A Randomized, Multicenter, Open-label, Phase II Trial to Evaluate the Efficacy and Safety of Palbociclib in Combination With Fulvestrant or Letrozole in Patients With HER2 Negative, ER+ Metastatic Breast Cancer
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: MedSIR

 
EudraCT#: 2014-004698-17 
 
Protocol#: MedOPP067 
Protocol Version: 9.0 
 
 
Date: 12th December 2019 
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Clinical Trial Protocol 
 
A randomized, multicentre, open-label, phase II trial to evaluate the efficacy and safety 
of palbociclib in combination with fulvestrant or letrozole in patients with HER2 negative, 
ER+ metastatic breast cancer. (PARSIFAL) 
Code: MedOPP067 
 
Study Drug(s):  
 
 
Palbociclib (PD-0332991) 
 
 
 
 
 
Fulvestrant 
 
 
 
 
 
Letrozole 
 
 
 
 
 
EudraCT#: 
 
 
 
2014-004698-17 
Clinical Trials.gov#: 
 
 
NCT02491983 
 
Protocol#:  
 
 
 
MedOPP067 
 
Protocol Date:   
 
 
12th December 2019 
 
Protocol Revision History 
Initial Version dated 
28th January 2015 (applicable globally) 
Version dated   
30th July 2015 (applicable in France, Russia, Saudi Arabia & UAE) 
Version dated   
7th October 2015 (applicable in Germany) 
Version dated   
20th January 2016 (applicable globally) 
Version dated   
30th June 2016 (applicable globally) 
Version dated  
20th December 2016 (applicable globally) 
Version dated  
12th May 2017 (applicable globally) 
Version dated  
14th November 2018 (applicable globally) 
Version dated  
12th December 2019 (applicable globally) 
 
FINAL PROTOCOL APPROVAL 
 
Name 
 
José Pérez, MD, PhD 
MedSIR Medical Monitor 
 
 
Date and signature 
CONFIDENTIAL: The information contained herein is confidential and property of the MedSIR. Their reproduction, partially or totally, without 
permission in writing from the MedSIR. These limitations also apply to all information considered privileged or confidential under the future and with 
respect to this research 
 

 
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KEY CONTACTS 
 
Sponsor 
Name:  
Medica Scientia Innovation Research (MedSIR) 
Contact Name:  Alicia García-Sanz, PhD 
Address: 
Rambla de Catalunya, 2 2D 08007 – Barcelona (Spain) 
Phone:  
+ 34 93 221 41 35 
Fax: 
 
+ 34 93 299 23 82 
E-mail:  
alicia.garcia@medsir.org 
 
Sponsor’s Medical Monitor 
Name:  
José Pérez MD, PhD 
Address: 
Rambla de Catalunya, 2 2D 08007 – Barcelona (Spain) 
Phone:  
+ 34 93 221 41 35 
Fax: 
 
+ 34 93 299 23 82 
E-mail:  
jose.perez@medsir.org 
 
Sponsor’s Safety Risk Management 
Address: 
Rambla de Catalunya, 2 2D 08007 – Barcelona (Spain) 
Phone:  
+ 34 93 221 41 35 
Fax: 
 
+ 34 976 20 44 02 
E-mail:  
ParsifalSAE@medsir.org 
 
 

 
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Principal Investigator 
Name:  
 
Antonio Llombart MD, PhD 
Email:  
 
antonio.llombart@medsir.org 
Position:  
 
Medical Oncologist. Chief of Oncology Department 
Institution: 
 
Arnau de Vilanova Hospital, Valencia (Spain) 
 
 
Steering Committee 
Javier Cortes  
Oncologist and Investigator 
jacortes@vhio.net 
Peter Schmid  
Oncologist and Investigator 
p.schmid@qmul.ac.uk 
Joseph Gligorov  
Oncologist and Investigator 
joseph.gligorov@tnn.aphp.fr 
Serena Di Cosimo  
Oncologist and Investigator 
Serena.DiCosimo@istitutotumori.mi.it 
Andreas Schneeweiss 
Oncologist and Investigator 
andreas.schneeweiss@med.uni-
heidelberg.de 
José Pérez 
Study Medical Monitor 
jose.perez@medsir.org 
Antonio Llombart 
Study Principal Investigator 
antonio.llombart@medsir.org 
Joan Albanell Mestres 
Principal 
Investigator 
for 
translational sub-study 
JAlbanell@parcdesalutmar.cat 
 

 
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Protocol Version: 9.0 
 
 
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Declaration of Investigators 
 
Protocol Title: A randomized, multicentre, open-label, phase II trial to evaluate the efficacy and safety of 
palbociclib in combination with fulvestrant or letrozole in patients with HER2 negative, ER+ metastatic breast 
cancer. 
I have received, reviewed and understand the following: 
a) 
Protocol: A randomized, multicentre, open-label, phase II trial to evaluate the efficacy and safety of 
palbociclib in combination with fulvestrant or letrozole in patients with HER2 negative, ER+ metastatic breast 
cancer, version dated on 12th December 2019. 
b) 
Investigator’s Brochure and SmPC for the IMPs used in the study (Palbociclib, Fulvestrant, 
Letrozole) with details of clinical and nonclinical data on the investigational product palbociclib (PD-0332991) 
that are relevant to the study of the product in human subjects 
 
I have been adequately informed about the development of the investigational product to date. 
 I will confirm the receipt of updated Investigator’s Brochure/SmPC 
I have read this study protocol and agree that it contains all the information required to conduct the study. 
 I agree to conduct the study as set out in this protocol. 
 
I fully understand that any changes instituted by the investigator(s) without previous agreement with the 
sponsor would constitute a violation of the protocol, including any ancillary studies or procedures performed 
on study patients (other than those procedures necessary for the wellbeing of the patients). I am aware I 
may only implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to 
trial subjects without prior IRB/IEC approval/favourable opinion and /or before sponsor’s agreement and, in 
this case, and as soon as possible, I will submit in written the implemented deviation or change and the 
reasons for it to the sponsor. 
 
I will not enrol the first subject in the study until I have received approval from the appropriate Institutional 
Review Board or Independent Ethics Committee (IRB/IEC) and until all legal and regulatory requirements in 
my country have been fulfilled. 
 
The study will be conducted in accordance with the moral, ethical, and scientific principles governing clinical 
research as set out in the Declaration of Helsinki and its amendments, the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines (ICH E6 GCP) and applicable regulations and 
laws. 
 
I agree to obtain, in the manner described in this protocol and in ICH E6 GCP, written informed consent by 
the subject or witnessed verbal informed consent to participate for all subjects whose participation in this 
study is proposed to and before any subject’s study specific procedure is done. 
 
I will ensure that the study drug(s) supplied by the sponsor are being used only as described in this protocol. 
I am aware of the requirements for the correct reporting of serious adverse events, and I commit to document 
and to report such events as required by the sponsor and in accordance with Health Authority Regulatory 
requirements. 
 

 
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I agree to supply – upon request – the Sponsor or Sponsor’s representative with evidence of current 
laboratory accreditation, the name and address of the laboratory, and a list of normal values and ranges. 
I agree with the use of results of the study for the purposes of national and international registration, 
publication, and information for medical and pharmaceutical professionals. 
 
I agree to keep all source documents and case report forms as specified in the relevant sections of this 
protocol. 
 
I will provide all required Regulatory Authority forms, up-to-date curriculum vitae of myself, sub-investigators 
and of any member of my study team (if requested) before the study starts, which may be submitted to 
regulatory authorities. 
 
I am aware of the possibility of being audited by the sponsor or its delegate or inspected by regulatory 
authorities for the performance of this study. I will permit monitoring, auditing and inspection and provide 
direct access to source data/documents and reports for these purposes. 
 
Furthermore, I confirm herewith that the sponsor is allowed to enter and utilize my professional contact 
details and function in an electronic database for internal purposes and for submission to Health Authorities 
worldwide. 
 
Name:   
_____________________________________________________________________ 
 
Signature:  
_________________________ 
 
Date:  
___________________________ 

 
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Protocol synopsis 
Investigational 
Medicine Product: 
Palbociclib (PD-0332991), Fulvestrant and Letrozole 
Protocol Number: 
MedOPP067 
EudraCT Number: 
2014-004698-17 
Protocol Title: 
A randomized, multicentre, open-label, phase II trial to evaluate the 
efficacy and safety of palbociclib in combination with fulvestrant or 
letrozole in patients with HER2 negative, ER+ metastatic breast 
cancer 
Target disease: 
ER positive HER2-negative locally advanced or metastatic breast 
cancer 
Subjects: 
Postmenopausal women and premenopausal women receiving LHRH 
analogues, aged ≥ 18 years with ER positive and HER2 negative 
locally advanced or metastatic breast cancer that had not received 
any therapy for the metastatic disease. Patients are not eligible if they 
are candidates for a local treatment with a radical intention. Subjects 
must have histologic confirmation of the 
estrogen and/or 
progesterone-positive and HER2 negative receptors breast cancer. 
Evidence of measurable or evaluable metastatic disease is required.  
Number of patients: 
486 patients (anticipated enrolment of 243 patients in Arm A and 243 
patients in Arm B). 
Selection criteria: 
Inclusion criteria 
 
1. Postmenopausal women, as defined by any of the following 
criteria: 
• 
Age 60 or over 
• 
Age 45 to 59 years and meets ≥ 1 of the following 
criteria: 
➢ 
Amenorrhea for ≥ 24 months  
➢ 
Amenorrhea for < 24 months and follicle-
stimulating hormone within the postmenopausal 
range (including patients with hysterectomy, prior 
hormone replacement therapy, or chemotherapy-
induced amenorrhea) 
• 
Over 18 years of age and bilateral oophorectomy 
OR 
Premenopausal women provided they are being treated 
with LHRH analogues for at least 28 days prior to study 
entry 
 
2. Eastern Cooperative Oncology Group (ECOG) score lower or 
equal to 2 
3. Histologically confirmed recurrent ER positive (oestrogen 
and/or progesterone) HER2-negative locally advanced or 
metastatic BC patients (Breast cancer that have at least 1% of 
cells staging positive for ER should be considered ER-positive 
according to NCCN and ASCO guidelines (1,2)) 

 
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4. Patients should not be candidates for a local treatment with a 
radical intention.  
5. No prior hormonal or chemotherapy line in the metastatic 
setting  
6. Patient must have measurable (according to RECIST 1.1) or 
non measurable disease with these exceptions 
a. Patients with only blastic bone lesions are not eligible 
b. Patients with only pleural, peritoneal or cardiac 
effusion, or meningeal carcinomatosis are not eligible 
7. Life expectancy grater or equal to 12 weeks 
8. Adequate organ function: 
a. Hematological: White blood cell (WBC) count >3.0 x 
109/L, absolute neutrophil count (ANC) >1.5 x 109/L, 
platelet count >75.0 x109/L, and hemoglobin >10.0 
g/dL (>6.2 mmol/L) 
b. Hepatic: bilirubin < 1.5 times the upper limit of normal 
(x ULN); alkaline phosphatase (ALP), aspartate 
transaminase (AST), and alanine transaminase 
(ALT) <2.5 times ULN. Patients with ALP ≥2.5 times 
ULN 
are 
eligible 
if 
ALP 
abnormalities 
are 
unequivocally related to bone lesions (radiological 
assessments performed within 4 weeks prior to 
randomization 
demonstrated 
bone 
metastatic 
disease). 
c. Renal: serum creatinine < 1.5 x ULN. 
9. Exhibit patient compliance and geographic proximity that 
allow for adequate follow-up. 
10. Patient has been informed about the nature of study, and has 
agreed to participate in the study, and signed the Informed 
Consent form prior to participation in any study-related 
activities. 
11. No other malignancies within the past five years except 
adequate treated basal cell or squamous cell skin cancer or 
carcinoma in situ of the cervix 
12. Resolution of all acute toxic effects of prior anti-cancer 
therapy or surgical procedures to NCICTCAE version 4.0 
Grade 1 (except alopecia or other toxicities not considered 
a safety risk for the patient at investigator's discretion). 
13. Patient has been informed about the translational sub-study 
and has agreed to participate in the collection of blood and 
tumor tissue samples by signing the Informed Consent form. 
 
Exclusion criteria 
Patients will be excluded from the study if they meet ANY of the 
following criteria: 
1. ER or HER2 unknown disease 
2. HER2 positive disease based on local laboratory results 
(performed by immunohistochemistry/FISH) 
3. Locally advanced breast cancer candidate for a radical treatment.  

 
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4. Prior endocrine therapy in the metastatic setting. (Neo)/Adjuvant 
endocrine therapy is allowed only if the disease-free interval 
between the end of endocrine therapy and the appearance of 
metastases in higher than 12 months.  
5. Patients with rapidly progressive visceral disease or visceral 
crisis. 
6. Have had a major surgery (defined as requiring general 
anaesthesia) or significant traumatic injury within 4 weeks of start 
of study drug, patients who have not recovered from the side 
effects of any major surgery or patients that may require major 
surgery during the course of the study. 
7. Patients with an active, bleeding diathesis. 
8. Have a serious concomitant systemic disorder (e.g. active 
infection including HIV, or cardiac disease) incompatible with the 
study (at the discretion of investigator), previous history of 
bleeding diathesis, or anti-coagulation treatment (The use of low 
molecular weight heparin is allowed as long as it is used as 
prophylaxis). 
9. Are unable to swallow tablets. 
10. History of malabsorption syndrome or other condition that would 
interfere with enteral absorption. 
11. Chronic daily treatment with corticosteroids with a dose of ≥ 
10mg/day methylprednisolone equivalent (excluding inhaled 
steroids).  
12. Known active uncontrolled or symptomatic CNS metastases, 
carcinomatous meningitis, or leptomeningeal disease as 
indicated by clinical symptoms, cerebral oedema, and/or 
progressive growth. Patients with a history of CNS metastases or 
cord compression are eligible if they have been definitively treated 
with local therapy (e.g., radiotherapy, stereotactic surgery) and 
are clinically stable off anticonvulsants and steroids for at least 4 
weeks before randomization 
13. Known hypersensitivity to letrozole, fulvestrant or any of their 
excipients, or to any PD-0332991 excipients. 
14. QTc >480 msec on basal assessments, personal history of long 
or short QT syndrome, Brugada syndrome or known history of 
QTc prolongation, or Torsade de Pointes (TdP). 
15. Uncontrolled electrolyte disorders that can compound the effects 
of a QTc-prolonging drug (e.g., hypocalcemia, hypokalemia, 
hypomagnesemia). 
 
Study objectives 
Primary Objective: To compare the efficacy of the combination of 
palbociclib plus fulvestrant versus palbociclib plus letrozole in terms 
of progression free survival (PFS) in patients with hormone-sensitive 
HER2-negative metastatic or locally advanced breast cancer. 
 
Secondary Objectives 
✓ To evaluate the safety and tolerability of the combination of 
palbociclib plus fulvestrant or letrozole. 

 
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✓ To correlate the safety profile of palbociclib combined with 
fulvestrant or letrozole with baseline patient characteristics. 
✓ To compare the time to progression (TTP) of the combination of 
palbociclib plus fulvestrant with palbociclib plus letrozole. 
✓ To compare the clinical response (in terms of clinical benefit and 
overall response) of the combination of palbociclib plus fulvestrant 
with palbociclib plus letrozole. 
✓ To compare the duration of response (DoR) of the combination of 
palbociclib plus fulvestrant with palbociclib plus letrozole. 
✓ To compare time to response (TTR) of the combination of 
palbociclib plus fulvestrant with palbociclib plus letrozole 
✓ To compare the overall survival (OS) of the combination of 
palbociclib plus fulvestrant with palbociclib plus letrozole.  
✓ To identify potential biomarkers to predict the benefit from 
Palbociclib combined with endocrine therapy  
✓ To identify mechanisms of resistance to palbociclib combined with 
endocrine therapy  
 
Type of study: 
This is an international, randomized, open-label, controlled, 
multicenter phase II study. 
 
Patients will be stratified by site of disease (visceral vs. non-visceral) 
and by onset of metastatic disease diagnose (patients metastatic de 
novo versus non de novo). 
Treatment: 
Patients will be randomized to one of two therapy regimens. 
 
Patients in Arm A will receive fulvestrant 500 mg/5mL i.m. injection 
administered on Days 1 of a 28-day cycle (loading dose on cycle 1 
requires administration also on Day 14). Palbociclib 125 mg capsules 
will be taken orally once daily beginning on Day 1 of fulvestrant and 
continuing through Day 21 of every 28-day cycle. 
 
Patients in Arm B will receive letrozole 2.5 mg tablet orally once daily 
beginning on Day 1 and continuing through Day 28 of a 28-day cycle. 
Palbociclib 125 mg capsules will be taken orally once daily beginning 
on Day 1 of letrozole and continuing through Day 21 of every 28-day 
cycle. 
 
Patients will continue to receive their assigned treatment until 
objective 
disease 
progression, 
symptomatic 
deterioration, 
unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  
 
Patients discontinuing the active treatment phase will enter a 
treatment follow-up period during which survival and new anti-cancer 
therapy information will be collected every 6 months from the last dose 
of investigational product. The treatment follow-up period will continue 
up to the end of the study.  
Efficacy and Safety 
assessments 
Disease assessments will be performed every 12 weeks (±7 days) 
from the date of randomization up to end of treatment period. Patients 
with bone lesions identified at baseline will also have repeat bone 
scans performed every 24 weeks (±7 days). Each assessment will be 
performed as scheduled according to the calendar regardless of any 
dosing delay to prevent the introduction of bias into the assessment 
of efficacy. Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for 
that time point. Tumor assessments will be performed until 

 
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radiographically and/or clinically documented PD as per RECIST 
v.1.1, study treatment discontinuation, initiation of new anticancer 
therapy or discontinuation of patient from overall study participation 
(e.g., death, patient's request, lost to follow-up), whichever occurs 
first. 
 
The occurrence and maximal grade of toxicity for the whole duration 
of treatment will be listed and tabulated by type and dose level. 
Adverse events reported as non-drug related by the responsible 
investigator will be reported as well. Toxicity will be evaluated in this 
study using the Common Terminology Criteria for Adverse Events by 
the NCI (CTCAE version 4.0). 
 
Blood samples at four time points: baseline, 2 weeks and 12 weeks 
after treatment start and at time of progression would be collected for 
translational biomarker research. Additionally, patients must consent 
to provide tissue samples at baseline and at time of progression (if 
biopsable lesion). For non de novo patients, tumor tissue at the time 
of metastatic disease diagnose will be requested as preferred option, 
though at least archived tissue samples from the primary tumor could 
be acceptable. 
Evaluation Criteria 
Primary Endpoint: The primary endpoint for this study is PFS, which 
is defined as the time from randomization until objective tumor 
progression or death, as assessed by the investigator per RECIST 
v1.1.  
 
Secondary Endpoint-Safety 
Patient safety and adverse events will be assessed using the National 
Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE), version 4 [1]. Grade 3 and 4 adverse events and serious 
adverse events will be assessed to determine the safety and 
tolerability of the different drug combinations.  
 
Secondary Endpoints-Efficacy 
The time to progression (TTP), overall survival (OS), overall response 
rate (ORR), duration of response (DoR), time to response (TTR) and 
clinical benefit rate (CBR) will be determined to assess the efficacy of 
the drug combinations.  
 
TTP is defined as the time from randomization to disease progression, 
as assessed by the investigator per RECIST v1.1. OS is defined as 
the time from randomization until death from any cause. The ORR is 
defined as the proportion of patients with best overall response of 
confirmed complete response (CR) or partial response (PR) based on 
local investigator’s assessment according to RECIST criteria 
guidelines (version 1.1). DoR is defined as the time from 
documentation of tumor response (either CR or PR) to disease 
progression. An objective response needs to be confirmed at least 4 
weeks after the initial response. TTR is defined as the time from 
randomization to the first overall tumor response (tumor shrinkage of 
≥30%) observed for patients who achieved a CR or PR. The CBR is 
defined as the percentage of patients who experience a CR, PR or 
stable disease for at least 24 weeks and assessed by modified 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 
v1.1) criteria. 
 
Secondary Endpoints-Translational sub-studies  
 

 
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Presence of different pattern of expression of ESR1 mutations and 
other CDK4/6 related biomarkers (i.e. Rb, Akt, PIK3, p53 CA cyclin 
D1, cyclin A2, E2F1...) in liquid biopsies and tissue samples. 
Proteomics analysis to evaluate differential pattern of protein 
expression from tissue samples. Exome and RNA sequencing will be 
performed in selected samples 
Interim analysis 
An interim-analysis will be performed at 22 months after 35% of the 
total PFS events (89 events) have been observed. Interim analysis 
will evaluate the primary end-point and all safety and efficacy 
secondary objectives.  
 
Efficacy and safety results of the interim analysis will be evaluated by 
the Steering Committee that will decide about the suitability of 
continuing with the study. 
Study period 
Patients should continue until trial efficacy decision criteria are met. 
EoS will occur with 254 PFS events and 486 patients included. 
 
 
 

 
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Table of abbreviations 
Abbreviation 
Definition 
ABC 
Advanced Breast Cancer 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AI 
Aromatase inhibitor 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
ALP 
Alkaline phosphatase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
AT 
Aminotransferase 
AUC 
Area under the serum concentration-time curve 
BC 
Breast cancer 
CBR 
Clinical benefit rate 
CCP 
comprehensive cancer panel 
CDK 
cyclin-dependent kinases 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum concentration 
CNS 
Central Nervous System 
CNV 
Copy-number Variation 
CR 
Complete response 
CRF 
Case Report Form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDI 
drug-drug interaction  
DoR 
Duration of Response 
DNA 
Deoxyribonucleic acid 
cfDNA 
Circulating free DNA 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDTA 
ethylenediaminetetraacetic acid 
EMA 
European Medicines Agency 
EoS 
End of Study 
ER 
Endocrine receptors 
ESA 
Erythropoiesis stimulating agents 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-Positron Emission Tomography 

 
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Abbreviation 
Definition 
FFPE 
Formalin-Fixed, Paraffin-Embedded (tissue) 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
HER2 
human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
ICH 
ILD 
International Conference on Harmonization 
Interstitial lung disease  
INR 
International normalized ratio 
IRB 
Independent Review Board 
ISH 
In situ hybridation 
ITT 
Intention to Treat 
LDH 
Lactate dehydrogenase 
mBC 
Metastatic Breast Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS 
Massive parallel targeted sequencing  
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
non-IMP 
Non Investigational Medicine Products 
OCT 
Organic Cation Transporter 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCR 
Polymerase chain reaction 
PD 
Progression Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PP  
Protocol compliant population 
PPI 
proton pump inhibitors 
PR 
Partial Response 
QTcF 
corrected QT interval using the Fridericia formula 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
miRNA 
micro RNA 
RP2D 
recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 

 
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Abbreviation 
Definition 
SmPC 
Summary of Product Characteristics 
TdP 
Torsade de Pointes 
TEAE 
Treatment-Emergent Adverse Events  
TMA 
Tissue microarrays 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
UPN 
Unique patient number 
WBC 
White blood cell 
 
 
 

 
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Table of contents 
KEY CONTACTS ........................................................................................................................... 2 
Protocol synopsis ........................................................................................................................... 6 
Table of abbreviations .................................................................................................................. 12 
Table of contents .......................................................................................................................... 15 
I. 
BACKGROUND AND RATIONALE ...................................................................................... 18 
1.1. 
Endocrine therapy in HER2-negative Metastatic Breast Cancer .................................. 18 
1.2. 
Interaction of Estrogens and Cyclin-Dependent Kinases (CDK) in Breast Cancer Cells
 
20 
1.3. 
Palbociclib (PD-0332991): Selective inhibitor of cyclin dependent kinases 4 and 6 
(CDK4/6) ................................................................................................................................... 21 
1.4. 
Rationale for combining letrozole with palbociclib ......................................................... 24 
1.5. 
Rational for combining palbociclib with fulvestrant ........................................................ 25 
1.6. 
Rational of the study ...................................................................................................... 25 
1.7. 
Rational of molecular part of the study .......................................................................... 27 
2. 
OBJECTIVES and ENDPOINTS ....................................................................................... 29 
2.1. 
Primary Objective: ......................................................................................................... 29 
2.2. 
Secondary objectives:.................................................................................................... 29 
3. 
STUDY OVERVIEW .......................................................................................................... 31 
3.1. 
Study Design ................................................................................................................. 31 
3.2. 
Study treatment management ....................................................................................... 31 
3.3. 
General Concomitant Medication and Supportive Care Guidelines.............................. 32 
3.4. 
Prohibited therapies ....................................................................................................... 33 
3.5. 
Duration of study treatment ........................................................................................... 35 
3.6. 
Duration of treatment follow-up period .......................................................................... 36 
3.7. 
End of Study (EoS) ........................................................................................................ 36 
4. 
PATIENT SELECTION ...................................................................................................... 36 
4.1. 
Target study population ................................................................................................. 36 
4.2. 
Inclusion criteria ............................................................................................................. 36 
4.3. 
Exclusion criteria ............................................................................................................ 38 
5. 
ASSESSMENTS AND STUDY PROCEDURES ............................................................... 39 
5.1. 
Patient entry procedures ............................................................................................... 39 
5.2. 
Study assessments........................................................................................................ 40 
5.3. 
Schedule of assessments .............................................................................................. 43 
5.4. 
Patient, study, and site discontinuation ......................................................................... 45 
6. 
STUDY DRUGS INFORMATION ...................................................................................... 46 
6.1. 
Drug supplies ................................................................................................................. 46 
6.2. 
Formulation and Packaging ........................................................................................... 46 
6.3. 
Preparation and Dispensing .......................................................................................... 47 

 
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6.4. 
Administration ................................................................................................................ 48 
6.5. 
Medication Errors and Overdose ................................................................................... 49 
6.6. 
Compliance .................................................................................................................... 50 
6.7. 
Drug Storage and Drug Accountability .......................................................................... 50 
6.8. 
Dose Modification .......................................................................................................... 51 
Fulvestrant Dose Modification .............................................................................................. 51 
Palbociclib Dose Modification ............................................................................................... 52 
6.9. 
Potential drug-drug interaction ...................................................................................... 56 
Palbociclib ............................................................................................................................. 56 
Fulvestrant ............................................................................................................................ 57 
Letrozole ............................................................................................................................... 58 
7. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ....................................... 58 
7.1. 
Adverse Events Definitions ............................................................................................ 59 
7.2. 
Adverse Event Reporting ............................................................................................... 62 
8. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ............................................ 64 
8.1. 
Sample Size ................................................................................................................... 64 
8.2. 
Analysis Sets ................................................................................................................. 66 
8.3. 
Primary efficacy endpoint .............................................................................................. 66 
8.4. 
Primary efficacy analysis ............................................................................................... 67 
8.5. 
Secondary efficacy analysis .......................................................................................... 67 
8.6. 
Safety Endpoints ............................................................................................................ 68 
8.7. 
Translational sub-studies ............................................................................................... 70 
8.8. 
Missing Data Management ............................................................................................ 71 
8.9. 
Interim analysis .............................................................................................................. 71 
8.10. 
Steering Committee Review ...................................................................................... 71 
9. 
ETHICAL CONSIDERATIONS .......................................................................................... 72 
9.1. 
Regulatory and Ethics Compliance ............................................................................... 72 
9.2. 
Institutional Review Board / Independent Ethic Committee: ......................................... 72 
9.3. 
Informed Consent .......................................................................................................... 72 
9.4. 
Data Protection .............................................................................................................. 73 
10. 
SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE . 74 
10.1. 
Source Data Documentation ...................................................................................... 74 
10.2. 
Study Monitoring and Source Data Verification ......................................................... 75 
10.3. 
Retention of records ................................................................................................... 75 
10.4. 
Data Quality Assurance ............................................................................................. 76 
11. 
DATA MANAGEMENT ...................................................................................................... 77 
11.1. 
Data Entry and Management ..................................................................................... 77 
11.2. 
Data Clarification ........................................................................................................ 77 
11.3. 
Data Coding Procedures ............................................................................................ 77 

 
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12. 
STUDY MANAGEMENT ................................................................................................... 78 
12.1. 
Discontinuation of the Study ...................................................................................... 78 
12.2. 
Changes to the Protocol ............................................................................................ 78 
12.3. 
Publication Policy Protection of Trade Secrets .......................................................... 78 
13. 
REFERENCES .................................................................................................................. 80 
Appendix 1: Schedule of assessments and study procedures .................................................... 88 
Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST criteria) guidelines (version 
1.1) ............................................................................................................................................... 91 
Appendix 3: Instructions for Scans in the Event of Isotope Shortage.......................................... 92 
Appendix 4: Translational evaluation of molecular biomarkers sub study ................................... 93 
I. 
Biomaterial......................................................................................................................... 94 
Blood sample collection ........................................................................................................ 94 
Tumor specimens ................................................................................................................. 94 
II. 
Biosample Requirements and Storage .......................................................................... 95 
III. 
Description of methods .................................................................................................. 95 
 
 
 

 
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I. BACKGROUND AND RATIONALE 
1.1. Endocrine therapy in HER2-negative Metastatic Breast Cancer 
Breast cancer is the most common tumor among women. In 2012, around 1.7 million 
new cases were diagnosed with breast cancer around the world. Approximately 232,340 
new cases of invasive breast cancer and 39,620 breast cancer deaths are expected to 
occur among US women in 2013 (3). 
The ER+/HER2- population is the largest subgroup among postmenopausal women with 
metastatic disease representing approximately 65% of cases. Most of these women will 
receive palliative hormonotherapy as their first approach against the oncological disease. 
Several large randomized trials have compared the third-generation aromatase inhibitors 
(letrozole, anastrozole and exemestane) (4–6) (7) to tamoxifen for first-line treatment of 
metastatic breast cancer (mBC). Overall, these trials have showed that aromatase 
inhibitors have superior clinical efficacy when compared to tamoxifen and different 
toxicity profile.  
The role of estrogens in breast cancer etiology and progression is well established. 
Modification of estrogen activity or synthesis represents the treatment of choice for 
postmenopausal women with hormonal receptor positive advanced breast cancer, 
particularly for those with slowly progressive disease and limited tumor-related 
symptoms. Letrozole (Femara®) is an oral non-steroidal aromatase inhibitor and it is 
approved worldwide for the first-line treatment of postmenopausal women with hormone 
receptor-positive advanced breast cancer (ABC). 
In a multicenter Phase 3 trial, 916 patients with hormone receptor-positive or hormone 
receptor-unknown ABC were randomized to receive either letrozole or tamoxifen until 
disease progression. Most of the patients (91%) had received no prior treatment for their 
advanced disease. Letrozole was superior to tamoxifen for time to tumor progression 
(median, 9.4 vs. 6.0 months, P<0.0001), time to treatment failure (median, 9 vs. 5.7 
months, P<0.0001), overall objective response rate (32%vs21%, P=0.0002), and overall 
clinical benefit (50% vs. 38%, P=0.0004). Median overall survival (OS) was slightly 
prolonged for the letrozole arm (34 vs. 30 months); however, approximately 50% of the 
patients in the tamoxifen arm crossed over to letrozole at disease progression. Letrozole 
was administered orally on a continuous 2.5 mg daily dosing regimen (5). 
 

 
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Fulvestrant is a novel estrogen-receptor antagonist that, unlike Tamoxifen, is devoid of 
any agonist activity. After binding to the ER, Fulvestrant induces a rapid degradation and 
loss of ER and the PgR(8) (9). As a result, there is less chance of the estrogen receptor 
being activated by alternative pathways that are believed to cause resistance (10).  
Fulvestrant has demonstrated similar activity than Tamoxifen when used as initial 
therapy for the treatment of ER+ metastatic breast cancer progressing on prior endocrine 
therapy with a clinical benefit rate (CBR) of 58% and a median time to progression (TTP) 
of 8.2 months. These data supported Fulvestrant approval by the U.S. Food and Drug 
Administration (FDA) and European Medicines Agency (EMEA) in this scenario (11). 
The combined results of two Phase III clinical trials have shown that Fulvestrant 250 mg 
had at least the same efficacy results as anastrozole when used in the treatment of 
patients with advanced breast cancer who had previously progressed on endocrine 
therapy with a CBR of 43.5% and a median TTP of 5.5 months. These results led to 
license Fulvestrant as second line endocrine therapy (12).  
However pharmacokinetic modelling and evidence of clinical efficacy in early trials, led 
to suggestions that increasing the Fulvestrant dose would lead to an improved benefit-
risk profile. The CONFIRM study is a double-blind, parallel-group, multicenter, phase III 
trial where more than 700 patients were randomly assigned to fulvestrant 500 mg (500 
mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days 
thereafter) or 250 mg every 28 days and followed until progression or death. The primary 
analysis showed a 1-month improvement in median PFS in the group that received the 
higher dose of Fulvestrant (6.5 versus 5.5 months, HR = 0.80; P=0.006). CBR was 45.6% 
for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. A recent release from the study 
(OS after 75% of the patients had died) has shown a significant gain in survival (OS) for 
the high dose fulvestrant (HR 0.80, P=.091). The higher dose did not significantly 
increase the risk of serious adverse events. Based on the results of the CONFIRM trial, 
whenever Fulvestrant is considered for the treatment of menopausal patients with ER 
positive advanced BC, the recommended dose is 500mg (13).  
Fulvestrant high dose (500 mg monthly) has shown great superiority in a phase II trial 
(FIRST study) over anastrozole (23.4 vs. 13.1 months, HR 0.66; 95% confidence 
interval0.47 – 0.92; P = 0.01) (14). The registration phase III trial (FALCON study) is a 
phase III, randomized, double-blind, multicenter study evaluating the efficacy and safety 
of fulvestrant 500mg monotherapy compared to anastrozole 1mg as first line treatment 
for postmenopausal women with hormone receptor-positive locally advanced or mBC 

 
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(NCT01602380)..  Recently, it has been published the results of FALCON study showing 
a median PFS in the fulvestrant arm of 16.6 months vs. 13,8 months in the control arm 
(HR 0.8, [95% CI 0.64-0,99, p = 0.0486). These results confirm the superior efficacy of 
fulvestrant over anastrozole as first-line treatment in postmenopausal women with 
hormone receptor-positive locally advanced or mBC.(16) 
 
1.2. Interaction of Estrogens and Cyclin-Dependent Kinases (CDK) in Breast 
Cancer Cells 
Studies of ER-positive breast cancer cell lines indicate that estrogens and antiestrogens 
act on sensitive populations of cells in early to mid-G1 phase. G1/S transition is under 
the control of CDKs activated by specific complex formation with regulatory cyclins. 
CDK4 and CDK6 are activated by binding to D-type cyclins and act early in G1 phase 
(17)(18) (19) (20). 
A primary target of CDK action in G1 phase is the retinoblastoma susceptibility gene 
product (pRb), which mediates G1 arrest through sequestration of transcriptional factors 
of the E2F-DP family. Phosphorylation of pRb and other members of the pocket protein 
family (p107 and p130) by active cyclin-CDK complexes leads to release of E2F and DP 
transcription factors and transcription of requisite genes for S-phase entry.10 D-type 
cyclins play an essential role in recognition of extracellular growth stimuli and initiation 
of G1 transit(21)(22) and several lines of evidence have linked estrogen regulation of 
cellular proliferation to cyclin D1 expression. Estrogen-induced proliferation of normal 
uterine and breast epithelium in vivo is associated with increased expression of cyclin 
D1 mRNA and protein (23)(24)(25)(26). Expression of cyclin D1 in breast tumor isolates 
correlates with ER-positive status (27)(28)(29).  
Antiestrogen-induced growth arrest of ER-positive breast cancer cells is associated with 
decreased cyclin D1 expression (30). These studies are consistent with a model of 
estrogen action in which receptor activation induces increased cyclin D1 expression, 
CDK4 activation, and cell cycle progression. An upstream role for cyclin D1 has been 
suggested by recent reports describing direct physical interactions between cyclin D1 
and the ER, leading to recruitment of steroid receptor coactivators and activation of ER-
dependent transcription. This occurs in the absence of hormone and is independent of 
D-type cyclin association with CDK4 (31)(32)(33)(34). Constraint upon CDK activity and 
G1 progression is provided by the universal CDK inhibitors of the Cip-Kip family, 
including gp21Cip1 and p27Kip1, and the specific CDK4 and CDK6 inhibitors of the INK4 

 
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family, typified by p16INK4a (22)(35)(36)(37)(38). Functional association of cyclin D1-
CDK4 is required for estrogen-induced CDK2 activation and G1/S transition and 
estrogen regulates expression of p21Cip1, p27Kip1, and Cdc25A independent of D-type 
cyclin-CDK4 function (39). 
 
1.3. Palbociclib (PD-0332991): Selective inhibitor of cyclin dependent kinases 
4 and 6 (CDK4/6) 
Palbociclib (PD-0332991) is an oral and selective inhibitor of cyclin dependent kinases 
4 and 6 (CDK4/6) with little or no activity against a large panel of 274 other protein 
kinases. The only known natural substrate for Cdk4/cyclin D1 is the retinoblastoma gene 
product, Rb. Palbociclib has shown to have no effect in Rb-negative tumor cells.  
Therefore, the phosphorylation status of Rb in treated tumors can serve as a biomarker 
for target modulation by palbociclib. CDK4/6 are involved in cell progression during 
phase G1 to phase S. Inhibition of both: CDK4 and 6 has been shown to prevent the 
deactivation of retinoblastoma susceptibility gene protein and interfere with tumor cell 
progression. In preclinical studies it has been shown that palbociclib inhibits cell growth 
and DNA replication through preventing cells from entering S phase. Palbociclib inhibited 
thymidine incorporation into the DNA of a panel of Rb-positive human breast, colon, and 
lung carcinomas as well as in leukemias and in non-transformed human epithelial cells 
and fibroblasts.  
 
Preclinical data for Palbociclib  
Data form preclinical studies indicate that palbociclib may have cytoreductive as well as 
cytostatic effects on tumor cells. In in vivo studies the MTD in mice was determined to 
be 150mg/kg/day during 14 days. At this regimen palbociclib had significant antitumor 
efficacy against multiple human tumor xenograft models (40). Again it was confirmed 
that Rb-negative tumors do not respond to palbociclib. The lack of efficacy in these cases 
is consistent with the lack of anti-proliferative activity observed in vitro (41).  
Taken together, these results support the proposed mechanism of palbociclib and the 
specificity of the compound demonstrated in enzyme activity test.  
Further studies investigated whether continuous daily dosing of palbociclib was needed 
for optimal efficacy. The results in breast and colon carcinoma models showed that a 

 
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similar degree of efficacy was attained among several schedules of treatment, implying 
that an intermittent regimen is feasible without compromising activity (42) (43).  
The primary toxicities observed in preclinical studies were to the hematolymphopoietic 
tissues and male reproductive organs, and the potential for QT prolongation and 
developmental toxicity. Palbociclib was also identified as an aneugen.  
 
Summary of safety and efficacy clinical data for palbociclib 
At least 15 studies have evaluated the safety, efficacy, pharmacodynamics and 
pharmacokinetics of palbociclib (as single agent or in combination) in solid tumors, 
multiple myeloma, lymphomas and breast cancer (44)(45). As of December 2014 cut-off 
date, 5 clinical studies in patients with palbociclib are on-going/initiated and 3 clinical 
studies have completed. Additionally, palbociclib has been investigated in 15 completed 
and 2 on-going Phase I clinical pharmacology studies in healthy volunteers. Four 
hundred healthy volunteers have received single doses of palbociclib ranging from 50 
mg to 150 mg, and twenty-six healthy volunteers have received multiple doses of 
palbociclib on a 125 mg QD regimen. 
The phase I dose-escalation study A5481001 evaluated two different schedules of 
palbociclib: Schedule 3/1 or 2/1 (two weeks on and 1 week off)(41). Overall the adverse 
events were manageable and reversible. The dose limiting toxicities were similar 
between both schedules and consisted primarily of myelotoxic events. A clear dose 
relationship was evident.  
With the recommended phase 2 dose on the 21-day schedule (125mg/day), 3 of 22 
patients had grade 3 toxic effects during the first cycle, but none had grade 4 toxicity. As 
for the 14-day schedule (with 200mg/day): 6 of 20 patients had grade 3 toxic effects but 
3 of 6 had grade 3/4 toxic effects at the immediately higher dose level. 
The most frequently reported treatment-emergent adverse events (TEAEs) of any grade 
were neutropenia (46%) fatigue (45%) diarrhoea, anaemia and nausea (25%). The most 
frequently reported grade 4 TEAEs was neutropenia (6.6%), thrombocytopenia (3.3%) 
leukopenia (2.2%) and anaemia (1%). No episodes of febrile neutropenia were observed. 
Neutropenia and thrombocytopenia were dose dependent with both nadirs observed at 
the end of the dose period.  
Therapeutic benefit was observed with both treatments schedules: On the 21-day 
schedule, 35% patients achieved stable disease for at least 2 cycles, of whom 6 had 

 
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stable disease for 10 or more cycles at doses ranging from 50 to 150 mg/d. On the 14-
day schedule, 1 patient had a partial response, 9 patients (29%) experienced stable 
disease lasting at least 2 cycles, and 3 patients (10%) had stable disease for 10 or more 
cycles at the 200-mg/d dose level. Greater long-term antitumor activity was observed 
with schedule 3/1, therefore this regimen was selected for further clinical development. 
The recommended phase II dose (RP2D) was 125 mg QD and 200mg QD respectively.  
In the phase II portion of the study A5481003 (phase I/2 study) patients were randomized 
to receive letrozole monotherapy or letrozole plus palbociclib. The most frequent TEAEs 
(≥20% of patients) any grade related to the study treatment were: neutropenia (72%), 
fatigue (28%), leukopenia (42%) and anaemia (28%). Grade 3 Neutropenia was present 
in more than 40% of patients, and leukopenia grade 3 in more than 20%.  
According with the toxicity observed in the previous phase I and phase II trials in the 
phase III study (A5481008) the most frequently reported grade 3 TEAEs were 
neutropenia (12%) and neutrophil count decreased (less than 10%) (46).  
A total of 400 healthy volunteers received single doses of palbociclib, ranging from 50 
mg to 150 mg, as of the December 2014 cut off date. 
The most frequently reported TEAEs of any grade, considered related to study treatment 
were headache (5.0%), nausea (2.8%), somnolence (2.3%) and abdominal distension 
(2.0%). No severe AEs, no serious AEs and no deaths have been reported from these 
studies.  
In summary, it can be concluded that the typical palbociclib toxicity is bone marrow 
toxicity that is generally manageable, predictable, reversible and dose dependent. 
Although phase I studies were not designed with a primary endpoint to test efficacy, 
response rate were evaluated. Stable disease lasting ≥2 cycles were observed in about 
30% of patients. In the A5481003 (PALOMA-1) the response data from the phase I 
portion of the study showed that 33% of patients achieved a PR and another 42% of 
patients had stable diseases for ≥ 6 months. The interim efficacy results form part 1 of 
the phase II portion of study A5481003 showed that the median progression-free survival 
was longer in the combination group (18.2 months vs. 5.7 months) as well as the clinical 
benefit rate (76 vs. 47%) was (47).  
More mature data from this study were reported later in the 2012 CTRC- San Antonio 
Breast Cancer Symposium and thereafter in the AACR (American Association for cancer 
research) Annual Meeting 2014. The final efficacy results from the Phase II portion of the 

 
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study showed that the median progression-free survival was significantly longer in the 
palbociclib plus letrozole arm than in the letrozole alone arm (20.2 months vs. 10.2 
months, respectively) with a hazard ratio of 0.488 (95% CI: 0.319-0.748) in favour of 
palbociclib plus letrozole (p=0.0004). 
The combination was also associated with a higher objective response rate and clinical 
benefit rate than letrozole alone (43% vs. 33% and 81% vs. 58%, respectively [in the 
intent-to-treat population based on investigator assessment]). 
Palbociclib has been authorized for marketing in the U.S. On 03 February 2015 the U.S. 
Food and Drug Administration (FDA) approved palbociclib capsules in combination with 
letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-
positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast 
cancer as initial endocrine-based therapy for their metastatic disease.  
 
1.4. Rationale for combining letrozole with palbociclib 
Preliminary data of the randomized phase II study PALOMA-1 (also known as Study 
1003) were presented at the 2012 CTRC- San Antonio Breast Cancer Symposium. In 
this trial women treated with the combination of palbociclib (125mg once daily for three 
out of four weeks in repeated cycles) + letrozole (letrozole 2.5mg once daily on a 
continuous regimen) achieved a statistically significant improvement in terms of median 
progression free survival (PFS) compared to women in the control arm (26.1 months vs. 
7.5 months) (48). Based on these data, palbociclib received the Breakthrough Therapy 
designation by the United States Food and Drug Administration (FDA). The updates of 
these data were recently reported in the AACR (American Association for Cancer 
Research) Annual Meeting 2014. Women receiving palbociclib + letrozole obtained a 
doubled median of progression-free survival when compared with women in the control 
arm (20.2 months vs. 10.2 months; HR = 0.488, 95%CI: 0.319 – 0.748, p=0.0004) and a 
trend toward increase overall survival (37.5 months vs. 33.3 months; HR = 0.813, 95% 
CI 0.492 – 1.345). The progression free survival results indicated a 51% reduction in the 
risk of disease progression with the addition of palbociclib. The combination arm was 
well-tolerated and the safety profile of the combination was consistent with previously 
reported data. The most common adverse events in the palbociclib arm were 
neutropenia, leukopenia, fatigue and anemia. 
The PALOMA-1 consisted in two different parts: part 1 enrolled 66 patients with 
ER+HER2- mBC, part 2 enrolled 99 additional patients whose tumors presented two 

 
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biomarkers: cyclin D1 amplification and/or p16 loss. The risk for progression of disease 
did not decrease further in patients whose tumors had the molecular targets specific for 
the drug.  
The PALOMA-2 study is a randomized (2:1), multicenter, double blind, placebo 
controlled phase III trial that evaluates palbociclib in combination with letrozole versus 
letrozole plus placebo as first-line treatment for post-menopausal patients with 
ER+/HER2- locally advanced or mBC patients (46). Recent results showed that the trial 
met its primary end-point, median PFS in women treated with the combination resulted 
in an improvement of 10 months in terms of PFS: 24,8 vs. 14,5 months in the control arm  
(HR 0.59; p <.00001) (49). 
 
1.5. Rational for combining palbociclib with fulvestrant 
In the PALOMA-3 study, the combination of palbociclib and fulvestrant was associated 
with significant improvements in progression-free survival compared with fulvestrant plus 
placebo in patients with metastatic breast cancer with disease relapse or progression 
after previous endocrine therapy for advanced disease . Median PFS was 9·5 months 
(95% CI 9·2-11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5-5·6) in 
the control arm (fulvestrant monotherapy) (HR 0·46, 95% CI 0·36-0·59, p<0·0001). (50) 
Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus 
palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The 
most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the 
fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), 
anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious 
adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant 
plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. 
Results from PALOMA-3 trial have supported the expanded indication of palbociclib to 
be used in combination with fulvestrant for treatment of women with HR+/HER2 
advanced or metastatic breast cancer (MBC) whose cancer has progressed after 
endocrine therapy. 
 
1.6. Rational of the study 
Palbociclib registration program includes two phase III trials evaluating palbociclib in 
combination with endocrine therapies in post-menopausal patients with ER+/HER2- 
locally advanced or mBC. The PALOMA-2 trial compares letrozole plus palbociclib to 

 
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single agent letrozole as first line therapy. The PALOMA-3 evaluates the combination of 
fulvestrant and palbociclib to single agent fulvestrant on patients with mBC who 
progressed to an aromatase inhibitor. Both trials are designed to demonstrate superiority 
of the combination arms in terms of progression free survival. However, even if the 
design of both trials is very similar, differing just on the line of therapy (first vs. second), 
their biological assumptions are largely different. While the front line PALOMA-2 trial has 
a solid backbone coming from the PALOMA-1 trial as well as preclinical models, 
PALOMA-3 relies on the assumption that the mechanisms of resistance to aromatase 
inhibitors are not driven or will overlap the cyclin machinery (51).  
On the other hand, FIRST, the phase II study that compared fulvestrant at optimal doses 
(fulvestrant high dose or fulvestrant HD) to anastrozole as front line therapy for ER-
positive mBC, provided robust data in favour of fulvestrant in terms of PFS. Recently, it 
has been announced that the registration phase III study (FALCON) that compares 
fulvestrant to anastrozole as first line treatment for postmenopausal women with no prior 
endocrine therapy has met its primary end-point confirming the superiority of fulvestrant 
HD vs. anastrozole in terms of PFS. However, median PFS in the fulvestrant arm (16.6 
months) though statistically superior to its control arm is inferior to the one achieved in 
the phase II FIRST study (23.4 months). 
An indirect comparison between data available for palbociclib (PALOMA- 1 and 
PALOMA-2) and fulvestrant HD (FIRST and FALCON) identifies favourable Hazard 
Ratios for letrozole-palbociclib and fulvestrant HD compared with standard aromatase 
inhibitors as front line endocrine therapy for ER-positive locally advanced or mBC.  
With two new but different standard of care as front line endocrine therapy for advanced 
breast cancer, exploring the combination of palbociclib plus fulvestrant in the front line 
setting seems mandatory, especially if preclinical data concerning mechanisms of 
resistance are confirmed.  
The present study (PARSIFAL) is an open-label, randomized, controlled, multicenter 
phase II study with the aim of assessing the efficacy and safety of the combination 
palbociclib plus fulvestrant vs. palbociclib plus letrozole in terms of PFS in women with 
ER-positive advanced BC. 
 

 
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1.7. Rational of molecular part of the study 
Estrogen Receptor is the primary therapeutic target in breast cancer and is 
overexpressed in 70% of cases. However, approximately 30% of ER-positive breast 
cancers exhibit de novo resistance, whereas 40% acquire resistance to these therapies. 
In addition to antiestrogen therapies, patients with ER-positive breast cancer are treated 
with aromatase inhibitors such as letrozole and exemestane. As with anti-estrogens, 
treatment with aromatase inhibitors results in the development of resistance, but this is 
presumably due to different mechanisms, as patients with breast cancer who develop 
resistance to aromatase inhibitors often still respond to anti-estrogen therapies. The 
molecular mechanisms of endocrine resistance in ER-positive breast cancer continue to 
be an active area of research. 
One of the best defined mechanisms of resistance to endocrine therapy in breast cancer 
is increased expression of genes related to proliferation, including cyclin D1 and genes 
regulated by MYC, E2F, and RB. These findings provided a strong justification to target 
proteins involved in the G1–S cell-cycle transition like cyclin CDK4/6 in order to 
overcome resistance.  
Palbociclib is a new drug that targets CDK4/6. Preclinical studies have identified the 
luminal estrogen receptor (ER) subtype, elevated expression of cyclin D1 and Rb 
proteins, and reduced p16 expression as associated with sensitivity to palbociclib. In the 
clinical setting, CCND1 amplification and/or loss of p16 were investigated as potential 
predictors of palbociclib sensitivity in the PALOMA-1 trial with little success (52). If little 
is known about markers of sensitivity to palbociclib, the lack of knowledge of the 
mechanisms that drive resistance is even greater and most of the studies in this area 
have been performed in preclinical models. In breast cancer cell lines it has been 
demonstrated that the chronic loss of Rb is specifically associated with evolution to a 
CDK4/6-independent state and, ultimately, resistance to palbociclib (53). On the other 
hand, models of resistance that retain Rb function are related to elevated expression of 
E2F target genes (CCNE1, CCNA2 and E2F1); and this elevated E2F signalling still 
shows sensitivity to palbociclib on a reduced magnitude. Finally, another suggested 
mechanism of palbocicib resistance is Cyclin E1 overexpression (54). 
The PARSIFAL trial offers an unique opportunity to gain insight in the mechanisms 
responsible for the acquisition of resistance to endocrine therapy and palbociclib in the 
clinical setting. The prognostic and predictive value of a variety of biomarkers will be 

 
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evaluated, with particular emphasis in mutations, amplifications and deletions, and 
expression profiles of selected genes. 
Intratumor genetic heterogeneity and clonal evolution/selection during therapy 
significantly compromise the usefulness of primary tumour tissue as a source to study 
predictive biomarkers for metastatic disease (55). For example, ESR1 mutations are 
rarely found within primary tumour tissue, even by means of ultra-deep sequencing, but 
are present in up to 20% of ER-positive metastases and confer resistance to estrogen 
deprivation, potentially increasing with the number of lines of treatment in this situation 
with a very low rate of mutation in non metastatic situation (56). These mutations seem 
to confer resistance to certain endocrine treatments, including aromatase inhibitors or 
tamoxifen, while fulvestrant might be effective in a dose dependant relation (57). 
Furthermore, recently published in vitro data also suggest a lack of sensitivity of ER 
mutated cell clones to CDK4/6 inhibitors such as palbociclib (58).  
Liquid biopsies allow the detection of mutations present within the primary tumour but 
also those which are exclusive to metastases (59). Also, the usefulness of circulating 
free DNA (cfDNA) for mutational analysis in breast cancer has recently been 
demonstrated (60). In view of this evidence, within the PARSIFAL study blood will be 
sequentially collected from patients and circulating free DNA (ctDNA) will be isolated () 
and used to monitor mutations However, due to the extreme fragmentation of cfDNA and 
the fact that mutated alleles are greatly diluted within a dominating population of 
“normal”, non-tumour derived cfDNA, genetic analysis in this setting remains technically 
challenging and it is not yet possible to investigate amplifications and deletions. In 
contrast, plasma has been demonstrate to constitute a useful source of material for RNA 
purification and gene expression analyses at least in some malignancies (61). 
Molecular alterations at the genomic as well as transcriptional level, including 
amplifications/deletions and gene expression profiles yield a wealth of potential 
predictive biomarkers Therefore the analysis of metastatic tissue to identify predictive 
biomarkers still remains indispensable even if this constitutes a more invasive and less 
convenient method than liquid biopsy (62)(63)(64) 
 

 
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2. OBJECTIVES and ENDPOINTS  
2.1. Primary Objective:  
To compare the efficacy of the combination of palbociclib plus fulvestrant versus 
palbociclib plus letrozole in terms of progression free survival (PFS) in patients with 
hormone-sensitive HER2-negative metastatic or locally advanced breast cancer.  
Primary Endpoint: to evaluate the progression-free survival. This is defined as 
the time from randomization until objective tumor progression or death by any 
cause.  
2.2. Secondary objectives: 
• 
To evaluate the safety and tolerability of the combination of palbociclib plus 
fulvestrant or letrozole. 
• 
To correlate the safety profile of palbociclib combined with fulvestrant or letrozole 
with baseline patient characteristics. 
• 
To compare the time to progression (TTP) of the combination of palbociclib plus 
fulvestrant with palbociclib plus letrozole.To compare the clinical response (in 
terms of clinical benefit and overall response) of the combination of palbociclib 
plus fulvestrant with palbociclib plus letrozole. 
• 
To compare the duration of response (DoR) of the combination of palbociclib plus 
fulvestrant with palbociclib plus letrozole. 
• 
To compare time to response (TTR) of the combination of palbociclib plus 
fulvestrant with palbociclib plus letrozole. 
• 
To compare the overall survival (OS) of the combination of palbociclib plus 
fulvestrant with palbociclib plus letrozole. 
• 
To identify potential biomarkers to predict the benefit from Palbociclib combined 
with endocrine therapy  
• 
To identify mechanisms of resistance to palbociclib combined with endocrine 
therapy  
 
Secondary Endpoint-Safety: Patient safety and adverse events will be assessed 
using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE), version 4[1]. Grade 3 and 4 adverse events and serious adverse events 
will be assessed to determine the safety and tolerability of the different drug 
combinations. 
 

 
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Secondary Endpoints-Efficacy: 
✓ The Time to progression (TTP), defined as the time from randomization to 
disease progression, as assessed by the investigator per RECIST v1.1. 
✓ The overall response rate (ORR), defined as the proportion of patients with best 
overall response of confirmed complete response (CR) or partial response (PR) 
based on local investigator’s assessment according to RECIST criteria guidelines 
(version 1.1) (65). An objective response needs to be confirmed at least 4 weeks 
after the initial response. 
✓ Duration of response (DoR) is defined as the time from documentation of tumor 
response (either CR or PR) to disease progression. 
✓ TTR is defined as the time from randomization to the first overall tumor response 
(tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR. 
✓ Clinical Benefit Rate (CBR) defined as the percentage of patients who experience 
a CR, PR or stable disease (for at least 24 weeks) and assessed by modified 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria.  
✓ The overall survival (OS), defined as the time from randomization until death from 
any cause. 
 
Secondary Endpoints-Translational sub-studies  
✓ Presence of different pattern of expression of ESR1 mutations and other CDK4/6 
related biomarkers (i.e. Rb, Akt, PIK3, p53 CA cyclin D1, cyclin A2, E2F1...) in 
liquid biopsies and tissue samples. 
✓ Proteomics analysis to evaluate differential pattern of protein expression from 
tissue samples. 
✓ Exome and RNA sequencing will be performed in selected samples 
 
 

 
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3. STUDY OVERVIEW 
3.1. Study Design 
This is an international, randomized, open-label, controlled, multicenter phase II clinical 
trial to investigate and compare the safety and efficacy of palbociclib combined with 
fulvestrant or letrozole in women with ER+, HER2- locally advanced or metastatic breast 
cancer. 
Eligible patients will have histologically proven diagnosis of adenocarcinoma of the 
breast with evidence of locoregionally recurrent or metastatic disease and will be 
candidates to receive letrozole as first-line treatment for their advanced disease. Patients 
could not be eligible if they are candidates for a local treatment with a radical intention. 
In order to avoid inclusion of patients who are refractory or resistant to endocrine therapy, 
patients who received endocrine therapy as a component of their (neo)adjuvant regimen 
may only enter the study if their disease did not progress while on or within 12 months 
from completion of their endocrine-containing (neo)adjuvant therapy. Patients should not 
have received endocrine therapy or prior chemotherapy for their advanced disease. 
Patients can have measurable disease as per RECIST v.1.1 or non-measurable disease 
(except for patients with only blastic bone lesions, patients with only pleural, peritoneal 
or cardiac effusion, or meningeal carcinomatosis).  
At least 486 eligible patients will be randomized 1:1 to receive either palbociclib (PD-
0332991) plus fulvestrant (Arm A: at least 243 patients) or palbociclib (PD-0332991) plus 
letrozole (Arm B: at least 243 patients).  
Patients will be stratified by site of disease (visceral1 vs. non-visceral2), and by the onset 
of metastatic disease diagnose (de novo metastatic versus non de novo patients). 
 
3.2. Study treatment management 
After signing the informed consent form, patients will be randomized (1:1) to one of two 
therapy regimens: 
 
• 
Patients in Arm A will receive fulvestrant 500 mg/5mL i.m. injection administered on 
Days 1 and 14, of a 28-day cycle on cycle one and one monthly thereafter. 
 
1 Visceral: refers to any lung (including pleura) and/or liver involvement 
2 Non-visceral: refers to absence of lung (including pleura) and/or liver involvement 

 
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Palbociclib 125 mg total dose will be taken orally once daily beginning on Day 1 of 
fulvestrant and continuing throughout Day 21 of every 28-day cycle. 
 
• 
Patients in Arm B will receive letrozole 2.5 mg orally once daily beginning on Day 1 
and continuing through Day 28 of a 28-day cycle. Palbociclib 125 mg capsules will 
be taken orally once daily beginning on Day 1 of letrozole and continuing throughout 
Day 21 of every 28-day cycle. 
 
Patients will continue to receive their assigned treatment until objective disease 
progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of 
consent, whichever occurs first.  
All patients who have not progressed and are still in receipt of study treatment at the end 
of the study (EoS), as defined here in section 3.7, at the discretion of the investigator 
might continue to receive the study treatment. In this case, the investigator should follow 
the patient appropriately as per standard clinical practice. Sponsor supply for study IMPs 
will continue after the end of the study if IMPs are not available in a reimbursed setting.  
Patients discontinuing the study treatment period will enter a treatment follow-up period 
during which survival and new anti-cancer therapy information will be collected every 6 
months from the last dose of investigational product. The study follow-up period will conclude 
when trial efficacy decision criteria are met. The final analysis should occur with 254 PFS events 
and 486 patients included. Efficacy analyses will be performed using the local 
radiologist’s/investigator’s tumour assessments as primary data source. 
 
3.3. General Concomitant Medication and Supportive Care Guidelines 
Concomitant therapy and pre-medications are defined as non-IMPs. Concomitant 
therapy includes any prescription medication, over-the-counter preparation, or herbal 
therapy between the 21 days preceding first treatment and the safety follow up visit (28 
+/- 7 days of last IMP administration). All concomitant therapies will be registered until 
the safety follow-up visit. Afterwards, only information about further anti-cancer therapies 
received by the patient once she goes off study will be collected. 
All concomitant medications will include the start date, stop date, brand or generic name, 
route of administration, dose and indication for the treatment.  

 
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No pre-medication for any study arm is required; however, pre-medication is allowed at 
the investigator’s discretion. 
The main target organ for toxicity is bone marrow. Erythropoiesis stimulating agents 
(ESAs) (such as Procrit®, Aranesp®, Epogen®) may be used for supportive care 
according to recommendations of National Comprehensive Cancer Network (NCCN) 
guidelines. Granulocyte-colony stimulating factors should not be used prophylactically 
but they may be used in treatment-emergent neutropenia in accordance NCCN 
guidelines. 
Once the patient is on study treatment, palliative radiotherapy may be permitted to treat 
pre-existing painful bone metastases or to treat brain metastases (for patients who have 
disease control outside of the brain). Please contact the Medical Monitor for approval. 
Other medications considered necessary for the patient’s safety and wellbeing may be 
given at the discretion of the investigator. Use of bisphosphonates or denosumab is 
permitted for the control of bone pain, prevention and/or treatment of bone metastases, 
and treatment of osteoporosis. If bisphosphonates are required either for the treatment 
of symptomatic malignancy-associated hypercalcemia or for pain control, tumor 
assessments should be performed to assess for potential disease progression. 
 
3.4. Prohibited therapies 
Use of the therapies described below is prohibited during the study prior to 
discontinuation of study treatment (collectively, these will be referred to as non-protocol 
therapy): 
Any therapies intended for the treatment of cancer, other than palbociclib, fulvestrant or 
letrozole whether they are approved by national health authorities or experimental, 
including cytotoxic chemotherapy, immunotherapy, hormonal therapy, and biologic or 
targeted agents are prohibited. 
Palbociclib is primarily metabolized by CYP3A4 enzymes, the concurrent use of strong 
CYP3A inhibitors or inducers may change the plasma concentrations of palbociclib. For 
this reason the concurrent use of strong CYP3A inhibitors or inducers should be avoided. 
Strong inhibitors of CYP3A include but are not limited to boceprevir, clarithromycin, 
conivaptan, delavirdine,, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
lopinavir/ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole, grapefruit juice and grapefruit. Strong inducers of CYP3A 

 
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include but are not limited to carbamazepine, enzalutamide, felbamate, nevirapine, 
phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s Wort 
Coadministration of moderate CYP3A inducers may also decrease the plasma exposure 
of palbociclib. Moderate CYP3A inducers including, but not limited to, bosentan, 
efavirenz, etravirine, modafinil, and nafcillin can be used concurrently with palbociclib 
when it cannot be avoided. No dosing adjustments are required.  
Palbociclib is a weak time -dependent inhibitor of CYP3A following daily 125 mg dosing 
to steady state in humans. The dose of the sensitive CYP3A substrate with a narrow 
therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be 
reduced as palbociclib may increase their exposure. 
Radiotherapy for unequivocal disease progression is not permitted while on study 
treatment, with the following exception of new central nervous system (CNS) metastases 
or isolated progression of previously treated CNS lesions. Patients who have disease 
control outside of the CNS, defined as confirmed PR or CR of any duration, or SD for ≥ 
3 months, but who have developed CNS metastases that are treatable with radiation will 
be allowed to continue to receive study therapy until they either experience systemic 
progression of their disease outside of the CNS and/or further progression in the CNS 
that cannot be treated with additional radiation. Patients must not miss more than one 
cycle of study treatment for the treatment of their CNS metastases and must have an 
ECOG performance status of 0, 1, or 2 to continue on study treatment. The Medical 
Monitor should be informed before a decision is made to resume study treatment after 
radiotherapy for CNS metastases. 
Drugs known to cause QT interval prolongation are also prohibited during the active 
treatment phase. 
In general, the following treatments are not prohibited but they are not recommended 
during the treatment phase:  
• 
Chronic immunosuppressive therapies including systemic corticosteroids. Steroids 
given for physiological replacement, as anti-emetics or inhaled as well as short 
course of oral/topical steroids given for allergic reactions or asthma flares are allowed 
if daily dose is below of 10 mg  of methylprednisolone equivalent. 
• 
 Herbal medicine. 
 

 
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3.5. Duration of study treatment 
The study treatment period is defined as the time between the study entry (date of 
randomization) and the last dose of interventional arm (Arm A) or control arm (Arm B) 
regimens. 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue with the protocol therapy, 
the study treatment should be discontinued and the reason(s) for discontinuation 
documented in the clinical records of the patient and corresponding case report form. 
Study treatment may continue until one of the following criteria applies: 
- 
Radiologically confirmed and documented unequivocal disease progression, with the 
following exception of new CNS metastases or isolated progression of previously 
treated CNS lesions. Patients who have disease control outside of the CNS, defined 
as confirmed PR or CR of any duration, or SD for ≥ 3 months, but who have 
developed CNS metastases that are treatable with radiation will be allowed to 
continue to receive study therapy until they either experience systemic progression 
of their disease outside of the CNS and/or further progression in the CNS that cannot 
be treated with additional radiation 
- 
Adverse event(s) that according to the protocol or in the judgment of the investigator 
may cause severe or permanent harm or which rule out continuation of study drug. 
Note: see detailed criteria for study treatment discontinuation due to toxicity in section 
7.  
- 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
- 
Serious non-compliance with the study protocol. 
- 
Investigator removes the patient from study. 
- 
Death. 
- 
Lost to follow-up. 
- 
Patient withdraws consent. 
- 
The study site or the sponsor decides to close the study. 
 
All patients who have not progressed and are still in receipt of study treatment at the end 
of the study (EoS), as defined here in section 3.7, at the discretion of the investigator 
might continue to receive the study treatment. In this case, the investigator should follow 
the patient appropriately as per standard clinical practice. Sponsor supply for study IMPs 
will continue after the end of the study if IMPs are not available in a reimbursed setting.  

 
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3.6. Duration of treatment follow-up period 
Patients should continue until trial efficacy decision criteria are met. The final analysis should 
occur with 254 PFS events and 486 patients included.  
 
3.7. End of Study (EoS) 
EoS will be achieved when trial efficacy decision criteria are met (final analysis expected with 254 
PFS events and 486 patients included), unless premature termination of the study. This will be 
the last data collection point, which can be a clinic visit or a laboratory sample. 
Patients discontinuing the study should be followed-up as per standard clinical practice.  
 
4.  
PATIENT SELECTION 
This study can fulfil its objectives only if appropriate patients are enrolled. The following 
eligibility criteria are designed to select patients for whom the protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient. 
4.1. Target study population 
This study will enrol postmenopausal patients or pre-menopausal patients under 
treatment with LHRH analogues with histologic confirmation of the ER (oestrogen and/or 
progesterone-positive) and HER2-negative locally advanced or metastatic BC. Breast 
cancer that have at least 1% of cells staging positive for ER should be considered ER-
positive according to NCCN and ASCO guidelines (1)(2). Evidence of measurable 
disease (as for RECIST 1.1) or non-measurable disease is required (Patients with only 
blastic bone lesions, only pleural, cardiac or peritoneal effusion or meningeal 
carcinomatosis are not eligible. Patients are not eligible if they are candidates for a local 
treatment with a radical intention.  
 
4.2. Inclusion criteria 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 

 
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Patients must meet all of the following inclusion criteria to be eligible for enrolment into 
the study: 
1. Postmenopausal women, as defined by any of the following criteria: 
• 
Age 60 or over 
• 
Age 45 to 59 years and meets ≥ 1 of the following criteria: 
o Amenorrhea for ≥ 24 months  
o Amenorrhea for < 24 months and follicle-stimulating hormone within the 
postmenopausal range (including patients with hysterectomy, prior 
hormone replacement therapy, or chemotherapy-induced amenorrhea) 
• 
Over 18 years of age and bilateral oophorectomy 
OR 
Premenopausal women provided they are being treated with LHRH analogues for at 
least 28 days prior to study entry 
2. Eastern Cooperative Oncology Group (ECOG) score lower or equal to 2 
3. Histologically confirmed recurrent ER positive (oestrogen and/or progesterone) 
HER2-negative locally advanced or metastatic BC patients (Breast cancer that 
have at least 1% of cells staging positive for ER should be considered ER-positive 
according to NCCN and ASCO guidelines (1,2)) 
4. Patients should not be candidates for a local treatment with a radical intention.  
5. No prior hormonal or chemotherapy line in the metastatic setting  
6. Patient must have measurable (according to RECIST 1.1) or non measurable 
disease with these exceptions 
▪ 
Patients with only blastic bone lesions are not eligible 
▪ 
Patients with only pleural, peritoneal or cardiac effusion, or meningeal 
carcinomatosis are not eligible 
7. Life expectancy greater or equal to 12 weeks 
8. Adequate organ function: 
• 
Hematological: White blood cell (WBC) count >3.0 x 109/L, absolute 
neutrophil count (ANC) >1.5 x 109/L, platelet count >75.0 x109/L, and 
hemoglobin >10.0 g/dL (>6.2 mmol/L) 
• 
Hepatic: bilirubin < 1.5 times the upper limit of normal (x ULN); alkaline 
phosphatase (ALP), aspartate transaminase (AST), and alanine 
transaminase (ALT) <2.5 times ULN. Patients with ALP ≥2.5 times ULN 
are eligible if ALP abnormalities are unequivocally related to bone lesions 
(radiological assessments performed within 4 weeks prior to 
randomization demonstrated bone metastatic disease). 

 
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• 
Renal: serum creatinine < 1.5 x ULN. 
9. Exhibit patient compliance and geographic proximity that allow for adequate 
follow-up. 
10. Patient has been informed about the nature of study, and has agreed to 
participate in the study, and signed the Informed Consent form prior to 
participation in any study-related activities. 
11. No other malignancies within the past five years except adequate treated basal 
cell or squamous cell skin cancer or carcinoma in situ of the cervix 
12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical 
procedures to NCICTCAE version 4.0 Grade 1 (except alopecia or other 
toxicities not considered a safety risk for the patient at investigator's discretion). 
13. Patient has been informed about the translational sub-study and has agreed to 
participate in the collection of blood and tumor tissue samples by signing the 
Informed Consent form. 
 
4.3. Exclusion criteria 
Patients will be excluded from the study if they meet ANY of the following criteria: 
1. ER or HER2 unknown disease 
2. HER2 positive disease based on local laboratory results (performed by 
immunohistochemistry/FISH) 
3. Locally advanced breast cancer candidate for a radical treatment. 
4. Prior endocrine therapy in the metastatic setting is not allowed. (Neo)/Adjuvant 
endocrine therapy is allowed only if the disease-free interval between the end of 
endocrine therapy and the appearance of metastases in higher than 12 months. 
5. Patients with rapidly progressive visceral disease or visceral crisis 
6. Have had a major surgery (defined as requiring general anaesthesia) or 
significant traumatic injury within 4 weeks of start of study drug, patients who 
have not recovered from the side effects of any major surgery or patients that 
may require major surgery during the course of the study 
7. Patients with an active, bleeding diathesis 
8. Have a serious concomitant systemic disorder (e.g. active infection including HIV, 
or cardiac disease) incompatible with the study (at the discretion of investigator), 
previous history of bleeding diathesis, or anti-coagulation treatment (The use of 
low molecular weight heparin is allowed as soon as it is used as prophylaxis 
intention). 

 
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9. Are unable to swallow tablets 
10. History of malabsorption syndrome or other condition that would interfere with 
enteral absorption 
11. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day 
methylprednisolone equivalent (excluding inhaled steroids).  
12. Known active uncontrolled or symptomatic CNS metastases, carcinomatous 
meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral 
oedema, and/or progressive growth. Patients with a history of CNS metastases 
or cord compression are eligible if they have been definitively treated with local 
therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable off 
anticonvulsants and steroids for at least 4 weeks before randomization  
13. Known hypersensitivity to letrozole, fulvestrant or any of their excipients, or to 
any PD-0332991 excipients. 
14. QTcF >480 msec on basal assessments, personal history of long or short QT 
syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade 
de Pointes (TdP). 
15. Uncontrolled electrolyte disorders that can compound the effects of a QTc-
prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia). 
 
5.  ASSESSMENTS AND STUDY PROCEDURES 
5.1. Patient entry procedures 
It should be obtained written patient informed consent prior to undergoing any study 
related procedures.  
Patients will be randomized into the study provided they have satisfied all patient 
selection criteria.  
At the time of randomization, information about patient demographics and stratification 
factors will be requested. Patients will be stratified based on: 
• 
Site of disease: visceral vs. non-visceral involvement 
• 
Onset of metastatic disease diagnose: Patients with metastasis de novo vs. 
relapse to prior therapy. 
Patients will be assigned to one of the two treatment groups based on a randomisation 
schedule prepared previously by the sponsor. 

 
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Each patient will be identified with a unique patient number (UPN) for this study by the 
sponsor. All data will be recorded with this identification number on the appropriate 
CRFs. 
 
5.2. Study assessments  
Medical History and Demographic Data: Medical history includes clinically significant 
diseases, surgeries, cancer history (including prior cancer therapies and procedures), 
smoking history, use of alcohol and drugs of abuse, and all medications (e.g., 
prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, nutritional 
supplements) used by the patient within 21 days prior to the screening visit. Demographic 
data will include age, sex, and self-reported race/ethnicity. 
Vital Signs: Vital signs will include measurements of height (at screening only), weight, 
respiratory rate, heart rate, blood pressure, and temperature. Abnormal or significant 
changes to vital signs from baseline should be recorded as adverse events, if 
appropriate.  
Physical Examinations: A complete physical examination should include the evaluation 
of head, eye, ear, nose, and throat; cardiovascular; dermatological; musculoskeletal; 
respiratory; gastrointestinal; and neurological systems. Changes from baseline 
abnormalities should be recorded at each subsequent physical examination. New or 
worsened abnormalities should be recorded as adverse events if appropriate. 
As part of tumour assessment, physical examinations should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
Limited physical examinations will be symptom-directed. 
Tumour and Response Evaluations: All patients are evaluable for disease response 
unless they come off study due any reason other than clinically or radiological confirmed 
disease progression and have not had any acceptable complete disease assessment. 
Measurable and no-measurable disease must be documented at screening and re-
assessed at each subsequent tumour evaluation. 
Disease assessment should be evaluated preferably by CT or MRI since these methods 
are the best currently available and reproducible techniques to measure lesions selected 
for response assessment. 

 
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In the event a positron emission tomography (PET)/CT scanner is used for tumor 
assessments, the CT portion of the PET/CT must meet criteria for diagnostic quality. 
Tumor assessments should include an evaluation of all known and/or suspected sites of 
disease, whenever possible. Patients should have lesions selected that can be evaluated 
at every tumor assessment. 
The same radiographic procedure used at screening must be used throughout the study 
(e.g., the same contrast protocol for CT scans). 
 If a bone scan cannot be performed during the course of the study because of the 
unavailability of the Tc-99m isotope, the investigator may choose an alternative imaging 
modality. See Appendix 3: Instructions for Scans in the Event of Isotope Shortage. 
Radiographic imaging should always be performed rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
examination. As per RECIST v.1.1 criteria, documentation by colour photography 
including a ruler to estimate the size of the lesion is recommended. 
At baseline all patients should be assessed as follows:  
• 
Assessment of thorax, abdomen, and pelvis 
• 
Bone scan 
o If bone involvement is identified at baseline, bone scan should be 
repeated every 24 weeks ( 7 days). If bone lesions meet RECIST 
criteria to be followed by CT, bone lesion can be followed-up as 
part of the 12-week periodical tumor assessments. 
 
o If no bone involvement is identified at baseline, it is no necessary 
to repeat the bone scan unless clinically or biochemically 
suspected bone progression.  
 
Bone lesions identified at baseline should be followed by bone scans every 24 weeks ( 
7 days) regardless that identified bone lesions could contain soft tissue that can be 
evaluated by CT or MRI. 
 
• 
CT or MRI of the brain must be obtained at screening only for those patients with 
clinical suspicion of central involvement. If during the study, patient is diagnosed 
with CNS metastases, but with disease control outside of the CNS, patient will be 
allowed to continue receiving study treatment. Medical monitor should be 

 
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contacted to agree the best approach to manage patients with CNS involvement 
on case by case basis. 
 
Tumor response assessments will be performed every 12 weeks (±7 days) from the date 
of randomization until radiographically and/or clinically documented PD as per RECIST 
v.1.1, study treatment discontinuation, initiation of new anticancer therapy or 
discontinuation of patient from overall study participation (e.g., death, patient's request, 
lost to follow-up), whichever occurs first. Initial tumor response assessment will be 
performed at the end of cycle 3. Each assessment will be performed as scheduled 
according to the calendar regardless of any dosing delay to prevent the introduction of 
bias into the assessment of efficacy. Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for that time point.  
Response assessments will be assessed by the investigator, based on physical 
examinations, CT or MRI scans, and bone scans using RECIST v. 1.1 (see Appendix 2: 
Response Evaluation Criteria in Solid Tumors (RECIST criteria) guidelines (version 1.1)). 
At the investigator’s discretion, CT scans, MRI scans, and/or bone scans may be 
obtained at any time when clinically indicated or if progressive disease is suspected. 
 
Laboratory Assessments 
Local Laboratory Assessments: Prospective endocrine receptors and HER2 status, 
haematology and biochemistry. Patients will be enrolled based on local results.  
 
Laboratory test will be performed as per local standard of care and clinical indication 
before treatment administration. These values should be included: hemoglobin, 
hematocrit, red blood cell count, platelet count, and white blood cell count with differential 
count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), sodium, 
potassium, calcium, chloride, magnesium, uric acid, total protein, alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase, gamm-glutamyl transferase, 
lactate dehydrogenase, total bilirubin, blood glucose and creatinine.  
 
Electrocardiograms: A 12-lead ECG should be obtained at baseline and be printed and 
kept with the patient’s record. Thereafter, the electrocardiograms will be performed every 
3 cycles starting on cycle 3 up to End of treatment visit. The QT interval corrected as per 
Fridericia’s formula must be recorded (QTcF).  
 

 
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ECOG Performance Status: Performance status will be measured using the ECOG 
performance status scale (see below). It is recommended, where possible, that a 
patient’s performance status be assessed by the same person throughout the study. 
 
Table 1. Scale of ECOG Performance Status 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, i.e., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
5 
Dead 
(http://www.ecog.org/general/perf_stat.html) 
 
Samples for translational evaluation of molecular biomarkers 
Blood samples will be collected from all patients participating in the study at four time 
points: baseline (prior to first treatment dose), after 2 and 12 weeks of treatment start 
and at time of progression (before starting new anti-tumor treatment). 
Additionally, patients must consent to provide tumor samples from metastatic tissue at 
baseline and at time of progression (if biopsable lesion at relapse). For non de novo 
patients, tumor tissue at the time of metastatic disease diagnose is requested as 
preferred option,though at least archived tissue sample from the primary tumor could be 
also acceptable. If available, archived primary tumor sample must be collected even 
though tissue sample corresponding to the advanced disease is also obtained prior to 
study treatment start. 
See Appendix 4: Translational evaluation of molecular biomarkers sub study for further details 
 
5.3. Schedule of assessments 
Study assessments are outlined in Appendix 1: Schedule of assessments and study 
procedures 
Written informed consent for participation in the study must be obtained before 
performing any study specific screening tests or evaluations. Informed Consent Forms 

 
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for enrolled patients and for patients who are not subsequently enrolled (screening 
failures) will be maintained at the study site.  
Results of standard of care tests or examinations performed prior to obtaining informed 
consent and within 28 days prior to study start may be used (for bone scans that period 
is up to 60 days prior to the start of study treatment); such tests do not need to be 
repeated for screening.  
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before study start. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Visits are based on scheduled 28-day cycles (if no treatment delay due to toxicity occurs). 
Dose delays and dose reductions will be allowed as outlined in section 6.8. All visits must 
occur within ± 3 business days from the scheduled date, unless otherwise noted in the 
schedule of assessments. All assessments will be performed on the day of the specified 
visit unless a time window is specified. Assessments scheduled on the day of study 
treatment administration should be performed prior to study treatment administration 
unless otherwise noted. If the timing of a protocol-mandated procedure falls within a 
holiday period and/or weekend, it should be performed on the nearest following date (i.e., 
within 3 business days).  
Local laboratory assessments scheduled on Day 1 of all cycles (additional hemograms 
on D14 of Cycle 1 and 2) must be performed within 72 hours prior to study treatment 
administration unless otherwise specified. Results of local laboratory assessments must 
be reviewed and the review documented prior to study treatment administration. 
All patients will be closely monitored for safety and tolerability during study treatment and 
at the follow up period. Patients should be assessed for toxicity prior to any study 
treatment administration; dosing will occur only if the clinical assessment and local 
laboratory test values are acceptable.  
 
Efficacy follow up: Initial tumour response assessment will be performed at the end of 
cycle 3. Thereafter, all patients will be followed up for efficacy every 12 weeks during the 
study period until progression, patient withdraws consent or death, whichever occurs 
first. Response and progression will be evaluated in this study using the Response 
Evaluation Criteria in Solid Tumors (RECIST version 1.1) (Appendix 2: Response 
Evaluation Criteria in Solid Tumors (RECIST criteria) guidelines (version 1.1)). 

 
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Treatment follow up: Patients who discontinue study drugs for any reason will be followed 
up to EoS (as defined in section 3.7) or up to study termination, whichever occurs first.  
The first safety follow up visit for the study treatment will be scheduled for all patients 28 
days (+/- 7 days) after the last dose of any IMP. 
Afterwards, patients will be followed every 6 months at least, up to EoS or the patient 
withdraws consent or until death, whichever occurs first. During these follow-up contacts 
it will be collected survival status and post study anticancer therapy evaluation. 
Telephone contact is acceptable. 
All ≥ grade 2 adverse events will be followed up until improvement to baseline levels, 
grade 1 or complete recovery, the patient withdraws consent, patient’s death or lost to 
follow-up. 
Summary of study assessments will be reported in Appendix 1: Schedule of 
assessments and study procedures 
 
5.4. Patient, study, and site discontinuation 
Patient discontinuation: Patients have the right to withdraw from the study at any time 
for any reason and without having to detail their reasons to do so. The investigator has 
the right to discontinue a patient from study treatment or from the study for any medical 
condition that the investigator determines may jeopardize the patient’s safety if she 
continues in the study, for reasons of non-compliance (e.g., missed doses, visits), if the 
patient becomes pregnant, or if the investigator determines it is in the best interest of the 
patient. 
Patients must be withdrawn from study treatment if they experience disease progression 
defined using RECIST v. 1.1. The exception to this is patients who develop isolated 
progression in the brain as described in section 3.4. 
Details of discontinuation due to toxicity are given in section 7. 
Patients who discontinue from study treatment prematurely will continue to be followed 
according to section 5.4 with the exception of patients who withdraw consent and have 
not the willingness to be followed up. The primary reason for discontinuation must be 
recorded on the appropriate Case Report Form (CRF) section. 
 

 
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Study discontinuation: Section 3.7 describes the EoS definition and discontinuation of 
study.  
A subject will be withdrawn from the study (i.e. from any further study procedure) for any 
of the following reasons: 
• 
Withdraws consent. 
• 
Lost to follow-up. 
In case a subject is lost-to-follow-up, every possible effort must be made by the study 
site personnel to contact the subject and determine the reason for discontinuation. The 
measures taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to 
be documented on the CRF and in the source documents. Subjects who withdraw will 
not be replaced. 
Prior to that, the Sponsor has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, the following: 
- 
The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to patients 
- 
Patient enrolment is unsatisfactory 
- 
Steering Committee’s recommendation after Interim-analysis results 
- 
Data recording is inaccurate or incomplete 
 
6. STUDY DRUGS INFORMATION 
6.1. Drug supplies 
.  
Palbociclib updated information is reported in the current version of the study document 
Palbociclib Investigator’s Brochure. 
Refer to Investigator’s Brochure for fulvestrant (Faslodex®) and summary of product 
characteristics (SmPC) for letrozole for additional administration instructions and further 
information. 
 
6.2. Formulation and Packaging 
Palbociclib (PD-0332991) will be supplied as capsules containing 75 mg, 100 mg, or 
125 mg equivalents of PD-0332991 free base. The sponsor will supply the oral drug 

 
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formulation to sites in HDPE (High-density polyethylene) bottles containing 75 mg, 100 
mg, or 125 mg capsules. The capsules can be differentiated by their size and colour (see 
below). 
 
Table 2. Palbociclib Capsule Characteristics 
Dosage 
Capsule colour 
Capsule size 
75 mg 
Sunset Yellow/Sunset Yellow 
2 
100 mg 
Caramel/Sunset Yellow 
1 
125 mg 
Caramel/Caramel 
0 
 
Fulvestrant: will be supplied as two pre-filled syringe (5 ml) that contains each one 250 
mg fulvestrant and other ingredients (excipients) like ethanol (96 per cent), benzyl 
alcohol, benzyl benzoate and castor oil. Fulvestrant is a clear, colourless to yellow, 
viscous solution in a pre-filled syringe fitted with a tamper-evident closure, containing 5 
ml solution for injection. Two syringes must be administered to receive the 500 mg 
recommended monthly dose. 
 
Letrozole: Commercially available letrozole 2.5 mg film-coated tablets will be used in 
the study. 
 
6.3. Preparation and Dispensing 
Palbociclib will be supplied in non-patient-specific bottles containing either 23 capsules.  
Fulvestrant will be supplied in non-patient-specific box containing two pre-filled syringe 
(5 ml). 
Commercially available letrozole will be supplied to the patients in non-patient-specific 
packages containing enough tablets to cover the treatment of the 28-day cycle. 
 
For Palbociclib: The unique patient number (UPN) should be recorded on the box label 
in the spaces provided at the time of assignment to patient. Site personnel must ensure 
that patients clearly understand the directions for self-medication. Patients should be 
given sufficient study medication to cover study treatment until their next study visit. 
Unused drug and/or empty bottles should be returned to the site at the next study visit. 
Returned unused medication MUST NOT be re-dispensed to patient. 
Palbociclib is an agent that must be handled and administered with care. Patients should 
be instructed to keep their medication in the bottles provided and not transfer it to any 

 
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other container. Due to possible unknown hazards associated with topical and 
environmental exposure to experimental agents, capsules must not be opened and/or 
emptied into any vehicle for oral ingestion; capsules must be swallowed intact. 
Only one bottle containing an specific capsule strength will be dispensed to the patient 
at each dispensing visit. In the event of dose modification, patient will be requested to 
return all previously dispensed medication to the clinic before new capsules are 
dispensed. 
 
For Fulvestrant: The unique patient number (UPN) should be recorded on the box label 
in the spaces provided at the time of assignment to patient. The administration of this 
medication should be done at the investigational center/hospital. Refer to the 
Investigators Brochure for Faslodex® for additional administration instructions. 
 
6.4. Administration 
For both palbociclib and letrozole: 
• 
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” 
the next day. 
• 
Patients who vomit any time after taking a dose must be instructed NOT to “make 
it up,” and to resume treatment the next day as prescribed. 
• 
Patients who inadvertently take 1 extra dose during a day must be instructed to 
skip the next day’s dose. Also refer to Section 6.5 for further details on medication 
errors and overdose. 
 
Palbociclib:  
• 
Patients should take palbociclib capsules with food. 
• 
Patients should be instructed to swallow palbociclib capsules whole and not to 
chew them prior to swallowing. 
• 
No capsule should be ingested if it is broken, cracked, or otherwise not intact. 
• 
Patients should be encouraged to take their dose at approximately the same time 
each day. 
• 
Patients should be instructed to record daily administration of the study drugs in 
the document Patient Diary. 
 

 
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Palbociclib will be administered orally once a day for 21 days of every 28-day cycle 
followed by 7 days off treatment. 
Patients experiencing investigational product related toxicity may have their dose 
modified according to Section 6.8. 
 
Fulvestrant injection should be administered as two consecutive 5 ml injections into the 
gluteus maximus muscle under pressure (one injection in each buttock). The injection 
should take approximately 1-2 minutes. The administration of fulvestrant should be done 
by qualified personnel. It is recommended to remove from the refrigerator for a short 
period of time until room temperature is reached or rolling the prefilled syringe between 
the palms of the hands for a short period of time prior to administration. It is important to 
make sure that the patient is comfortable before the administration. The patient either 
can lie in a prone or semi-prone position or can stand while leaning forward. 
Fulvestrant should be administered every 28 days. During the first cycle it is necessary 
a loading dose (it will be administered on Days 1, and 14). 
 
Letrozole: Letrozole will be administered orally once daily continuously together with 
palbociclib or alone in the event of palbociclib dosing interruption.  
 
6.5. Medication Errors and Overdose 
Medication errors may result in this study from the administration or consumption of the 
wrong drug, by the wrong patient, at the wrong time, or at the wrong dosage strength. 
Such medication errors occurring to a study participant are to be captured on the 
appropriate CRF section. In the event of medication dosing error, the sponsor should be 
notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving patient exposure to the investigational product; 
• 
Potential medication errors or a use outside of what is foreseen in the protocol 
that does or does not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error should be captured on the adverse event (AE) page. 
 

 
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6.6. Compliance 
At the beginning of each cycle patients will be required to return all bottles of palbociclib 
and all packages of letrozole as well as the completed patient diary for drug 
accountability. The fulvestrant drug accountability will be required to the investigational 
site staff.  
Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug 
supply for the next cycle. The number of remaining capsules/tablets or the number of 
injection i.m. administered will be documented and recorded. 
To be considered compliant, each study patient must have received at least 80% of the 
planned number of doses of primary therapy based on the number of days of actual dose 
administration. Dose adjustments must follow instructions provided in the section 6.8. 
 
6.7. Drug Storage and Drug Accountability 
Storage conditions stated in the Study Reference Safety Document (i.e., Investigator’s 
Brochure (IB), Summary of Product Characteristics (SmPC), or Local Product Document 
(LPD) may be superseded by the label storage. 
Investigators and site staff are reminded to continuously monitor room storage 
temperatures and ensure that thermometers are working correctly as required for proper 
storage of investigational products. This requirement includes thermometers for both the 
room storage and refrigerator storage. Any temperature excursions must be reported 
immediately to the sponsor and documented. Once a deviation is identified, the 
investigational products MUST be quarantined and not used until the sponsor provides 
documentation of permission to use the investigational product. 
At the end of the trial, the sponsor will provide instructions as to disposition of any unused 
investigational product. If the sponsor authorizes destruction at the trial site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
the sponsor. Destruction must be adequately documented. 
Palbociclib: Palbociclib capsules should be stored at controlled room temperature (15-
30ºC, 59-86ºF) in their original container. 
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements. Returned medication should be stored separately 
from medication that needs to be dispensed. 

 
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To ensure adequate records, palbociclib capsules will be accounted for as instructed by 
the sponsor. Patients are requested to return previously dispensed containers as well as 
their completed patient diary to the clinic at each visit for accountability purposes even if 
they will not be issued with new medication at that visit. 
 
Fulvestrant: Store and transport in a refrigerator (2°C - 8°C).  
Temperature excursions outside 2°C - 8°C should be limited. This includes avoiding 
storage at temperatures exceeding 30°C, and not exceeding a 28 day period where the 
average storage temperature for the product is below 25°C (but above 2°C - 8°C). After 
temperature excursions, the product should be returned immediately to the 
recommended storage conditions (store and transport in a refrigerator 2°C - 8°C). 
Temperature excursions have a cumulative effect on the product quality and the 28-day 
time period must not be exceeded over the duration of the 4-year shelf life of Fulvestrant. 
Exposure to temperatures below 2°C will not damage the product providing it is not 
stored below – 20°C. Store the pre-filled syringe in the original package in order to protect 
from light. 
Letrozole tablets must be stored according to the instructions detailed in the local 
package insert.  
 
6.8.  Dose Modification 
Every effort should be made to administer study treatment on the planned dose and 
schedule. However, in the event of significant treatment-related toxicity, administration 
of study drugs (fulvestrant, palbociclib or letrozole) may need to be adjusted as described 
in the following sections. Depending on the nature of the toxicity observed, dosing 
adjustment might be required for just one or both study drugs in the combination. In the 
event treatment interruption is deemed necessary for just one of the study drugs in the 
combination, treatment with the other study drug will continue as planned. 
Dose modifications for letrozole will be aligned to the summary of product characteristics 
approved locally. 
 
Fulvestrant Dose Modification 
No dose adjustment for fulvestrant is permitted but dosing interruptions are allowed. 
Treatment interruption for fulvestrant-related toxicities will be performed as per the 
investigator’s best medical judgment. Patients discontinuing fulvestrant treatment 

 
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permanently due to treatment-related toxicity will be discontinued from the active 
treatment phase of the study and enter the follow-up phase.  
 
Palbociclib Dose Modification 
In the event of significant treatment-related toxicity, palbociclib dosing may be interrupted 
or delayed and/or reduced as described below. In the event of multiple toxicities, dose 
modification should be based on the worst toxicity observed. Patients are to be instructed 
to notify Investigators at the first occurrence of any adverse sign or symptom. 
Dose modifications may occur in three ways: 
• 
Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 
• 
Between cycles: next cycle administration may be delayed due to persisting 
toxicity when a new cycle is due to start;  
• 
In the next cycle: dose reduction may be required in a subsequent cycle based 
on toxicity experienced in the previous cycle. 
Patients discontinuing palbociclib treatment permanently due to treatment-related 
toxicity may continue on the active treatment phase of the study receiving fulvestrant or 
letrozole monotherapy as per the investigator’s discretion. 
 
Palbociclib: Dosing Interruptions 
Management of dose modifications as result of hematologic toxicities is summarised 
below: 
• 
Grade 1 or 2 : No dose adjustment is required. 
• 
Grade 3 (any haematological toxicity except for lymphopenia unless associated 
with clinical events, i.e., opportunistic infections). 
 
On day 1 of cycle: Withhold palbociclib, repeat whole blood monitoring as 
soon as possible (within a week). When recovered to grade ≤2, start 
treatment at the same palbociclib dose level. 
 
On day 14 of initial two cycles: Continue palbociclib treatment at current 
dose level. Repeat blood count on day 21. Consider dose reduction if 
prolonged (> 1 week) recovery from grade 3 neutropenia or recurrent 
grade 3 neutropenia in  subsequent cycles. 
• 
Grade 3 ANC + Fever ≥38.5 C and/or infection: Withhold palbociclib and 

 
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initiation of next cycle until recovery to grade ≤2 (≥1.0 x 109/L). Resume at next 
lower dose.  
• 
Grade 4: Withhold palbociclib and initiation of next cycle until recovery to grade 
≤2. Resume at next lower dose.  
 
For non-hematologic toxicities (interstitial lung disease (ILD) and/or pneumonitis not 
included): 
• 
Grade 1 or 2 : No dose adjustment is required. 
• 
Grade  3 : withhold palbocicib until recovery to grade <1 (or  to grade ≤2 if not 
considered a safety risk for the patient). Resume at next lower dose.  
 
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator.  
Doses may be held as needed until toxicity resolution. Depending on when the adverse 
event resolved, a treatment interruption may lead to the patient missing all subsequent 
planned doses within that same cycle or even to delay the initiation of the subsequent 
cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, 
then re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within 
the same cycle. The need for a dose reduction at the time of treatment resumption should 
be based on the criteria defined in following section (Dose Reductions) unless expressly 
agreed otherwise following discussion between the investigator and the sponsor. If a 
dose reduction is applied in the same cycle, the patient will need to return to the clinic to 
receive new drug supply. In the event of a treatment interruption for reasons other than 
treatment-related toxicity (e.g., non-cancer related surgery) lasting >2 weeks, treatment 
resumption will be decided in consultation with the sponsor. 
If a treatment delay results from decline in hematologic parameters, the frequency of 
blood count assessments should be increased as clinically indicated. 
If these parameters are met within 2 weeks of treatment interruption or cycle delay, 
palbociclib may be resumed. Please refer to Section Dose Reductions for adverse events 
requiring dose reduction at the time of treatment resumption. 
If these parameters have not been met after 2 weeks of dose interruption (including the 
scheduled 1 week off treatment) or 2 weeks of cycle delay, permanent discontinuation 
of palbociclib treatment should be considered. Treatment resumption for patients 

 
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recovering from treatment-related toxicity after >2 weeks of treatment interruption or 
cycle delay but deemed to be deriving obvious clinical benefit per the investigator’s best 
medical judgment is left at the investigator’s discretion after sponsor consultation. On a 
per case basis and after sponsor consultation, in patients with repetitive drug-related 
toxicities requiring recurrent dose modifications and that are having a clinical benefit, it 
might be agreed adjustments to the standard dose schedule or to the dose modification 
guidelines. 
In the event that the start of a new cycle is delayed due to treatment related toxicity, all 
procedures other than tumor assessments scheduled by protocol are required on Day 1 
of the given cycle will be performed when palbociclib is resumed (just before palbociclib 
is restarted) (please note that tumor assessment protocol schedule has to be 
maintained). New cycle Day 1 procedures (i.e., physical examination, ECOG 
performance status, ECG, blood chemistry, hematology) that were performed prior to 
knowing the need to delay the start of the cycle do not need to be repeated (1) if not 
required to determine whether study drug may be resumed and (2) if performed within 7 
days prior to study drug resumption. 
 
For ILD and/or pneumonitis: 
Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated 
with palbociclib when taken in combination with endocrine therapy. Patients must be 
monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, 
dyspneoa). In patients who have radiological findings suspected of ILD and/or 
pneumonitis or new or worsening respiratory symptoms and are suspected to have 
developed ILD/pneumonitis, the administration of palbociclib must be interrupted and 
patient must be evaluated. 
• 
Grade 1: Palbociclib can be resumed at one dose level lower if the event is fully 
resolved to Grade 0 within 28 days after last palbociclib dose. In any other case, 
permanently discontinue subject from palbociclib treatment. 
• 
Grade 2, 3, or 4: Permanently discontinue subject from palbociclib treatment. 
 
 
Palbociclib: Dose Reductions 
Following dose interruption or cycle delay the palbociclib dose may need to be reduced 
when treatment is resumed. No specific dose adjustments are recommended for Grade 

 
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1/2 treatment-related toxicity (with the exception of ILD and/or pneumonitis. See dosing 
interruptions for ILD/pneumonitis). 
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances. 
Dose reduction of palbociclib by 1 and, if needed, 2 dose levels (Table 3) will be allowed 
depending on the type and severity of toxicity encountered. Patients requiring more than 
2 dose reductions will be discontinued from the study and entered into the follow-up 
phase. All dose modifications/adjustments must be clearly documented in the patient's 
source notes and the CRF. 
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required. Dose re-
escalation is not allowed. 
 
Table 3. Dose reduction of palbociclib 
Dose level 
Palbociclib for 3 out of 4 weeks (3/1 schedule) 
Starting dose 
125 mg/d 
-1 
100 mg/d 
-2 
 75 mg/d 
 
Discontinue study treatment 
 
 
QTc prolongation management 
In the event of QTc prolongation of, possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to 
prolong the QTc interval should be evaluated. 
If such reversible causes are identified, then they should be corrected accordingly (i.e., 
correction of electrolyte abnormalities with supplements to within normal limits and/or 
discontinuation (if possible) of concomitant medications known to prolong the QT 
interval). 
Recommended dose modifications for palbociclib in the event of QTc prolongation are 
common to other non-hematological toxicities.   
 

 
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6.9. Potential drug-drug interaction  
 
Palbociclib 
In vitro data indicate palbociclib is primarily metabolized by CYP3A4 and sulfotransferase 
enzyme SULT2A1. Palbociclib is a weak time-dependent inhibitor of CYP3A following 
daily 125 mg dosing to steady state in humans. 
CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate 
that coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg 
palbociclib dose increased palbociclib AUCinf and the Cmax by approximately 87% and 
34%, respectively, relative to a single 125 mg palbociclib dose given alone. 
CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=14) indicate 
that coadministration of multiple 600 mg daily doses of rifampin with a single 125 mg 
palbociclib dose decreased palbociclib AUCinf and the Cmax by 85% and 70%, 
respectively, relative to a single 125 mg palbociclib dose given alone. 
CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following 
daily 125 mg dosing to steady state in humans. In a drug interaction trial in healthy 
subjects (N=26), coadministration of midazolam with multiple doses of palbociclib 
increased the midazolam AUCinf and the Cmax values by 61% and 37%, respectively, 
as compared with administration of midazolam alone. 
Gastric pH Elevating Medications: Drug-Drug interaction studies show that Concurrent 
administration of single 125 mg dose of palbociclib with multiple doses of the proton 
pump inhibitors (PPI) rabeprazole had limited impact on AUCinf (13% decrease). This 
reduction in overall exposure is not thought to be clinically relevant. Given the reduced 
effect on gastric pH of H2 receptors antagonists and local antacids compared to PPIs, 
the effect of dosing these classes of acid-reducing agents palbociclib exposure when 
given simultaneously with palbociclib free base capsules under fed conditions is 
expected to be minimal. In another healthy subject study, coadministration of a single 
dose of palbociclib with multiple doses of the PPI rabeprazole under fasted conditions 
decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared 
with a single dose of palbociclib administered alone. 
Effect of Palbociclib on Transporters: In vitro evaluations indicate that palbociclib has low 
potential to inhibit the activities of drug transporters P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic cation 

 
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transporter (OCT)2 and organic anion transporting polypeptide (OATP)1B1, OATP1B3 
and bile salt export pump (BSEP) at clinically relevant concentrations. 
Effect of Transporters on Palbociclib: Based on in vitro data, P-gp and BCRP mediated 
transport are unlikely to affect the extent of oral absorption of palbociclib at therapeutic 
doses.  
Pharmacokinetic data from study A5481001 indicate that plasma pharmacokinetics of 
palbociclib are low to moderately variable with generally dose proportional exposures 
over the dose range evaluated. palbociclib is slowly absorbed and has an elimination 
half-life of 27 hours. Preliminary results from recently performed phase I study A5481021 
(palbociclib in healthy volunteers to estimate the effect of food on the bioavailability of 
palbociclib) suggest that the administration of palbociclib with food results in more 
consistent drug uptake and exposure, thus it was concluded that patients should be 
instructed to take palbociclib with food.  
The potential drug-drug interaction (DDI) between palbociclib and letrozole was 
assessed in the phase I portion of the study A5481003. No potential for drug-drug 
interaction between both drugs was observed when administered in combination.  
Data for DDI between palbociclib and fulvestrant is available from study A5481023. The 
concurrent administration of fulvestrant did not have a clinically relevant impact on the 
plasma PK of palbociclib. Likewise, the concurrent administration of palbociclib did not 
have a clinically relevant impact on the plasma PK of fulvestrant. Therefore, there is no 
clinically relevant DDI between palbociclib and fulvestrant when the 2 drugs are 
coadministered.  
Patients using drugs known to cause QT prolongation should be monitored closely with 
serial electrocardiograms.  
 
Fulvestrant 
There are no known DDI requiring dose adjustment.  
Fulvestrant does not significantly inhibit any of the major Cytochrome P450 (CYP) 
isoenzymes in vitro, and results from a clinical pharmacokinetic trial involving co-
administration of fulvestrant with midazolam also suggest that therapeutic doses of 
fulvestrant will have no inhibitory effects on CYP3A4.  
In addition, available data indicate that there is not clinically relevant change in 
fulvestrant clearance as result of induction or inhibition of CYP3A4 with rifampicin or 

 
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ketoconazole, respectively. Dosage adjustment is not necessary in patients co- 
prescribed CYP3A4 inhibitors or inducers. 
 
Pregnancy and lactation  
As expected with a potent anti-estrogen, studies in animals have shown reproductive 
toxicity. Fulvestrant is found in rat milk at levels significantly higher than those in rat 
plasma. The potential risk for humans is unknown. Therefore, use of fulvestrant should 
be avoided in pregnant or lactating women.  
Patients of childbearing potential should use effective contraception during treatment 
with fulvestrant and for 2 years after the last dose of fulvestrant-containing regimen. 
 
Letrozole 
No study relevant DDIs are known for letrozole. Refer to local SmPC for further details. 
 
7. SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording protocol-defined AEs, 
adverse events of special interest (AESIs) and SAEs; measurement of protocol-specified 
hematology, clinical chemistry, measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study 
drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with International Conference on Harmonization (ICH) guidelines, European 
Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements.  
The Sponsor or its designee is responsible for reporting unexpected fatal or life-
threatening events associated with the use of the study drug to the regulatory agencies 
and competent authorities by telephone or fax within 7 calendar days after being notified 
of the event. The Sponsor or its designee will report other relevant SAEs associated with 
the use of the study medication to the appropriate competent authorities (according to 
local guidelines), investigators, and central Institutional Review Boards/Ethics 
Committees (IRBs/ECs) by a written safety report within 15 calendar days of notification. 
 

 
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7.1. Adverse Events Definitions 
An adverse event is any untoward medical occurrence in a clinical study patient 
administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavourable 
and/or unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a medicinal (investigational) product, regardless of 
whether it is considered related to the medicinal (investigational) product. Abnormal test 
findings should only be reported as an AE if meets any of the following criteria is 
associated with accompanying symptoms and a general diagnostic term including the 
symptoms and the abnormal test finding cannot be defined, or requires additional 
diagnostic testing or medical/surgical intervention, leads to a change in study drug(s) 
dosing or discontinuation from the study, needs additional concomitant drug treatment 
or is considered to be an AE by the investigator or by the Sponsor.  
The causal relationship between an adverse event and the Investigational Medicinal 
Product (IMP) will be defined as below: 
 
Not related: The temporal association between the adverse event and the IMP makes a 
causal 
relationship 
unlikely, 
or 
the 
patient’s 
clinical 
state 
or 
the 
study 
procedure/conditions provide a sufficient explanation for the adverse event. 
Related: The temporal association between the adverse event and the IMP makes a 
causal relationship possible and the patient’s clinical state or the study 
procedure/conditions do not provide a sufficient explanation for the adverse event. 
Each adverse event must be assessed by the investigator as to whether or not there is 
a reasonable possibility of causal relationship to palbociclib, fulvestrant, letrozole and/or 
their combination. 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-4_QuickReference_5x7.pdf).  
 
The intensity (severity) of an adverse event will be recorded as one of the following:  
- 
Mild - Easily tolerated and does not interfere with normal daily activities, CTCAE 
Grade 1. 

 
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- 
Moderate - Causes some interference with daily activities, intervention or 
treatment may be needed. CTCAE Grade 2.  
- 
Severe - Normal daily activities are substantially impaired, hospitalization and/or 
intervention or treatment is required, CTCAE Grade 3 or 4. 
- 
Fatal - Death, CTCAE Grade 5. 
- 
Not applicable (Clinically significant and asymptomatic laboratory test 
abnormalities or abnormal assessments, for which no CTCAE grading guidance 
is applicable but which are considered as AEs). 
 
A mild, moderate or severe AE may or may not be serious. These terms are used to 
describe the intensity of a specific event. However, a severe event (such as severe 
headache) may be of relatively minor medical significance and is not necessarily serious. 
For example, nausea lasting several hours may be rated as severe, but may not be 
clinically serious. Fever of 39 °C that is not considered severe may become serious if it 
prolongs hospital discharge by a day. Seriousness rather than severity serves as a guide 
for defining regulatory reporting obligations. 
Adverse Drug Reactions: All noxious and unintended responses to an IMP (i.e. where a 
causal relationship between an IMP and an adverse event is at least a reasonable 
possibility), related to any dose should be considered adverse drug reactions. For 
marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of 
diseases or for modification of physiological function, is to be considered an adverse 
drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or 
severity of which is not consistent with the applicable product information. 
 
Serious Adverse Events 
Per definition, a Serious Adverse Event is defined as any adverse event that either: 
• 
Results in death, 
• 
is life threatening, 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person ability to conduct normal life functions), 
• 
is a congenital anomaly/birth defect. 
 

 
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Definition of Life Threatening: An adverse event is life threatening if the patient was at 
immediate risk of death from the event as it occurred, i.e. does not include a reaction 
that might have caused death if it had occurred in a more serious form. For instance, 
drug induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life threatening even though drug induced hepatitis can be fatal. 
Definition of Hospitalization: Adverse events requiring hospitalization should be 
considered serious. In general, hospitalization means that the patient has been admitted 
(usually involving an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate at the study site. When in doubt 
as to whether hospitalization occurred or was necessary, the adverse event should be 
considered as serious. 
Social admission, hospitalization for pre-planned treatments or surgical procedures, 
elective surgery or routine clinical procedures, which are not the result of an adverse 
event, need not to be considered adverse events. If anything untoward is reported during 
the procedure, this must be reported as an adverse event and either ‘serious’ or ‘non-
serious’ attributed according to the usual criteria. 
 
Definition of clinically/medically significant event: 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Clinically/medically significant events MUST be reported as SAEs. 
In this clinical trial and as defined in this protocol, serious adverse events and 
hospitalizations unequivocally and solely related to established tumor disease 
progression will NOT be treated as serious adverse events for reporting obligations. 
Serious adverse events, if brought to the attention of the Investigator at any time after 
the cessation of the study treatment and considered by the Investigator to be possibly 
related to the study treatment (so, in fact serious adverse reactions), will be reported to 
the Sponsor. 
 

 
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7.2. Adverse Event Reporting 
Adverse events will be collected from the signature of informed consent until the safety 
follow up visit to be done 28 days (+/- 7 days) after the last day of study treatment. All 
study patients will be carefully monitored for the occurrence of adverse events during 
this period. 
Signs, symptoms and abnormal diagnostic procedure results that are clearly related 
should be grouped together and reported as a single diagnosis or syndrome whenever 
possible. Any additional events that fall outside this definition should also be reported 
separately.  
All adverse events must be recorded in the CRF. 
 
Serious Adverse Event Reporting and Timeframe 
Reporting requirements will comply with all applicable local regulations for safety 
reporting.  
All protocol defined SAEs and AESIs will be reported to the Sponsor (MedSIR) within 24 
hours of when the Investigator or anyone of the site study team becomes aware of it as 
follows: 
• 
Report all SAEs and AESIs (as defined in this protocol), irrespective of the study 
drug received by the patient, whether or not this event is considered by the Investigator 
to be related to study drug, to MedSIR immediately, but in any event no later than 24 
hours of any site study team staff becoming aware of the event. 
• 
Full details of the SAE and AESI should be collected and fully documented using 
the Serious Adverse Event (SAE) form and sent to MedSIR.  
• 
Follow-up information, copies of the results of any tests, the outcome of the event 
plus the investigator’s opinion of IMP relationship to the SAE(s) and AESI(s), and other 
document when requested and applicable, will accompany the SAE form as available on 
the day of reporting or provided as soon as possible thereafter. 
• 
The original SAE Report Form and the fax/email confirmation from the sponsor 
must be kept with the CRF documentation at the study site(s). 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor 
(MedSIR) by email and fax as noted below: 
email: ParsifalSAE@medsir.org 
fax: + 34 976 20 44 02 

 
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SAEs and AESIs will be followed until resolved, a stable outcome is reached, patient is 
lost to follow-up or dies. 
MedSIR will be responsible for ensuring that events are reported within the mandated 
timeframe to the EMA, and other Competent Authorities, IECs/IRBs and investigator(s), 
as necessary. 
 
Adverse Events of Special Interest (AESIs) 
AESIs must be reported by the Investigator to the Sponsor expeditiously (see section 
7.2), regardless of their seriousness (i.e. no more than 24 hours after learning of the 
event). AESIs for this study include: 
o Suspected transmission of an infectious agent by a medication, whereby any 
organism, virus or infectious particle (e.g. prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an 
infectious agent. Transmission of an infectious agent may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient 
exposed to a medicinal product. This term ONLY applies when contamination of 
a medication is suspected and DOES NOT apply to infections supported by the 
mode of action, e.g. immunosuppression. 
o Potential drug-induced liver injury as assessed by laboratory criteria for Hy’s law. 
The following laboratory abnormalities define potential Hy’s law cases and must 
be reported as an AESI: 
- 
Aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) elevations that are >3 × upper limit of normal (ULN) 
- 
Concurrent elevation of total bilirubin >2 × ULN (or clinical jaundice if total 
bilirubin measures are not available), except in patients with documented 
Gilbert’s syndrome. For patients with Gilbert’s syndrome, elevation of 
direct bilirubin >2 × ULN should be used instead. 
- 
 
Noncompliance 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human subjects’ research to follow the determinations of the IRBs/IECs. Non-compliance 
may occur due to lack of knowledge or due to deliberate choice to ignore regulations, 
institutional policies, or determinations of the IRB/IECs. 
Report non-compliance immediately, within 24hours to MedSIR, to the study site 
Principal Investigator and, as necessary, to the IRB/IEC. 

 
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Serious Noncompliance  
Definition: noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
Report serious non-compliance immediately, within 24hours to MedSIR, to the study site 
Principal Investigator and, as necessary, to the IRB/IEC. 
 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Ethics Committees 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
- 
Palbociclib Investigator's Brochures 
- 
Fulvestrant Investigator’s Brochure 
- 
Letrozole, European public assessment report (EPAR) 
 
The Sponsor will compare the severity of each event and the cumulative event frequency 
reported for the study with the severity and frequency reported in the applicable 
reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
 
8. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
8.1. Sample Size 
The study is a randomized, open label, controlled, Phase II clinical trial. The primary 
endpoint is progression-free survival (PFS) according to RECIST version 1.1. The 
primary analysis is to compare the efficacy of palbociclib in combination with fulvestrant 
(interventional arm) versus palbociclib plus letrozole (control arm). 
Superiority analysis: 
Based on published efficacy data for palbociclib and fulvestrant in similar target 
population, the investigator hypothesis (H1) is that median PFS in the palbociclib plus 
fulvestrant arm (31.3 months) will be higher (Hazard Ratio = 0.7) than in the palbociclib 
plus letrozole group (22 months). Therefore, we will test the null hypothesis (H0) that 
median PFS survival is equal in both groups.  

 
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The analysis will be performed with Log-Rank test. We assumed an exponential survival 
function. We estimate a 24 months (mo.) accrual period and a 12 mo. treatment period 
(maximum follow-up of 36 mo.). We planned a randomization (1:1).  
Regarding type I and type II errors, we assumed a power of 80% and a two-sided overall 
alpha error of 5%. An interim analysis will occur at 22 mo. with 89 events (35% of total 
events expected). The final analysis will be performed at approximately 36 mo. with 254 
events and 486 patients included (52% PFS event rate assumed). 
According to Lan-DeMets O'brien-Fleming approximation spending function, the two-
sided local type I error for testing the null-hypothesis within one interim and final analysis 
will be 0.001 and, 0.0498, respectively.     
Therefore, we should include 243 patients in the control arm and 243 patients in the 
interventional arm. A total of 486 patients will be included in this study.  
The randomization will be stratified. It can be expected that including factors of 
prognostic importance in the cox regression model as defined for the confirmatory 
analysis will increase the power as compared to the log-rank test. However, we preferred 
to take a conservative approach and we accept the sample size calculated without 
adjusting for prognostic factors. 
 
Non-inferiority analysis: 
As per EMEA guidelines, we will switch to non-inferiority analyses if the superiority 
criteria cannot be met (CPMP/EWP/482/99 EMEA guideline). We will declare non-
inferiority if the upper bound 95% confidence interval (95%CI) of HR between median 
PFS in palbociclib plus letrozole and palbociclib plus fulvestrant arms, will fall within the 
non-inferiority margin of 1.21. Non-inferiority margin is justified according with the FDA 
guidance in non-inferiority studies (FDA GUIDANCE: Non-Inferiority Clinical Trials to 
Establish Effectiveness). They propose to estimate the average effect of the active 
control over placebo in historical studies and selecting the 95%CI lower bound. Finally, 
this value should be adjusted to retain at least 50% of the historical effect of active control 
versus placebo arms. Accordingly the combined effect of PALOMA-1 and 2 studies are 
(HR: 1.79. 95%CI: 1.47 to 2.18) and the non-inferiority margin is 1.21. With 254 PFS 
events, if the HR ≤ 0.94 or median PFS in palbociclib plus letrozole is 22 mo. vs. 
palbociclib plus fulvestrant 23.3 mo. or better, the upper bound 95% of CI will fall within 
the non-inferiority margin of 1.21, allowing for the determination that both combinations 
have a similar treatment effect. 

 
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The sample size estimation was made using R (package gsDesign), according to the 
formulas published by Lachin JM and Foulkes MA (1986).(66) 
8.2. Analysis Sets 
We propose to test efficacy analysis using two analysis sets; the intention-to-treat set, 
considering all patients randomized regardless of whether they received the randomized 
treatment, and the “per protocol” analysis set, considering all patients randomized and 
received the protocol required study drug exposure and processing. Criteria for 
determining the “per protocol” group assignment would be established by the Steering 
Committee before the statistical analysis begins. Given our expectation that very few 
patients will crossover or be lost to follow-up, these analyses should agree very closely. 
We propose declaring the superiority of interventional therapy, only if shown to be 
superior using both the “intention to treat” and “per protocol” analysis sets. 
We propose to analyses safety profile of treatments using the safety analysis set, 
considering all patients that receive one drug exposure. 
8.3.  Primary efficacy endpoint 
The primary endpoint is to evaluate the progression-free survival defined as the time 
from randomization until objective tumor progression or death by any cause. Patients 
with no progression or death will be censored at the date of their last evaluable imaging. 
Censoring rules are specified in Table 5. 
 
Table 5. Censoring rules for PFS 
Situation 
Date of progression or censoring 
Outcome 
Progression 
documented 
between 
scheduled visits  
Earliest of: 
• Date of radiological assessment showing new 
lesion (if progression is based on new lesion); 
or 
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions). 
Progressed  
Death before first PD assessment 
Date of death. 
Progressed  
Death between adequate assessment 
visits  
Date of death. 
Progressed  
No progression 
Date of last radiological assessment of measured 
lesions. 
Censored 

 
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Treatment 
discontinuation 
for 
undocumented progression  
Date of last radiological assessment of measured 
lesions. 
Censored 
Treatment discontinuation for toxicity or 
other reason 
Date of last radiological assessment of measured 
lesions. 
Censored 
Death or progression after more than 
one missed visit 
Date of last radiological assessment of measured 
lesions. 
Censored 
PD: Progression disease. 
8.4. Primary efficacy analysis 
The progression-free survival will be compared between the two groups using a two-
sided stratified log-rank test with site of disease (visceral vs. non-visceral) and by the 
onset of metastatic disease diagnose (de novo metastatic vs. non de novo patients) as 
strata. We will test the primary endpoint at a nominal levels of 0.001 and 0.0498 at interim 
and final analysis, respectively.  
In the interim analysis after 89 PFS events:  
- 
We will declare that the PFS of palbociclib plus fulvestrant arm is superior from 
control group if the upper limit of 99,9% confidence interval for the hazard ratio is lower 
than 1.  
- 
Otherwise, non-inferiority will be declared if the upper limit of 99,9% confidence 
interval for the hazard ratio is lower than non-inferiority margin of 1.21. 
In the final analysis after 254 PFS events:  
- 
We will declare that the PFS of palbociclib plus fulvestrant arm is superior from 
control group if the upper limit of 95% confidence interval for the hazard ratio is lower 
than 1.  
- 
Otherwise, non-inferiority will be declared if the upper limit of 95% confidence 
interval for the hazard ratio is lower than non-inferiority margin of 1.21. 
The ITT population will be considered the primary population for superiority analysis. In 
contrast, per-protocol (PP) population will be the primary population for non-inferiority 
analysis. 
 
8.5. Secondary efficacy analysis 
The intervention arm (palbociclib in combination with fulvestrant) will be compared 
against the control (palbociclib in combination with letrozole) for all analysis. For timed 
endpoints (TTP, OS, DoR and TTR), we will use the Kaplan-Meier method and Log-Rank 

 
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test followed by multivariable Cox proportional hazards model for adjusting for stratified 
randomization variables. For binary outcomes (ORR and CBR) we will use chi-squared 
test for binary outcomes followed by multivariate logistic regression for adjusting for 
stratified randomization variables. We will examine the residuals to assess model 
assumptions. 
Patients will be stratified by site of disease (visceral vs. non-visceral), and the onset of 
metastatic disease diagnose (de novo metastatic versus non de novo patients) as strata.  
We will calculate Relative Risk (RR) and Hazard ratios (HR) with corresponding 95% 
confidence intervals to compare dichotomous and time to event variables, respectively. 
Up-to-date versions of R will be used to conduct analyses. For all tests, we will use two-
sided p-values with alpha ≤ 0.05 level of significance.  
To assess the impact of potential clustering for patients cared by the same site, we will 
use mixed cox regression models (see table 6).  
Analysis will he performed on the ITT, and per-protocol populations. ITT population will 
be considered the primary population for the analysis. 
8.6. Safety Endpoints 
Analysis of safety-related data will be considered at four levels:  
• 
First, the extent of exposure (dose, duration, number of patients) will be examined 
to determine the degree to which safety can be assessed from the study. 
• 
Second, we will describe and compare clinically relevant test, concomitant 
medications and adverse events reported in every study group. For adverse 
events, we will report intensity, causality, body system, action taken, and 
outcome.  
• 
Third, serious adverse events, deaths and study discontinuations will be 
described and examined in every study group.  
• 
Finally, patient grade 3 and 4 toxicities in every study group will be classified by 
MedDRA system organ class and compared between patient baseline 
characteristics. 
The relation between baseline characteristics and severe adverse events (classified in 
MedDRA SOCs) will be analyzed with chi-squared test followed by multivariate logistic 
regression with appropriate interaction terms (baseline characteristic × treatment group) 
(see table 5). 

 
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Analysis will he performed on the safety population. 
 
Table 6. Methods of analysis for each variable. 
Variable/Outcome 
Hypothesis 
Outcome measure 
Method of analysis 
1) Primary efficacy 
 
 
 
Progression free 
survival (PFS)  
Intervention > control arm 
(ITT population) 
RECIST criteria, v1.1 
(time to event) 
Stratified log-Rank test 
 
Intervention = control arm 
(PP population) 
RECIST criteria, v1.1 
(time to event) 
Stratified log-Rank test 
2) Secondary efficacy 
  
  
Time to progression 
(TTP) 
Intervention > control arm 
RECIST criteria, v1.1 
(time to event) 
Kaplan-Meier survival 
analysis (Log-Rank 
test) 
 
Overall response rate 
(ORR) 
Intervention > control arm 
RECIST criteria, v1.1 
(Binary) 
Chi-squared test /  
Logistic regression 
 
Duration of response 
(DoR) 
Intervention > control arm 
RECIST criteria, v1.1 
(time to event) 
Kaplan-Meier survival 
analysis (Log-Rank test) 
 
Time to response 
(TTR) 
Intervention > control arm 
RECIST criteria, v1.1 
(time to event) 
Kaplan-Meier survival 
analysis (Log-Rank test) 
 
Clinical Benefit Rate 
(CBR) 
Intervention > control arm 
RECIST criteria, v1.1 
(Binary) 
Chi-squared test / 
Logistic regression 
 
Overall survival (OS) 
Intervention > control arm 
All causes (time to 
event) 
Kaplan-Meier survival 
analysis (Log-Rank 
test) 
3) Safety 
 
 
 
Adverse events 
Intervention ≠ control arm 
MedDRA (categorical) 
Descriptive methods 
Toxicities G3-4 
Differences according 
baseline characteristics 
MedDRA (categorical) 
Chi-squared / Mann 
Whitney test/ Logistic 
regression. 
4) Sensitive analysis  
  
  
a) Per protocol 
analysis 
Intervention > control arm 
All outcomes 
Kaplan-Meier survival 
analysis (Log-Rank 
test)/ Chi-squared test 

 
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b) Adjusting for 
baseline and stratified 
randomization factors 
Intervention > control arm 
PFS/TTP/OS 
Multivariable Cox 
regression models 
c) clustering among 
individuals within a 
site 
Intervention > control arm 
PFS 
Mixed Cox regression 
models 
8.7. Translational sub-studies 
The objective of the statistical analyses of biomarkers is the identification of those 
markers or combinations of markers which show best association with positive or 
negative clinical outcome of palbociclib plus fulvestrant or letrozole. 
The biomarker analyses will be exploratory. They aim at exploring the potential to predict 
clinical benefit, by each marker separately and/or by suitable combinations.  
Further data on markers will be analyzed, dependent on its availability. According to 
experience many biomarkers show a skewed statistical distribution across subjects and 
within subject. Appropriate transformations will be applied to transform these 
measurements into distributions with an approximate Gaussian shape. These 
transformations do not change the order of the values, such that non-parametric 
analyses based on ranks or cut-offs remain unchanged by the transformation. The basic 
statistics and interdependencies of the different markers will be descriptively 
investigated.  
Markers will be evaluated on a univariate level regarding their potential for prediction 
(e.g. search or adaptation of cut-offs) of the clinical endpoints. Further multivariate 
techniques (e.g. Multiple Logistic Regression, Principal Component Analysis with 
Rotation, Cluster Analysis) will be employed in order to study combinations of markers. 
Biomarker and Response correlations with clinical covariates will be investigated. It will 
be checked whether covariates can improve the prediction and whether there is an 
interaction with the biomarkers. Relevant covariates could become a part of the statistical 
prediction model. Candidate groupings derived from biomarkers will be checked with 
time to event variables (e.g. Kaplan-Meier curves, Cox proportional hazard model, log-
rank test).  

 
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8.8. Missing Data Management 
The analysis of the primary and secondary timed endpoints (progression and death) will 
be based on a log-rank or Cox regression tests and, therefore, not affected by patient 
withdrawals (as they will be censored) provided that dropping out is unrelated to 
prognosis. Patients with missing information in other outcomes, such as clinical benefit 
rate or overall response, will be considered as no responders. Furthermore, we will report 
reasons for withdrawal for each randomization group and compare the reasons 
qualitatively.  
 
8.9. Interim analysis 
One interim analyses will be performed at 22 months, after 35% of the total PFS events 
(89 events) have been observed. Interim analysis will evaluate the primary end-point and 
all safety and efficacy secondary objectives. The trial may be stopped for superiority or 
non-inferiority at interim according with mentioned decision criteria (refer to 8.1). 
However, the decision to stop the trial should be agreed by the SC after reviewing the 
interim safety and efficacy data. The trial may also stop for inferiority if palbociclib plus 
fulvestrant arm is significantly worse than palbociclib plus letrozole. 
 
8.10. 
Steering Committee Review 
A Steering Committee (SC) has been established for this study. Initially, it is composed 
of the investigators, the study medical monitor, and the Scientific Global Coordinator. The 
SC will meet on demand to review, discuss and evaluate all of the gathered safety data. 
In case of any arising safety concern, these meetings can also be called at any time at 
request of a participating investigator. At these meetings, MedSIR and the participating 
investigators must reach a consensus on safety data. MedSIR will prepare minutes from 
these meetings and circulate them to each investigator for comment prior to finalization.  
The study site Investigators and MedSIR will review patient data at least every four 
months. Each study site Investigator will monitor patients’ data for serious toxicities on 
an on-going basis.  
 
 

 
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9. ETHICAL CONSIDERATIONS 
9.1. Regulatory and Ethics Compliance 
The study will be performed and reported in accordance with the guidelines of the 
International Conference on Harmonization (ICH), and the ethical principles laid down in 
the Declaration of Helsinki. The study will be also compliance with European Directive 
2001/20/EC and any applicable local regulations. 
 
9.2. Institutional Review Board / Independent Ethic Committee: 
Conduct of the study must be approved by an appropriately constituted IRB/IEC. 
Approval is required for the study protocol, protocol amendments, informed consent 
forms, study subject information sheets, and advertising materials. The IRB/IEC must 
also be contacted in the event of any major protocol violation. 
The investigator, and/or the sponsor when required, must communicate with the IRB/IEC 
to ensure accurate and timely information is provided at all phases during the study. 
The Principal Investigator, and/or the sponsor when required, is responsible for providing 
written summaries of the status of the study to the IRB/EC annually or more frequently 
in accordance with the requirements, policies, and procedures established by the 
IRB/EC. Investigators are also responsible for promptly informing the IRB/EC of any 
protocol amendments. 
In addition to the requirements to report protocol-defined AEs to the Sponsor, 
investigators are required to promptly report to their respective IRB/EC all unanticipated 
problems involving risk to human patients. Some IRBs/ECs may want prompt notification 
of all SAEs, whereas others require notification only about events that are serious, 
assessed to be related to study treatment, and are unexpected. Investigators may 
receive written safety reports or other safety related communications from the Sponsor. 
Safety reports should be made available to IRB/EC to be reviewed and processed in 
accordance with regulatory requirements and with the policies and procedures 
established by their IRB/EC and archived in the site’s study file. 
 
9.3. Informed Consent 
For each study subject, written informed consent will be obtained prior to any protocol 
related activities. As part of this procedure, the study site Investigator or designee must 

 
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explain orally and in writing the nature, duration, and purpose of the study, and the action 
of the drugs in such a manner that the study subject is aware of the potential risks, 
inconveniences, or adverse effects that may occur. The study subject should be informed 
that she is free to withdraw from the study at any time and with no obligation to specify 
her reasons. The subject will receive all information that is required by local regulations 
and ICH guidelines. 
The Consent Form must be signed and dated by the patient before her participation in 
the study. The case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained prior to 
participation in the study. 
A separate consent form will be signed for patients that participate in the evaluation of 
molecular biomarkers sub-study This informed consent will be optional to the consent for 
the main study. 
A copy of each signed Consent Form must be provided to the patient. 
All signed and dated Consent Forms must remain in each patient’s study file and must 
be available for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. 
For any updated or revised Consent Forms, the case history for each patient shall 
document the informed consent process and that written informed consent was obtained 
for the updated/revised Consent Form for continued participation in the study. The final 
revised IRB/EC-approved Informed Consent Form must be provided to the Sponsor for 
regulatory purposes. 
 
9.4. Data Protection 
The sponsor will ensure the confidentiality of patient’s medical information in accordance 
with all applicable laws and regulations. 
The sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data, confirms herewith compliance to Regulation (EU) 2016/679 of the European 
Parliament and of the Council, of 27 April 2016 in all stages of Data Management. 

 
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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, the Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
 
10. SOURCE 
DOCUMENTATION, 
STUDY 
MONITORING, 
AND 
QUALITY 
ASSURANCE 
10.1. 
Source Data Documentation 
Source data refers to all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 
Source documents are original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial). 
Sponsor’s Quality Assurance group may assist in assessing whether electronic records 
generated from computerized medical record systems used at investigational sites can 
serve as source documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 
At a minimum, source documentation must be available to substantiate subject 
identification, eligibility, and participation; proper informed consent procedures; dates of 
visits; adherence to protocol procedures; adequate reporting and follow-up of AEs; 
administration of concomitant medication; study drug receipt/dispensing/return records; 
study drug administration information; and date of completion and reason. 
Data recorded on the eCRF will be verified by checking the eCRF entries against source 
documents (i.e., all original records, laboratory reports, medical records) in order to 

 
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ensure data completeness and accuracy as required by study protocol. The Investigator 
and/or site staff must make eCRFs and source documents of subjects enrolled in this 
study available for review by MedSIR or its representative at the time of each monitoring 
visit. 
The source documents must also be available for inspection, verification, and copying, 
as required by regulations, officials of the regulatory health authorities (e.g., FDA, EMEA, 
and others), and/or ECs/IRBs. The Investigator and study site staff must comply with 
applicable privacy, data protection, and medical confidentiality laws for use and 
disclosure of information related to the study and enrolled subjects. 
The patient must also allow access to the patients’ medical records. Each patient should 
be informed of this requirement prior to the start of the study. 
 
10.2. 
Study Monitoring and Source Data Verification 
Study progress will be monitored by MedSIR or its representative (e.g., a CRO) as 
frequently as necessary to ensure: 
That the rights and well-being of human subjects are protected; 
- 
the reported trial data are accurate, complete, and verifiable from the source 
documents; and 
- 
the conduct of the trial is in compliance with the current approved 
protocol/amendment(s), GCP, and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be identified in a hand-out 
located in the Investigator Site File. 
Data recorded on the eCRF will be verified by checking the eCRF entries against source 
documents (i.e., all original records, laboratory reports, medical records, subject diaries) 
in order to ensure data completeness and accuracy as required by study protocol. The 
Investigator and/or site staff must make eCRFs and source documents of subjects 
enrolled in this study available for inspection by the sponsor or its representative at the 
time of each monitoring visit. 
 
10.3. 
Retention of records 
Investigators must retain all study records required by the applicable regulations in a 
secure and safe facility. The Investigator must consult a sponsor representative before 

 
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disposal of any study records and must notify the sponsor of any change in the location, 
disposition, or custody of the study files. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. “Essential 
documents” are defined as documents that individually and collectively permit evaluation 
of the conduct of a trial and the quality of the data produced. These documents should 
be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. The CHMP requires retention for the 
maximum period of time permitted by the institution, but not less than 15 years (ICH E6, 
4.9.5). It is the responsibility of the sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained (ICH E6, 5.5.12). 
The study site Investigator must not dispose of any records relevant to this study without 
either (1) written permission from the Sponsor or (2) providing an opportunity for the 
Sponsor to collect such records. The study site Investigator shall take responsibility for 
maintaining adequate and accurate electronic or hard copy source documents of all 
observations and data generated during this study. Such documentation is subject to 
inspection by the Sponsor and the FDA and/or EMA (or respective individual EU country 
regulatory authorities). 
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 
10.4. 
Data Quality Assurance 
During and/or after completion of the study, quality assurance auditor (s) named by the 
MedSIR or the regulatory authorities may wish to perform on-site audits. The 
Investigators are expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested. 
The Sponsor’s representatives are responsible for contacting and visiting the 
Investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the clinical study (e.g., CRFs and other pertinent data) provided that 
patient confidentiality is respected. 

 
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The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing CRFs, 
are resolved. 
In accordance with ICH E6 Good Clinical Practice (GCP) and the Sponsor’s audit plans, 
this study may be selected for audit by representatives from the Sponsor’s (or 
designee’s) Quality Assurance Department. Inspection of site facilities (e.g., pharmacy, 
drug storage areas, laboratories) and review of study-related records will occur to 
evaluate the study conduct and compliance with the protocol, ICH GCP (ICH E6), and 
applicable country regulatory requirements. 
 
11. DATA MANAGEMENT 
11.1. 
Data Entry and Management 
In this study, all data will be entered on to eCRFs in a timely fashion by the Investigator 
and/or the Investigator’s dedicated site staff. 
The Investigator must review data recorded in the eCRF to verify their accuracy. 
Reconciliation of the data will be performed by the designated CRO. At the conclusion 
of the study, the occurrence of any protocol violations will be identified and recorded as 
part of the clinical database. After these actions have been completed and the database 
has been declared to be complete and accurate, it will be locked and will become 
available for statistical data analysis. 
 
11.2. 
Data Clarification 
As part of the conduct of the trial, MedSIR may have questions about the data entered 
by the site, referred to as queries. The monitors and the sponsor are the only parties that 
can generate a query. 
 
11.3. 
Data Coding Procedures 
Coding of AEs, medical history, and prior and concomitant medications will be performed 
using standard dictionaries as described in the Data Management Plan. 
 

 
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12. STUDY MANAGEMENT 
12.1. 
Discontinuation of the Study 
MedSIR  reserves the right to discontinue the study for safety or administrative reasons 
at any time. Should the study be terminated and/or the site closed for whatever reason, 
all investigational drugs pertaining to the study must be returned to MedSIR. Any actions 
required to assess or maintain study subject safety will continue as required, in spite of 
termination of the study. 
 
12.2. 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment or 
administrative letter that must be approved by MedSIR, the Scientific Global Coordinator, 
the study site Investigator and the IRB/IEC before implementation. This requirement for 
approval should in no way prevent any immediate action from being taken by the study 
site Investigator or MedSIR in the interests of preserving the safety of all subjects 
included in the trial. If an immediate change to the protocol is felt to be necessary by the 
study site Investigator and is implemented for safety reasons, MedSIR should be notified 
as soon as possible (within 24 hours if possible) and the IRB/IEC should be informed as 
necessary. 
 
12.3. 
Publication Policy Protection of Trade Secrets 
All information generated in this study must be considered highly confidential and must 
not be disclosed to any persons not directly concerned with the study without prior written 
permission from the Scientific Global Coordinator and MedSIR. However, authorized 
regulatory officials, the Scientific Global Coordinator or the study site Investigator, and 
MedSIR personnel (or their representatives) will be allowed full access to inspect and 
copy the records. All clinical investigational drug, patient bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless 
otherwise agreed to in writing by Scientific Global Coordinator or the study site 
Investigator and MedSIR. 
The sponsor will ensure that as far as possible results of this study will be published as 
scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such 
manuscripts will be made with full collaboration of principal Investigators and in 
accordance with the current guidelines of Good Publication Practice. 

 
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The sponsor must be notified of any intent to publish data collected from the study. Prior 
approval from sponsor must be obtained before publication of any study related results. 
 
 

 
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Bose P, Simmons GL, Grant S. Cyclin-dependent kinase inhibitor therapy 
for hematologic malignancies. Expert Opin Investig Drugs. 2013 Jun;22(6):723–
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NCT01740427 NCT. A Study of Palbociclib (PD-0332991) + Letrozole vs. 
Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- 
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Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, 
Randolph SS, et al. Phase I, dose-escalation trial of the oral cyclin-dependent 

 
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kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in 
patients with advanced cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 
2012 Jan 15;18(2):568–76.  
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Finn RS. Results of a randomized phase 2 study of PD 0332991, a cyclin-
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alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). In San 
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Richard S. Finn, Miguel Martin, Hope S. Rugo, Stephen E. Jones, Seock-
Ah Im, Nadia Harbeck, et al. PALOMA-2: Primary results from a phase III trial of 
palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal 
women with ER+/HER2– advanced breast cancer (ABC). In: J Clin Oncol. 
Chicago; p. (suppl; abstr 507).  
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Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, Masuda N, et al. 
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of 
hormone-receptor-positive, HER2-negative metastatic breast cancer that 
progressed on previous endocrine therapy (PALOMA-3): final analysis of the 
multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 
2016 Apr;17(4):425–39.  
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Giessrigl B, Schmidt WM, Kalipciyan M, Jeitler M, Bilban M, Gollinger M, 
et al. Fulvestrant induces resistance by modulating GPER and CDK6 expression: 
implication of methyltransferases, deacetylases and the hSWI/SNF chromatin 
remodelling complex. Br J Cancer. 2013 Nov 12;109(10):2751–62.  
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Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The 
cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole 
versus letrozole alone as first-line treatment of oestrogen receptor-positive, 
HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised 
phase 2 study. Lancet Oncol. 2015 Jan;16(1):25–35.  
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Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. 
Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and 
failure. Oncogene. 2010 Jul 15;29(28):4018–32.  
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A, et al. Cyclin E2 overexpression is associated with endocrine resistance but not 
insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. 

 
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circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol. 2014 Sep 
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Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer. N Engl 
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expression levels of BRCA1 and TS as potential predictive biomarkers for 
chemotherapy in gastric cancer. J Transl Med. 2014;12:355.  
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loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015 Feb 
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of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res Off J Am 
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Noncompliance, and Stratification.Lachin JM La. Biometrics. 1986;42:507–19.  
 
 

 
  
 
 
 
 
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Appendix 1: Schedule of assessments and study procedures 
Study Period 
Screening 
Treatment period 
Treatment follow up period 
Day 
-28 to -1 
Each cycle 
(every 28 ± 3 days) 
28±7 days after 
last dose 
treatment 
Every 6 months15 
Informed Consent1 
X 
 
 
 
ER and HER2 status2 
X 
 
 
 
Baseline sings/symptoms 
x 
 
 
 
Check of inclusion/exclusion criteria 
X 
 
 
 
Post-menopausal status confirmation 
X 
 
 
 
Medical History3 
X 
 
 
 
Physical Examination and ECOG status4,5 
X 
X 
X 
 
Weight and Vital signs 
X 
X 
X 
 
Concomitant Medication Reporting6 
X 
X 
X 
 
Review Patient Diary 
 
X 
 
 
AE reporting7 
X 
X 
X 
 
12-lead ECG8 
X 
X 
X 
 
Tumor Assessments9 
X 
X 
X 
X 
Samples for translational sub-study: 
 
 
 
 
Primary tumor biopsy10 
X 
 
 
 
Blood samples for translational sub-study11 
X 
X 
X 
 
Biopsies from metastatic lesions12 
X 
X 
 
 
Standard Laboratory Procedures: 
 
 
 
 
Hematology13 
X 
X 
X 
 

 
  
 
 
 
 
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Biochemistry14 
X 
X 
X 
 
Treatment Administration 
 
 
 
 
Arm A:  
 
Fulvestrant 500 mg/5mL (i.m. Injection) 
 
D1, D14  
On cycle one and D1 thereafter 
 
 
Palbociclib 125 mg total dose (capsules) 
 
D1 to D21 
 
 
Arm B: 
Letrozole 2.5 mg total dose (tablets) 
 
D1 to D28 
(Continuously) 
 
 
Palbociclib 125 mg total dose (capsules) 
 
D1 to D21 
 
 
1. 
Signed written informed consent obtained prior to any trial-specific procedure.  
2. 
Confirmation of histological diagnosis and specified estrogen, progesterone and HER2 receptors status  
3. 
Complete medical history and demographics (including age, gender, ethnic origin) and all medications taken the last 28 days prior to enrolment will be collected.  
4. 
Physical examination and vital signs (including respiratory rate, blood pressure measurements, heart rate, and body temperature) and weight measurement will be performed prior to enrolment.  
5. 
ECOG performance status will be assessed at screening and before trial drug administration at each cycle. 
6. 
Relevant concomitant medication (including any prescription medication, over-the-counter preparation, or herbal therapy) will be recorded between 21 days preceding first treatment dose until the 
safety follow up visit (28 +/- 7 days of last IMP dose administration).  
7. 
All AEs occurring during the trial from signature of informed consent until the safety follow up visit (28 +/- 7 days of last IMP dose administration) have to be recorded graded according to NCI-
CTCAE, version 4.0. 
8. 
ECG at screening and every 3 cycles starting at cycle 3 and till end of treatment follow-up visit (ECGs should be monitored more frequently, if clinically indicated). 
9. 
Baseline assessments of the, thorax, abdomen and pelvis (preferably CT or MRI in case of contrast allergy) must be performed no more than 28 days before the first trial treatment. Baseline bone 
scan must be performed no more than 60 days before the first trial treatment Post-baseline assessments are to be performed every 12 weeks +/- 7 days using the same imaging method and where 
possible obtained at the same institution for an individual patient as used during screening until PD. Bone scans are to be performed every 24 weeks (+/- 7 days) if it has been demonstrated (or if it 
is clinicaclly or biochemically suspected) bone involvement regardeless if the bone involvement could be identified in the CT scan. CT or MRI of the brain is not mandatory at baseline unless clinical 
suspicion of central involvement. 
10. Primary tumor samples should be collected from non-de novo patients.  
11. Blood samples for translational sub studies. collected from all patients . at baseline, after 2 and 12 weeks of treatment start and at tumour progression (prior to start alternative anticancer therapy). 
12. Tumor samples must be collected from all patients at baseline and at progression (if biopsable lesion). For non de novo patients if collection of tumor tissue at the time of metastatic disease diagnose 
is  not feasible,  at least archived tissue sample from the primary tumor must be provided.. 
13. Laboratory test will be performed as per local standard of care and clinical indication,. At least hemogram should be performed on D1 and D14 at cycle 1 and cycle 2, and D1 for subsequent 
cycles.before treatment administration. Parameters assessed should include hemoglobin, hematocrit, red blood cell count, platelet count, and white blood cell count with differential count (neutrophils, 
lymphocytes, mnocytes, eosinophils, basophils). 

 
  
 
 
 
 
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14.  Laboratory test will be performaed as per local standard of care and clinical indication. At least biochemistry results should be available before treatment administration on D1 of each cycle. 
Parameters assessed should include sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, alkaline phosphatase, aspartate aminotrnsferase, alanine aminotransferase, gamm-glutamyl 
transferase, actate dehydrogenase, total bilirubin, blood glucose and creatinine.  
15. Treatment follow up period: After discontinuation of study treatment, post -treatment follow-up (including survival status and post study anticancer therapy evaluation) will be collected every 6 months 
(±7 days) from the last dose of study treatment. Telephone contact is acceptable. If patient discontinued treatment for any reason other than progression, tumor assessment will be included in the 
assessment. 
 

 
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Appendix 2: Response Evaluation Criteria in Solid Tumors (RECIST criteria) 
guidelines (version 1.1) 
New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). EUROPEAN JOURNAL OF CANCER 45 (2009) 228 – 247 
 
 
 

 
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Appendix 3: Instructions for Scans in the Event of Isotope Shortage 
Two key suppliers of Tc-99m generators (Chalk River Reactor, Canada and High Flux 
Reactor, the Netherlands) are expected to close. Supplies from other reactor sources 
will be unable to meet the expected worldwide patient-care needs. As a result, significant 
shortages of Tc 99m are expected, and the instructions listed below should be followed: 
- 
Tc-99m bone scans should be obtained as part of the baseline tumor assessment 
in all patients and should be repeated to confirm a CR or if progression of existing 
bone lesions and/or the development of new bone lesions is clinically suspected. 
If a bone scan cannot be performed at baseline or if the investigator suspects that a bone 
scan may not be able to be repeated during the course of the study because of the Tc-
99m shortage, the investigator may choose F-18 NaF or FDG-PET scan as an 
alternative. 
- 
If bone lesions are selected as index non-target lesions, they must be apparent 
on baseline CT scans or other radiographic modalities (e.g., skeletal X-rays that 
can be repeated in subsequent tumor assessments). Additional scans may be 
obtained to follow clinically important bone lesions if not visualized on the chest, 
abdomen, or pelvic CT scan. 
These measures are intended to ensure that the same method of assessment and the 
same imaging technique is used throughout the study for each patient. If there is a 
question regarding the choice of alternatives in the event that a standard bone scan 
cannot be obtained during screening and/or during the study, please contact the Medical 
Monitor. 
 
 
 

 
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Appendix 4: Translational evaluation of molecular biomarkers sub study  
The PARSIFAL protocol requires the collection and submission of blood and tumor 
samples from patients enrolled the study.  
Translational sub-studies will be implemented after required regulatory and ethics 
committee approval..  
The blood and tumor samples collected in this study will be used for analysis related for 
this study as described in the protocol and for studies to be conducted in the future 
related to the purposes of the Parsifal study but not currently described in the protocol. 
In addition, as scientific discoveries are made and as science evolves, valuable research 
can be done in the future on samples collected in the study patients. For this reason, 
patients would be given the option of consenting for biobanking and use also the samples 
collected for future research with a broader scope. The procured specimens will not be 
used for hereditary genetic studies involving genes conferring susceptibility to cancer or 
other diseases unless additional consent is obtained or an anonymization process is 
used.  
 
 

 
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I. Biomaterial 
Blood sample collection 
At specified timepoints (study entry, after 2 and 12 weeks of treatment start, time to 
progression) blood samples (up to 2 x 10 ml EDTA/STRECK in whole blood tubes for 
plasma processing, up to 1 x 10 ml non-EDTA in whole blood tubes for serum 
processing), are required for consenting patients. 
The serum and plasma will be obtained and alliquoted to be stored at -20C or 
preferentially at -80 C. For RNA analysis plasma alliquots preseved in trizol will be used. 
Futher details on samples preparation and storage will be provided in a separate manual.  
All samples will be properly labelled to uniquely identify patient, specimen and time point 
of collection. 
At appropriate time intervals, shimpment of samples to the central storage location will 
be arranged.  
 
Tumor specimens 
Cytological and fine-needle aspiration biopsy samples are not acceptable. The samples 
must be accompanied by an associated pathology report.  
The minimum tissue size is 0.5 x 0.5 x 0.2 cm with ≥10% tumour content or 0.5 x 0.25 x 
0.2 cm with ≥20% tumour content or 0.25 x 0.25 x 0.2 cm with ≥ 40% tumour content.  
Tumour blocks are preferred, but in the event that local regulations prevent the shipment 
of tumour blocks, 20 unstained, serially-cut 4-μm-thick slides are requested.  
Multiple blocks, or blocks plus slides, can be combined to achieve the minimum 
requirements indicated. 
Futher details on samples preparation and storage will be provided in a separate manual.  
The sample collection date, the exact time of collection, and the time of exposure to 
fixative (formalin) will be properly documented.  
 
A. Biopsies from metastatic lesions 
Biopsies from metastatic lesions will be obtained at the time of metastatic disease 
diagnosis and at the time to progression. Wherever feasible, two samples should be 
obtained at each time point. The first sample should be placed immediately into 10% 
buffered formalin. The second biopsy will be placed in sterile tubes, snap frozen in liquid 
nitrogen or dry ice and stored frozen at ≤ -70°C. Other freezing methods can be 

 
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acceptable. If only one sample is available, it should be preserved as a formalin-fixed, 
paraffin-embedded (FFPE) specimen. 
In addition, fresh tissue from patients at defined centres might be obtained for specific 
analysis (e.g.: patient-derived xenografts studies) 
 
B. Specimens from primary tumor 
In case a sample is available, it must be obtained a representative FFPE tumour 
specimen that with adequate viable tumour cells in a tissue block.  
 
II. Biosample Requirements and Storage 
At specific time points, samples will be shipped to the central storage facility (Parc de 
Recerca Biomedica de Barcelona) where the samples will be logged into the database 
and assigned a Code Number.  
  
Biomaterials or components extracted from these biomaterials may be transferred to 
collaborating institutions to perform specific analyses. Samples will not include patient 
identifiable data and prior to sending any tissue material transfer agreements will be in 
place with the appropriate parties/collaborators. 
 
III. Description of methods 
The multiple assays, described below, may be performed with the material derived from 
FFPE tumour samples and/or the blood samples collected from each patient as part of 
this study.  
Multiple assays may be performed with the material derived from each patient, but it is 
likely that not all assays will be performed on samples provided by each patient (possibly 
because of insufficient tumour material or inadequate sample quality). 
All analyses are primarily exploratory in nature. We will employ both a hypothesis-driven 
and a discovery-based approach.  
Analysis to be conducted might include but are not limited to the following: 
 
A. DNA mutation caracterization: sequencing genes in plasma DNA 

 
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Mutational analysis in serum and plasma circulating free DNA (cfDNA) will be performed 
at study entry, during treatment (2 and 12 weeks after treatment start) and at time to 
progression (or withdraw by toxicity). Results will be used to estimate the amount of 
tumour-derived cfDNA relative to the total amount of cfDNA for quantitative analyses and 
case selection for more detailed genetic and epigenetic analyses. Samples with sufficient 
tumour-derived cfDNA will be subjected to more detailed analysis of mutations or copy 
number alterations (CNV). Polymerase chain reaction (PCR)-based methods and 
Massive parallel targeted sequencing (MPS) will be applied to analyze alterations in 
relevant oncogenes and tumour suppressor genes. 
Specifically, the presence of activating Akt1,PIK3CA and ESR1 mutations will be 
determined. In addition, aberrant methylation of CpG islands of target genes will be 
performed using sequencing or PCR based techniques.  
 
B. DNA mutation caracterization: sequencing genes in tissue specimens 
DNA obtained from FFPE sections of the tissue specimens (primary tumour, diagnosis 
of metastatic lesion and biopsy with confirmed progression) will be analysed for 
mutations and copy number alterations. Massive parallel targeted sequencing (MPS) will 
be applied to determine alterations in relevant oncogenes and tumour suppressor genes 
using a comprehensive cancer panel (CCP). 
Specifically, presence of activating Akt1 or PIK3R1 mutations, inactivating PTEN 
mutations, ESR1 mutations and alterations in the CCND1 and FGFR1 pathways will be 
determined. In addition, aberrant methylation of CpG islands of target genes will be 
performed using sequencing or PCR based methods. 
 If sufficient DNA remains after the assays above have been performed, genome-wide 
methods for mutation detection, epigenetic analyses and potentially DNA copy number 
profiling may be performed. Whole genome-amplified material will be used where 
necessary. Identified genetic aberrations will be used to anchor subsequent cfDNA 
analyses. 
C. Immunohistochemisry (IHC) 
The following antigens will be assayed by IHC: ER, PR, Ki67, cyclin D1, cyclin A1, pRb 
and others. 
Depending on the final number of specimens, tissue microarrays (TMA) may be 
constructed.  
 

 
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D. Fluorescence In Situ Hybridization (FISH) 
HER2, Cyclin D1 and ESR1 gene amplification will be assayed by FISH 
E. Exome and RNA sequencing 
DNA and RNA will be isolated from snap frozen biopsies according to established 
protocols. Exome and RNA sequencing will be performed on an Illumina HiSeq Platform. 
CNV data will be derived from exome sequencing analysis.  
In parallel, exosomes will be extracted from plasma samples. Extracted exosomes will 
subsequently be subjected to RNA, miRNA and protein analyses using appropriate 
methods including next generation RNA sequencing, PCR-based methods and mass 
spectrometry. 
 
F. Proteomics: differential protein expression analyses by mass spectrometry 
Proteomics has been developed as a complementary approach to the massive sequence 
of genes and genomes and analysis at the RNA level.  
Total protein will be extracted or snap frozen samples.  
The identification of early markers of resistance and de novo mechanisms of resistance 
will require the use of biopsies obtained at relapse (study entry). A comparison of protein 
expression will be made between patients progressing in the first 3 months vs. the 
remaining patients. Additionally, findings will be assessed in archival biopsies obtained 
at the initial diagnosis of breast cancer. 
The identification of mechanisms of acquired resistance will require the use of biopsies 
obtained at initial relapse and at progression. The comparison between these two types 
of samples will be performed in patients having a progression after 4 months of therapy. 
Additionally, comparison of samples B2F and B2L would allow the identification of 
specific mechanisms of resistance depending on the companion hormonal therapy.  
The identification of patients who differentially benefit from fulvestrant or letrozole will 
require the use of biopsies obtained at relapse. The comparison should be established 
between patients progressing in the first 3-4 months in both treatment groups. 
in addition, integrated-genomic biomarkers (iBx) of treatment response will be identified 
combining drug response parameters and genomic biomarkers based on bioinformatics 
pipelines designed for PDX data analysis. 
 

 
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G. Clinical trial-matched patient derived xenografts (PDX) models from 
patients treated with the palbociclib plus fulvestrant/letrozol. 
Tumor samples will be implanted into immunosuppressed mice. For those tumor biopsies 
implanting successfully, the activity of palbociclib plus anti-hormonal therapy (fulvestrant 
or letrozol) will be tested in vivo as well as using the 3D-ex vivo assay. In vivo studies 
will assess efficacy of treatment combination and mechansims of cross-resistance. 3D-
ex vivo studies would allow to explore treatment combinations that maximize the anti-
proliferative activity of palbociclib, including fulvestrant, other SERDs, letrozol and PI3K-
pathway inhibitors  
in addition, integrated-genomic biomarkers (iBx) of treatment response will be identified 
combining drug response parameters and genomic biomarkers based on bioinformatics 
pipelines designed for PDX data analysis.