an SAE: 
 
A hospitalization or prolongation of hospitalization needed for a procedure required by 
the protocol or as part of another routine procedure; or 
 
A hospitalization for a pre-existing condition that has not worsened. 
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
This is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma  
(e.g., sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
 
Is a congenital anomaly/birth defect 
Also, appropriate medical judgment should be exercised in deciding whether SAE reporting is 
required in other situations, such as important medical events that may not result in death, be life-
threatening, or require hospitalization, but may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the other outcomes listed in the definition of an SAE 
(Section 10.3).  Examples of such events are intensive treatment in an emergency room or at 

 
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home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or development of drug dependency or drug abuse. 
10.4 
Events requiring expedited reporting 
All events listed in Section 10.4 must be reported in an expedited manner according to the 
instructions in Section 10.7. 
10.4.1 SAEs 
All events meeting the definition of an SAE (Section 10.3) require expedited reporting. 
10.4.2 Other events requiring expedited reporting 
Other events that must be recorded, reported, and followed up as indicated for an SAE 
(see Sections 10.4 and 10.6 for reporting procedures).  This includes the following 
events: 
 
Inadvertent or accidental exposure to study therapy, with or without an AE 
 
Medication errors involving study therapy with an AE, including overdose, product 
confusion and potential product confusion.  (A medication error is any preventable 
event that may cause or lead to inappropriate use or harm while the study therapy is 
in control of the healthcare professional or patient.  Examples of reportable 
medication error include administration of unassigned treatment and administration 
of expired palbociclib, when associated with an AE/SAE.) 
 
Death, excluding death due to progression of breast cancer 
 
Potential Hy's Law cases (see Sections 8.5.2 and 10.6.2) 
10.4.3 Clinical laboratory abnormalities 
 
Not every laboratory abnormality qualifies as an AE.  A laboratory test results should 
be reported as an AE (and SAE) if it meets any of the following criteria: 
 
Accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy 
 
Clinically significant in the investigator's judgment 
 
Special reporting requirements related to Hy’s Law: All cases confirmed on repeat 
testing as meeting one of the criteria described in Section 8.5.2 with no other cause 
for LFT abnormalities identified at the time should be considered potential Hy’s Law 
cases regardless 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 serious adverse events (see Section 10.6.2). 
 
 

 
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10.4.4 Disease-related events and/or disease-related outcomes not qualifying as SAEs 
An event which is part of the natural course of breast cancer does not need to be reported 
as an SAE.  Progression and recurrence of breast cancer will be reported on the 
appropriate page of the eCRF. 
10.5 
Grading the severity of the AE 
The NCI CTCAE v4.0 must be used to determine the event and the grade of the AE.  The 
CTCAE provides descriptive terminology and a grading scale for each AE listed.  Information 
regarding the CTCAE can be found on the CTEP homepage at 
http://ctep.info.nih.gov/reporting/ctc.html.  If you need further assistance, contact DSSM (see 
Information Resources on page iii). 
10.6 
Expedited reporting instructions 
10.6.1 Time period for reporting SAEs and other events requiring expedited reporting 
 
All SAEs and other events as noted in Sections 10.3 and 10.4 regardless of 
relationship to study therapy will be reported in an expedited manner as described in 
Section 10.6.2.  Reporting SAEs (and other applicable events) regardless of 
relationship to study therapy begins with the first dose of study therapy and continues 
until 30 days after the last dose of study therapy. 
 
Any SAE assessed as related to study participation (e.g., protocol-mandated 
procedures) will be recorded from the time a patient consents to participate in the 
study up to and including the 30 day post study trial assessment. 
 
Following the AE assessment 30 days after the last dose of study therapy, only SAEs 
determined to be related to study therapy will be reported in an expedited manner 
using FB-11 Form SAER. 
 
The investigator must follow up on all SAEs until the events have subsided, until 
values have returned to baseline, or until the condition has stabilized. 
10.6.2 Reporting instructions 
 
All SAEs and other events requiring expedited reporting must be reported using  
FB-11 Form SAER and submitted to DSSM within 1 working day of the study site 
personnel's initial notification of the event (see Information Resources on  
page iii). 
 
When reporting potential Hy's Law cases, Form SAER should include the following: 
 
Seriousness Criteria = Important Medical Event 
 
Narrative: Include the term “Potential Hy’s Law case” in the narrative; the text 
should also detail what additional study results are available at the time of 
reporting and what other studies are planned or results pending to further 
investigate alternative causes of the abnormal ALT/AST or bilirubin that 
triggered the report.  The timing of planned patient follow-up should also be 
noted. 
 
NSABP will forward expedited report forms and their supporting documentation for 
SAEs that meet reporting requirements to the FDA and also to Pfizer. 
 
Investigators are responsible for reporting AEs that meet specific criteria to their 
local IRBs. 

 
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10.7 
Time period and frequency for routine reporting of AEs 
 
Patients will be monitored for the occurrence of AEs at each scheduled assessment and 
during any contact with the patient during the study. 
 
All AEs, including SAEs and other AEs that have been reported on FB-11 Form SAER, 
regardless of relationship to study therapy, will be recorded on Form AE of the eCRF from 
the first dose of study therapy until 30 days after the last dose of study therapy (up to the date 
that a new therapy begins after disease recurrence/progression or second primary). 
 
For routine reporting, all  grade 1 AEs will be reported on Form AE of the eCRF. 
 
The investigator must follow up on all AEs until the events have subsided, until values have 
returned to baseline, or until the condition has stabilized. 
 
Following the AE assessment 30 days after the last dose of study therapy, routine reporting is 
no longer required.  (See Section 10.6.1 for expedited reporting requirements.) 
10.8 
Documentation requested following death 
For deaths that occur within 30 days of the last dose of study therapy: 
 
Autopsy reports should be secured whenever possible and should be submitted to the DSSM. 
 
A copy of the death certificate should be forwarded to DSSM if it is readily available or if it 
contains important cause-of-death information that is not documented elsewhere. 
 
Please submit the last clinic/office note made before the death or the investigator’s note 
summarizing events resulting in death. 
 
 

 
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11.0 
ASSESSMENT OF EFFECT 
For the purposes of this study, all clinical response assessments will be performed by ultrasound 
and physical examination of the breast and the axilla using the ECOG response criteria.15  (See 
Appendix D.) 
11.1 
Timing of clinical response assessments 
Tumor measurement by ultrasound is required at baseline (prior to study entry) to determine 
eligibility.  To document the presence or absence of cCR, protocol-required tumor assessments by 
ultrasound and physical exam must be performed after completion of study therapy, at 14 weeks. 
11.1.1 Definition of measurable lesions at baseline 
During the baseline assessment and before the start of protocol therapy, all lesions 
detected in the breast and the axilla are classified as measurable lesions if they meet the 
following criteria: 
Lesions on baseline physical examination 
 
Breast tumors  2.0 cm 
 
Axillary nodes  2.0 cm 
Lesions on baseline by ultrasound 
 
Breast tumors  2.0 cm 
 
Axillary nodes  1.5 cm 
11.1.2 Evaluation of cCR 
The following criteria will be employed at the time of the assessments for cCR at the end 
of study therapy: 
 
resolution of all measurable lesions identified at baseline, and 
 
no new lesions or other signs of disease progression. 
11.1.3 Progressive disease 
Criteria to be used for determination of progressive disease are at the investigator's 
discretion. 
11.2 
Pathologic assessment of effect 
11.2.1 Timing of evaluation 
The determination of pCR will be performed by the local pathologist following 
examination of tissue (breast and nodes) removed at the time of surgery. 
11.2.2 Criteria for evaluation of pathologic complete response 
 
Pathologic complete response in breast and axillary lymph nodes as well as  
non-axillary SN (pCR breast & nodes) 
 
No histologic evidence of invasive tumor cells in the surgical breast specimen or 
axillary nodes after neoadjuvant treatment. 
 
Pathologic complete response in the breast (pCR breast) 
 
No histologic evidence of invasive tumor cells in the surgical breast specimen. 

 
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12.0 
PATIENT ENTRY PROCEDURES 
12.1 
Patient consent form 
Before study entry, the consent form including any addenda, must be signed and dated by the 
patient and the person obtaining informed consent.  In addition, before study entry, a copy of 
the signed and dated consent form must be forwarded to DSSM.  All patient signatures 
(except initials of first, middle, and last names) should be expunged prior to submission. 
12.2 
Study entry 
DSSM will verify that the institution has current IRB approval for the study.  Entry will not take 
place if the IRB approval is not current for the institution with IRB oversight responsibility. 
All patients must be enrolled through DSSM.  Once the entry eCRFs have been completed, 
submit the redacted signed consent form, and supporting source documents to 
. 
The entry material must be received by DSSM staff no later than 4:00 p.m. Eastern Time, 
Monday through Friday, excluding holidays.  Once received the review process will begin.  
When the review is complete and approved, an enrollment confirmation will be sent.  This 
process could involve some unavoidable delays.  Therefore, it is necessary to plan adequate 
time (at least 24 hours) between study entry and the initiation of the patient’s study 
therapy. 
12.3 
Patient study number and treatment assignment 
After all the entry materials have been reviewed, the institution will receive the following via  
e-mail: 1) confirmation of registration and study entry; 2) the patient’s study number; and  
3) the study Arm assignment. 
12.4 
Investigator-initiated discontinuation of study therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study therapy if one of the following occurs: 
 
the patient develops a serious side effect that cannot be tolerated or that cannot be controlled 
with other medications, 
 
the patient’s health gets worse, 
 
the patient is unable to meet the study requirements, or 
 
new information about the study drugs or other treatments for breast cancer becomes 
available. 
If study therapy is stopped, study data and other materials should be submitted according to the 
study schedule unless the patient withdraws from the study. 
12.5 
Patient-initiated discontinuation of study therapy 
Even after a patient agrees to take part in this study, she may stop study therapy at any time.  If 
study therapy is stopped but she still allows the study doctor to submit information, study data 
and other materials should be submitted according to the study schedule.  
12.6 
Patient-initiated withdrawal from the study 
If a patient chooses to have no further interaction regarding the study, the investigator must 
document the patient’s decision to fully withdraw from the study in writing and submit to DSSM.  
Any data collected up to the time of withdrawal from the study will continue to be used. 

 
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13.0 
DATA HANDLING AND RECORDKEEPING 
Please refer to the "FB-11 eCRF Completion Guidelines" for detailed instructions regarding data 
collection, AE reporting, and electronic case report form completion. 
 
 

 
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14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Statistical design and sample size justification 
A total of 284 evaluable patients are required in FB-11.  Allowing for a 5% non-evaluable rate for 
the co-primary endpoints and for the total sample size to be multiple of 9 for each stratification 
level (due to the 3:2:2:2 allocation ratio), the recruitment target for FB-11 is 306 patients. 
FB-11 uses a conventional comparative design with alpha split between two endpoints (clinical 
response rate and Ki67). 
Clinical response rate (ECOG): α=4% one-sided, β=10% 
Allocation is 2:1, comparing combined outcome in the three combination groups (B+C+D on 
combination from 2 to 14 weeks) versus the control letrozole alone group (A). Improvement 
sought is from example scenario CR: 21%, PR: 54%, SD: 15%, PD 5% to CR: 31%, PR: 57%, 
SD: 5%, PD 2% (5% not evaluable for both).  Analysis will treat response as an ordinal outcome 
by the Mann Whitney test corrected for ties.  The sample size was estimated by simulation with 
sampling probabilities for each of the response categories as given.  The letrozole alone response 
rates are based on results from ACOSOG Z1031.16  The sample size required is 284 (n=189:9). 
Ki67: α=1% one-sided, β=10% 
The comparison groups will be as for clinical response.  The sample size is determined based on 
the assumption that Ki67 reduction at the 14-week time-point compared to baseline for patients 
treated with letrozole alone is 80%, data from three studies of Ki67 fall in response to AI 
treatment gave an overall fall of 82% (95%CI: 78% to 85%, n=210).17 
It has been assumed that Ki67 reduction is increased to 90% for patients treated with palbociclib 
combined with letrozole.  The addition of palbociclib to letrozole has therefore been assumed to 
reduce residual Ki67 by 50% (i.e. 20% residual Ki67 for letrozole alone to 10% residual Ki67 for 
letrozole plus palbociclib) which equates to a log-fold change of -0.693 (ln(0.5)) under H1.  The 
standard deviation of the log-fold change from baseline to week-14 Ki67 has been assumed to be 
1.5 based on estimates of approximately 1.1 for baseline to two week change and 1.4 for baseline 
to 12 week change.  Assuming a sample size calculation based on a one-sided T test, the number 
of evaluable patients required is 279 (n=186:93). 
14.2 
Treatment allocation 
FB-11 is a randomized, four Arm study.  Participants will be randomized to: A) letrozole alone; 
B) letrozole for 2 weeks followed by letrozole + palbociclib to week 14; C) palbociclib for 2 
weeks followed by letrozole + palbociclib to week 14; D) letrozole + palbociclib to week 14. 
Analysis of each co-primary end points will compare group A with the combination groups B, C, 
and D.  A 1:2 ratio of the combined 3 groups treated with palbociclib compared with control 
gives a corresponding allocation ratio of (3:2:2:2) for the control compared with each of the 
individual palbociclib treatment groups. 
Treatment allocation is by computer generated random permuted blocks.  Randomization will be 
stratified by country; one randomization list produced for the USA and Canada and another for 
the UK. 

 
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14.3 
Endpoint definition 
14.3.1 Primary endpoint 
This study has two co-primary endpoints: change in the proliferation marker Ki67  
(% positive tumor cells) as tested by IHC after 14 weeks treatment with letrozole with or 
without palbociclib; and clinical response as measured by ultrasound according to ECOG 
criteria after 14 weeks treatment with letrozole with or without palbociclib. 
14.3.2 Secondary endpoints 
The secondary aims include looking at the effect of 2 weeks of palbociclib on Ki67, the 
effect of adding letrozole at 2 weeks (to 14 weeks) in this group and the effect of adding 
palbociclib (2 to 14 weeks) in the group which was initiated with 2 weeks of letrozole.  
Lastly, a major focus of this trial is the correlative science, one of the main goals being to 
determine whether it is possible to identify a pre-treatment marker or markers which are 
predictive of benefit from palbociclib. This will involve, for example, univariate 
Spearman rank correlation between pre-treatment biomarker levels and Ki67/clinical 
response. In addition, if multiple candidates emerge, multiple linear regression with 
dependent variables log Ki67 fold change (or logistic regression with a 50% fall in Ki67, 
or PR/CR vs none as the response variables) and biomarker levels, patient characteristics, 
the treatment given and interactions as independent variables. 
14.4 
Statistical Analysis Plan 
14.4.1 Change in Ki67 
The log fold change in Ki67 from baseline to 14 weeks will be compared between group 
A and groups B+C+D combined using a one-sided test (or non-parametric equivalent).  
Linear regression will be used investigate the relationship between treatment and other 
known prognostic factors on log fold change in Ki67.  Consideration will also be given to 
the use of logistic regression with a 50% fall in Ki67 as the response variable. 
14.4.2 Clinical response 
A one-sided Mann-Whitney test (correcting for ties) will be used to compare ECOG 
clinical response between group A and groups B+C+D combined.  Proportional odds 
modelling will also be used investigate relationship between treatment and other known 
prognostic factors on clinical response at 14 weeks.  Consideration will also be given to 
the use of logistic regression with PR/CR vs. none as the response variable. 
 
Effect of palbociclib on Ki67 after 2 weeks and the added effect of letrozole from 
weeks 2-14 (within group) – descriptive analyses will be performed, with waterfall 
plots used to display changes in Ki67 from baseline to 2 weeks and from  
2 to 14 weeks 
 
Effect of letrozole on Ki67 after 2 weeks and the added effect of palbociclib from 
weeks 2-14 (within group) – as above. 
 
pCR rates after letrozole with or without 14 weeks palbociclib – the proportion of 
patients with pCR will be compared between group A and the combination of groups 
B, C and D  using a Chi-squared test (or Fisher’s exact test as appropriate). 
Consideration will also be given to the use of logistic regression with pCR vs. not as 
the response variable. pCR will be evaluated using the criteria described  
Section 11.2.2. 

 
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 
Comparison of surgical intent at baseline, after 14 weeks, and actual surgery 
performed, following treatment with letrozole with or without palbociclib – surgical 
intent at baseline and surgical intent at week 14 of peri-operative treatment will be 
cross-tabulated: first for all patients, and then separately for group A, and the 
combination of groups B, C, and D.  The proportion of patients whose intended 
surgery at baseline was mastectomy for whom surgical intent has changed to breast 
conservation at week 14  will be presented separately for group A and the 
combination of groups B, C, and D along with associated 95% confidence intervals.  
Proportions will be compared between group A and the combination of groups B, C, 
and D using Fisher's exact test.  In addition, the overall proportion of patients with 
breast conservation intended at week 14 will be calculated for each of these groups 
and compared using Fisher's exact test. 
The same approaches as above will be used to compare surgical intent at baseline and 
actual surgery received. 
 
PEPI score after letrozole with or without 14 weeks palbociclib - PEPI score will be 
calculated for each patient and summarized within each randomized treatment group.  
 
Assessment of safety and tolerability – The proportion of patients experiencing each 
toxicity (any grade) will be presented separately  for group A and the combination of 
groups B, C and D. Groups will be compared by Chi-squared test (or Fisher’s exact 
test as appropriate). The proportion of patients experiencing grade 3 or greater 
toxicity will also be presented. Listings of all dose delays/reductions by randomized 
treatment group will also be produced. 
A major focus of this trial is the correlative science, one of the main goals being to 
determine whether it is possible to identify a pre-treatment marker or markers which are 
predictive of benefit from palbociclib.  This will involve, for example, univariate 
Spearman rank correlation between pre-treatment biomarker levels and Ki67/clinical 
response.  In addition, if multiple candidates emerge, multiple linear regression with 
dependent variables log Ki67 fold change (or logistic regression with a 50% fall in Ki67, 
or PR/CR vs none as the response variables) and biomarker levels, patient characteristics, 
the treatment given and interactions as independent variables. 
US (FB-11) and UK (PALLET) data will be pooled centrally at ICR-CTSU and shared 
with IDDI for interim and final analyses. Further details of analysis methods will be 
specified in a Statistical Analysis Plan in accordance with ICR-CTSU Standard Operating 
Procedures and with the agreement of NSABP statisticians. 
14.5 
Interim analyses and stopping rules 
Final analysis is intended to occur once data (284 evaluable patients) is available. 
Interim analyses are planned at 25% and 50% of trial information (data available from 71 and 142 
evaluable patients).  Trial results will be reviewed by an Independent Data Monitoring Committee 
(IDMC) which will recommend termination of the trial if there is evidence that harm from 
palbociclib, outweighs any plausible therapeutic gain.  The decision rules applied by the IDMC 
for the harm analysis (25% of information) are not formally documented but will incorporate 
information on toxicity and benefit available from FB-11 and PALLET and assessable from all 
contemporaneous palbociclib trials.  The trial will be terminated for futility at the second interim 
analysis when 142 patients are evaluable (50% of information) if there is no evidence either of the 
primary endpoints favors palbociclib.18  As this is a futility stopping rule and there is no scope for 

 
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concluding the efficacy of palbociclib at this stage, no adjustment to the overall alpha is required 
(i.e., the probability of a false positive is not increased.) 
14.6 
Monitoring 
 
A medical review team comprised of the Protocol Chair, Protocol Officer, NSABP Medical 
Director, study statistician, Director of DSSM, designated physician(s) of the DSSM Core 
Group, and designated DSSM staff will formally monitor the study on a monthly basis to 
identify accrual, toxicity, and any endpoint problems that might be developing. 
 
All grades for each type of toxicity will be recorded for each patient, and frequency tables 
will be reviewed to determine toxicity patterns. 
 

 
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15.0 
PUBLICATION INFORMATION 
The publication or citation of study results will be made in accordance with the publication policy 
of the NSABP that is in effect at the time the information is to be made publicly available. 

 
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16.0 
REFERENCES 
1. Cancer Research UK.  Breast cancer key facts: Cancer Research UK; 2010.  
http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/breastcancer/cancerstats-
key-facts--on-breasat-cancer#Breast. 
2. U.S. Cancer statistics Working Group.  United States Cancer Statistics: 1999-20'0 Incidence 
and Mortality Web-based Report.  Atlanta (GA): Department of Health and Human Services, 
Centers for Disease Control and Prevention, and National Cancer Institute; 2013. 
3. Cancer Research UK.  Breast cancer incidence statistics: Cancer Research UK; 2012 [updated 
03/05/201 http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/incidence#age. 
4. Hammond ME, Hayes DF, Dowsett M, et al.  American Society of Clinical Oncology/ 
College of American Pathologists guideline recommendations for immunohistochemical 
testing of estrogen and progesterone receptors in breast cancer.  J. Clin Oncol. 
2010:28(16):2784-95. 
5. Finn RS, Crown JP, Lang I, et al.  Results of a randomized phase 2 study of PD 0332991, a 
cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone 
for first-line treatment of ER+/HER2-advanced breast cancer (BC).  Cancer Research. 
2012;72 (24 supplement3):91s. 
6. Roberts PJ, Bisi, JE, Strum JC, et al.  Multiple roles of cyclin-dependent kinase 4/6 inhibitors 
in cancer therapy.  J Natl Cancer Inst. 2012;104(6):476-87. 
7. Finn RS, Dering J, Conclin D, et al.  PD0332991, a selective cyclin D kinase 4/6 inhibitor, 
preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer 
cell lines in vitro.  Breast Cancer Res. 2009; 11(5):R77. 
8. Cynthia Huang, Pfizer, Personal Communication, 2014. 
9. Palbociclib PD-0332991 Investigator Brochure.  December 2013. 
10. Smith IE, Walsh G, Skene A, et al.  A phase II placebo-controlled trial of neoadjuvant 
anastrozole alone or with gefitinib in early breast cancer.  J Clin Oncol. 2007:25(25)3816-22. 
11. The criteria Committee of the New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th ed. Boston, Mass: Little Brown & 
Co. 1994:253-256. 
12. FDA-Guidance.  Drug-Induced Liver Injury: Premarketing Clinical Evaluation; July 2009.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf(2009). 
13. Temple R.  Hy's law: predicting serious hepatotoxicity.  Pharmacoepidemiol Drug Safety 
2006;15:241-243. 
14. Pfizer Oncology.  Letter to Investigators re: Investigator Initiated Studies using Palbociclib 
(PD-0332991) Phase III Yellow Caramel Formulation Dec. 30, 2013. 
15. Oken MM, Creech RH, Tomey DC, et al.  Toxicity and response criteria of the Eastern 
Cooperative Oncology Group.  Am J Clin Oncol. 1982;5(6):649-655. 
 
 

 
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16. Ellis MJ, Suman VJ, Hoog J, et al.  Randomized phase II neoadjuvant comparison between 
letrozole, anastrozole, and exemestane for postmenopausal women and estrogen receptor-rich 
stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the 
baseline PAM50-based intrinsic subtype—ACOSOG Z1031.  J Clin Oncol. 
2011;29(17):2342-2349. 
17. Dowsett M, Ebbs SR, Dixon JM, et al.  Biomarker changes during neoadjuvant anastrozole, 
tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer—a 
study from the IMPACT trialists.  J Clin Oncol. 2005;23(11):2477-92. 
18. Freidlin B, Korn EL, and Garay R.  A general inefficacy interim monitoring rule for 
randomized clinical trials.  Clin Trials 2010; 7(3):197-208. 
 
 

APPENDIX A 
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ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING 
 
1.0 
DETERMINATION OF PERFORMANCE STATUS 
 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on all pre-
disease performance without 
restriction 
90–100% 
1 
Restricted in physically strenuous 
activity but ambulatory 
70–80% 
2 
Ambulatory and capable of self-care, 
but unable to carry out any work 
activities 
50–60% 
3 
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours 
30–40% 
4 
Completely disabled 
10–20% 
 
 
2.0 
NCI DEFINITION FOR ACTIVITIES OF DAILY LIVING 
 
 
Activities of daily living (ADL) are the tasks of everyday life.  These activities include: 
 
eating 
 
dressing 
 
getting into or out of bed or chair 
 
taking a bath or shower 
 
using the toilet

APPENDIX B 
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CONCOMITANT MEDICATIONS AND OTHER SUBSTANCES PROHIBITED 
DURING STUDY THERAPY 
 
 
TABLE B1.  List of selected inhibitors and inducers of the Cytochrome P450 CYP3A4, 5, 7 
isoenzymes 
INHIBITORS* 
INDUCERS* 
3A4 
OTHER 
34A 
OTHER 
Clarithromycin 
Amiodarone 
Carbamazepine 
Barbiturates 
Erythromycin 
Cannabinoids 
Dexamethasone** 
Cotrimoxazole 
Fluvoxamine 
Fluoxetine 
Phenobarbital 
Efavirenz 
Grapefruit juice 
Lopinavir 
Phenytoin 
Ethosuximide 
Grapefruit-containing 
products 
Metronidazole 
Primidone 
Methadone 
Indinavir 
Quinine 
Rifabutin 
Metyrapone 
Ketoconazole 
Sertraline 
Rifampin 
Mexiletine 
Mibefradil 
Zafirlukast 
St John's Wort 
Nevirapine 
Miconazole 
 
 
Oral contraceptives 
Nefazodone 
 
 
Troglitazone 
Nelfinavir 
 
 
 
Norfloxacin 
 
 
 
Ritonavir 
 
 
 
Saquinavir 
 
 
 
Troleandomycin 
 
 
 
Voriconazole 
 
 
 
 
* 
In boldface are identified strong CYP3A4, 5, 7 inducers/inhibitors.  This list is not meant to be 
considered all inclusive.  From:  Tatro BO.  Drug Interaction Facts 2003: The Authority on Drug 
Interactions, 2003. 
 
Consult updated lists such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  

APPENDIX C 
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FB-11 TREATMENT SCHEDULE 
 
 
TABLE C1 
FB-11 treatment schedule 
 
 
Core 
Core (prior to beginning Week 3 study therapy) 
Core 
 
 
Groups 
Weeks 
Between 
15-18 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Letrozole 
 
 
Palbociclib 
 
Note: 
 
Patients on Arms B, C, and D will remain on palbociclib up to Week 14 (or if there has been delay in 
treatment, until they have completed 14 days of palbociclib in the final treatment cycle).   
 
All patients should continue letrozole until surgery.  Letrozole may continue beyond surgery in all 
groups as per treating physician's choice but will no longer be considered study therapy after surgery. 
 
Surgery will be scheduled for 15-18 weeks post randomization.  If gross residual disease  1.0 cm 
remains, tumor samples will be collected following definitive surgery. 

APPENDIX D 
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ECOG RESPONSE CRITERIA18 
 
Complete Response 
Clinical: 
 
Complete disappearance of all clinically detectable malignant disease. 
Pathologic: 
 
Pathologic proof of a clinically complete response after repeat biopsy of 
areas of known malignant disease. 
Partial Response 
 50% decrease in tumor area, without increase in size of any area of known 
malignant disease of  25% or appearance of new areas of malignant disease. 
Stable Disease 
No significant change in measurable or evaluable disease: 
 
No increase in size of any known malignant disease 
 
No appearance of new areas of malignant disease 
 
This designation includes: 
 
decrease in malignant disease of  50% 
OR 
 
decrease in uni-dimensional measurable disease of  30% 
OR 
 
increase in malignant disease of  25% in any site 
 No deterioration in ECOG performance status of  1 level related to 
malignant disease 
Progressive Disease 
 
Significant increase in size of lesions present at the start of therapy or 
after a response ( 25% in any site) 
OR 
 
Appearance of new metastatic lesions known not to be present at the start 
of therapy 
OR 
 
Stable objective disease associated with deterioration in ECOG 
performance status of  1 level related to malignancy