Clinical trial NCT02028507
Conditions: Metastatic Breast Cancer
Keywords: Palbociclib Capecitabine Hormonal Receptor positive HER2 negative Metastatic Breast Cancer Resistance to non-steroidal Aromatase inhibitors Fulvestrant Exemestane Aromatase inhibitor
Sponsor: Spanish Breast Cancer Research Group
Start date: 2014-03-13; Completion date: 2021-01-11
Enrollment: 693 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an international (4 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to endocrine therapy (cohort 1: exemestane 25 mg daily, cohort 2: fulvestrant 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2 MBC are eligible if resistant to previous nonsteroidal aromatase inhibitors (NSAI) (letrozole or anastrozole) in cohort 1 or previous aromatase inhibitors (AI) (letrozole, anastrozole or exemestane) in cohort 2 defined as: recurrence while on or within 12 months after the end of adjuvant treatment with NSAI/AI or progression while on or within 1 month after the end of treatment with NSAI/AI for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease.

Detailed description:
296 patients have been randomized 1:1 between the experimental arm (Arm A: approximately 125 patients treated with palbociclib plus exemestane) and the control arm (Arm B: approximately 125 patients treated with capecitabine) before the approval of this protocol version (Cohort 1).

Approximately 300 patients will be randomized 1:1 between the experimental arm (Arm A: approximately 150 patients treated with palbociclib plus fulvestrant) and the control arm (Arm B: approximately 150 patients treated with capecitabine) from the approval of this protocol version (Cohort 2).

Arms: arm 1: \- Cohort 1:Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily. arm 2: Cohort 1: Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age. arm 3: \- Cohort 2: Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle. arm 4: Cohort 2:Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.
Interventions: intervention 1: Palbociclib intervention 2: Capecitabine intervention 3: Exemestane intervention 4: Fulvestrant
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
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Protocol GEICAM/2013-02 
Phase III study of Palbociclib (PD-0332991) in combination with 
Endocrine therapy (exemestane or fulvestrant) versus 
chemotherapy (capecitabine) in Hormonal Receptor (HR) 
positive/HER2 negative Metastatic Breast Cancer (MBC) patients 
with Resistance to Aromatase inhibitors  
“The PEARL study” 
 
Sponsor: GEICAM (Spanish Breast Cancer Research Group Foundation) 
Avenida de los Pirineos 7, planta 1ª, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid), Spain 
Phone: 0034 916 592 870 
 
Fax: 0034 916 510 406 
Email: geicam@geicam.org 
Protocol-specific Sponsor contact information can be found in the Administrative Binder. 
 
COORDINATING INVESTIGATOR: 
Dr. Miguel Martín. Hospital General Universitario Gregorio Marañón, Madrid, Spain 
 
 
Sponsor Study Code: GEICAM/2013-02 
EudraCT Number: 2013-003170-27 
 
Protocol Approved by GEICAM: 05Nov2019 
 
CONFIDENTIAL 
The information and data included in this protocol contain secrets and privileged or confidential information which is 
the property of GEICAM. No one is authorized to make this information public without the written permission of 
GEICAM. These limitations shall also be applied to all the information considered to be privileged or confidential and 
provided in the future. This material can be disclosed and used by its equipment and collaborators as necessary for 
conducting the clinical trial. 


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Protocol Number: GEICAM/2013-02 
Protocol Tittle: Phase III study of Palbociclib (PD-0332991) in combination with Endocrine 
therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in Hormonal Receptor 
(HR) positive/HER2 negative Metastatic Breast Cancer (MBC) patients with Resistance to 
Aromatase inhibitors. “The PEARL study” 
EudraCT Number: 2013-003170-27 
Version: 8.0 
Version Date: 05Nov2019 
 
 
__________________________________________                      _____________________ 
Coordinating Investigator: Dr. Miguel Martín                                 Date 
 
 
__________________________________________                      _____________________ 
Scientific Director: Dr. Eva Carrasco                                             Date 
 
 
__________________________________________                      _____________________ 
Coordinating Statistician: Mª Isabel Casas                                          Date 
 
 
__________________________________________                      _____________________ 
Protocol Manager: Victoria Ruiz                                                      Date 
 
 


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SUMMARY OF THE STUDY PROTOCOL 
Study Title: Phase III study of Palbociclib (PD-0332991) in combination with Endocrine therapy 
(exemestane or fulvestrant) versus chemotherapy (capecitabine) in Hormonal Receptor (HR) 
positive/HER2 negative Metastatic Breast Cancer (MBC) patients with Resistance to Aromatase 
inhibitors. “The PEARL study” 
Sponsor Study Code: GEICAM/2013-02 
Sponsor: GEICAM (Spanish Breast Cancer Research Group Foundation)   
Countries: Austria, Hungary, Israel and Spain. 
Study Rationale: 
Endocrine therapy is the cornerstone treatment for patients with hormone-receptor (HR)–positive, 
HER2 negative breast cancer. In postmenopausal patients, aromatase inhibitors (e.g., letrozole 
and anastrozole) have become the treatment of choice. Unfortunately, not all patients respond to 
endocrine therapy (primary or de novo resistance), and even patients who have a response will 
eventually relapse (acquired resistance). 
On early disease recurrence/progression, the treatment options include other classes of aromatase 
inhibitors, estrogen-receptor (ER) antagonists/degrader or chemotherapy; being chemotherapy the 
most accepted one for the resistant patients. Within the chemotherapy regimens, capecitabine 
seems one of the best options. 
The research focusing on resistance to endocrine therapies in HR-positive breast cancer has 
aimed to identify new therapeutic strategies that would enhance the efficacy of endocrine 
therapies. 
Published preclinical data suggest that estrogen receptor positive (ER-positive) /HER2 negative 
breast cancers are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function and that 
inhibition of this target may be an effective translational therapeutic strategy. The Pfizer 
compound, palbociclib, is an oral novel CDK4/6 inhibitor that seems to be synergistic with anti-
hormonal therapy in preclinical and clinical studies. Results from a randomized phase II study of 
letrozole vs letrozole plus palbociclib (PALOMA-1) confirmed the safety and tolerability of the 
combination and demonstrated an exciting efficacy with a hazard ratio for progression-free 
survival of 0.488 (95% CI 0.319–0.748; one-sided p=0.0004), with a median PFS increase from 
10.2 to 20.2 months. The most common adverse event from the drug has been asymptomatic 
leucopenia which is an “on-target” effect. Although the study was not designed to perform a 
formal hypothesis testing for overall survival (OS) analysis due to the small sample size, it was 


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performed recently. It showed that the median OS was numerically longer in the palbociclib plus 
letrozole arm than in the letrozole alone arm, but results were not statistically significant (37.5 
months vs 34.5 months; hazard ratio for death was 0.897 [95% CI:0.623, 1.294]; p = 0.281). 
Based on these results, an international, randomized Phase III study comparing letrozole to 
letrozole + palbociclib as first-line treatment for ER-positive metastatic breast cancer (PALOMA-
2) was also performed, which results are already available. PALOMA-2 included 666 
postmenopausal patients with no prior systemic therapy for advanced breast cancer that were 
randomised 2:1 to receive palbociclib (oral 125 mg/day; 3 weeks on/1 week off) + letrozole (2.5 
mg/day continuously) or placebo + letrozole every 28 days until disease progression, consent 
withdrawal or death. Patients were stratified by disease site, disease-free interval from end of 
(neo) adjuvant therapy, and prior hormone therapy (yes/no). The primary endpoint was 
investigator-assessed PFS, and the secondary endpoints included: overall survival, objective 
response rate, clinical benefit rate (CR + PR + SD ≥24 weeks), patient-reported outcomes, 
pharmacokinetics and safety. Baseline characteristics were well balanced between both treatment 
groups. The primary analysis showed a median PFS of 24.8 months (95% confidence interval 
[CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months 
(95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or 
death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). ORR was improved with palbociclib + letrozole 
(42.1% vs. 34.7%, p=0.031; 55.3% vs. 44.4% in patients with measurable disease [p=0.013]). 
CBR was 84.9% vs. 70.3% (p<0.0001). The most common grade 3 or 4 adverse events were 
neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the 
placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% 
vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group 
and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study 
treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole 
group and in 13 patients (5.9%) in the placebo-letrozole group. At the time of this primary 
analysis, the percentage of PFS events was less than 50% (43.7%) in the palbociclib plus 
letrozole arm. Due to that an updated analysis of PFS based on the investigator assessment was 
recently performed when the PFS event rate reached approximately 60% for the entire study 
population (55% in the palbociclib plus letrozole arm), which data confirmed the benefit for the 
addition of palbociclib to letrozole. The updated median PFS was 27.6 months (95% CI: 22.4, 
30.3) in the palbociclib plus letrozole arm and 14.5 months (95% CI: 12.3, 17.1) for placebo plus 
letrozole. The observed hazard ratio for disease progression or death was 0.563 (95% CI: 0.461, 
0.687; stratified 1-sided p<0.000001) in favor of palbociclib plus letrozole treatment. OS data 
was immature in both analysis and the final OS information is still pending.  
In addition, a randomized, double blinded placebo control, global phase III study was completed 
to evaluate  the efficacy of palbociclib + fulvestrant  vs fulvestrant + placebo  (+/- Goserelin 
depending of menopausal status) in  HR-positive/HER2-negative breast cancer patients whose 
disease has progressed on endocrine  therapy either during or within 12 months of completion of 
adjuvant endocrine therapy or while receiving or within 1 month of endocrine therapy for 


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advanced disease (PALOMA-3 study). The primary end point was investigator-assessed 
progression-free survival. A pre-planned interim analysis was performed by an independent data 
and safety monitoring committee after 195 events of disease progression or death had occurred. 
The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not 
estimable) with palbociclib–fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo–
fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001).  
The most common grade 3 or 4 adverse events (AEs) in the palbociclib + fulvestrant group were 
neutropenia (62.0%, vs. 0.6% in the placebo + fulvestrant group), leukopenia (25.2% vs. 0.6%), 
anaemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile 
neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated 
patients. The rate of discontinuation due to AEs was 2.6% with palbociclib and 1.7% with 
placebo.  
Additionally, the results of a prespecified analysis of OS in the PALOMA-3 study showed that 
the median OS was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib + fulvestrant group and 
28.0 months (95% CI, 23.6 to 34.6) in the placebo + fulvestrant group (HR for death, 0.81; 95% 
CI, 0.64 to 1.03; P = 0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the 
completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. 
Among 410 patients with sensitivity to previous ET, the median OS was 39.7 months (95% CI, 
34.8 to 45.7) in the palbociclib + fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the 
placebo + fulvestrant group (HR, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). 
The median duration of subsequent therapy was similar in the two groups, and the median time to 
the receipt of CT was 17.6 months in the palbociclib + fulvestrant group, as compared with 8.8 
months in the placebo + fulvestrant group (HR, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new 
safety signals were observed with 44.8 months of follow-up. 
The PFS curve of PALOMA-1 and PALOMA-3 studies, however, seems to indicate that the 
effect of the drug on PFS was mainly due to the prevention of early progressions. In the first 4 
months of the PALOMA-1 trial (AI sensitive patients), 40% of the patients in the letrozole arm 
had progressed vs only 20% in the letrozole + palbociclib arm; in the first 2 months of the 
PALOMA-3 trial (endocrine resistant patients), 37% of the patients in the fulvestrant arm had 
progressed vs only 20% in the fulvestrant + palbociclib arm. Those curves suggest that the main 
effect of palbociclib is the reversal of resistance to the anti-hormonal treatment. 
A similar effect in that population of patients has been shown with the addition of the mTOR 
inhibitor everolimus to exemestane. The PFS with the combination of exemestane plus 
everolimus was 6.9 vs 2.8 months with exemestane alone. The combination of exemestane plus 
everolimus, however, produces significant toxicity.  
Taking all this into consideration, the combination of anti-hormonal therapy with CDK4/6 
inhibitors such as palbociclib may play an important role in HR-positive patients that have 
become resistant to hormones and should be compared to the standard of care in patients with 


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hormone-resistant HR-positive tumors, i.e. cytotoxic chemotherapy.  
The initially proposed Phase III study was designed to provide the opportunity to confirm the 
clinical benefit of palbociclib in combination with exemestane. The study was designed to 
demonstrate that this combination provides superior clinical benefit compared to capecitabine in 
postmenopausal women with HR+/HER2- metastatic breast cancer who are resistant to non-
steroidal aromatase inhibitors.   
Emerging data suggest that the choice of endocrine partner with palbociclib is particularly 
important to create optimal synergy in endocrine resistance setting. Studies of resistance to 
hormonal therapies and ER biology have highlighted the important role of ER receptor degraders 
for sequential endocrine treatment after patients progressed on aromatase inhibitors (AIs). Recent 
studies revealed that the acquisition of ESR1 mutations is a major mechanism of resistance to 
AIs. ESR1 mutations were found to be associated with exposure to AIs during the adjuvant and 
metastatic settings. Patients with ESR1 mutations had a substantially shorter PFS on subsequent 
AI-based therapy. In addition, the high incidence rate of ESR1 mutation has been reported among 
patients who have been treated with AIs in MBC patients (BOLERO-2, PALOMA-3). More 
recently, data from PALOMA-3 and other studies suggest that fulvestrant may be active among 
patients whose tumors had ESR1 mutation, while exemestane may be inactive. Thus among 
patients who have progressed on AIs, fulvestrant may be a better endocrine partner for 
palbociclib. 
The present design provides the opportunity to confirm the clinical benefit of palbociclib in 
combination with endocrine therapy in relation to ESR1 mutational status. The primary study 
objectives are to demonstrate that: 1) fulvestrant plus palbociclib provides superior clinical 
benefit compared to capecitabine in postmenopausal women with HR+/HER2- metastatic breast 
cancer who are resistant to aromatase inhibitors and that 2) endocrine therapy (fulvestrant or 
exemestane) in combination with palbociclib provides superior clinical benefit compared to 
capecitabine in postmenopausal women with HR+/HER2- metastatic breast cancer and whose 
tumor had estrogen receptor (ESR1) mutational status as wild type at study entry. 
 
Study Design and Treatment: 
This is an international, multicenter, open label, controlled, randomized phase III study 
comparing the efficacy and safety of palbociclib in combination with endocrine therapy 
(exemestane or fulvestrant) versus capecitabine in postmenopausal women with HR 
positive/HER2 negative MBC whose disease was resistant to previous aromatase inhibitors (AI: 
exenestane, letrozole or anastrozole), defined as recurrence while on or within 12 months after the 
end of adjuvant treatment or progression while on or within 1 month after the end of treatment for 
advanced disease. It is not mandatory to have exemestane, letrozole or anastrozole as the most 
recent treatment before randomization but recurrence or progression while receiving or after the 
end of (in the metastatic setting immediately after the end of) the most recent systemic therapy 


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had to be documented before randomization. Patients must have measurable disease or at least 
one bone lesion, lytic or mixed (lytic + blastic), which has not been previously irradiated and is 
assessable by CT/MRI in the absence of measurable disease.  
Approximately 300 patients were to be randomized 1:1 between the experimental arm (Arm A: 
150 patients treated with palbociclib plus exemestane) and the control arm (Arm B: 150 patients 
treated with capecitabine) before the approval of the protocol version 5.0 dated 09Mar2016. 
(Cohort 1). 
Approximately 300 additional patients will be randomized 1:1 between the experimental arm 
(Arm A: approximately 150 patients treated with palbociclib plus fulvestrant) and the control arm 
(Arm B: approximately 150 patients treated with capecitabine) from the approval of the protocol 
version 5.0 dated 09Mar2016 (Cohort 2). 
Study Design: 
Cohort 1 
 
Patients will be stratified by site of disease (visceral vs non-visceral), by the prior sensitivity to 
hormonal treatment (yes vs no), by prior chemotherapy for MBC (yes vs no) and by country. 
Patients randomized to Arm A (experimental arm) will receive: 
 Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 followed by 7 days off 
treatment given as every 28 days cycles; 
in combination with 
 Exemestane, 25 mg, orally once daily (continuously). 
In patients within the Pharmacokinetic (PK) sub-study, exemestane will be administered daily 


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during a 7-day lead-in period (day minus-7 through day minus-1) immediately preceding cycle 1.  
NOTE: The start date of each cycle will be given by the start date of palbociclib intake.  
Patients randomized to Arm B (control arm) will receive: 
 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, 
given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 
twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in 
patients over 70 years of age. 
 
Cohort 2 
 
Patients will be stratified by site of disease (visceral vs non-visceral), by the prior sensitivity to 
hormonal treatment (yes vs no), by prior chemotherapy for MBC (yes vs no) and by country. 
Patients randomized to Arm A (experimental arm) will receive: 
 Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 followed by 7 days off 
treatment given as every 28 days cycles; 
in combination with 
 Fulvestrant 500 mg, two 5ml intramuscular injections (one in each buttock) on Days 1 and 
15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 days Cycle (± 3 days). 
 NOTE: The start date of each cycle will be given by the date of administration of 
fulvestrant.  
Patients randomized to Arm B (control arm) will receive: 
 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, 


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given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 
twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in 
patients over 70 years of age. 
In both Cohorts 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 with permanent discontinuation of palbociclib for a reason 
different 
than 
progression 
(i.e., 
toxicity 
due 
to 
palbociclib) 
will 
continue 
with 
exemestane/fulvestrant (in the active treatment phase) until objective disease progression, clinical 
progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, 
whichever occurs first. Patients with permanent discontinuation of exemestane/fulvestrant will be 
discontinued from the active treatment phase and entered into the follow-up phase. 
Primary Objectives: 
 To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine 
in prolonging Progression-Free Survival (PFS) in postmenopausal women with HR 
positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors, 
regardless of the ESR1 mutational status. 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal women with 
HR positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors and 
whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry. 
ESR1 mutational status will be determined by circulating free DNA (cDNA) and will be 
prospectively determined before the interims or final analyses. Patient tumor ESR1 
mutational status will be blinded to patients, investigators and study team. 
 
Primary Endpoint: 
 Progression-Free Survival (PFS) based on the investigator’s assessment according to the 
RECIST version 1.1. 
Secondary Objectives: 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal women with 
HR positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors 
regardless of ESR1 mutational status at study entry.  
 To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine 
in prolonging Overall Survival (OS) in postmenopausal women with HR positive/HER2 
negative MBC whose disease was resistant to aromatase inhibitors. 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 


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fulvestrant) is superior to capecitabine in prolonging OS in postmenopausal women with 
HR positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors and 
whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry.  
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging OS in postmenopausal women with 
HR positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors 
regardless of ESR1 mutational status at study entry.  
 To compare other efficacy measures between the treatment arms: Objective Response 
Rate (ORR), Clinical Benefit Rate (CBR) and Response Duration (RD). 
 To compare safety and tolerability between the treatment arms. 
 To compare health-related quality of life between the treatment arms. 
 To evaluate the Pharmacokinetics (PK) of the combination of exemestane with palbociclib 
(in selected sites and only in patients accepting to participate). 
Secondary Endpoints: 
 The following efficacy endpoints will be measured: 
o Overall Survival (OS). 
o Objective Response (OR): Complete Response (CR) plus Partial Response (PR) 
based on the investigator’s assessment according to the RECIST version 1.1 in 
patients randomized with measurable disease. 
o Clinical Benefit (CB): CR plus PR plus stable disease based on the investigator’s 
assessment lasting more than 24 weeks according to the RECIST version 1.1 in all 
randomized patients (ITT population). 
o Response Duration (RD) based on the investigator’s assessment according to the 
RECIST version 1.1. 
 Safety will be assessed by standard clinical and laboratory tests (hematology, serum 
chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0. 
 The PK will determine whether palbociclib influences the pharmacology of exemestane. 
Blood samples will be taken at the time defined in the protocol in patients included in the 
experimental arm of Cohort 1 (palbociclib plus exemestane) in selected sites. Enrollment 
of these patients were to be finalised at the completion of cohort 1 recruitment, samples 
from approximately 20 PK-evaluable patients were to be collected. .    
 EORTC QLQ-C30, QLQ-BR23 and EQ-5D questionnaires. 
Exploratory Objectives: 


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 To prospectively evaluate whether the magnitude of PFS and OS prolongation of 
palbociclib in combination with fulvestrant is the same in patients with ESR1 mutational 
status as wild type and patients with ESR1 mutational status positive at study entry.  
 To prospectively evaluate whether PFS and OS of palbociclib in combination exemestane 
is better among those patients with ESR1 mutational status as wild type than those patients 
with ESR1 mutational status positive at study entry.   
 To prospectively evaluate PFS and OS of capecitabine by ESR1 mutational status.  
 To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle (e.g, 
CCND1 amplification, CDKN2A deletion), drug targets (e.g. CDK 4/6), tumor sensitivity 
and/or resistance (e.g. Ki67, pRb, PIK3CA mutation, CCNE1 expression) or breast cancer 
(e.g. PTEN, ERBB2, BRCA 1 and BRCA2). 
Exploratory Endpoints: 
Baseline biomarker values from most recently obtained tumor tissue (deeply recommended from 
metastatic tumor) will be used for central assessment of biomarkers related to breast tumor 
sensitivity and/or resistance to palbociclib (e.g., Ki67, p16/CDKN2A, pRb, CyclinD and others) 
or breast cancer (e.g. PTEN, ERBB2, BRCA1 and BRCA2). A whole blood sample will be 
collected for potential pharmacogenomic analyses related to drug response or adverse drug 
reactions. For example, putative safety biomarkers, drug metabolizing enzyme genes, drug 
transport protein genes, or genes thought to be related to the drug mechanism of action may be 
examined. Correlative plasma samples will be collected for exploratory analysis to analyze the 
pharmacodynamic (PD) treatment effects on circulating free DNA or RNA and explore specific 
breast cancer and efficacy predictive biomarkers (e.g. PIK3CA mutation). Sample will be 
collected from all patients, unless prohibited by local regulations. 
Justification of Sample size determination and interim analyses: 
The primary objectives of this study are to demonstrate that the combination of palbociclib and 
fulvestrant is superior to capecitabine in prolonging PFS in postmenopausal women with 
HR+/HER2- metastatic breast cancer, whose tumors are resistant to prior aromatase inhibitors 
(Cohort 2) and to demonstrate that palbociclib in combination with endocrine therapy 
(exemestane or fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal 
women with HR positive/HER2 negative MBC whose disease was resistant to aromatase 
inhibitors and whose tumor had estrogen receptor (ESR1) mutational status as wild type at study 
entry (Cohort 1 + Cohort 2). All patients from Cohort 2 and patients with ESR1 mutational status 
as wild type from Cohort 1 + Cohort 2 are eligible for the two primary inferential assessments of 
efficacy. 
Cohort 2 will have an 80% power to detect a difference between the control arm with a median 
PFS of 6 months and the experimental arm (palbociclib plus fulvestrant) with a median PFS of 9 
months, for a hazard ratio of 0.667, with a 5% significance level. Assuming a non-uniform 
accrual accomplished over a period of about 26 months, and a follow up period for the final PFS 


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analysis of about 28 months from the start of study randomization of Cohort 2, a total sample size 
of approximately 300 patients (150 in each treatment arm) will be required and the necessary 
number of events for the final PFS analysis is determined to be 193. 
Cohort 1 + Cohort 2 (ESR1 wild type) should have an approximately 80% power to detect a 
difference between the control arm with a median PFS of 6 months and the experimental arm 
(palbociclib plus fulvestrant or exemestane) with a median PFS of 9 months, for a hazard ratio of 
0.667, with a 5% significance level in ESR1 mutation status as wild type patients. The sample 
size will be similar to Cohort 2. Approximately 308 patients and 193 PFS events will be 
accumulated if we assume 80% cDNA collection/detect rate and 70% of patients will have tumors 
with ESR1 mutational status as wild type at study entry (approximately 140 mutational status as 
wild type from 250 patients from Cohort 1 and 168 mutational status as wild type from 300 
patients from Cohort 2). 
The study is designed to have two interim analyses and the final analysis based on the primary 
endpoint of PFS. The first interim analysis will be performed after approximately 150 patients 
have documented progressive disease or death in Cohort 1 and only patients randomized to 
Cohort 1 will be included. The enrollment of Cohort 2 will not be affected by the outcome of the 
first interim analysis. The purposes for the first interim analyses are to assess the safety of the 
patients and to potentially re-evaluate the assumption of the proportion of patients with ESR1 
wild type randomized to the study which may affect the sample size determination for Cohort 1 + 
Cohort 2 (ESR1 wild type) analyses. The second interim analysis will be performed on Cohort 2 
and Cohort 1 + Cohort 2 (ESR1 wild type) after approximately 116 patients have documented 
progressive disease or death in Cohort 2 (approximately 60% of the total events expected for 
Cohort 2). The purposes for the second interim analyses are to allow for early stopping of the 
study for efficacy, futility, to assess the safety of the combination regimens and to potentially re-
estimate the sample size of the trial. The significance level will be allocated to the second interim 
and final analyses with a Bonferroni method, such as alpha=0.002 for the second interim analysis, 
and alpha=0.048 for the final analysis.  
The sample size described above will also allow the assessment of differences in the secondary 
endpoint of overall survival (OS). The median OS for women with advanced or metastatic breast 
cancer treated with capecitabine is assumed to be 22 months. With an overall significance level of 
10% and one interim analysis of OS (at the time of PFS final analysis), Cohort 2 will have 
approximately 80% power to detect a hazard ratio of 0.667 (representing a 50% increase in 
median OS from 22 months to 33 months) when approximately 152 deaths have occurred after an 
approximate follow up of 50 months from the start of study randomization of Cohort 2.  Similar 
sample size determination also applies to Cohort 1 + Cohort 2 (ESR1 wild type). 
An early safety review has been performed by the external Independent Data Monitoring 
Committee (IDMC) recommending continuing the study as planned. In addition, the interim PFS 
analyses will provide the potential to identify early any unexpected safety issues associated with 
the palbociclib combinations.  
Additionaly a planned PK sub-study of the palbociclib and exemestane combination has been 
performed showing a lack of a clinically meaningful drug-drug interaction (DDI) between 


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palbociclib and exemestane when administered in combination.  
Statistical: 
 Demographics and Baseline Characteristics 
Standard descriptive statistics, such as the mean, median, range and proportion, will be 
used to summarize the patient sample and to estimate parameters of interest. Ninety-five 
percent confidence intervals will be provided for estimates of interest wherever possible.  
 Safety Analyses 
Adverse events data and serious adverse events will be reported in frequency tables 
(overall and by intensity). The safety analysis will be performed in the population that has 
received at least one dose of the drugs.  
 Efficacy Analyses 
PFS, CBR, and OS will be evaluated in the ITT and ESR1 wild type populations. ORR, 
will be evaluated in the ITT and ESR1 wild type populations with measurable disease, RD 
will be evaluated in the responding patients. 
A modification of Hochberg’s method will be used for the two primary treatment 
comparisons to provide control of experiment-wise Type 1 error at a 5% significance 
level. With this closed testing method, statistical significance applies to both p1 for Cohort 
2 and p2 for Cohort 1 + Cohort 2 (ESR1 wild type) if p1<0.05 and p2<0.05; or it applies 
only to Cohort 2 if p1≤0.025 when Cohort 1 + Cohort 2 (ESR1 wild type) has p2>0.05; or 
it applies only to Cohort 1 + Cohort 2 (ESR1 wild type) if p2≤0.025 when Cohort 2 has 
p1>0.05 (assuming the analyses results represented by both p1 for Cohort 2 and p2 for 
Cohort 1 + Cohort 2 (ESR1 wild type) demonstrate that the combination of palbociclib 
and fulvestrant and palbociclib and endocrine therapy respectively are superior to 
capecitabine in prolonging PFS).  
Study population and main inclusion and exclusion criteria: 
Patients with hormonal receptor positive and HER2 negative MBC who are resistant to prior AI 
therapy.   
Inclusion Criteria:  
Patients are eligible to be included in the study only if they meet all of the following criteria: 
1. The patient has signed the informed consent document. 
2. a) Patients included in Cohort 1: Females with histologically confirmed MBC whose disease 
was resistant to previous non-steroidal aromatase inhibitors (letrozole or anastrozole), 
defined as: 
 Recurrence while on or within 12 months after the end of adjuvant treatment with non-
steroidal aromatase inhibitors (NSAI) or 
 Progression while on or within 1 month after the end of treatment with NSAI for 


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advanced disease.  
b) Patients included in Cohort 2: Females with histologically confirmed MBC whose disease 
was resistant to previous aromatase inhibitors (exemestane, letrozole or anastrozole), defined 
as: 
 Recurrence while on or within 12 months after the end of adjuvant treatment with an 
AI or 
 Progression while on or within 1 month after the end of treatment with an AI for 
advanced disease.  
3. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or first line 
therapy for MBC (chemotherapy administered as “second adjuvant therapy” for locoregional 
recurrence should be considered as first line chemotherapy for MBC).  
4. It is not mandatory to have exemestane, letrozole or anastrozole as the most recent treatment 
before randomization but recurrence or progression of breast cancer while receiving or after 
the end of (in the mestastatic setting immediately after the end of) the most recent systemic 
therapy has to be documented before randomization.  
5. Hormonal receptor positive (HR+) breast cancer based on local laboratory determination. 
HR+ defined as ≥ 1% positive cells by IHC for ER and/or PgR.  
6. Documented HER2 negative breast cancer based on local laboratory determination on most 
recent tumor biopsy. HER2 negative tumor is determined according to recommendations of  
ASCO/CAP 2013 guidelines, as IHC score 0 or 1+ or negative by ISH (FISH/CISH/SISH) 
defined as a HER2/CEP17 ratio < 2 with an average HER2 copy number <4.0 or for single 
probe assessment a HER2 copy number < 4.  
7. Measurable disease or at least one bone lesion, lytic or mixed (lytic+blastic), which has not 
been previously irradiated and is assessable by CT/MRI in the absence of measurable disease 
according to RECIST 1.1 criteria.  
8. Patient is at least 18 years of age. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. 
10. Life expectancy ≥ 12 weeks. 
11. Adequate organ and bone marrow function defined as follows: 
 ANC ≥ 1,500/mm3 (1.5x109/L) 
 Platelets ≥ 100,000/mm3 (100x109/L) 
 Hemoglobin ≥ 9g/dL (90g/L) 
 Serum creatinine ≤ 1,5xULN and estimated creatinine clearance ≥ 60 mL/min as 
calculated using the standard method for the institution 
 Total serum bilirubin ≤ 1,5xULN (≤ 3.0xULN if Gilbert´s disease) 
 AST and ALT ≤ 3.0xULN (≤5.0xULN if liver metastases present) 
 Alkaline phosphatase ≤ 2.5xULN (≤5.0xULN if bone or liver metastases present) 
12. Postmenopausal women defined as women with: 


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 Prior bilateral surgical oophorectomy, or 
 Age > 60 years 
 Age < 60 year and medically confirmed post-menopausal status defined as spontaneous 
cessation of regular menses for at least 12 consecutive months with no alternative 
pathological or physiological cause or follicle-stimulating hormone (FSH) and estradiol 
blood levels in their respective postmenopausal ranges.   
13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to 
NCI CTCAE version 4.0 Grade ≤ 1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator´s discretion). 
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures.  
Exclusion Criteria:   
Patients will be excluded from the study if they meet any of the following criteria: 
1. Have received more than 1 prior chemotherapy regimen for MBC. (NOTE: Chemotherapy 
administered as “second adjuvant therapy” for locoregional recurrence should be considered 
one prior chemotherapy for MBC). Other previous anticancer endocrine treatments for 
advanced disease are allowed.  
2. Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening 
complications in the short term (including patients with massive uncontrolled effusions 
[pleural, pericardial, peritoneal], pulmonary lymphangitis and over 50% liver involvement).   
3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or 
leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or 
progressive growth. Patients with a history of CNS metastases or cord compression are 
eligible if they have been definitively treated with local therapy (eg, radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 
weeks before randomization.  
4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor [any agent whose mechanism of 
action is to inhibit the PI3 kinase-mTOR pathway] or capecitabine.  
5. a) Patients included in Cohort 1: Prior treatment with exemestane in the metastatic setting. If 
the patient has received exemestane in the adjuvant setting and developed MBC, she will be 
eligible for the study provided: 
 She has received letrozole/anastrozole as first-line MBC and progressed. 
 At least 1 year has elapsed since the end of adjuvant exemestane treatment.  
b) Patients included in Cohort 2: Prior treatment with fulvestrant in the metastatic setting. If 
the patient has received fulvestrant in the adjuvant setting and developed MBC, she will be 
eligible for the study provided: 


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 She has received letrozole/anastrozole/exemestane as first-line MBC and progressed. 
 At least 1 year has elapsed since the end of adjuvant fulvestrant treatment. 
6. Patients treated within the last 7 days prior to randomization with: 
 Food or drugs that are known to be CYP3A4 inhibitors 
 Drugs that are known to be CYP3A4 inducers 
 Drugs that are known to prolong the QT interval 
7. Patients who received before randomization:  
 Any investigational agent within 4 weeks. 
 Chemotherapy within a period of time that is < the cycle length used for that 
treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicin or < 1 week for 
weekly chemotherapy). 
 Previous endocrine therapy is permitted without any window. 
 Radiotherapy within 2 weeks (all acute toxic effects must be resolved to NCI CTCAE 
version 4.0 grades <1, except toxicities not considered a safety risk for the patient at 
investigator´s discretion) but patients who received prior radiotherapy to >25% of 
bone marrow are not eligible independent of when it was received. 
 Major surgery or other anti-cancer therapy not previously specified within 4 weeks: 
all acute toxic effects must be resolved to NCI CTCAE version 4.0 grades < 1, except 
toxicities not considered a safety risk for the patient at investigator´s discretion. 
8. Diagnosis of any other malignancy within 3 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.  
9. QTc > 480msec, family or personal history of long or short QT syndrome, Brugada 
syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP). 
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug 
(eg, hypocalcemia, hypokalemia, hypomagnesemia). 
11. Any of the following within 6 months of randomization: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ≥ 2, 
atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident including transient ischemic attack, or 
symptomatic pulmonary embolism. 
12. Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting 
gastrointestinal function, resection of the stomach or small bowel, or active inflammatory 
bowel disease or chronic diarrhea.  
13. Known hypersensitivity to palbociclib, capecitabine or to exemestane (patients of cohort 1) 
or to fulvestrant (patients of cohort 2) or any of their excipients. 


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14. Any of the following contraindications for chemotherapy with capecitabine:  
 Known deficiency or family history of deficiency of dihydropyrimidine 
dehydrogenase.  
 Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or 
chemically related analogues, such as brivudine.  
15. Only for patients in Cohort 2 any of the following contraindications for treatment with 
fulvestrant:  
 Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor 
deficiency) or long-term (>6 months) anticoagulant therapy other than antiplatelet 
therapy and low dose coumarin derivatives, provided that the International 
Normalised Ratio (INR) is less than 1.6.  
16. Known human immunodeficiency virus infection.  
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study.  
18. Recent or active suicidal ideation or behavior.  


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Table of Contents 
           Section                                                                                             Page 
1. 
Introduction .......................................................................................... 26 
1.1. 
Overview of Breast Cancer ............................................................. 26 
1.2. 
Treatment options for Hormonal Receptor (HR) positive patients 
resistant to an AI ............................................................................. 26 
1.3.  Role of Capecitabine in the Treatment of HR-positive Metastatic 
Breast Cancer .................................................................................. 28 
1.4. 
Interaction of Estrogens and Cyclin-Dependent Kinases in 
Breast Cancer Cells ......................................................................... 29 
1.5. 
Deregulation of Cell Cycle Related Genes and Proteins in Breast 
Cancer ............................................................................................. 30 
1.6. 
Overview of Palbociclib .................................................................. 31 
1.6.1. 
Preclinical Data ....................................................................... 31 
1.6.2. 
Human Pharmacokinetic (PK) Data (85) ................................ 31 
1.6.3. 
QTc Evaluation Data (85) ....................................................... 34 
1.6.4. 
Palbociclib Dose Rationale (85) ............................................. 35 
1.6.5. 
Palbociclib data in Combination with Letrozole in 
Advanced Breast Cancer ......................................................... 35 
1.6.6. 
Palbociclib data in Combination with fulvestrant in 
Advanced Breast Cancer ......................................................... 39 
1.7. Interstitial Lung disease/pneumonitis data:......................................... 40 
1.8. Role of ESR1 mutations in the mechanism of resistance to 
endocrine therapy ............................................................................ 41 
1.9.  Study Rationale ............................................................................... 44 
2. 
Objectives ............................................................................................. 47 
2.1. 
Primary Objectives .......................................................................... 47 
2.2.  Primary Endpoint ............................................................................ 47 
2.3. 
Secondary Objectives ...................................................................... 47 
2.4.  Secondary Endpoints ....................................................................... 48 
2.5. 
Exploratory Objectives .................................................................... 48 
2.6. 
Exploratory Endpoints .................................................................... 49 
3. 
Investigational Plan .............................................................................. 50 
3.1. 
Study Design ................................................................................... 50 
3.1.1. 
Early Safety Review and Pharmacokynetic analysis .............. 54 
3.2. 
Duration of the study ....................................................................... 54 
4. 
Study Population .................................................................................. 56 
4.1. 
Inclusion Criteria ............................................................................. 56 


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4.2. 
Exclusion Criteria ............................................................................ 57 
4.3. 
Discontinuations .............................................................................. 60 
4.3.1. 
Discontinuation of Study Treatment ....................................... 60 
4.3.2. 
Discontinuation of Study Sites ............................................... 61 
4.3.3. 
Discontinuation of Study ........................................................ 61 
5. 
Treatment ............................................................................................. 62 
5.1. 
Treatments Administered ................................................................ 62 
5.1.1. 
Palbociclib .............................................................................. 62 
5.1.2. 
 Exemestane ............................................................................ 62 
5.1.3. 
Capecitabine............................................................................ 62 
5.1.4. 
Fulvestrant .............................................................................. 62 
5.2. 
Materials and Supplies .................................................................... 62 
5.2.1.  
Storage, preparation and administration ................................. 63 
5.2.1.1. 
Palbociclib ......................................................................... 63 
5.2.1.2. 
Exemestane ....................................................................... 64 
5.2.1.3. 
Capecitabine ...................................................................... 65 
5.2.1.4. 
Fulvestrant ......................................................................... 65 
5.2.2. 
 Accountability ........................................................................ 65 
5.3. 
Method of Assigning a Patient to a Treatment ................................ 65 
5.4. 
Special Treatment Considerations. Dose Adjustments of Study 
Treatment ........................................................................................ 66 
5.4.1.  
Palbociclib .............................................................................. 67 
5.4.1.1. 
Dosing Interruption ........................................................... 67 
5.4.1.2. 
Re-treatment criteria ......................................................... 68 
5.4.1.3. 
Dose Reductions ............................................................... 69 
5.4.2. 
 Exemestane ............................................................................ 72 
5.4.3. 
Fulvestrant .............................................................................. 72 
5.4.4. 
Capecitabine............................................................................ 72 
5.4.4.1. 
Hematological Toxicity..................................................... 73 
5.4.4.2. 
Non-Hematological Toxicity ............................................ 75 
5.5. 
Medication Errors and Overdose .................................................... 78 
5.6. 
General Concomitant Medication and Supportive Care 
Guidelines ....................................................................................... 78 
5.6.1. 
Prohibited Medications ........................................................... 78 
5.6.2. 
Medications Not Recommended ............................................. 79 
5.6.3. 
Permitted Medications ............................................................ 80 
5.7. 
Treatment Compliance .................................................................... 82 
6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments . 83 


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6.1. 
Efficacy Assessments ...................................................................... 83 
6.1.1. 
Primary Efficacy Assessments................................................ 83 
6.1.2. 
Secondary Efficacy Assessments............................................ 83 
6.2. 
Safety Assessments ......................................................................... 84 
6.2.1. 
Timing of Assessments ........................................................... 84 
6.2.2. 
Definitions .............................................................................. 84 
6.2.3 
Management, Timing and Assessment of Adverse Events..... 87 
6.2.4. 
Management, Timing and Assessment of SAEs ..................... 89 
6.2.5. 
Management, Timing and Assessment of SUSARs ............... 94 
6.3. 
Other Assessments .......................................................................... 95 
6.3.1.   Pharmacokinetic Assessments .................................................... 95 
6.3.2. 
Biomarker, Pharmacogenomic and Pharmacodynamic 
Assessments ............................................................................ 97 
6.3.3 
Patient Reported Outcomes .................................................... 98 
7. 
Data Quality Assurance ...................................................................... 100 
7.1. 
Data Management and Registries file ........................................... 100 
8. 
Sample Size and Statistical Methods ................................................. 101 
8.1. 
Determination of Sample Size ...................................................... 101 
8.1.1. 
Sample Size determination ................................................... 101 
8.2. 
Statistical and Analytical Plans ..................................................... 102 
8.2.1. 
General Considerations ......................................................... 102 
8.2.1.1. 
Patient Populations .......................................................... 102 
8.2.2. 
Patient Disposition ................................................................ 102 
8.2.3. 
Patient Characteristics........................................................... 103 
8.2.4. 
Concomitant Therapy ........................................................... 103 
8.2.5. 
Treatment Compliance .......................................................... 103 
8.2.6. 
Efficacy Analyses ................................................................. 103 
8.2.6.1. 
Analyses of Primary Endpoint ........................................ 104 
8.2.6.2. 
Analysis of Secondary Endpoints ................................... 104 
8.2.7. 
Safety Analyses..................................................................... 106 
8.2.8. 
Other Analyses ...................................................................... 106 
8.2.8.1. 
Pharmacokinetic Analysis ............................................... 106 
8.2.8.2. 
Biomarker, Pharmacogenomic and Pharmacodynamic 
Analysis ........................................................................... 107 
8.2.8.3.  
Patient Reported Outcomes ............................................. 107 
8.2.9. 
Subgroup Analyses ............................................................... 108 
8.2.10. 
Interim Analysis .................................................................... 108 
8.2.11. 
Data Monitoring Committees ............................................... 108 
8.2.12. 
Criteria for End of Study ...................................................... 109 


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9. 
Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations ................................................................. 110 
9.1. 
Informed Consent .......................................................................... 110 
9.2. 
Respect of Confidentiality ............................................................. 110 
9.3. 
Responsibility Insurance ............................................................... 110 
9.4. 
Regulatory Considerations ............................................................ 111 
9.4.1. 
Investigator Information ....................................................... 111 
9.4.2. 
Protocol Signatures ............................................................... 111 
10. Practical Considerations ..................................................................... 112 
10.1.  Monitoring, Audit and Inspections .............................................. 112 
10.3.  Preservation of Study Documentation ......................................... 112 
10.4.  Protocol Modification .................................................................. 112 
10.5.  Use of the Information and Publication ....................................... 112 
10.5.1 
Clinical Trial Registration .................................................... 113 
10.5.2 
Clinical Trial Results Disclosure .......................................... 113 
10.6.  Ethics Committees and/or IRBs ................................................... 113 
11. References .......................................................................................... 115 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status ............................................................................. 129 
Protocol Attachment 3. List of Drugs Known to Predispose to Torsade 
de Pointes ........................................................................................... 130 
Protocol Attachment 4. Capecitabine Dose Calculation According to 
Body Surface Area ............................................................................. 133 
Protocol Attachment 5. Capecitabine Interruptions and Extended Rest 
Periods ................................................................................................ 136 
Protocol Attachment 6. Palbociclib/Fulvestrant Interruptions and 
Extended Rest Periods ........................................................................ 137 
Protocol Attachment 7. Palbociclib, Exemestane and Capecitabine 
Diaries ................................................................................................ 139 
Protocol Attachment 8. Adverse event (AE) non defined in CTCAE ........ 140 
Protocol Attachment 9. Adverse Events / Serious Adverse Events 
Assessment Guide .............................................................................. 141 
Protocol Attachment 10. QLQ-C30, QLQ-BR23 and EQ-5D 
Questionnaires .................................................................................... 142 


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Abbreviations and Definitions 
ABC 
Advanced Breast Cancer 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
ALT/ALAT (SGPT) 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
AR 
Adverse Reaction 
ASCO 
American Society of Clinical Oncology 
AST/ASAT (SGOT) 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CAP 
College of American Pathologist 
cDNA 
Circulating free DNA 
CDK 
Cyclin-Dependent Kinase 
CISH 
Chromogenic In Situ Hybridization 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computed Tomography Scan 
DDI 
Drug-Drug Interaction 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
eCRF 
Electronic Case Report Form (sometimes referred to as Clinical Report Form). An 
electronic form for recording study participants’ data during a clinical study, as 
required by the protocol. 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
End of Study (Trial) 
The end of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active patient in the study. 


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Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned a registration number and treatment. 
Enter 
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients 
entered into a trial are those who sign the informed consent document directly or 
through their legally acceptable representatives. 
ER 
Estrogen Receptor 
ERB/IRB 
Ethical review board/Institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical professional and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical trial are protected. 
ESR 
Expedited Safety Report 
ESR1 
Estrogen Receptor 1 
ER-LBD 
Estrogen Receptor-Ligand  Binding Domain 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
GEICAM 
Spanish Breast Cancer Research Group 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GI 
GastroIntestinal 
HER2 
Human Epidermal Growth Factor Receptor 2 
Hgb 
Hemoglobin 
HR 
Hormonal Receptor 
ICD 
Informed Consent Document  
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator. 


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ISH 
In Situ Hybridization 
ITT 
Intent To Treat 
Legal Representative 
An individual, judicial, or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical trial. 
LLN 
Lower Limit of Normal 
LFT 
Liver Function test 
MBC 
Metastatic Breast Cancer 
MID 
Minimally important difference 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
NCI 
National Cancer Institute 
NSAI 
Non-Steroidal Aromatase Inhibitor 
ORR 
Objective Response Rate 
OS 
Overall Survival 
Patient 
A subject with a defined disease. 
PD 
Progressive Disease or Pharmacodynamic depending on the context 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PK 
Pharmacokinetic 
PR 
Partial Response 
QD 
Once A Day 
RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II Dose 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAI 
Steroidal aromatase inhibitor 


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SC 
Steering Committee 
SD 
Stable Disease 
SISH 
Silver In Situ Hybridization 
SOP 
Standard Operating Procedure 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TdP 
Torsade de Pointes 
TEAE 
Treatment-Emergent Adverse Event 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
WNL 
Within Normal Limits 
 
 


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Phase III study of Palbociclib (PD-0332991) in combination with 
Endocrine therapy (exemestane or fulvestrant) versus 
chemotherapy (capecitabine) in Hormonal Receptor (HR) 
positive/HER2 negative Metastatic Breast Cancer (MBC) patients 
with Resistance to Aromatase inhibitors                                              
“The PEARL study” 
1. 
Introduction 
1.1. 
Overview of Breast Cancer 
Breast cancer (BC) is the most common invasive cancer in women, with more than one million 
cases and over 411,000 deaths occurring worldwide annually (1). Although age-adjusted 
mortality from breast cancer has been decreasing since 1990, the median survival for patients 
with metastatic disease is still only approximately 18 to 24 months (2) and the medical need for 
more active agents in this clinical setting remains very high. 
1.2. 
Treatment options for Hormonal Receptor (HR) positive patients resistant to an AI  
Approximately two-thirds of breast cancers express estrogen receptor (ER) (3) and the role for 
estrogens in breast cancer etiology and progression is well established. Endocrine therapy is the 
treatment of choice for most women with metastatic hormone receptor (HR) positive breast 
cancer. It is an effective treatment with a relatively low toxicity that enables preservation of 
quality of life. For many years tamoxifen was the gold standard for first-line therapy, but in 
postmenopausal women aromatase inhibitors or ‘inactivators’ have been shown to be superior 
(4). 
In postmenopausal women, the synthesis of estrogen takes place almost exclusively in extra-
ovarian tissues, with the conversion of androstenedione to estrone in the peripheral adipose 
tissue. Aromatase inhibitors prevent the cytochrome p-450 aromatase enzyme from catalysing 
the steroid hydroxylation reactions involved in the conversion of androstenedione to estrone. 
The first developed aromatase inhibitor was aminoglutethimide, which proved to be at least as 
effective as tamoxifen, but with significant toxicities of drowsiness and rash (5). Second-
generation aromatase inhibitors (formestane and fadrozole) were developed to have improved 
specificity for the aromatase enzyme and were soon superseded by third-generation compounds 
with greater specificity, potency, bioavailability and tolerability. 
The three commonly used third-generation aromatase inhibitors (anastrozole, letrozole and 
exemestane) differ between each other with respect to basic pharmacological characteristics 
and can be divided according to whether they are nonsteroidal (NSAIs; with a reversible 


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mechanism of action) or steroidal (SAIs; with an irreversible mechanism of action). Only 
exemestane is steroidal and binds irreversibly to aromatase to compete with the precursors of 
estrogen for the enzyme. 
The most effective sequence of tamoxifen and both SAIs and NSAIs has been extensively 
studied in the adjuvant setting. Unfortunately, not all patients respond to endocrine therapy 
(primary or de novo resistance), and even patients who have a response will eventually relapse 
(acquired resistance). The treatments options for women with early disease recurrence or 
progression to initial NSAI therapy have received relatively little attention. Patients with 
strongly estrogen receptor/progesterone receptor-expressing tumors might benefit more from 
alternative endocrine therapy, including SAIs (exemestane) and the estrogen-receptor (ER) 
down-regulator fulvestrant. Exemestane was studied in this setting in several trials from which 
only 2 were randomized and reported information about Time to Progression (TTP) or 
Progression Free Survival (PFS), which was ranging between 2.8 to 3.7 months (6,7). In the 
EFECT study, Fulvestrant with a loading-dose regimen (500 mg on day 0, 250 mg on days 14, 
28, and 250 mg every 28 days thereafter) was compared with exemestane  in 693 women with 
HR positive advanced breast cancer (ABC) progressing or recurring after nonsteroidal AIs. 
Median TTP was 3.7 months in both groups (hazard ratio: 0.963; 95% CI: 0.819 to 1.133; 
p=0.6531). The overall response rate (7.4% v 6.7%; p=0.736) and clinical benefit rate (32.2% v 
31.5%; p=0.853) were similar between fulvestrant and exemestane respectively. Median 
duration of clinical benefit was 9.3 and 8.3 months, respectively (6). However, there is 
evidence to suggest that doses of fulvestrant higher than 250mg may have greater 
pharmacodynamic activity against the ER pathway. A phase III clinical trial [CONFIRM trial] 
was completed in 736 postmenopausal women with advanced breast cancer who had disease 
recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy 
for advanced disease. The results of a trial comparing 250 mg of fulvestrant to high-dose 
fulvestrant (500 mg monthly), showed a median PFS for 500mg of 6.5 months compared to 5.5 
months for 250mg (hazard ratio: 0.63; 95%CI, 0.39 to 1.00; p-value 0.0496). Median OS was 
26.4 months for 500mg versus 22.3 months for 250mg (hazard ratio: 0.81, CI95%: 0.69, 0.96; 
p-value 0.016), but we have to take into consideration that less than half of the patients in this 
trial had previously received an AI (8-9). Also, a pilot Japanese study showed that fulvestrant at 
the 500mg dose resulted in plasma levels approximately double those seen with 250mg 
fulvestrant (10). Additionally, a neoadjuvant study comparing fulvestrant low-dose and high-
dose reported a significantly greater Ki67 and ER downregulation with the high-dose compared 
with the low-dose regimen (11). 
Taking into account those disappointing results most clinicians would think about 
recommending chemotherapy for their patients resistant to AIs. In a recently published study, 
the median PFS in patients with HR-positive disease with the administration of capecitabine 
and taxanes or anthracyclines as first-line therapy, was 6.2 and 8.2 months respectively (12). 
An additional trial also published recently showed a median PFS of 6 months in patients with 
HR-positive disease when treated with several chemotherapy options in second line (13). 


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In addition to the administration of chemotherapy, there is a huge investment in the 
identification of new therapeutic strategies that would enhance the efficacy of endocrine 
therapies. 
To date only one drug, Everolimus (Afinitor®), has been successful in this fight, and is already 
approved by the most relevant regulatory Agencies for patients that have received previously 
an AI. 
Everolimus is a rapamycin derivative that inhibits mTOR [one of the pathways thought to be 
implicated in both the primary or acquired resistance to hormonal therapy (14)] through 
allosteric binding to mTORC1 (15). 
In preclinical models, the use of everolimus in combination with AIs resulted in synergistic 
inhibition of the proliferation and induction of apoptosis (16). In a randomized, phase II study 
comparing neoadjuvant everolimus plus letrozole with letrozole alone in patients with newly 
diagnosed ER-positive breast cancer, the response rate for the combination was higher than that 
for letrozole alone (17).  
Based on this data, the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study 
evaluated the efficacy and safety of the combination of everolimus and exemestane in patients 
with HR-positive breast cancer refractory to NSAIs (7). The interim results from this trial 
showed that the median PFS according to the investigator assessment for everolimus plus 
exemestane was 6.9 months, more than 2-fold that for the exemestane plus placebo (2.8 
months), with a hazard ratio for progression or death of 0.43 (95% confidence interval [CI], 
0.35 to 0.54; P<0.001). The median PFS according to central assessment was 10.6 months and 
4.1 months, respectively (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). The most 
common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus- exemestane 
group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 
1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%) and pneumonitis (3% vs. 0%). In 
addition, serious adverse events, were reported among 23% of patients in the combination-
therapy group (11% attributed to study treatment) and 12% in the exemestane-alone group (1% 
attributed to study treatment). A higher percentage of patients discontinued everolimus in the 
combination-therapy group than discontinued placebo in the control group because of adverse 
events (19% vs. 4%) and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, 
the corresponding numbers were 7% versus 3% and 7% versus 2%. 
This was a perfect proof of concept trial but did not solve the definitive question of what can 
everolimus offer in these AIs resistant patients, because most physicians would not have 
administered exemestane monotherapy but chemotherapy to these patients, implying that the 
control arm was not the most appropriate one and leaving the role of everolimus treatment in 
this patient population ill-defined.  
1.3.  
Role of Capecitabine in the Treatment of HR-positive Metastatic Breast Cancer 
Capecitabine (Xeloda; F. Hoffmann-La Roche, Basel, Switzerland) is an oral antimetabolite 
of the fluoropyrimidine family that is converted to 5-fluorouracil in a three-step enzymatic 


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process. The final step is catalyzed by the thymidine phosphorylase (TP) enzyme, whose 
quantity and function are increased in various tumor types, including breast cancer, compared 
with adjacent healthy tissue (18). Final activation of capecitabine to 5-fluorouracil therefore 
occurs preferentially in the tumor cells and limits the appearance of adverse effects in other 
organs (19,20). 
Capecitabine is approved in more than 90 countries as single agent in patients who previously 
failed to paclitaxel and anthracyclines, or who cannot receive these drugs (21). Capecitabine in 
combination with docetaxel is also approved for advanced breast cancer patients who have 
experienced treatment failure with anthracyclines. 
Capecitabine is currently considered to be one of the most active drugs available in advanced 
breast cancer, and its efficacy has been amply demonstrated in monotherapy in either 
previously treated patients or as first-line therapy for metastatic disease (22-26). When 
administered alone in previously treated patients, capecitabine efficacy achieved median 
TTP/PFS ranging from 2.8 to 5.9 months (which increased in patients with HR-positive 
disease) and overall survival times of 9.3 to 18.1 months (27). 
The capecitabine label recommends a dose in monotherapy for advanced breast cancer patients 
of 1250 mg/m2 twice daily, on days 1 to 14 of every 21-day period (21). Administered at these 
doses and according to this regimen, capecitabine shows a toxicity profile with undesirable 
adverse effects, with the most frequent being Grade 3 or 4 hand-foot syndrome (16%), diarrhea 
(10%), fatigue (5%), stomatitis (3%), and vomiting (3%) (27).  
Based on these data we selected capecitabine for our control arm for this study. 
1.4. 
Interaction of Estrogens and Cyclin-Dependent Kinases in Breast Cancer Cells 
Studies of ER-positive breast cancer cell lines indicate that estrogens (28) and antiestrogens 
(29) 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 (30-33). 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 (33). 
D-type cyclins play an essential role in recognition of extracellular growth stimuli and initiation 
of G1 transit (34,35), 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 (36-39). Expression of cyclin D1 in breast tumor isolates correlates with ER-positive 
status (40-42). MCF-7 breast cancer cells treated with estrogen exhibit increased expression of 
cyclin D1 mRNA and protein, formation of active cyclin D1-CDK4 complexes, and 


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phosphorylation of pRb leading to G1/S transition (43-46). Estrogen-induced S-phase entry in 
these cells is inhibited by microinjection of antibodies to cyclin D1 (47). Antiestrogen-induced 
growth arrest of ER-positive breast cancer cells is associated with decreased cyclin D1 
expression (48). Collectively, these studies are consistent with a model of estrogen action in 
which the 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 (49-52). 
Constraint upon CDK activity and G1 progression is provided by the universal CDK inhibitors 
of the Cip-Kip family, including gp21Cip1 and p27Kip1, and the specific CDK4 and CDK6 
inhibitors of the INK4 family, typified by p16INK4a (35,53-56). The CDKN2A gene product 
inhibits formation of active D-type cyclin-CDK complexes through specific binding 
interactions with CDK4 or CDK6 that prevent D-type cyclin-CDK association (57-59). Over 
expression of p16INK4a in cells with functional pRb results in inhibition of both CDK4-and 
CDK6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest 
(57,58). In addition, inhibition of D-type cyclin-CDK4 complex formation by p16INK4a 
prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to 
suppression of cyclin E-CDK2 activity (60-62). 
Overexpression of p16INK4a through adenoviral transduction of CDKN2A into MCF-7 cells 
leads to G1 arrest associated with inhibited CDK activity (63,64). Cell cycle progression 
induced by estradiol requires action of the steroid through mid-G1, well beyond the point of 
cyclin D1-CDK4 activation (44). 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 (65). 
1.5. 
Deregulation of Cell Cycle Related Genes and Proteins in Breast Cancer 
Cell cycle related genes and proteins are frequently deregulated in breast cancer. 
Approximately 15%–20% of human breast cancers exhibit amplification of the 
cyclin D1 (CCND1) gene (66-68), while the majority of human mammary carcinomas over 
express cyclin D1 protein (69-71). Over expression of cyclin D1 is seen early in breast cancer, 
and it is maintained at all stages of breast cancer progression, including metastatic lesions 
(69,72). Amplification of the CDK4 gene, located at 12q13-q14, has been shown as an 
alternative genetic alteration to CDKN2A inactivation in various human tumor including breast 
cancer (73,74). There is a mounting body of evidence linking a specific CCND1 polymorphism 
(G/A870) to increased risk of cancer and outcome in a variety of tumor types including breast 
cancer. This polymorphism results in a splice variant, altered protein structure and enhanced 
oncogenic activity in experimental models (75). The continued presence of CDK4-associated 
kinase activity is actually required to maintain breast tumorigenesis (76). Direct analyses of 
primary tumors have revealed loss of pRb expression in 20–35% of tumors, and loss of 


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heterozygosity or other alterations of the Rb locus in 7-37% of tumors (77-80). In preclinical 
models, Rb depletion appears to be associated with resistance to antiestrogen therapy (81). 
Finally, virtually all ER-positive cell lines harbor loss of p16INK4a (82-83) expression, and 
low expression of CDK inhibitors p21 and p27 and high expression level of cyclin E and D1 
have all been associated with resistance to anti-estrogen therapy. 
1.6. 
Overview of Palbociclib  
Palbociclib (Molecular Weight: 447.53) is an orally active potent and highly selective 
reversible inhibitor of CDK4 and CDK6. The compound prevents cellular DNA synthesis by 
prohibiting progression of the cell cycle from G1 into the S phase. 
1.6.1. 
Preclinical Data 
Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied by 
the inhibition of specific pRb phosphorylation by CDK4 or CDK6 on residues serine  
-780 and -795 of pRb. The IC50 values for reduction of pRb phosphorylation at serine -780 and 
-795 in MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 µM, respectively. The 
IC50 values for reduction of pRb phosphorylation are similar to the IC50 values of inhibition of 
thymidine incorporation across a range of cultured tumor and normal cells. 
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines. 
Results from these experiments indicate that those cell lines that are more sensitive to 
palbociclib (IC50 < 150 nM) have low levels of CDKN2A (p16) and high levels of Rb1, while 
resistant cell lines show the opposite characteristics. Sensitive cell lines in this panel represent 
mostly the luminal ER+ subtype (84).  
The combination of palbociclib with tamoxifen has recently been tested in vitro in ER+ human 
breast cancer cell lines indicating a synergistic interaction (84) and provides a biologic 
rationale for evaluating the combination of palbociclib with anti-hormonal therapy in the clinic. 
Also, recently data from Julie Kan´s group in hormone resistant models (MCF7-CYP19) 
indicate a significant benefit of the combination of palbociclib and letrozole as well as 
palbociclib and fulvestrant over the single agents letrozole and fulvestrant (Pfizer, unpublished 
data). 
1.6.2. 
Human Pharmacokinetic (PK) Data (85) 
Single-Dose Pharmacokinetics 
The single-dose pharmacokinetics (PK) of palbociclib have been evaluated in a total of 24 
clinical studies, of which 3 were conducted in patients with advanced malignant disease  
(Studies A5481001, A5481010 and A5481019) and 21 were conducted in healthy subjects 
(Studies A5481009, A5481011, A5481013 [also included subjects with hepatic impairment], 
A5481014 [also included subjects with renal impairment], A5481015, A5481016, A5481017, 
A5481018, A5481020, A5481021, A5481022, A5481026, A5481032, A5481036, A5481038, 


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A5481039, A5481040, A5481041, A5481079, A548081 and 5481091). Among these studies, 2 
studies in healthy subjects (Studies A5481009 and A5481011) also evaluated PK of PF-
05089326, the active lactam metabolite of palbociclib, after administration of a single 
palbociclib dose. 
Patients With Advanced Malignant Disease: Single dose PK was evaluated in patients with 
advanced malignant disease following doses ranging from 25 mg to 225 mg in Study 
A5481001, which was an open-label, noncomparative, dose-finding, first in patients study. 
Following administration of a single 125 mg dose of palbociclib, the median time of maximum 
concentration (Tmax) was observed at 7 hours post-dose. Palbociclib AUCinf and t½ could not be 
estimated after single-dose administration in this study, because the last blood samples for PK 
evaluations were obtained at 10 hours after dosing. The palbociclib geometric mean Cmax was 
42.7 ng/mL after palbociclib single-dose administration to fasting patients and 59.1 ng/mL after 
palbociclib single-dose administration to fed patients in the food effect portion of Study 
A5481001 after normalizing for a 125 mg dose. The geometric mean AUC(0-10) was 290 
nghr/mL in fasting patients and 371 nghr/mL in fed patients after normalizing for a 125 mg 
dose. These results suggest that the administration of palbociclib with food results in more 
consistent drug absorption and exposure than administration of palbociclib in a fasted state. As 
a result of these findings, patients should be instructed to take palbociclib with food.  
  
Single dose PK was also evaluated in patients with advanced malignant disease following doses 
of 100 mg and 125 mg in Study A5481010, which was an open-label, noncomparative, dose-
finding, first in a Japanese patients study. After a single 125-mg palbociclib dose in Study 
1010, median Tmax was 4 hours, the geometric mean Cmax was 104 ng/mL, the geometric mean 
AUCinf was 2483 ng•hr/mL, and median t½ was 23.9 hours. 
Single dose PK was also evaluated in patients with ER-positive, HER2-negative advanced 
breast cancer following a dose of 125 mg in Study A5481019, which was an open-label, 
noncomparative, PK bridging study in Chinese patients. Following administration of a single 
125 mg dose of palbociclib, the median Tmax was 8 hours, the geometric mean Cmax was 82.1 
ng/mL, the geometric mean AUCinf was 2386 ng•hr/mL, and median t½ was 23.5 hours. 
 
Healthy Subjects: As of the data cutoff date of 31 August 2017, single dose PK profiles have 
been collected from 550 healthy volunteers following 1350 doses of palbociclib ranging from 
50 mg to 150 mg. Palbociclib PK profiles and parameters following single 125 mg doses 
appeared to be generally comparable across studies conducted in healthy subjects. After a 
single oral 125 mg dose of palbociclib, the median Tmax was observed between 6 hours and 8 
hours after oral dosing. Following attainment of Cmax, plasma palbociclib concentrations 
declined in a multiexponential manner, with mean t½ values ranging between 19.4 hours and 
26.4 hours. The palbociclib geometric mean plasma Cmax values ranged from approximately 
28.0 ng/mL to 72.1 ng/mL, while the geometric mean AUCinf values ranged from 1087 
ng•hr/mL to 2136 ng•hr/mL. The palbociclib geometric mean Vz/F values ranged between 


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1907 L and 4007 L, which is significantly greater than total body water (42 L), indicating that 
palbociclib extensively distributes to peripheral tissues. The palbociclib geometric mean CL/F 
values ranged between 58.5 L/hr and 115 L/hr. 
Multiple-Dose Pharmacokinetics 
The multiple-dose PK of palbociclib was evaluated in a total of 5 studies in patients with 
advanced solid malignant tumors (Studies A5481001, A5481003, A5481008, A5481010 and 
A5481019). Following repeated 125 mg QD dosing to steady state, palbociclib was absorbed 
with a median Tmax ranging from approximately 4 hours to 8 hours post-dose. Palbociclib was 
eliminated slowly, with a mean t½ ranging from 23.2 hours to 28.8 hours. Palbociclib 
accumulated after repeated dosing (median Rac = 1.9 - 2.4), which was consistent with its 
terminal t½. The palbociclib geometric mean plasma Cmax values ranged from 94.9 ng/mL to 
186.0 ng/mL, while the geometric mean plasma AUC24 values ranged from 1633 ng•hr/mL to 
2838 ng•hr/mL. 
Palbociclib is metabolized to multiple metabolites in a qualitatively similar manner in rat, dog 
and human liver microsomes. In vitro, data indicate that CYP3A and sulfotransferase (SULT) 
enzyme SULT2A1 are mainly involved in the metabolism of palbociclib. An exploratory 
evaluation of the circulating metabolites for palbociclib was conducted in plasma samples 
obtained from patients treated with palbociclib 200 mg QD (Schedule 2/1) in Study A5481001. 
Preliminary assessment of the pooled plasma samples on Day 14 of Cycle 1 indicated that the 
glucuronide conjugate of palbociclib and the lactam of palbociclib (PF-05089326) were the 
main metabolites present in plasma. Other metabolites observed were the glucuronide 
conjugates of hydroxylated palbociclib and the glucuronide conjugate of reduced palbociclib. 
PF-05089326 was also observed in the circulation of rats following repeated daily oral 
administration of palbociclib at the dose levels of 50 and 100 mg/kg/day. Plasma protein 
binding of palbociclib and PF-05089326 is ~85% and 95%, respectively. 
Concomitant administration of agents which increase gastric pH can alter the solubility and 
absorption of palbociclib free base formulations.  
Study A5481038 evaluated the effects of staggered dosing of the H2-receptor antagonist 
(H2RA) famotidine, and of the staggered dosing of the local antacid Mi-Acid Maximum 
Strength Liquid, on the PK of a single oral 125 mg palbociclib final Phase 3/commercial free 
base capsule given with food in healthy subjects. The results indicated that administration of 
palbociclib under fed conditions with staggered famotidine and staggered Mi-Acid Maximum 
Strength Liquid dosing had no impact on the exposure of palbociclib. 
Study A5481038 also evaluated the effects the coadministration of a single 125 mg dose of the 
free base capsule of palbociclib following multiple doses of the proton pump inhibitor (PPI) 
rabeprazole under fed conditions in healthy volunteers. Concurrent administration of 
rabeprazole with palbociclib decreased palbociclib Cmax by 41%, but had limited impact on 
AUCinf (13% decrease) compared with a single dose of palbociclib administered alone. This 
13% reduction in overall exposure is not thought to be clinically relevant. 


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Given the reduced effect on gastric pH of H2RAs and local antacids compared to PPIs, the 
effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is 
expected to be minimal. 
PK data from Study A5481023 was analyzed to evaluate the potential for DDIs between 
palbociclib and fulvestrant, as well as between palbociclib and goserelin, at steady-state. These 
data indicate a lack of any clinically relevant DDIs between palbociclib, fulvestrant, and 
goserelin when administered in combination. 
1.6.3. 
QTc Evaluation Data (85) 
The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using 
time-matched electrocardiograms (ECGs) evaluating the change from baseline and 
corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib did not 
prolong QTc to any clinically relevant extent at the recommended dose of 125 mg daily  
A pharmacokinetic/pharmacodynamic analysis to evaluate the relationship between palbociclib 
exposure and ECG endpoints (RR and QTc intervals) were developed using pooled data from 3 
clinical trials in patients with advanced malignant disease (Studies A5481001, A5481002, and 
A5481003). The study population consisted of 48 men and 136 women with a median (range) 
body weight of 73.0 (37.9-123) kg and age of 61.5 (22-89) years old. Palbociclib doses ranged 
from 25 mg to 225 mg QD. The data collected from 184 patients consisted of 569 ECG-
palbociclib concentration-matched pairs; the observed plasma concentrations had a median 
(range) of 55.2 (2.51-329) ng/mL. The average heart rate, RR, QT, QT corrected for heart rate 
according to Bazett (QTcB), QT corrected for heart rate according to Fridericia (QTcF), and 
QTcS (QT interval corrected for heart rate according to a study-specific correction factor) at 
baseline for ECG-palbociclib concentration matched data were 76.8 beats per minute, 808 
msec, 380 msec, 425 msec, 409 msec, and 412 msec, respectively. 
The results of the analysis indicate that palbociclib does not appear to have a concentration-
dependent effect on heart rate. A slight positive linear relationship between palbociclib 
concentration and QTcS was observed; however, at the mean or median steady-state 
palbociclib Cmax following administration of the recommended clinical dose of palbociclib 
(125 mg QD) in patients with cancer, the upper bound of the one-sided 95% CI for the increase 
in QTcS fell below the threshold of 10 msec, suggesting that QT prolongation is not a safety 
concern for palbociclib at the recommended clinical dose according to the criteria described in 
the ICH guidance for Industry E14. Similar results were obtained when QTcF and QTcB were 
used. 
In Study A5481023 in women with breast cancer treated with palbociclib or placebo in 
combination with fulvestrant, no notable differences were seen between baseline and end-of 
treatment in the mean and median values for RR interval, heart rate, QT interval, QTcB 
interval, and QTcF interval, in either treatment arm. There were also no relevant differences 
between treatment arms for any of the ECG parameters. The mean and median changes from 


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baseline to any post-baseline timepoint were generally minor for all parameters and did not 
show any relevant differences between treatment arms. None of the patients in either treatment 
arm showed post-baseline ECG findings of a maximum QT interval ≥500 ms. The percentage 
of patients with postbaseline QTcB interval ≥500 ms was slightly higher in the palbociclib plus 
fulvestrant arm than in the placebo plus fulvestrant arm (5.5% vs 1.4%). 
Post-baseline QTcF intervals ≥500 ms were not observed in any patient in the palbociclib plus 
fulvestrant arm, and were observed in 1 (1.4%) patient in the placebo plus fulvestrant arm. 
1.6.4. 
Palbociclib Dose Rationale (85) 
Palbociclib has been tested in a Phase I dose escalation Study (A5481001) in 74 patients with 
advanced cancer. Two dosing schedules were evaluated: Schedule 3/1 (3 weeks on treatment/1 
week off treatment) and Schedule 2/1 (2 weeks on treatment/1 week off treatment). 
All DLTs observed in this study were related to myelosuppression and mainly consisted of 
Grade 3 neutropenia lasting more than 7 days after the end of the treatment cycle. However, 
neutropenia was reversible and non-cumulative. The most common non-hematological adverse 
events included fatigue, anemia, diarrhea, constipation, vomiting and dyspnea, all with mild to 
moderate severity. A greater proportion of patients on the 2/1 schedule had treatment-related 
TEAEs during and after Cycle 1 than patients on the 3/1 schedule although the proportion of 
patients with treatment-related neutropenia was similar with respect to the 2 dosing schedules, 
both during and after Cycle 1. One partial response was reported in a patient with testicular 
cancer. A total of 13/37 patients treated with Schedule 3/1 evaluable for efficacy experienced 
stable disease (SD), including 6 patients with SD lasting 40 weeks or longer. One of these 
patients was a woman with ER+ breast cancer who had previously received 7 lines of treatment 
for her disease. This patient remained on treatment for 80 weeks (7 cycles at 50 mg/d and 13 
cycles at 75 mg/d) and eventually discontinued treatment due to disease progression. Based on 
the relatively improved safety profile of Schedule 3/1, and the efficacy results from this study, 
the Schedule 3/1 was selected for further clinical development and the RP2D for this schedule 
was determined to be 125 mg/d. This schedule and associated RP2D was further explored in 
combination with letrozole in the Phase I/II study in patients with ABC described below.  
1.6.5. 
Palbociclib data in Combination with Letrozole in Advanced Breast Cancer 
Based on the preclinical evidence that palbociclib is highly active in ER(+) cell lines and the 
encouraging safety and PK profiles observed in the initial clinical studies, a randomized, 
multicenter active-controlled Phase I/II Study (A5481003 better known as PALOMA-1) was 
designed to assess the efficacy, safety and pharmacokinetics of letrozole 2.5mg QD 
(continuously) in combination with palbociclib 125mg QD (schedule 3/1) versus single agent 
letrozole 2.5mg QD (continuously) for the first-line treatment of ER(+), HER2 (-) ABC in 
postmenopausal women. Letrozole was selected as the active control based on its worldwide 


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approval and use as standard of care for the first-line hormonal treatment of postmenopausal 
women with ER(+) ABC. Patients were stratified by disease site and disease-free interval. 
Study PALOMA-1 was comprised of a limited Phase I portion, aimed at confirming the safety 
and tolerability of the combination and excluding a PK interaction with the combination, and a 
randomized Phase II portion aimed at evaluating the efficacy and safety of letrozole in 
combination with palbociclib when compared to letrozole alone in the first-line treatment of 
postmenopausal patients with ER(+), HER2(-) ABC. The Phase II portion consisted of 2 parts.  
In Part 1, patient selection was based only on ER/HER2 status. In Part 2, patients were 
prospectively selected also taking into account tumors with amplification of cyclin D1 
(CCND1) and/or loss of p16 (INK4A or CDKN2A), or both.  The primary endpoint was 
investigator-assessed progression-free survival in the intention-to-treat population. Accrual to 
Cohort 2 was stopped after an unplanned interim analysis of Cohort 1 and the statistical 
analysis plan for the primary endpoint was amended to a combined analysis of  Cohorts 1 and 2 
(instead of Cohort 2 alone).  
Enrollment was closed with 177 patients included in this study.  Twelve were enrolled in the 
Phase I portion and 165 (66 and 99 in Part 1 and 2, respectively) were enrolled in the Phase II 
portion.  
The Phase I portion included a two-way DDI assessment between palbociclib (125 mg QD, 3/1 
schedule) and letrozole (2.5mg QD, continuously) and showed no PK interaction between 
palbociclib and letrozole (86). The exposure of palbociclib was similar in the absence and 
presence of letrozole. In addition, the exposure of letrozole was similar in the absence and 
presence of palbociclib. Therefore, there is no meaningful metabolic drug interaction. The 
RP2D was determined to be 125mg QD on Schedule 3/1 (3 weeks continuous treatment 
followed by 1 week off treatment) in combination with letrozole 2.5mg QD continuously. 
Partial responses were reported for 4 (33%) patients with measurable disease.  Another 6 
patients (50%) had stable disease for ≥ 24 weeks and the clinical benefit rate (PR + SD ≥ 24 
weeks) was 83%. Eight (66.7%) patients discontinued from the study due to disease 
progression, including 2 patients with clinical progression, 1 patient withdrew consent and 
3 patients are still ongoing.  
The phase II portion randomized 165 patients, 84 to palbociclib plus letrozole and 81 to 
letrozole alone. At the time of the final analysis for progression-free survival (median follow up 
29.6 months [95% CI 27.9–36.0] for the palbociclib plus letrozole group and 27.9 months 
[25.5–31.1] for the letrozole group), 41 progression-free survival events had occurred in the 
palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival 
was 10.2 months (95% CI 5.7–12.6) for the letrozole group and 20.2 months (13.8–27.5) for 
the palbociclib plus letrozole group (hazard ratio 0.488, 95% CI 0.319–0.748; one-sided 
p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months (2.6–10.5) for 
the letrozole group and 26.1 months (11.2–not estimable) for the palbociclib plus letrozole 
group (hazard ratio 0.299, 0.156–0.572; one-sided p<0.0001); in cohort 2 (n=99), median 


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progression-free survival was 11.1 months (7.1–16.4) for the letrozole group and 18.1 months 
(13.1–27.5) for the palbociclib plus letrozole group (hazard ratio 0.508, 0.303–0.853; one-sided 
p=0.0046). Grade 3–4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib 
plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 
(19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that 
occurred in more than one patient in the palbociclib plus letrozole group were pulmonary 
embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of 
febrile neutropenia or neutropenia-related infections were reported during the study. Eleven 
(13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group 
discontinued the study because of adverse events (87). Although the study was not designed to 
perform a formal hypothesis testing for overall survival (OS) analysis due to the small sample 
size, it was performed recently. Median overall survival data with 116 OS events, were 37.5 
months (95% CI: 31.4, 47.8) in the palbociclib plus letrozole group and 34.5 months (95% CI: 
27.4, 42.6) in the letrozole alone group (hazard ratio for death was 0.897 [95% CI: 0.623, 
1.294]; two-sided p=0.281). Median OS was 37.5 vs 33.3 months (hazard ratio for death = 
0.837; P= 0.280) for Part 1 and 35.1 vs 35.7 months (hazard ratio = 0.935; P= 0.388) for Part 2. 
78.6% of pts in the P+L arm received post-study systemic therapy vs 86.4% in the L arm. More 
pts in the L arm received ≥3 lines of therapy (37% vs 18%) (102). 
These results indicate that the combination of palbociclib with letrozole is well tolerated with 
AEs similar to those seen with either palbociclib or letrozole when administered alone. 
Additionally, the combination demonstrated antitumor activity which was consistent with the 
sensitivity of ER(+) breast cancer observed in the preclinical models.  
These encouraging findings have been tested in a confirmatory phase III study (PALOMA-2) 
that included 666 postmenopausal patients with no prior systemic therapy for advanced breast 
cancer that were randomised 2:1 to receive palbociclib (oral 125 mg/day; 3 weeks on/1 week 
off) + letrozole (2.5 mg/day continuously) or placebo + letrozole every 28 days until disease 
progression, consent withdrawal or death. Patients were stratified by disease site, disease-free 
interval from end of (neo) adjuvant therapy, and prior hormone therapy (yes/no). The primary 
endpoint was investigator-assessed PFS, and the secondary endpoints included: overall 
survival, objective response rate, clinical benefit rate (CR + PR + SD ≥24 weeks), patient-
reported outcomes, pharmacokinetics and safety. Baseline characteristics were well balanced 
between both treatment groups. Median PFS was 24.8 months (95% confidence interval [CI], 
22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% 
CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 
0.58; 95% CI, 0.46 to 0.72; P<0.001). ORR was improved with palbociclib + letrozole (42.1% 
vs. 34.7%, p=0.031; 55.3% vs. 44.4% in patients with measurable disease [p=0.013]). CBR was 
84.9% vs. 70.3% (p<.0001). The most common grade 3 or 4 adverse events were neutropenia 
(occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-
letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 
0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group 


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and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any 
study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-
letrozole group and in 13 patients (5.9%) in the placebo-letrozole group (101). At the time of 
this primary analysis, the percentage of PFS events was less than 50% (43.7%) in the 
palbociclib plus letrozole arm. Updated PFS data based on the investigator assessment with an 
event rate of approximately 60% for the entire study population (55% in the palbociclib plus 
letrozole arm) have recently confirmed the benefit of the addition of palbociclib to letrozole 
with a median PFS of 27.6 months (95% CI: 22.4, 30.3) in the palbociclib plus letrozole arm 
and 14.5 months (95% CI: 12.3, 17.1) for the placebo plus letrozole arm. The observed hazard 
ratio for disease progression or death was 0.563 (95% CI: 0.461, 0.687; stratified 1-sided 
p<0.000001) in favor of palbociclib plus letrozole treatment (104, 105). OS data was immature 
in both analysis and the final OS information is still pending. 
However if we pay attention to the PFS curve of PALOMA-1 study (see Figure 1), it seems to 
indicate that the effect of the drug on PFS was mainly due to the prevention of early 
progressions. In the first 4 months of the study, 40% of the patients in the letrozole arm had 
progressed vs only 20% in the letrozole + palbociclib arm, suggesting that the main effect of 
palbociclib is the reversal of resistance to the anti-hormonal treatment. 
Figure 1. PALOMA-1 Progression-Free Survival  
 
 
 
 
 
 
 
 
 
 
 
 
 
If this hypothesis is true, the inhibition of the CDK4/6 function by palbociclib in combination 
with anti-hormonal therapy could play an important role in ER-positive patients that have 
become resistant to hormones.  


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1.6.6. 
Palbociclib data in Combination with fulvestrant in Advanced Breast Cancer 
PALOMA-3 is randomized 2:1 phase III study testing the efficacy of palbociclib + fulvestrant  
vs fulvestrant alone (+/- Goserelin depending of menopausal status) in the treatment of breast 
cancer patients whose disease has progressed on endocrine therapy either within 12 months of 
completion of adjuvant endocrine therapy or within 1 month of endocrine therapy for advanced 
disease (88). The primary end point was investigator-assessed progression-free survival 
according to RECIST, version 1.1. Secondary end points included overall survival; survival 
probability at 1, 2, and 3 years; objective response; duration of response; rate of clinical 
benefit; patient-reported outcomes; pharmacokinetics; and safety. The trial met its primary end 
point at the pre-planned interim analysis (after 195 events of disease progression or death had 
occurred) on the basis of the recommendation by the independent data and safety monitoring 
committee. The median progression-free survival was 9.2 months (95% confidence interval 
[CI], 7.5 to not estimable) with palbociclib–fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) 
with placebo–fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 
0.56; P<0.001). Approximately 40% of the patients (211) were randomly selected for central 
imaging assessment by blinded independent review. The results were consistent with the 
primary end point; the median progression-free survival was not estimable with palbociclib–
fulvestrant and was 3.7 months (95% CI, 3.4 to 7.2) with placebo–fulvestrant (hazard ratio for 
disease progression or death, 0.27; 95% CI, 0.16 to 0.46; P<0.001). Rates of overall objective 
response were 10.4% (95% CI, 7.4 to 14.1) with palbociclib–fulvestrant and 6.3% (95% CI, 3.2 
to 11.0) with placebo–fulvestrant (P = 0.16). The rate of clinical benefit was 34.0% (95% CI, 
29.0 to 39.3) with palbociclib–fulvestrant and 19.0% (95% CI, 13.4 to 25.6) with placebo–
fulvestrant (P<0.001).. The most common grade 3 or 4 adverse events in the palbociclib–
fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo–fulvestrant group), 
leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and 
fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of patients in each arm. The 
rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. 
Global quality of life was generally maintained with palbociclib–fulvestrant but deteriorated 
significantly with placebo–fulvestrant (mean overall change from baseline in QLQ-C30 score 
[range, 0 to 100, with higher scores indicating a higher quality of life], −0.9 points vs. −4.0 
points; P = 0.03). 
Additionally, the results of a prespecified analysis of OS in the PALOMA-3 study showed that 
the median OS was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib + fulvestrant group 
and 28.0 months (95% CI, 23.6 to 34.6) in the placebo + fulvestrant group (HR for death, 0.81; 
95% CI, 0.64 to 1.03; P = 0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment 
after the completion of the trial regimen occurred in 16% of the patients in the placebo–
fulvestrant group. Among 410 patients with sensitivity to previous ET, the median OS was 39.7 
months (95% CI, 34.8 to 45.7) in the palbociclib + fulvestrant group and 29.7 months (95% CI, 


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23.8 to 37.9) in the placebo + fulvestrant group (HR, 0.72; 95% CI, 0.55 to 0.94; absolute 
difference, 10.0 months). The median duration of subsequent therapy was similar in the two 
groups, and the median time to the receipt of CT was 17.6 months in the palbociclib + 
fulvestrant group, as compared with 8.8 months in the placebo + fulvestrant group (HR, 0.58; 
95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of 
follow-up (106). 
However if we pay attention to the PFS curve of the study (see Figure 2), it seems to indicate 
that the effect of the drug on PFS was mainly due to the prevention of early progressions. In the 
first 2 months of the study, 37% of the patients in the fulvestrant arm had progressed vs only 
20% in the fulvestrant + palbociclib arm, suggesting again that the main effect of palbociclib is 
the reversal of resistance to the anti-hormonal treatment. 
 
Figure 2. PALOMA-3 Progression-Free Survival  
 
1.7. Interstitial Lung disease/pneumonitis data: 
Following a recent aggregate review of cases potentially consistent with interstitial lung disease 
or pneumonitis mainly from post-marketing sources, but including those from clinical trials, a 
decision was made to consider interstitial lung disease or pneumonitis to be an adverse drug 
reaction of palbociclib. While a definitive causal association between palbociclib and 
ILD/pneumonitis could not be established, the aggregate data suggested the possibility of a 
causal relationship. No special precautions other than standard clinical monitoring are 
recommended (85). 


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1.8. Role of ESR1 mutations in the mechanism of resistance to endocrine therapy 
Recent studies revealed that the acquisition of mutations in the ER gene (ESR1) is a major 
mechanism of resistance to AIs.  
ESR1 mutations are rarely detectable in primary breast cancer or patients that are first exposed 
to AIs (5.8%) and are found at an appreciable frequency and markedly higher after the AI 
treatment, either during the adjuvant and metastatic settings (36.4%) (89). Moreover, a high 
frequency of ESR1 mutations had been reported in patients who have been treated with AIs 
using more contemporaneous tumor biopsy through circulating free DNA (cDNA), as can be 
seen in figure 3 (89). 
Figure 3. ESR1 mutations assessed in cDNA 
 
 
In addition, it has been also reported a high frequency of ESR mutations detected in cDNA in 
the BOLERO-2 and PALOMA-3 studies. In BOLERO-2, 28.8% of the two most common 
subtypes (which represented 50-60% of all activating ESR1 mutations) (90) were found in the 
exemestane arm among patients who progressed on NSAIs.  In PALOMA-3, the detection rate 
of ESR1 mutation in cDNA was 37.2% among patients who progressed on endocrine therapy 
(steroidal and/or non-steroidal AI for post-menopausal women) (91). 
More importantly patients with ESR1 mutations had a substantially shorter PFS on subsequent 
AI-based therapy what may partially explain the poor performance of sequential AI therapy in 
those patients. In fact Gaia Schiavon et al (89) reported that patients with ESR1 mutations had a 
substantially shorter PFS on subsequent AI-based therapy (hazard ratio of 3.1, 95% CI 1.9 to 
23.1; p=0.0041. Also data from BOLERO-2 presented at the SABCS 2015 showed that mPFS 
of exemestane in patients with ESR1 mutation wild type (n=116) was 3.94 months vs. 2.76 
months in patients with ESR1 mutation (n=51) (hazard ratio = 1.13, p= 0.16) (90). These 
findings are also confirmed with data from another phase III study in the exemestane treatment 
arm (Turner et al, personal communication). See table 1. 
Table 1. Frequency of ESR1 mutations and performance of AI post-AI treatment in MBC 
setting  
Study 
#  of Patients 
ESR1 mutation 
frequency post-AI 
Median PFS post AI 


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treatment 
Schiavon, et al (89) 
171 
36.4% 
hazard ratio =3.1 (shorter 
PFS) 
P=0.0041 
BOLERO-2 
Chandarlapaty S, 
(90) 
541 
28.8% 
(two most common 
mutations only, represent 
50-60% of all mutations)
Exemestane Arm 
PFS= 3.9  in wild type vs 
2.7 with D538G mutation 
hazard ratio = 1.44 
Preclinical and clinical data indicated that the ER degrader (SERD), fulvestrant, may exhibit 
non-cross-resistance to tamoxifen or AIs. As shown in Table 2, in the endocrine resistance 
setting, a number of large randomized Phase II (FERGI), 3 studies (CONFIRM, PALOMA-3, 
BELLE-2) have shown consistent PFS of ~ 5 to 6 months with fulvestrant 500mg.  In contrast, 
exemestane has shown mPFS of 3-4 months (SoFEA, EFECT and BOLERO-2).  
 
Table 2. Performance of fulvestrant 500mg and exemestane in patients who have been treated 
with ET 
Trials 
Treatment 
# of Patients 
Median PFS, Months 
Performance of Fulvestrant 500mg 
PALOMA-3 
(88) 
Palbociclib + Fulvestrant vs 
Placebo + Fulvestrant 500mg 
347 
174 
 
4.7 
CONFIRM (9) 
Fulvestrant 250 mg vs 
Fulvestrant 500 mg 
374 
362 
 
6.5 
FERGI (92) 
GDC 0941 + Fulvestrant  vs 
Placebo + Fulvestrant 500mg 
84 
84 
 
5.1 
BELLE-2 (93) 
BKM120 + Fulvestrant vs 
Placebo + Fulvestrant 500mg 
576 
571 
 
5 
Performance of Exemestane 
SoFEA (94) 
Fulvestrant  + Anastrozole vs 
Fulvestrant plus placebo vs. 
Exemestane 
243 
231 
249 
 
 
3.4 
BOLERO-2 (7) 
Everolimus + Exemestane vs 
Placebo + Exemestane 
485 
239 
 
3.2 
EFECT (6) 
Fulvestrant  vs. 
351 
 
3.7 


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Exemestane 
342 
In addition, preclinical and clinical data indicated that SERD, fulvestrant, is active in ESR1 
mutant tumors. Preclinical efficacy data recently generated showed that fulvestrant is active in 
most common ESR1 mutant subtypes (95) (Table 3). Also, unpublished data from PALOMA-3 
suggest that there is no difference in mPFS of fulvestrant (control arm) by ESR1 status; patients 
without ESR1 mutation (n=79) had a median PFS of 114 days compared with 151 days in 
patients with ESR1 mutation (n=51) (91).  
 
Table 3. Fulvestrant in ESR1 mutation models (Pfizer Research Unit)  
Erα context  
Fulvestrant IC50 (μM)
FC/ESR1 
 
 
ESR1 wt 
0.016 
− 
D538G 
0.279 
17.4 
D538G/S463P 
0.199 
12.4 
Y537N 
0.057 
3.6 
Y537S 
0.173 
10.8 
Y537S.D538G 
>1 
>63 
Y537N.S463P 
0.083 
5.2 
 
 
 
Importantly, there is preclinical data showing that Palbociclib is active in multiple ERS mutant 
PDX models (96). This was confirmed in clinic with PALOMA-3 data. The analysis 
demonstrated that there was no difference in the magnitude of benefit from palbociclib in 
combination with fulvestrant by ESR1 status. In patients with ESR1 mutations, the median PFS 
was 9.6 months in the palbociclib arm compared with 5.0 months in the control arm (p=0.002); 
in patients without ESR1 mutations, the median PFS was 11.2 months versus 3.8 months, 
respectively (p<0.001) (91)  
However, the interim analysis from the TRend (To Reverse ENDocrine Resistance) study, 
where  palbociclib was added to the same prior endocrine therapy agent (exemestane) vs given 
alone at the progression of endocrine therapy (exemestane), showed similar non-progression 
rates at 12 weeks between palbociclib plus endocrine therapy and palbociclib alone (per 
principal investigator personal communication). Although both arms were clinically active, 
these data suggest that there is no synergy between palbociclib and an AI (exemestane) after 


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progression to an AI. Thus switching to other class endocrine therapy (such as fulvestrant) in 
the endocrine resistance setting may be a better strategy for patients because fulvestrant is 
active regardless ERS1 mutational status. 
1.9.  
Study Rationale 
Endocrine therapy is the cornerstone treatment for patients with hormone-receptor (HR)–
positive, HER2 negative breast cancer. In postmenopausal patients, aromatase inhibitors (e.g., 
letrozole and anastrozole) have become the treatment of choice. Unfortunately, not all patients 
respond to endocrine therapy (primary or de novo resistance), and even patients who have a 
response will eventually relapse (acquired resistance). 
On early disease recurrence/progression, the treatment options include other classes of 
aromatase inhibitors, estrogen-receptor (ER) antagonists or chemotherapy; being the latest the 
most accepted one for the resistant patients. Within the chemotherapy regimens, capecitabine 
seems one of the best options. 
The research focusing on resistance to endocrine therapies in HR-positive breast cancer has 
aimed to identify new therapeutic strategies that would enhance the efficacy of endocrine 
therapies. 
Published preclinical data suggest that estrogen receptor positive (ER-positive)/HER2 negative 
breast cancers are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function and that 
inhibition of this target may be an effective translational therapeutic strategy. Palbociclib is an 
oral novel CDK4/6 inhibitor that seems to be synergistic with anti-hormonal therapy in 
preclinical and clinical studies. Results from a randomized phase II study and a phase III study 
of letrozole vs letrozole plus palbociclib (PALOMA-1 and PALOMA-2) confirmed the safety 
and tolerability of the combination and demonstrated an exciting efficacy. In addition, a further 
randomized 2:1 phase III study tested the efficacy of palbociclib + fulvestrant  vs fulvestrant 
alone (+/- Goserelin depending of menopausal status) in the treatment of breast cancer patients 
whose disease has progressed on endocrine therapy either within 12 months of completion of 
adjuvant endocrine therapy or within 1 month of endocrine therapy for advanced disease 
(PALOMA-3 study) demonstrated an exciting efficacy with a hazard ratio for progression-free 
survival of 0.42 (95% CI, 0.32 to 0.56; P<0.001). The results of a prespecified analysis of OS 
in the PALOMA-3 study showed that the median OS was 34.9 months (95% CI, 28.8 to 40.0) 
in the palbociclib + fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo + 
fulvestrant group (HR for death, 0.81; 95% CI, 0.64 to 1.03; P = 0.09; absolute difference, 6.9 
months). 
In fact based on all these data, on February the 19th 2016, the US FDA granted full approval to 
palbociclib (IBRANCE®) in combination with fulvestrant (with or without goserelin) for the 
treatment of women with HR-positive, HER2-negative advanced breast cancer whose disease 
progressed after prior endocrine therapy based on the favorable benefit/risk profile observed in 
Study PALOMA-3. In addition, on November the 9th 2016, the EU Commission decision was 
issued for palbociclib for the treatment of HR-positive, HER2-negative locally advanced or 


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metastatic breast cancer: in combination with an aromatase inhibitor or in combination with 
fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal 
women, the endocrine therapy should be combined with a luteinizing hormone-releasing 
hormone (LHRH) agonist. Additionally, palbociclib is approved in more than 80 countries 
globally. 
The PFS curve of the two studies, however, seems to indicate that the effect of the drug was 
mainly due to the prevention of early progressions, suggesting that the main effect of 
palbociclib is the reversal of resistance to the anti-hormonal treatment. Taking all this into 
consideration, the combination of anti-hormonal therapy with palbociclib may play an 
important role in HR-positive patients that have become resistant to hormones and should be 
compared to the standard of care in patients with hormone-resistant HR-positive tumors, i.e. 
cytotoxic chemotherapy.  
 The initially proposed Phase III study was designed to provide the opportunity to confirm the 
clinical benefit of palbociclib in combination with exemestane. The study was designed to 
demonstrate that this combination provides superior clinical benefit compared to capecitabine 
in postmenopausal women with HR+/HER2- metastatic breast cancer who are resistant to non-
steroidal aromatase inhibitors.  
However, emerging data suggests that the choice of endocrine partner with palbociclib is 
particularly important to create optimal synergy in endocrine resistance setting. 
Studies of resistance to hormonal therapies and ER biology have highlighted the important role 
of ER receptor degraders for sequential endocrine treatment after patients progressed on 
aromatase inhibitors (AIs). Recent studies have also revealed that the acquisition of ESR1 
mutations is a major mechanism of resistance to AIs and patients with ESR1 mutations had a 
substantially shorter PFS on subsequent AI-based therapy. In addition, it has been reported a 
high rate of ESR1 mutations among patients who have been treated with AIs in MBC patients. 
More recently, data from PALOMA-3 and other studies suggest that fulvestrant may be active 
among patients whose tumors had ESR1 mutation, while exemestane is inactive (unpublished 
data, disclosure planned). Thus among patients who have progressed on AIs, fulvestrant may be 
a better endocrine partner for palbociclib. 
The present trial design proposes a Phase III study to provide the opportunity to confirm the 
clinical benefit of palbociclib in combination with endocrine therapy. The study is designed to 
demonstrate that:  
1) Fulvestrant plus palbociclib provides superior clinical benefit compared to capecitabine 
in postmenopausal women with HR+/HER2- metastatic breast cancer who are resistant 
to aromatase inhibitors and  
2) Endocrine therapy (fulvestrant or exemestane) in combination with palbociclib provides 
superior clinical benefit compared to capecitabine in postmenopausal women with 


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HR+/HER2- metastatic breast cancer and whose tumor had estrogen receptor (ESR1) 
mutational status as wild type at study entry.  
Taken all these together, the proposed amendment will allow us to address several scientific 
novel questions:  
 The study will be able to prospectively test the hypotheses that palbociclib plus 
fulvestrant is superior to chemotherapy in endocrine resistance setting regardless ESR1 
mutational status as primary study objective. In the endocrine resistant setting, 
capecitabine, as an oral, cytotoxic chemotherapy is frequently used with mPFS at ~ 6 
months but with increased toxicity and reduced quality of life. 
 The study will be able to prospectively evaluate whether palbociclib in combination 
with endocrine therapy (exemestane or fulvestrant) is superior to capecitabine in 
prolonging PFS in postmenopausal women with HR positive/HER2 negative MBC 
whose disease was resistant to aromatase inhibitors and whose tumors had ESR1 
mutation status as wild type at study entry.   
 
To our knowledge, this will be the first study prospectively testing the activity of 
chemotherapy by ESR1 mutational status and compared with an emerging standard of 
care (palbocicilib plus fulvestrant) in this population. 
 The findings will inform the clinical community if we are ready to stratify treatment by 
endocrine resistant mechanisms (i.e. treating patients with ESR1 mutation with SERD in 
combination a CDK 4/6 inhibitor; treating patients with ESR1 mutation wild type with 
AI or SERD with a CDK4/6 inhibitor; or chemotherapy by ESR1 mutational status). 
This has important clinical relevance to advance our clinical care by stratifying, 
sequencing treatment options based on resistance mechanism while preserving best 
quality of life for HR+/HER2- MBC patients who have progressed on prior endocrine 
therapy.   


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2. 
Objectives 
2.1. 
Primary Objectives 
 
 
 To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine 
in prolonging Progression-Free Survival (PFS) in postmenopausal women with HR 
positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors, 
regardless of the ESR1 mutational status. 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal women with 
HR positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors and 
whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry. 
ESR1 mutational status will be determined by circulating free DNA (cDNA) and will be 
prospectively determined before the interims or final analyses. Patient tumor ESR1 
mutational status will be blinded to patients, investigators and study team. 
2.2.  
Primary Endpoint 
Progression-Free Survival (PFS) based on the investigator’s assessment according to the 
RECIST version 1.1. 
2.3. 
Secondary Objectives 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal women with 
HR positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors 
regardless of ESR1 mutational status at study entry.  
 To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine 
in prolonging Overall Survival (OS) in postmenopausal women with HR positive/HER2 
negative MBC whose disease was resistant to aromatase inhibitors. 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging OS in postmenopausal women with HR 
positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors and 
whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry 
 To demonstrate that palbociclib in combination with endocrine therapy (exemestane or 
fulvestrant) is superior to capecitabine in prolonging OS in postmenopausal women with HR 
positive/HER2 negative MBC whose disease was resistant to aromatase inhibitors regardless 
of ESR1 mutational status at study entry.  
 To compare other efficacy measures between treatment arms: Objective Response Rate 
(ORR), Clinical Benefit Rate (CBR) and Response Duration (RD). 
 To compare safety and tolerability between the treatment arms. 


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 To compare health-related quality of life between the treatment arms. 
 To evaluate the Pharmacokinetics (PK) of the combination of exemestane with palbociclib 
(in selected sites and only in patients accepting to participate). 
2.4.  
Secondary Endpoints 
 The following efficacy endpoints will be measured: 
o Overall Survival (OS). 
o Objective Response (OR): Complete Response (CR) plus Partial Response (PR) 
based on the investigator’s assessment according to the RECIST version 1.1 in 
patients randomized with measurable disease.  
o Clinical Benefit (CB): CR plus PR plus stable disease based on the 
investigator’s assessment lasting more than 24 weeks according to the RECIST 
version 1.1 in all randomized patients (ITT population). 
o Response Duration (RD) based on the investigator’s assessment according to the 
RECIST version 1.1. 
 Safety will be assessed by standard clinical and laboratory tests (hematology, serum 
chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0. 
 The PK analysis will determine whether palbociclib influences the pharmacokinetics of 
exemestane. Blood samples will be taken at the time defined in the protocol in patients 
included in the experimental arm of Cohort 1 (palbociclib plus exemestane) in selected 
sites. Enrollment of these patients were to be finalised at the same time as completion of 
cohort 1 recruitment, samples from approximately 20 PK-evaluable patients were to be 
collected. 
 The EORTC QLQ-C30, QLQ-BR23 and EQ-5D-3L questionnaires. 
2.5. 
Exploratory Objectives 
 To prospectively evaluate whether the magnitude of PFS and OS prolongation of 
palbociclib in combination with fulvestrant is the same in patients with ESR1 mutational 
status as wild type and patients with ESR1 mutational status positive at study entry.  
 To prospectively evaluate whether PFS and OS of palbociclib in combination with 
exemestane is better among those patients with ESR1 mutational status as wild type 
than those patients with ESR1 mutational status positive at study entry.   
 To prospectively evaluate PFS and OS of capecitabine by ESR1 mutational status.  
 To characterize alterations in genes, proteins, and RNAs relevant to the cell cycle (e.g, 
CCND1 amplification, CDKN2A deletion), drug targets (e.g. CDK 4/6), tumor 


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sensitivity and/or resistance (e.g. Ki67, pRb, PIK3CA mutation, CCNE1 expression) or 
breast cancer (e.g. PTEN, ERBB2, BRCA 1 and BRCA2). 
2.6. 
Exploratory Endpoints 
 Baseline biomarker values from most recently obtained tumor tissue (deeply 
recommended from metastatic tumor) will be used for central assessment of biomarkers 
related to breast tumor sensitivity and/or resistance to palbociclib (e.g., Ki67, 
p16/CDKN2A, pRb, CyclinD and others) or breast cancer (e.g. PTEN, ERBB2, BRCA 1 
and BRCA2). A whole blood sample will be collected for potential pharmacogenomic 
analyses related to drug response or adverse drug reactions. For example, putative 
safety biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or 
genes thought to be related to the mechanism of drug action may be 
examined.Correlative plasma samples will be collected for exploratory analysis to 
analyze the pharmacodynamic (PD) treatment effects on circulating free DNA or RNA 
explore specific breast cancer and  efficacy predictive biomarkers (e.g. PIK3CA 
mutations). Samples will be collected from all patients, unless prohibited by local 
regulations. 
 


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3. 
Investigational Plan 
3.1. 
Study Design 
This is an international, multicenter, open label, controlled, randomized phase III study 
comparing the efficacy and safety of palbociclib in combination with endocrine therapy 
(exemestane or fulvestrant) versus capecitabine in postmenopausal women with HR 
positive/HER2 negative MBC whose disease was resistant to previous aromatase inhibitors 
(exemestane, letrozole or anastrozole), defined as recurrence while on or within 12 months 
after the end of adjuvant treatment or progression while on or within 1 month after the end of 
treatment for advanced disease. It is not mandatory to have exemestane, letrozole or 
anastrozole as the most recent treatment before randomization but recurrence or progression 
while receiving (or immediately after the end of) the most recent systemic therapy has to be 
documented before randomization. Patients must have measurable disease or at least one bone 
lesion, lytic or mixed (lytic + blastic), which has not been previously irradiated and is 
assessable by CT/MRI in the absence of measurable disease.  
 Approximately 300 patients were to be randomized 1:1 between the experimental arm 
(Arm A: approximately 150 patients treated with palbociclib plus exemestane) and the 
control arm (Arm B: approximately 150 patients treated with capecitabine) before the 
approval of the protocol version 5.0 dated 09Mar2016 (Cohort 1). 
 Approximately 300 patients will be randomized 1:1 between the experimental arm 
(Arm A: approximately 150 patients treated with palbociclib plus fulvestrant) and the 
control arm (Arm B: approximately 150 patients treated with capecitabine) from the 
approval of protocol version 5.0 dated 09Mar2016 (Cohort 2). 
Patients will be stratified by: 
 Site of disease: visceral vs non-visceral (visceral are all lesions not included in the 
following list: breast, skin, subcutaneous tissue and other soft tissue, lymph node, or 
bone). 
 Prior sensitivity to hormonal treatment:  
o Yes defined as: 
 At least 24 months of endocrine therapy before recurrence in the 
adjuvant setting in patients who have not received previous endocrine 
therapy in the metastatic setting. 
 Response or stabilization for at least 24 weeks of the most recent line of 
endocrine therapy in patients who have received previous endocrine 
therapy in the metastatic setting. 
o No: all other options 


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 Prior chemotherapy for MBC: yes (chemotherapy administered as “second adjuvant 
therapy” for locoregional recurrence should be considered as prior chemotherapy for 
MBC) vs no. 
 Country. 
Figure 4. Study Design Cohort 1 
 
 
Patients randomized to Arm A (experimental arm) will receive: 
 Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 followed by 7 days off 
treatment on every 28 days cycles; 
in combination with 
 Exemestane, 25 mg, orally once daily (continuously). 
In patients within the PK sub-study, exemestane will be administered daily during a 7-day lead-
in period (day minus-7 through day minus-1) immediately preceding cycle 1. 
NOTE: The start date of each cycle will be given by the start date of palbociclib intake.  
Patients randomized to Arm B (control arm) will receive: 
 Capecitabine, 1,250mg/m2 twice daily for 2 weeks followed by a 1 week rest period, 
given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000mg/m2 
twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in 
patients over 70 years of age. 


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Figure 5. Study Design Cohort 2 
 
Patients randomized to Arm A (experimental arm) will receive: 
 Palbociclib, 125 mg, orally once daily on Day 1 to Day 21 followed by 7 days off 
treatment given as every 28 days cycles; 
in combination with 
 Fulvestrant 500 mg, two 5ml intramuscular injections (one in each buttock) on Days 1 
and 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 days Cycle (± 3 
days). 
NOTE: The start date of each cycle will be given by the date of administration of the first 
fulvestrant dose.  
Patients randomized to Arm B (control arm) will receive: 
 Capecitabine, 1,250mg/m2 twice daily for 2 weeks followed by a 1 week rest period, 
given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000mg/m2 
twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in 
patients over 70 years of age. 
In both Cohorts 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 with permanent discontinuation of palbociclib for a reason 
different than progression (i.e., toxicity due to palbociclib) will continue with 
exemestane/fulvestrant (in the active treatment phase) until objective disease progression, 
clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of 
consent, 
whichever 
occurs 
first. 
Patients 
with 
permanent 
discontinuation 
of 


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exemestane/fulvestrant will be discontinued from the active treatment phase and entered into 
the follow-up phase. 
Disease assessments will be performed at baseline and every 8 weeks (± 7 days) from the start 
of treatment and every 12 weeks (±7 days) after 120 weeks of treatment. All lesion 
measurements must be recorded in the eCRF. Disease assessment for all patients at baseline 
will include: 
 CT scan or MRI of the chest, abdomen and pelvis (CAP). PET-CT scan will be 
accepted in case the CT scan of this imaging test is meeting with the RECIST version 
1.1 requirements for tumour lesion evaluation. 
 Bone scan is mandatory if the patient has bone disease or if there is any suspicious of 
bone metastases. PET scan will be also accepted to assess the already known or newly 
suspected bone metastatic disease. Any suspicious abnormalities (ie, hotspots) 
identified on the bone or PET scan at baseline must be confirmed by X-ray (only if 
there are other measurable lesions), CT scan with bone windows or MRI (if only bone 
disease is present).  
 Brain CT scan or MRI is mandatory if the patient has CNS metastases or if there is any 
suspicious of CNS metastases.   
 CT scan or MRI scan of any other sites of disease as clinically indicated. 
 Clinical assessment of superficial disease by callipers which will include colour 
photographs of all superficial metastatic lesions including a rule to estimate the size of 
the lesion. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective.   
Patients with bone lesions identified at baseline will repeat the bone scans as clinically 
indicated (ie, patient describes new or worsening bone pain, or has increasing alkaline 
phosphatase level, or other signs and symptoms of new/progressing bone metastases) and to 
confirm a complete response. The method chosen to confirm the bone metastases at baseline 
(X-ray, if there are other measurable lesions, CT scan with bone windows or MRI, if only bone 
disease is present) must follow the same assessment schedule as for measurable lesions, every 8 
weeks (± 7 days) from the start of treatment and every 12 weeks (±7 days) after 120 weeks of 
treatment.   
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. While patients are on study therapy, tumor assessments will be 
performed until radiographically and/or clinically (ie, for photographed or palpable lesions) 
documented PD as per RECIST v.1.1, initiation of new anticancer therapy or discontinuation of 
patient from overall study participation (eg, death, patient's request, lost to follow up), 
whichever occurs first.  


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Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie for photographed or palpable lesions) documented PD as per RECIST v.1.1 will 
continue to have tumor assessments performed during the follow up visits every 12 weeks (± 7 
days) from the last tumor assessment and bone scans (if applicable) as clinically indicated until 
RECIST-defined disease progression, initiation of new anticancer therapy or discontinuation of 
patient from overall study participation (eg, death, patient's request, lost to follow up), 
whichever occurs first. 
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as primary data source.  
Patients discontinuing the tumor assessments for the primary endpoint will enter a follow up 
period during which survival and new anti-cancer therapy information will be collected every 6 
months (± 14 days) from the last tumor assessment. The follow up period will conclude at the 
time of the final OS analysis. Crossover will not be allowed in the trial.  
3.1.1. 
Early Safety Review and Pharmacokynetic analysis 
The safety of the combination of palbociclib plus exemestane at the recommended doses will 
be assessed with a limited number of patients exposed to it.  
An early safety review was performed which data was evaluated by the Independent Data 
Monitoring Committee (IDMC). The IDMC made the recommendation to continue the study as 
planned based on the proportion of grade 4 neutropenia, grade 4 thrombocytopenia or grade 3 
QTc prolongations. The Steering Committee (SC) took the decision to accept this 
recommendation. 
PK analysis sub-study of the palbociclib and exemestane combination has been performed. The 
PK data indicate a lack of a clinically meaningful drug-drug interaction (DDI) between 
palbociclib and exemestane when both drugs are coadministered (103). 
3.2. 
Duration of the study  
The study accrual has been completed in 52 months.  
All patients included will receive study therapy until radiographic or symptomatic progression, 
unacceptable toxicity or withdraw of the informed consent, whatever occurs first.  
For safety reasons all patients will have a visit 30 (±5) days after finishing the study treatment. 
This post-treatment visit must be performed before the initiation of any new anticancer therapy 
and may be advanced when a new anticancer therapy is scheduled before 30 (±5) days after 
finishing the study treatment. 
After progression all patients will be followed till death or data cut-off date (estimated to be 
approximately 76 months from the inclusion of the first patient) to evaluate the OS objective. 
According to what is outlined above, the length of study will be approximately 6.3 years.  


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The end date of study is the date of the database lock and it will be independent of performing 
the analyses of the exploratory objectives. 
 


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4. 
Study Population 
4.1. 
Inclusion Criteria 
 Patients are eligible to be included in the study only if they meet all of the following criteria: 
1. The patient has signed the informed consent document. 
2. a) Patients included in Cohort 1: Females with histologically confirmed MBC whose 
disease was resistant to previous non-steroidal aromatase inhibitors (letrozole or 
anastrozole), defined as: 
 Recurrence while on or within 12 months after the end of adjuvant treatment 
with a NSAI or  
 Progression while on or within 1 month after the end of treatment with NSAI for 
advanced disease.  
b) Patients included in Cohort 2: Females with histologically confirmed MBC whose 
disease was resistant to previous aromatase inhibitors (exemestane, letrozole or 
anastrozole), defined as: 
 Recurrence while on or within 12 months after the end of adjuvant treatment 
with an AI or 
 Progression while on or within 1 month after the end of treatment with an AI for 
advanced disease.  
3. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or first line 
therapy for MBC (chemotherapy administered as “second adjuvant therapy” for 
locoregional recurrence should be considered as first line chemotherapy for MBC).  
4. It is not mandatory to have exemestane, letrozole or anastrozole as the most recent 
treatment before randomization but recurrence or progression of breast cancer while 
receiving or after the end of (in the mestastatic settingimmediately after the end of) the 
most recent systemic therapy has to be documented before randomization.  
5. Hormonal receptor positive (HR+) breast cancer based on local laboratory determination. 
HR+ defined as ≥ 1% positive cells by IHC for ER and/or PgR.  
6. Documented HER2 negative breast cancer based on local laboratory determination on most 
recent tumor biopsy. HER2 negative tumor is determined according to recommendations of  
ASCO/CAP 2013 guidelines, as IHC score 0 or 1+ or negative by ISH (FISH/CISH/SISH) 
defined as a HER2/CEP17 ratio < 2 with an average HER2 copy number <4.0 or for single 
probe assessment a HER2 copy number < 4. 
7. Measurable disease or at least one bone lesion, lytic or mixed (lytic+blastic), which has not 
been previously irradiated and is assessable by CT/MRI in the absence of measurable 
disease according to RECIST 1.1 criteria.  
8. Patient is at least 18 years of age. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. 
10. Life expectancy ≥ 12 weeks. 


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11. Adequate organ and marrow function defined as follows: 
 ANC ≥ 1,500/mm3 (1.5x109/L) 
 Platelets ≥ 100,000/mm3 (100x109/L) 
 Hemoglobin ≥ 9g/dL (90g/L) 
 Serum creatinine ≤ 1,5xULN and estimated creatinine clearance ≥ 60 mL/min as 
calculated using the standard  method for the institution 
 Total serum bilirubin ≤ 1,5xULN (≤ 3.0xULN if Gilbert´s disease) 
 AST and ALT ≤ 3.0xULN (≤5.0xULN if liver metastases present) 
 Alkaline phosphatase ≤ 2.5xULN (≤5.0xULN if bone or liver metastases present) 
12. Postmenopausal women defined as women with: 
 Prior bilateral surgical oophorectomy, or 
 Age > 60 years, or 
 Age < 60 years and medically confirmed post-menopausal status defined as 
spontaneous cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause or follicle-stimulating hormone (FSH) 
and estradiol blood levels in their respective postmenopausal ranges.  
13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to 
NCI CTCAE version 4.0 Grade ≤ 1 (except alopecia or other toxicities not considered a 
safety risk for the patient at investigator´s discretion). 
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Have received more than 1 prior chemotherapy regimen for MBC. (NOTE: Chemotherapy 
administered as “second adjuvant therapy” for locoregional recurrence should be 
considered one prior chemotherapy for MBC). Other previous anticancer endocrine 
treatments for advanced disease are allowed.  
2. Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening 
complications in the short term (including patients with massive uncontrolled effusions 
[pleural, pericardial, peritoneal], pulmonary lymphangitis and over 50% liver 
involvement).   


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3. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or 
leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or 
progressive growth. Patients with a history of CNS metastases or cord compression are 
eligible if they have been definitively treated with local therapy (eg, radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 
weeks before randomization.  
4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor [any agent whose mechanism 
of action is to inhibit the PI3 kinase-mTOR pathway] or capecitabine.  
5. a) Patients included in Cohort 1: Prior treatment with exemestane in the metastatic setting. 
If the patient has received exemestane in the adjuvant setting and developed MBC, she will 
be eligible for the study provided: 
 She has received letrozole/anastrozole as first-line MBC and progressed. 
 At least 1 year has elapsed since the end of adjuvant exemestane treatment.  
b) Patients included in Cohort 2: Prior treatment with fulvestrant in the metastatic setting. 
If the patient has received fulvestrant in the adjuvant setting and developed MBC, 
she will be eligible for the study provided: 
 She has received letrozole/anastrozole/exemestane as first-line MBC and 
progressed. 
 At least 1 year has elapsed since the end of adjuvant fulvestrant treatment. 
6. Patients treated within the last 7 days prior to randomization with: 
 Food or drugs that are known to be CYP3A4 inhibitors 
 Drugs that are known to be CYP3A4 inducers 
 Drugs that are known to prolog the QT interval 
7. Patients who received before randomization: 
 Any investigational agent within 4 weeks. 
 Chemotherapy within a period of time that is < the cycle length used for that 
treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1 week 
for weekly chemotherapy). 
 Previous endocrine therapy is permitted without any window. 
 Radiotherapy within 2 weeks (all acute toxic effects must be resolved to NCI 
CTCAE version 4.0 grade <1, except toxicities not considered a safety risk for the 
patient at investigator´s discretion) but patients who received prior radiotherapy to 
>25% of bone marrow are not eligible independent of when it was received. 
 Major surgery or other anti-cancer therapy not previously specified within 4 weeks, 
(all acute toxic effects must be resolved to NCI CTCAE version 4.0 grade < 1, 


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except toxicities not considered a safety risk for the patient at investigator´s 
discretion). 
8. Diagnosis of any other malignancy within 3 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.  
9. QTc > 480msec, family or personal history of long or short QT syndrome, Brugada 
syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP). 
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug 
(eg, hypocalcemia, hypokalemia, hypomagnesemia). 
11. Any of the following within 6 months of randomization: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ≥ 
2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident including transient ischemic attack, or 
symptomatic pulmonary embolism. 
12. Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting 
gastrointestinal function, resection of the stomach or small bowel, or active inflammatory 
bowel disease or chronic diarrhea.  
13. Known hypersensitivity to palbociclib, capecitabine or to exemestane (only patients of 
cohort 1) or to fulvestrant (patients of cohort 2) or any of their excipients.  
14. Any of the following contraindications for chemotherapy with capecitabine:  
 Known deficiency or family history of deficiency of dihydropyrimidine 
dehydrogenase.  
 Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or 
chemically related analogues, such as brivudine.  
15. Only for patients in Cohort 2 any of the following contraindications for treatment with 
fulvestrant:  
 Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting 
factor deficiency) or long-term (>6 months) anticoagulant therapy, other than 
antiplatelet therapy and low dose coumarin derivatives, provided that the 
International Normalised Ratio (INR) is less than 1.6.  
16. Known human immunodeficiency virus infection.  
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study.  
18. Recent or active suicidal ideation or behavior. 


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4.3. 
Discontinuations 
4.3.1. 
Discontinuation of Study Treatment 
The criteria for enrollment must be followed explicitly. If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be discontinued from the study 
treatment, but can be allowed to continue in the study in order to provide the follow up data 
needed for the analysis of the entire population. An exception may be granted if the patient, in 
the opinion of the investigator, is having benefit from the study treatment. In these cases, the 
investigator must obtain documented approval from GEICAM which in agreement with the 
Coordinating Investigator and after confirming that this deviation does not affect patient´s 
safety may allow the patient to continue to receive the study treatment. 
Patients can be discontinued from the study therapy in the following circumstances: 
 
Patient’s own request. 
 
Unacceptable toxicity as defined in the protocol. 
 
Tumor progression as defined in the protocol. 
 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the patient. 
 
Termination of the study by GEICAM. 
 
Physician’s decision, including need of other anti-cancer therapy, not specified in the 
protocol.  
 
If the patient is non-compliant with study procedures.  
 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g. infectious disease) 
illness. 
 
All patients will be discontinued from the active treatment phase and entered into the 
follow-up phase in case of a delay of more than 4 weeks or permanent discontinuation of 
exemestane/fulvestrant unless there is an obvious clinical benefit per the investigator’s 
medical judgment and after discussion with GEICAM. Patients with a delay of more than 4 
weeks or permanent discontinuation of palbociclib for a reason different than progression 
(i.e., toxicity due to palbociclib) will continue with exemestane/fulvestrant (in the active 
treatment phase) until objective disease progression, clinical progression (under investigator 
criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.  
 
All patients will be discontinued from the active treatment phase and entered into the 
follow-up phase in case of a delay of more than 3 weeks or permanent discontinuation of 


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capecitabine unless there is an obvious clinical benefit per the investigator’s medical 
judgment and after discussion with GEICAM.  
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the study treatment. 
All permanent treatment discontinuation should be recorded by the Investigator in the eCRF 
when considered as confirmed. 
4.3.2. 
Discontinuation of Study Sites 
Study Site participation may be discontinued if GEICAM, the investigator or the IRB of the 
study site judges it necessary for any reason.  
4.3.3. 
Discontinuation of Study 
The study may be discontinued by GEICAM if this is medically reasonable and consistent with 
applicable regulations of Good Clinical Practice (GCP). Stopping the study for medical reasons 
may be required if patients experienced adverse reactions under the treatment with the study 
treatment or if new information about the safety or effectiveness of the study treatment justifies 
it. 


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5. 
Treatment 
5.1. 
Treatments Administered 
5.1.1. 
Palbociclib 
Palbociclib will be administered at a dose of 125mg PO daily on Day 1 to Day 21 following a 1 
week of rest period, given as 4 weeks cycles.  
5.1.2.  Exemestane 
Exemestane will be administered at a dose of 25 mg PO daily (continuously).  
5.1.3. 
Capecitabine 
Capecitabine will be administered at a dose of 1,250mg/m2 twice daily for 2 weeks followed by 
a 1 week of rest period, given as 3 weeks cycles. 
Capecitabine must be administered at a dose of 1,000mg/m2 twice daily for 2 weeks followed 
by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age. 
Capecitabine Dose will be calculated for each patient in mg/m2, it is recommeded to calculate 
the dose according to the Protocol Attachment 4. The real Body Surface Area (BSA) of the 
patient determined in the baseline visit will be the reference BSA throughout the study. The 
BSA and the capecitabine dose will be recalculated in the event that patients experience body 
weight variations greater than 10% during the treatment period. 
5.1.4. 
Fulvestrant 
Fulvestrant will be administered at a dose of 500mg, as two 5ml intramuscular injections (one 
in each buttock), on days 1 and 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 
28 days Cycle (± 3 days). Time windows extended to ±7 days after 24 weeks. 
5.2. 
Materials and Supplies 
The definition of Investigational Medicinal Product [IMP] is a drug that is being studied or 
used as a reference, even as placebo, in the context of a clinical trial, regardless of its 
authorization. 
All IMPs used in the trial will be named as study treatment along the protocol.  
GEICAM will provide the study sites with palbociclib, exemestane and fulvestrant with the 
appropriate label for clinical trial use for the purpose of this study.  
Since capecitabine is a marketed product approved for this indication and is administered 
according to the label it will not be provided by the Sponsor.  


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5.2.1.  
Storage, preparation and administration 
Investigators and site staff are reminded to continuously monitor room and fridge storage 
temperatures and ensure that thermometers are working correctly as required for proper storage 
of study treatment. These include thermometers for both the room storage and refrigerator 
storage.  
For palbociclib, exemestane and fulvestrant provided by the sponsor, any temperature 
excursions must be reported immediately to GEICAM and documented. Once a deviation is 
identified, the study treatment MUST be quarantined and not used until GEICAM provides 
documentation of permission to use the study treatment product.  
Palbociclib, exemestane and fulvestrant should be kept in a secured locked area at the study site 
in accordance with applicable regulatory requirements. Returned study treatment provided by 
the Sponsor should be stored separately from study treatment that needs to be dispensed. 
Refer to the current capecitabine SmPC for details regarding the storage and handling of 
capecitabine. Any issue or deviation that affect the storage conditions or handling of 
capecitabine must be reported to the sponsor for its information. 
Storage area temperature conditions must be monitored and recorded daily. A daily temperature 
log will also be kept at the study site. 
5.2.1.1. 
Palbociclib 
Palbociclib will be supplied as capsules containing 75mg, 100mg or 125mg equivalents of 
palbociclib free base. GEICAM will supply the oral drug formulation to sites in HDPE bottles 
containing 75mg, 100mg or 125mg capsules. The capsules can be differentiated by their size 
and color (see Table 4). 
Table 4. Palbociclib Capsule Characteristics 
Dosage 
Capsule color 
Capsule size 
75mg 
Sunset Yellow/ Sunset Yellow 
2 
100mg 
Sunset Yellow/Caramel 
1 
125mg 
Caramel/ Caramel 
0 
 
Palbociclib will be provided in non-patient-specific bottles containing 75mg, 100mg or 125mg 
capsules.  
Storage conditions stated in the Study Reference Safety Document may be superseded by the 
label storage. 
Palbociclib capsules should be stored at controlled room temperature (15-30ºC) in their original 
container.  


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The patient number should be recorded on the bottle label in the spaces provided by site 
personnel at the time of assignment to patient. Site personnel must ensure that patients clearly 
understand the guidelines for self-medication. Patients should be given a sufficient supply to 
last until their next study visit. Unused drug and/or empty bottles should be returned to the site 
at the next study visit. Returned unused medication MUST NOT be re-dispensed to patient. 
Palbociclib is an agent that must be handled and administered with care. Patients should be 
instructed to keep their medication in the bottles provided and not transfer it to any other 
container. Due to possible unknown hazards associated with topical and environmental 
exposure to experimental agents, capsules must not be opened and/or emptied into any vehicle 
for oral ingestion; capsules must be swallowed intact. 
Only one capsule strength will be dispensed to the patient at each dispensing visit. In the event 
of dose modification, request should be made of the patient to return all previously dispensed 
medication to the clinic and new capsules will be dispensed. 
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 treatment in a patient 
diary. 
In Cohort 1 palbociclib will be administered together with exemestane. In both Cohorts patients 
should take palbociclib with food. 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 5.4.1. 
For both palbociclib and exemestane:  
 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 5.5. for further details on medication errors and 
overdose. 
5.2.1.2. 
Exemestane 
Commercially available exemestane 25mg coated tablets will be supplied to sites by GEICAM. 
Complete information about exemestane formulation and storage conditions can be found in the 
Summary of Product Characteristics (SPC) for Aromasin®. 
Exemestane tablets will be provided in blister packs.  


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Exemestane will be administered orally in a daily basis and continuously (together with 
palbociclib for the first 3 weeks and in monotherapy for the fourth week in 28-days cycles).  
5.2.1.3. 
Capecitabine 
Investigators should consult the locally approved prescribing information for storage and 
administration instructions.  
5.2.1.4. 
Fulvestrant 
Fulvestrant (Faslodex®) is supplied as two 5-mL clear neutral glass (Type 1) barrels, each 
containing 250mg/5mL of fulvestrant solution for intramuscular injection and fitted with a 
tamper evident closure. The syringes are presented in a tray with polystyrene plunger rod and 
safety needles (SafetyGlideTM) for connection to the barrel.  
Refer to the Summary of Product Characteristics (SmPC) for fulvestrant (Faslodex®) for 
storage conditions and instructions and steps necessary for drug preparation and administration. 
Drug preparation and administration will be performed at the site by a physician, registered 
nurse or other qualified health care provider. 
Fulvestrant 500mg will be administered intramuscularly into the buttocks slowly (1-2 minutes 
per injection) as two 5mL injections, one in each buttock.  
5.2.2. 
 Accountability 
It is the responsibility of the investigator to ensure that a current record of palbociclib, 
exemestane and fulvestrant disposition is maintained at each study site where study treatment 
provided by the Sponsor are inventoried and disposed. Records or logs must comply with 
applicable regulations and guidelines. 
GEICAM will provide forms to facilitate inventory control if the staff at the investigational site 
does not have an established system that meets these requirements.  
Palbociclib, exemestane and fulvestrant provided by the Sponsor will be preferably destroyed 
at each participating site. The site must obtain written authorization from the Sponsor before 
they are destroyed, and this destruction must be documented on the appropriate form. 
It is also the responsibility of the investigator to ensure that current records of capecitabine 
dispensations are available to assure traceability. 
5.3. 
Method of Assigning a Patient to a Treatment 
All patients who meet all criteria for enrollment will be randomized to receive palbociclib in 
combination with endocrine therapy (exemestane or fulvestrant) versus chemotherapy with 
capecitabine.  
All patients will be screened by one of the investigators prior to entry on this study. An 
explanation of the study and discussion of the expected side effects and presentation of the 


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informed consent document will take place. Eligible and consenting patients (entered) will be 
enrolled into the study. In selected sites, patients enrolled in Cohort 1 were offered the 
participation in the PK study in the experimental arm. 
No patients can receive protocol treatment until registration with GEICAM has taken place. All 
eligibility criteria must be met at the time of registration. There will be no exceptions. Any 
question should be addressed with GEICAM prior to registration. The eligibility checklist must 
be completed and signed by the Principal Investigator or Sub-Investigator before enrolling each 
patient to confirm all inclusion/exclusion criteria and stratifications factors. This eligibility 
checklist should be filed with the study documentation. Once the eligibility checklist is 
completed, the study personnel at the site will randomize the patient through the eCRF and the 
system will send the unique randomization number of the patient and the assigned treatment to 
the site.  
Only after the assigned arm has been confirmed the patient can receive the study treatment.  
All patients enrolled in the study will be registered in a Patient Enrollment and Identification 
Log that will be only maintened at the site. 
Trial treatment must be administered within 7 days from registration.  
5.4. 
Special Treatment Considerations. Dose Adjustments of Study Treatment 
All dose modifications should be based on the worst preceding toxicity.  
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 
treatment may need to be adjusted as described in the following sections. Depending on the 
nature of the toxicity observed, dosing adjustments may be required for just one or both study 
treatment in the combination. In the event treatment interruption is deemed necessary for just 
palbociclib, treatment with the other study treatment (exemestane or fulvestrant) will continue 
as planned.  
For patients in Cohort 1, dose modifications of any nature must not alter the pre-planned 
schedule of cycles starting with the first palbociclib dose on cycle 1, day 1.  
For patients in Cohort 2, if there is dose delay of palbociclib, the administration of fulvestrant 
should be continued as pre-planned schedule, though every effort should be made to re-
synchronize the day 1 palbociclib administration and fulvestrant injection using the allowed 
visit windows as defined in the study schedule. Fulvestrant can also be delayed by a maximum 
of 7 days, or longer if required for satisfactory recovery of the platelet count (see Protocol 
Attachment 6. Fulvestrant/Palbociclib Interruptions and Extended Rest Periods). 
All dose modifications/adjustments must be clearly documented in the patient's source notes 
and the appropriate section of the eCRF. 


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5.4.1.  
Palbociclib 
In the event of significant treatment-related toxicity, palbociclib dosing may be interrupted or 
delayed and/or reduced as described below. 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 will 
continue with exemestane/fulvestrant (in the active treatment phase) until objective disease 
progression, clinical progression (under investigator criteria), unacceptable toxicity, death or 
withdrawal of consent, whichever occurs first. 
5.4.1.1. 
Dosing Interruption 
Patients experiencing the following adverse events must interrupt/delay their treatment:  
 Grade 3-4 anemia (<8 g/dL; transfusion indicated and/or Life-threatening 
consequences); 
 Grade 3-4 neutropenia (ANC<1,000/mm3) either complicated or not; 
 Grade 3-4 thrombocytopenia (Platelet count <50,000/mm3); 
 Grade 3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment); 
 Grade 3 QTc prolongation (QTc ≥501 msec on at least two separate ECGs). 
 Concurrent ALT  3 x ULN and total bilirubin  2 x ULN. 
 Interstitial Lung Disease (ILD)/pneumonitis of any grade. In patients who have new or 
worsening respiratory symptoms (e.g. hypoxia, cough, dyspneoa, etc) and are suspected 
to have developed ILD/pneumonitis, interrupt palbociclib immediately and evaluate the 
patient. 
Appropriate follow up assessments should be done until adequate recovery occurs as assessed 
by the Investigator. Criteria required before treatment can resume are described in Section 
5.4.1.2. 


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Doses may be held as needed until toxicity resolution. Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned doses 
within that same cycle or even to delay the initiation of the subsequent cycle.  
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the same 
cycle. The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in Section 5.4.1.3. unless expressly agreed otherwise following discussion 
between the investigator and GEICAM. If a dose reduction is applied in the same cycle, the 
patient will need to return to the clinic to receive new drug supply. 
In the event of a treatment interruption for reasons other than treatment-related toxicity (eg, 
non-cancer related surgery) lasting >4 weeks, treatment resumption will be decided in 
consultation with GEICAM. 
In the event that the start of a new cycle is delayed, procedures required on Day 1 of the given 
cycle will be performed when treatment is resumed. New cycle Day 1 procedures (ie. physical 
examination, ECOG performance status, Quality of Life questionnaires, blood chemistry, 
hematology) that were performed prior to knowing the need to delay the start of the cycle do 
not need to be repeated (1) if not required to determine whether study treatment may be 
resumed and (2) if performed within 7 days prior to study treatment resumption. 
5.4.1.2. 
Re-treatment criteria 
Retreatment following treatment interruption for treatment related toxicity or at the start of any 
new cycle may not occur until all of the following parameters have been met: 
 Hemoglobin > 8g/dL 
 Platelet count  50,000/mm3;  
 ANC  1,000/mm3 and no fever; 
 Grade 3 or higher treatment-related non-hematologic AEs (including, nausea, vomiting, 
diarrhea, and hypertension only if persisting despite optimal medical treatment), with 
the exception of alopecia, have recovered to Grade ≤ 1 or baseline (or, at the 
investigator’s discretion for Grade ≤ 2 if not considered a safety risk for the patient). 
 QTc <501 msec and potential reversible causes (eg, electrolyte imbalance, concomitant 
medications known to prolong QTc) corrected. If QTc remains above 480 msec, ECG 
should be monitored more frequently as per the investigator’s best medical judgement 
until QTc≤480 msec. 
 Patients who experience concurrent ALT>3xULN and total bilirubin >2xULN 
suspected to be treatment-related (Hy´s law) should be permanently discontinued from 
the study. 


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 Patients who experience Grade ≥3 of ILD/pneumonitis should be permanently 
discontinued from palbociclib. If < Grade 3, symptomatic treatment could be given and 
maintain the same dose, or reduce the dose, as per investigator’s judgment, taking into 
consideration the clinical situation of the patient, whether the patient has prior 
respiratory pathology or not, and the benefit obtained with the study treatment. 
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 4 weeks of treatment interruption or cycle delay, palbociclib 
may be resumed. Please refer to Section 5.4.1.3. for adverse events requiring dose reduction at 
the time of treatment resumption.  
If these parameters have not been met after 4 weeks of dose interruption (including the 
scheduled 1 week off treatment) or 4 weeks of cycle delay, permanent discontinuation of 
palbociclib treatment should be considered. Treatment resumption for patients recovering from 
treatment-related toxicity after > 4 weeks of treatment interruption or cycle delay, but deemed 
to be deriving obvious clinical benefit per the investigator’s best medical judgment, should be 
discussed with GEICAM. 
5.4.1.3. 
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 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances. 
Dose reduction of palbociclib by 1 and, if needed, 2 dose levels (Table 5) will be allowed 
depending on the type and severity of toxicity encountered. Patients requiring more than 2 dose 
reductions will be discontinued from palbociclib treatment and will continue with 
exemestane/fulvestrant in the active treatment phase. In exceptional cases a break on day 10-12 
or a prolonged holiday of up to 2 weeks after 2 weeks of treatment are further options to modify 
dose according to tolerability (if in investigator judgment such schedule is manageable and 
preferred). 
This 
should 
be 
previously 
discussed 
with 
GEICAM. 
All 
dose 
modifications/adjustments must be clearly documented in the patient's source notes and 
Investigational product administration eCRF.  
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 5. Available Dose Levels 
Dose Level 
Palbociclib for 3 out of 4 weeks (3/1 schedule) 
Starting dose 
125mg/d 


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-1 
100mg/d 
-2* 
75mg/d 
Discontinue Study Treatment or consider 75mg/d 2/2 schedule  
*Palbociclib dose de-escalation below 75mg/d is not allowed. The schedule may move to 75mg/day two 
weeks on followed by two weeks off after discussion with GEICAM. 
Palbociclib mandatory dose modifications for treatment related toxicities requiring treatment 
interruption/delay or persisting despite optimal medical treatment are described in Table 6.  
 
 
Table 6. Palbociclib Dose Modifications for Treatment Related Toxicities Requiring Treatment 
Interruption/Delay or Persisting Despite Optimal Medical Treatment. 
Toxicity 
Restart palbociclib Treatment at: 
Grade 3 anemia (<8 g/dL, transfusion indicated) 
Same dose level* 
Uncomplicated Grade 3 neutropenia 
(ANC<1000/mm3) 
Same dose level* 
Grade 3 neutropenia (ANC<1,000/mm3) associated 
with a documented infection or fever 38.3C with a 
single measure, or ≥38ºC sustained for more than 
one hour 
 1 Dose Level 
Grade 3  thrombocytopenia (Platelet count 
<50,000/mm3) 
Same dose level* 
Grade 4 anemia (Life-threatening consequences) 
 1 Dose Level 
Grade 4 neutropenia (ANC<500/mm3) 
 1 Dose Level 
Grade 4 thrombocytopenia (Platelet count 
<25,000/mm3) 
 1 Dose Level 
Grade 3 non-hematologic toxicity (including, 
nausea, vomiting, diarrhea, and hypertension only if 
persisting despite optimal medical treatment) 
 1 Dose Level 
Grade < 3 ILD/pneumonitis 
Same dose level or  1 dose level as 
per investigator’s judgment 
Grade ≥ 3 ILD/pneumonitis 
Permanently discontinue 
* If there is significant delay of recovery to grade 2 (≥7 days in addition to the 1 week off) or repeated grade 3, 
reduce one dose level. 
 
QTc prolongation management 


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In the event of QTc prolongation, any possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong 
the QTc interval should be evaluated.  
If such reversible causes are identified, then they should be corrected accordingly (ie, 
correction of electrolyte abnormalities with supplements to within normal limits and/or 
discontinuation, if possible, of concomitant medications known to prolong the QT interval).  
Mandatory dose modifications in the event of QTc prolongation are provided in Table 7.  
 
 
 
 
Table 7. Palbociclib Dose Modifications in the Event of QTc Prolongation 
 
Toxicity (NCI CTC Grade, Version 4.0) 
 
Grade 2 QTc prolongation
Grade 3 QTc prolongation 
Grade 4 QTc 
prolongation 
Reversible 
cause 
identified  
Treat reversible cause  
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc≤480 
msec  
Continue at the same dose 
level (1) 
Treat reversible cause  
Withhold treatment until 
QTc<501 msec  
Resume treatment at the same 
dose level. 
Monitor ECG more frequently 
as per investigator’s best 
medical judgment until 
QTc≤480 msec.   
Discontinue 
treatment 
permanently  
No 
reversible 
cause 
identified 
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc≤480 
msec  
Continue at the same dose 
level (1) 
Withhold treatment until 
QTc<501 msec  
Resume treatment at the next 
lower dose level (2) 
Monitor ECG more frequently 
as per investigator’s best 
medical judgment until 
QTc≤480 msec. 
Discontinue 
treatment 
permanently 
1. If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence 
of other alternative causes or despite correction of alternative causes, dose adjustment and/or discontinuation 
should be considered in consultation with a cardiologist and GEICAM, taking into account the emerging 
safety data from palbociclib trials and the investigator’s best medical judgment. 


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2. If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment and/or 
discontinuation should be discussed with GEICAM in consultation with a cardiologist, taking into 
consideration the emerging safety data from palbociclib trials and the investigator’s best medical judgment. 
5.4.2. 
 Exemestane 
No dose adjustment for exemestane is permitted but dosing interruptions are allowed. 
Treatment interruption for exemestane-related toxicities will be performed as per the 
investigator´s best medical judgment.  
Patients discontinuing exemestane treatment due to treatment-related toxicity will be 
discontinued from the active treatment phase of the study (discontinuing also palbociclib) and 
entered into the follow-up phase. 
5.4.3. 
Fulvestrant 
No dose adjustment for fulvestrant is permitted. A single fulvestrant dose can be skipped a 
single time in case of a fulvestrant-related toxicity. Treatment delay for fulvestrant-related 
toxicities will be performed as per the investigator’s best medical judgment, but by no more 
than 7 days.  
In the event of a toxicity requiring dosing delay of palbociclib, the administration of fulvestrant 
should be continued as pre-planned schedule, though every effort should be made to re-
synchronize the day 1 palbociclib administration and fulvestrant injection using the allowed 
visit windows as defined in the study schedule. Fulvestrant can also be delayed by a maximum 
of 7 days, or longer if required for satisfactory recovery of the platelet count, as it should not be 
administered if the platelet count is <50,000/mm3 (see Protocol Attachment 6. 
Fulvestrant/Palbociclib Interruptions and Extended Rest Periods). 
Patients discontinuing fulvestrant permanently due to treatment-related toxicity will be 
discontinued from the active treatment phase of the study (discontinuing also palbociclib) and 
entered into the follow-up phase. 
 5.4.4. 
Capecitabine 
Toxicity due to capecitabine administration may be managed by symptomatic treatment, dose 
interruption and dose adjustment. Once a patient’s capecitabine dose has been reduced, it 
should not be increased in subsequent treatment cycles. Capecitabine treatment interruptions 
are regarded as lost treatment days and the planned treatment schedule should be maintained. 
Missed doses due to treatment interruptions should not be replaced. Further, if a rest period is 
extended beyond the beginning of the next scheduled treatment cycle, the complete 14-day 
capecitabine dosing should be administered when capecitabine treatment is re-initiated and the 
study treatment schedule should be maintained (see Protocol Attachment 5. Capecitabine 
Interruptions and Extended Rest Periods).  
The patient may begin a new 3-week treatment cycle if the absolute neutrophil count (ANC) is 
≥1.5x109/L, the platelet count is ≥75x109/L and she has recovered from non-haematologic 


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toxicity to baseline or grade ≤ 1 and then start treatment with doses indicated below. Otherwise, 
treatment will be delayed until recovery. If recovery has not occurred after a delay of 3 weeks, 
then the patient should discontinue from the active treatment phase of the study and entered 
into the follow-up phase, unless there is an obvious clinical benefit per the investigator’s 
medical judgment and after discussion with GEICAM.  
In the event that the start of a new cycle is delayed, procedures required on Day 1 of the given 
cycle will be performed when capecitabine is resumed. New cycle Day 1 procedures (ie. 
physical examination, ECOG performance status, Quality of Life questionnaires, blood 
chemistry, hematology) that were performed prior to knowing the need to delay the start of the 
cycle do not need to be repeated (1) if not required to determine whether study treatment may 
be resumed and (2) if performed within 7 days prior to study treatment resumption. 
5.4.4.1. 
Hematological Toxicity 
Guidelines for capecitabine dose modifications due to hematological toxicities are shown in 
Table 8, Table 9 and Table 10.  
Dose reduction of capecitabine is not required unless the ANC is <1.0x109/L, or the platelet 
count is <50x109/L. In addition, no dose reductions or interruptions will be required for anemia 
(non-hemolytic) as it can be satisfactorily managed by transfusions. 
Table 8. Dose Modifications for Neutropenia  
Neutrophil 
Count (ANC) 
Grade 2  
≥1.0 - <1.5 x109/L 
Grade 3 
≥0.5 - <1.0 x109/L 
Grade 4 
< 0.5 x109/L 
Laboratory value at start of a treatment cycle: delay treatment start until ANC ≥ 
1.5x109/L, platelets  ≥ 75x109/L, and recovery from non-haematologic toxicity to 
baseline or grade ≤ 1, then start treatment with doses indicated below 
1st occurrence 
No dose adjustment 
 
capecitabine 75% of  the 
current dose*  
capecitabine 50% 
of the current dose* 
2nd occurrence 
No dose adjustment 
capecitabine 75% of the 
current dose*  
Discontinue 
treatment 
permanently 
3rd occurrence 
No dose adjustment 
Discontinue treatment 
permanently unless the 
Investigator considers it 
is in the best interest of 
the patient to continue 
with capecitabine at 50% 
of the current dose once 
toxicity has resolved to 
grade 0-1*. 
Not applicable 


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* It is recommeded to calculate the dose according to the Protocol Attachment 4 by using the current 
value of the BSA. Dose adjustment > 50% of the initial dose for capecitabine should be previously 
discussed with GEICAM. 
 
 
 
 
 
 
 
 
 
 
 
 
Table 9. Dose Modifications for Thrombocytopenia 
Platelet Count 
Grade 2          
≥ 50 - < 75 x109/L
Grade 3           
≥ 25 - < 50 x109/L 
Grade 4              
< 25 x109/L 
Laboratory value at start of a treatment cycle: delay treatment start until ANC ≥ 
1.5x109/L, platelets  ≥ 75x109/L, and recovery from non-haematologic toxicity to 
baseline or grade ≤ 1, then start treatment with doses indicated below 
1st occurrence 
No dose 
adjustment 
capecitabine 75% of 
the current dose*  
capecitabine 50% of 
the current dose*  
2nd occurrence 
No dose 
adjustment 
capecitabine 75% of 
the current dose*  
Discontinue treatment 
permanently 
3rd occurrence 
No dose 
adjustment 
capecitabine 50% of 
the current dose*  
Not applicable 
* It is recommeded to calculate the dose according to the Protocol Attachment 4, by using the current value of 
the BSA. Dose adjustment > 50% of the initial dose for capecitabine should be previously discussed with 
GEICAM. 
 
In case of certain hematological toxicities, the administration of capecitabine must be 
interrupted during a treatment cycle, and the doses of capecitabine must be reduced as follows 
in the present and subsequent treatment cycles (see Table 10). 
Table 10. Dose Modification Guidelines for Hematological toxicities within a Treatment Cycle 
Toxicity 
Capecitabine 
Grade 4 neutropenia for more than 5 days 
50% of the current dose of capecitabine***  
Grade 4 thrombocytopenia 
50% of the current dose of capecitabine***  
Grade 3 febrile neutropenia* 
(ANC < 1.0, fever ≥ 38.3oC with a single 
measure, or ≥ 38ºC sustained for more 
than 1 hour) 
75% of the current dose of capecitabine*** 


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Grade 4 febrile neutropenia 
(ANC < 1.0, fever ≥ 38.3oC with a single 
measure, or ≥ 38ºC sustained for more 
than 1 hour, and life-      threatening 
sepsis) 
 
Discontinue 
capecitabine 
treatment 
permanently 
unless 
the 
Investigator 
considers it is in the best interest of the 
patient to continue with capecitabine at 50% 
of the current dose once toxicity has 
resolved to grade 0-1**. 
* On second occurrence of grade 3 febrile neutropenia, discontinue capecitabine treatment permanently unless it is 
in the best interest of the patient to treat with capecitabine at 50% of current dose.  
** If the decision has been to continue, on second occurrence of grade 4 febrile neutropenia, discontinue 
capecitabine treatment permanently. 
***It is recommeded to calculate the dose according to the Protocol Attachment 4, by using the current value of 
the BSA. Dose adjustment > 50% of the initial dose for capecitabine should be previously discussed with 
GEICAM. 
 
5.4.4.2. 
Non-Hematological Toxicity 
For toxicities which are considered by the Investigator unlikely to develop into serious or life–
threatening events (e.g. alopecia, altered taste etc.), treatment will be continued at the same 
dose without reduction or interruption. If any grade 1 toxicity or any grade of alopecia occurs, 
treatment will be continued at the initial dose without interruption.  
Guidelines for capecitabine dose modifications due to non-hematological toxicity are described 
in general in Table 11 with additional instructions provided below.  
Table 11. General Capecitabine Dose Modification Guidelines for Non-Hematological 
Toxicity 
 
Grade 2 and 3 
Grade 4 
Laboratory value at start of a treatment cycle: delay treatment start until ANC ≥ 1.5x109/L, 
platelets  ≥ 75x109/L, and recovery from non-haematologic toxicity to baseline or grade ≤ 1, 
then start treatment with doses indicated below 
1st 
occurrence 
Interrupt treatment until recovery to 
grade 0-1, continue capecitabine at 75% 
of the current dose* with prophylaxis 
where possible. 
Discontinue capecitabine treatment 
permanently- unless Investigator 
considers it to be in the best interest 
of the patient to continue at 50% of 
the current dose* for capecitabine  
2nd 
occurrence 
Interrupt treatment until recovery to 
grade 0-1, continue capecitabine at 75% 
of the current dose*.  
Not applicable 
3rd 
occurrence 
Discontinue 
capecitabine 
treatment 
permanently- 
unless 
Investigator 
considers it is in the best interest of the 
Not applicable 


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Grade 2 and 3 
Grade 4 
Laboratory value at start of a treatment cycle: delay treatment start until ANC ≥ 1.5x109/L, 
platelets  ≥ 75x109/L, and recovery from non-haematologic toxicity to baseline or grade ≤ 1, 
then start treatment with doses indicated below 
patient to continue on capecitabine 
treatment at 75% of the current dose*, 
this dose adjustment should be discussed 
previously with GEICAM. 
*Dose adjustment > 50% of the initial dose for capecitabine should be previously discussed with GEICAM. 
 
If the creatinine clearance decreases during treatment to a value <30 ml/min, capecitabine 
must be permanently discontinued. 
If grade >2 cardiotoxicity occurs which is attributable to capecitabine, then capecitabine must 
be permanently discontinued.  
 
Diarrhea: Capecitabine can induce diarrhea, which can sometimes be severe. In patients 
receiving capecitabine, the median time to first occurrence of grade 2-4 diarrhea is 31 days, and 
median duration of grade 3 or 4 diarrhea is 4.5 days. Patients with severe diarrhea should be 
carefully monitored and, if they become dehydrated, should be given fluid and electrolyte 
replacement. If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine must be 
immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. 
Following grade 2 or higher diarrhea, subsequent doses of capecitabine must be decreased (see 
Table 12). Standard anti-diarrhea treatments (e.g. loperamide) should be initiated, as medically 
appropriate, as early as possible. Capecitabine cannot be re-started until diarrhea has resolved 
to grade 0–1 with the last loperamide dose given at least 24 hours beforehand. 
Table 12. Capecitabine Dose Modification Guidelines for Diarrhea 
 
Grade 2 
Grade 3 
Grade 4 
1st 
occurrence 
Interrupt capecitabine until 
recovery to grade 0-1, 
continue capecitabine at 75% 
of the current dose with 
prophylaxis where possible. 
Interrupt capecitabine until 
recovery to grade 0-1, then 
continue at 75% of the 
current dose  
Permanently 
discontinue 
capecitabine. 
 
2nd 
occurrence 
Interrupt capecitabine until 
recovery to grade 0-1, then 
continue with  the current 
dose  
Interrupt capecitabine until 
recovery to grade 0-1, then 
continue at 75% of the 
current dose*  
Not applicable 


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Grade 2 
Grade 3 
Grade 4 
3rd 
occurrence 
Interrupt capecitabine until 
recovery to grade 0-1, then 
continue at 75% of the 
current dose*. 
Discontinue capecitabine 
permanently. 
 
Not applicable 
4th 
occurrence 
Discontinue capecitabine 
permanently.  
 
Not applicable 
Not applicable 
* Dose adjustment > 50% of the initial dose for capecitabine should be previously discussed with GEICAM. 
 
Grade ≥ 2 Nausea/Vomiting: For nausea and vomiting, patients must be supplied with anti-
emetics in order to self-medicate in case nausea or vomiting occurs at home. The 
administration of metoclopramide +/- 5-HT3 antagonists is recommended for capecitabine-
induced nausea. Adequate secondary therapeutic and prophylactic treatment has to be initiated 
once nausea or vomiting has occurred. If the nausea or vomiting recurs despite adequate 
prophylaxis, then dose modifications must also be made according to Table 11 above. 
Grade 2/3 Stomatitis: If grade 2/3 stomatitis occurs, administration of capecitabine should be 
interrupted until the event resolves or decreases in intensity to grade 1. The stomatitis should be 
treated symptomatically. Subsequent doses of capecitabine must be administered as in Table 
11.  
Grade 2/3 Hand-Foot Syndrome: Hand-foot syndrome (palmar-plantar erythrodysesthesia) is 
a cutaneous toxicity. If grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine 
should be interrupted until the event resolves or decreases in intensity to  grade 1. Subsequent 
doses of capecitabine must be decreased and administered as per Table 11. Hand-foot 
syndrome should be treated symptomatically (i.e. use of emollients and/or vitamin E is 
recommended). The use of vitamin B6 pyridoxine (50 to 150 mg BID) has been reported to be 
of possible benefit and is permitted for symptomatic or secondary prophylactic treatment of 
hand-foot syndrome.  
Hepatic Insufficiency: In patients with mild to moderate hepatic dysfunction due to liver 
metastases, caution should be exercised when capecitabine is administered but no dose 
reduction is necessary. The effect of severe hepatic dysfunction on capecitabine is not known. 
Hyperbilirubinemia and transaminase elevation: Administration of capecitabine must be 
interrupted if treatment-related elevations in bilirubin of >3.0xULN or treatment-related 
elevations in hepatic aminotransferases (ALT, AST) of >2.5xULN occur. Treatment may be 
resumed when bilirubin decreases to <3.0xULN and hepatic aminotransferases decrease to 
<2.5xULN. 


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5.5. 
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 adverse event (AE) page of the 
eCRFs and on the SAE form when appropriate. In the event of medication dosing error, 
GEICAM 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 product; 
 Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error and, if applicable, any associated adverse event(s) is captured 
on an adverse event (AE) eCRF page (refer to Management, Timing and Assessment of 
Adverse Events section for further details). 
5.6. 
General Concomitant Medication and Supportive Care Guidelines 
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator. Any medications 
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior to 
the start of study treatment and up to 30 days following the last dose of investigational product 
and the reason for their administration must be recorded on the eCRF.  
Routine postoperative care, such as dressing changes, suture removal, drain removal, or venous 
access (central or peripheral), does not need to be recorded. Anesthetics used for any surgical 
procedures performed during the patient’s participation in the study can be recorded as 
“unspecified anesthesia” on the concomitant treatment records; it is not necessary to list the 
specific anesthetics. Palliative and supportive care for cancer-related symptoms will be offered 
to all patients in this study. 
5.6.1. 
Prohibited Medications 
The following treatments are prohibited throughout the duration of the active treatment phase:  
 Anticancer agents: No additional investigational or commercial anticancer agents such 
as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or 
endocrine therapy other than exemestane will be permitted during the active treatment 
phase. In general, any drugs containing “for the treatment of breast cancer” on the 
product insert are not permitted on study. 


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 Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (eg, 
raloxifene) are prohibited during the active treatment phase. 
 Any concurrent radiotherapy (except palliative radiotherapy as specified under 
Section 5.6.3.) is prohibited throughout the duration of the active treatment phase of the 
study. Patients requiring this procedure will be discontinued from the active treatment 
phase and will enter the follow-up phase. This radiotherapy will be considered an 
alternative cancer therapy and will result in censoring the patient for the PFS endpoint. 
In addition and only in patients randomized to arm A (Cohort 1 and Cohort 2): 
 Strong CYP3A inhibitors/inducers: palbociclib is metabolized to multiple metabolites 
in a qualitatively similar manner in rat, dog and human liver microsomes. In vitro data 
indicate that CYP3A and sulfotransferase (SULT) enzyme SULT2A1 are mainly 
involved in the metabolism of palbociclib. Coadministration of a strong CYP3A 
inhibitor (itraconazole) increased the AUC of palbociclib in healthy subjects by 87%. 
Based on that, the concomitant use of strong CYP3A inhibitors (e.g., amprenavir, 
atazanavir, 
boceprevir, 
conivaptan, 
delavirdine, 
diltiazem, 
erythromicyn, 
fosamprenavir, mibefradil, miconazole, clarithromycin, indinavir, itraconazole, 
ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, verapamil, and voriconazole) and grapefruit or grapefruit juice 
are prohibited. Coadministration of a strong CYP3A inducer (rifampin) decreased the 
plasma exposure of palbociclib in healthy subjects by 85%. Based on that, the 
concomitant use of strong CYP3A inducers (such as phenobarbital, rifampin, phenytoin, 
rifampicin, carbamazepine, rifabutin, rifapentin, clevidipine, enzalutamide, felbamate, 
nevirapine, primidone and St. John’s Wort) are prohibited. 
 Drugs known to cause QT interval prolongation are prohibited during the active 
treatment phase. Refer to Protocol Attachment 3 for a list of drugs known to predispose 
to Torsade de Pointes. 
In addition and only in patients randomized to arm A (Cohort 2): 
 Long-term (>6 months) anticoagulant therapy (other than antiplatelet therapy and 
low dose coumarin derivatives provided that the International Normalised Ratio (INR) 
is less than 1.6, in this case, if the investigator considers use this therapy it is 
recommended to place ice in the injection area after the administration of fulvestrant for 
5 minutes).   
5.6.2. 
Medications Not Recommended 
The following treatments are not recommended throughout the duration of the active treatment 
phase. Alternative therapies should be considered whenever possible. If usage of the following 
treatments is deemed necessary, consultation and agreement with GEICAM is required prior to 
treatment initiation.  


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 Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids. Steroids given for physiological replacement, as anti-emetics or inhaled 
as well as short course of oral/topical steroids given for allergic reactions or asthma 
flares are allowed. 
 The use of herbal medicine is not recommended during the active treatment phase. 
In addition and only in patients randomized to arm A (Cohort 1 and Cohort 2): 
 Moderate CYP3A Inducers: Coadministration of moderate CYP3A inducers may also 
decrease the plasma exposure of palbociclib. Based on that, the concomitant use of 
moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and 
nafcillin) is not recommended. 
 CYP3A Substrates: PK data are available from a midazolam drug-drug interaction 
study. Midazolam is a sensitive CYP3A4/5 probe substrate. When midazolam was co-
administered with palbociclib, median plasma midazolam concentrations were slightly 
higher than with midazolam given alone. Coadministration of midazolam with multiple 
doses of palbociclib increased the midazolam plasma exposure by 61%, in healthy 
subjects, compared with administration of midazolam alone. This is consistent with a 
weak time-dependent CYP3A inhibition mediated by palbociclib. The dose of sensitive 
CYP3A substrates with narrow therapeutic indexes (e.g., alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus 
and tacrolimus) may need to be reduced as palbociclib may increase their exposure. 
 Erythropoietin should be avoided as it is not indicated for patients under the therapies 
proposed in this arm and may induce thrombotic events. 
In addition and only in patients randomized to arm B: 
 Proton Pump Inhibitors (PPIs): Coadministration of PPIs may impair the activity of 
the oral chemotherapeutic agent capecitabine. Based on that, investigators should be 
cautious when prescribing PPIs to patients on the capecitabine arm. If needed, 
alternative antacid therapies may be used including H2-receptor antagonists, and locally 
acting antacids. 
5.6.3. 
Permitted Medications 
The following treatments are permitted throughout the duration of the active treatment phase:  
 Standard therapies for pre-existing medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care (eg, 
analgesics, antidiarrheals, antidepressants) may also be used at the investigator’s 
discretion. All medications should be recorded.  
 Bisphosphonates and receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitors for the treatment of osteoporosis or management of existing bone 
metastases may be continued for patients who have been receiving them prior to 


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randomization. However the need to initiate or increase the dose of these therapies 
during the study will be considered as indicative of disease progression leading to the 
discontinuation of patient from the active treatment phase unless disease progression 
can be completely ruled out and the exact reason for the use of these therapies clearly 
documented in the patient’s source documentation. 
 Hematopoietic growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF]): Primary prophylactic 
use of granulocyte-colony stimulating factors is not permitted but they may be used to 
treat treatment-emergent neutropenia as indicated by the current American Society of 
Clinical Oncology (ASCO) guideline. If neutropenic complications are observed in a 
cycle in which primary prophylaxis with CSFs was not received, secondary prophylaxis 
may be given at the discretion of the investigator, but only if dose reduction or delay are 
not considered to be a reasonable alternative. 
 Erythropoietin may be used in arm B at the investigator's discretion for the supportive 
treatment of anemia.  
 Anticoagulant treatment: coumarin derivatives will be permitted if INR is less than 
1.6. Those patients on coumarin derivatives with an INR target higher or equal than 1.6 
may be switched to low molecular weight heparin (LMWH) if the investigator considers 
it is on the best interest of the patient, but LMWH should be discontinued 12-24 hours 
prior to fulvestrant injection and resumed 12-24 hours later and it is recommended to 
place ice in the injection area after the administration of fulvestrant for 5 minutes).   
 Palliative radiotherapy is permitted for the treatment of painful bony lesions or any 
other metastatic lesions as per investigator’s judgment, provided that the lesions were 
known to be present at the time of study entry and the investigator clearly documents 
that the need for palliative radiotherapy is not indicative of disease progression. In view 
of the current lack of data about the interaction of palbociclib with radiotherapy, 
palbociclib must be interrupted during palliative radiotherapy, stopping 1 day before 
and resuming treatment 1 week after. For patients with bone involvement, it is 
suggested to administer palliative radiotherapy before study initiation if possible and 
clinically appropriate. (eg, lesions at risk for spontaneous micro-factures or painful 
lesions). The dates on which palliative radiotherapy is administered should be recorded 
in concomitant medication.  
Areas that have received palliative radiotherapy cannot be used to assess response to 
study treatment. 
 Caution is advised on theoretical grounds for any surgical procedures during the study. 
The appropriate interval of time between surgery and palbociclib required to minimize 
the risk of impaired wound healing and bleeding, if any, has not been determined. 
Based on the available pharmacokinetic data showing a half-life of 27 hours, 
palbociclib should be completely washed out within a period of 7 days. Patients should 


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therefore not have elective surgery within this time period after last intake of 
palbociclib. Postoperatively, the decision to resume palbociclib treatment should be 
based on a clinical assessment of satisfactory wound healing and recovery from surgery. 
5.7. 
Treatment Compliance 
Patients will be required to return all bottles of palbociclib and all blisters of exemestane as 
well as the completed patient diary at the beginning of each cycle for drug accountability. Drug 
accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for 
the next cycle. The number of remaining capsules/tablets of palbociclib and exemestane will be 
documented and recorded.  
The patient number should be recorded on the bottle/blister label at time of assignment to a 
patient. Site personnel must ensure that patients clearly understand the directions for self-
medication. Patients should be given a sufficient supply to last until their next study visit. 
Unused drug and/or empty bottles/blister should be returned to the site at the next visit. 
Patients included in the control arm (capecitabine) will be given a patient diary and will be 
asked to return the completed diary at each study visit in order to assess the capecitabine 
compliance.  
To be considered compliant, each study patient must have received at least 80% of the planned 
number of doses of primary therapy based on the number of days of actual dose administration. 
Dose adjustments must follow instructions provided in the dose adjustment guidelines section.  
Fulvestrant will be administered at the hospital. Its administration will be supervised by the 
investigator or his/her designee. 


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6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments 
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule, Protocol Attachment 1. 
6.1. 
Efficacy Assessments 
Patients must have at least one demonstrated metastatic lesion at screening to be eligible for 
inclusion. 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
6.1.1. 
Primary Efficacy Assessments 
The primary efficacy variable is PFS based on the investigator’s assessment. 
PFS is defined as the time from randomization to the first documented progressive disease 
based on the investigator’s assessment, using RECIST version 1.1, or death from any cause, 
whichever occurs first. 
ESR1 mutational status will be determined in circulating free DNA (cDNA) obtained from 
baseline plasma samples and will be prospectively determined before the interims or final 
analyses. ESR1 mutational status will be blinded to the patients, investigators and study team. 
6.1.2. 
Secondary Efficacy Assessments 
Secondary efficacy assessments are OR, CB, RD and OS. 
 Overall Survival (OS): is defined as the time from the date of randomization to the date 
of death from any cause. 
 Objective Response (OR): Tumor response will be assessed based on the investigator’s 
assessment according to the RECIST version 1.1. Tumor assessment will be performed 
at baseline, the same method of measurement used at baseline will be used for further 
evaluations, that will be conducted every 8 weeks (±7days). The best response across 
treatment will be recorded. OR is defined as the complete plus partial responses out of 
the patients who had measurable disease at baseline.  
 Clinical Benefit (CB): is defined as complete response (CR), partial response (PR), or 
stable disease (SD) based on the investigator´s assessment  lasting more than 24 weeks 
according to the RECIST version 1.1 in all randomized patients (ITT population) 
 Response Duration (RD): is defined as the time from the first documentation of 
objective tumor response (CR or PR) to the first documented progressive disease using 
RECIST version 1.1 and based on the investigator’s assessment, or to death due to any 
cause, whichever occurs first.   


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6.2. 
Safety Assessments 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting GEICAM to any event that seems unusual. 
The investigator is responsible for appropriate medical care of patients during the study. 
The investigator remains responsible for following, through an appropriate health-care option, 
adverse events that are serious or that caused the patient to discontinue before completing the 
study. The patient should be followed until the event is resolved or explained. Frequency of 
follow-up evaluation is left to the discretion of the investigator. 
During the course of the study, all patients entering the trial must be evaluated according to the 
schedule outlined in the flow charts and described below. The results of the evaluation will be 
recorded in the eCRF pages until the patients are not followed anymore. 
6.2.1. 
Timing of Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
Vital signs assessments will include blood pressure, pulse and body temperature. Baseline 
standard 12-lead ECG is mandatory to determine the QTc interval; on the other visits they will 
be only performed if clinically indicated. 
The following safety laboratory assessments will be performed by the local laboratories, at the 
times specified in the Study Schedule: 
 Hematology: hemoglobin, WBC, absolute neutrophils, platelet count. 
 Blood Chemistry: 
- 
At baseline visit: fasting glucose, alkaline phosphatase, ALT, AST, total 
bilirubin, serum creatinine, sodium, potassium, magnesium, total calcium.  
- 
At treatment visit: fasting glucose, alkaline phosphatase, ALT, AST, total 
bilirubin, serum creatinine, total calcium 
All AEs (and their relatedness to the study treatment) occurring during the study will be 
documented in the eCRF. AEs will be graded according to NCI-CTCAE version 4.0. 
6.2.2. 
Definitions 
The safety definitions are described in the table 13. 
Table 13: Safety definitions 
Concept 
Definition 
Adverse Event  (AE) 
Any new untoward medical occurrence or worsening of a pre-
existing medical condition in a patient or clinical investigation 
subject administered an investigational (medicinal) product and 
that does not necessarily have a causal relationship with this 


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treatment.  
An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of 
investigational product, whether or not considered related to the 
investigational product.  
Laboratory abnormalities should be reported as AE only in case 
they lead to an action on study treatment or if they are serious.  
Any temporary increase in the severity of a symptom or 
previous sickness that happens after the baseline of the study is 
considered also as an adverse event. 
Adverse Reaction (AR) 
All untoward and unintended responses to a medicinal product 
related to any dose administered.  
All expected ARs are listed in the Investigator's Brochure (IB) 
in case of not authorized investigational product or Summary of 
Product Characteristics [SmPC] in case of an authorized 
investigational product. If the nature or the severity of an 
adverse reaction is not consistent with the applicable product 
information, the AR is defined as unexpected. The basis for the 
decision is the current version of the corresponding reference 
document that has been submitted and approved by the 
competent authority and the ethics committees. 
Accountability criteria 
The sponsor will classify the adverse event, based in their 
causation relation with the investigational product, following 
the Karch y Lasagna (1977) algorithm, as: 
o Final: there is reasonable temporal sequence between 
the drug administration and the existence of the adverse 
event. This event matches with the adverse reaction 
described for the investigational product, improves with 
the omission and reappears after its re-administration 
and can’t be explained by other causes. 
o Probable: there is reasonable temporal sequence 
between the investigational product administration and 
the appearance of the adverse event. This event matches 
with the adverse reaction described for the drug, 
improves with the omission and can’t be explained by 
other causes. 
o Possible: there is reasonable temporal sequence between 
the investigational product administration and the 


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appearance of the adverse event. This event matches 
with the adverse reaction described for the drug but can 
be explained by other causes. 
o Conditional or improbable: there is reasonable temporal 
sequence 
between 
the 
investigational 
product 
administration and the appearance of the adverse event. 
This event does not matches with the adverse reaction 
described for the drug and can be explained by other 
causes. 
o Not related: there is no reasonable temporal sequence 
between the investigational product administration and 
the appearance of the adverse event. This event does not 
matches with the adverse reaction described for the drug 
and can be explained by other causes. 
For expedited reporting purposes it is considered as related the 
categories: final, probable and possible from Karch y Lasagna 
(1977) algorithm and as not related the category conditional or 
improbable of that algorithm.  
The determination of the possible relation with the study 
treatment is responsibility of the principal investigator of the 
site or the person designated by him.  
Serious Adverse Event 
(SAE) and Serious 
Adverse  Reaction (SAR) 
Any  adverse event or adverse reaction that, at any dose: 
o is fatal (results in death), 
o initial or prolonged inpatient hospitalization, 
o a life-threatening experience (that is, immediate risk of 
dying, defined as an event in which the patient was at 
risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death 
if it were more severe), 
o persistent or significant disability/incapacity, 
o congenital anomaly/birth defect or 
o an important medical event, defined as a medical event 
that may not be immediately life-threatening or result in 
death or hospitalization but, based on appropriate 
medical and scientific judgment, may jeopardize the 
patient or may require intervention (eg. medical, 
surgical) to prevent one of the other serious outcomes 
listed above.  


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Do not confuse the concept “serious”, described before, with 
“severe” which refers to the intensity of the AE or AR 
(minor/mild/severe). 
The following events will be considered as AEs of Special 
Interest (AESIs) and they have to be documented as a SAE and 
notified to the Pharmacovigilance Department of GEICAM 
immediately: cancer (except for breast cancer), overdose, 
misuse and abuse.   
 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
Any serious adverse reaction whose nature, intensity or 
consequences do not correspond with the reference information 
for the investigational product (example, Investigator Brochure 
[IB] in case of not authorized investigational product or 
Summary of Product Characteristics [SmPC] in case of an 
authorized investigational product).  
The unexpected nature of an adverse reaction is based in the 
fact of not being observed previously and not in what could be 
advanced based on the pharmacological properties of the drug.  
6.2.3 
Management, Timing and Assessment of Adverse Events 
AE Classification  
 
Adverse events should be classified following version 4.0 of 
the Common Terminology Criteria for Adverse Events 
(CTCAE) of the National Cancer Institute (NCI).  A copy can 
be 
downloaded 
in 
the 
NCI 
web 
site: 
http://evs.nci.nih.gov/ftp1/CTCAE. The investigators team 
must have access to the CTCAE-NCI version 4.0.  
The AE not included in the CTCAE will be classified as 
described on Protocol Attachment 8. 
The causal relation between the investigational product and the 
AE will be assessed by the investigator using the Karch y 
Lasagna (1977) algorithm. 
Procedure to notify an 
AE to GEICAM 
The site must notify to GEICAM, through eCRF, the following 
events: 
o All adverse events that occur after the signature of the 
Informed Consent Form. 
o Preexisting conditions that get worse during the study.  
o The evaluation of the possible relationship of each 


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adverse event to the study treatments or protocol 
procedure.  
o The circumstances and data that causes the suspension 
of the treatment of a patient due to an adverse event. 
o The events related with progression will not be recorded 
as adverse events, unless the investigator believes they 
could have been caused by the study treatments.  
o The events leading to the clinical outcome of death from 
disease progression will be included in the efficacy 
analysis and are not recorded as adverse events, unless 
the investigator believes they could have been caused 
by the study treatments.  
Timing and assessment 
of AE (see Protocol 
Attachment 9) 
The site staff will report on the eCRF the information of the AE 
in the following  periods: 
 Baseline (after ICD and before study treatments): 
study site personnel will note the occurrence and nature 
of each patient´s medical condition(s) and preexisting 
conditions in the appropriate section of the eCRF. If a 
patient never receives study treatments but experiences 
an adverse event after the ICD is signed, ONLY events 
the investigator believes may have been caused by a 
protocol procedure will be reported to GEICAM via 
eCRF. 
 During treatment with the study treatments: during 
the study, site personnel will record any change in the 
condition(s) and the occurrence and nature of any 
adverse events. A CTCAE grade rating will be assigned 
before each cycle for any adverse event experienced 
during the previous cycle.  
 30-day (±5 days) post-treatment follow-up period: 
each patient will have a 30-day post-treatment follow-
up evaluation approximately 30 days following the 
discontinuation of study treatment and before initiation 
of new anticancer therapy. Patients should be closely 
followed for study treatment adverse events in order to 
detect delayed toxicity. If study treatment-related 
toxicity is present beyond 30 days post-discontinuation, 
patients must be followed until the toxicity resolves or 
improved to baseline, the relationship is reassessed as 
unrelated, the investigator confirms that no further 


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improvement can be expected, another therapy is 
initiated, or death.  
 Long-Term Follow-up Period (after the 30-day (±5 
days) 
post-discontinuation/post-treatment): 
only 
new and ongoing SAEs thought to be related to study 
treatments 
or 
protocol 
procedures 
should 
be 
documented on the eCRF and immediately reported to 
GEICAM via the designated transmission method, even 
if the study has been closed.  
 SAES related with study treatment should be 
collected and analyzed until they are solved or until the 
toxicity is considered irreversible. 
Reporting of Study 
Specific AE 
In case serum creatinine increase fulfills criteria to be reported 
as AE, the cause of the renal function impairment should be 
reported and the renal function impairment should be 
considered in the grade of the reported AE according to NCI-
CTCAE version 4.0. If no cause can be identified and 
creatinine increase is considered serious or has an action taken 
on study treatment (dose reduction, dose delay, dose 
interruption or permanent discontinuation), the “creatinine 
increase” term should be preferred rather than the “renal 
failure” term.  
Any case of renal function impairment should be documented 
at least by a creatinine value and creatinine clearance. Tests 
will be repeated until recovery or stabilization and all results 
will be recorded in the eCRF. Any complementary exams made 
to explore renal function or the cause of renal failure should be 
reported in the eCRF and product contrast administration for 
CT scan should be recorded in concomitant medication. 
6.2.4. Management, Timing and Assessment of SAEs 
Timing of  SAEs (see 
Protocol Attachment 9) 
All the SAEs (either spontaneously or during the trial visits) 
will be collected since the patient signs the Informed Consent 
Document (ICD). 
All the SAEs must be documented in the medical record of the 
patient and in the eCRF. A follow up of all the SAEs should be 
done until they are solved or until the toxicity is considered 
irreversible.  


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SAEs which do not need 
to be notified to the 
Pharmacovigilance 
Department of GEICAM 
The following events are not considered SAEs: 
o A visit to the emergency room or other hospital 
department lasting less than 24 hours that does not 
result in admission (unless considered an “important 
medical event” or a life-threatening event). 
o Elective surgery planned before signing consent. 
o Hospitalization which is due solely to a planned study 
visit and without prolongation. 
o Routine health assessment requiring admission for 
baseline/trending 
of 
health 
status 
(eg. 
routine 
colonoscopy). 
o Medical/surgical admission for purpose other than 
remedying ill health state that was planned before study 
entry. Appropriate documentation is required in these 
cases. 
o Admission encountered for another life circumstance 
that carries no bearing on health status and requires no 
medical/surgical intervention (eg. lack of housing, 
economic 
inadequacy, 
caregiver 
respite, 
family 
circumstances, administrative). 
o Progression of the malignancy during study (including 
signs and symptoms of progression), unless the outcome 
is fatal and death occurred before end of treatment. 
Thereafter death due to disease progression has not to 
be reported as SAE.  
o Hospitalization due to signs and symptoms of disease 
progression. 
o An overnight stay in the hospital that is only due to 
transportation, 
organization 
or 
accommodation 
problems and without medical background.  
They will be reported in the eCRF and in the patient record. 
The rest of SAEs must be notified as described as follows. 
Procedure to notify a  
SAE to the  
Pharmacovigilance 
Department of GEICAM 
The SAEs must be notified to the Pharmacovigilance 
Department of GEICAM. A member of the investigator team 
must complete and sign the GEICAM SAE notification form 
which will be sent by fax/mail, immediately and always during 
the 24 hours following knowledge of the SAE: 


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Pharmacovigilance Department of GEICAM  
Fax: +34 917 374 199 
farmacovigilancia@geicam.org  
GEICAM will review the received form and, if necessary, will 
ask more information to the investigator. 
When additional information is obtained about the SAEs, or 
this is solved or is improbable it will change, a follow-up report 
must be also completed and sent by fax/mail, immediately and 
always 
during 
the 
following 
the 
24 
hours 
to 
the 
Pharmacovigilance Department of GEICAM. 
If GEICAM suspects that the SAE could be a SUSAR, the 
investigator should give the follow up information requested. 
All SAEs/AESIs from the time the patient have the first dose of 
the study treatments through 30 days following the last 
administration of study treatments must be reported according 
to the procedure described below. All SAE regardless of timing 
must be reported, if considered related to study treatment. 
Likewise, progression of a patient's underlying condition 
leading to one of the above should also not be reported as a 
SAE, but documented as primary study endpoint. 
GEICAM will report all SAEs and AESIs immediately to the 
Coordinating Investigator.  
All SAEs and AESIs will be followed-up by the investigator 
until satisfactory resolution. Annually all SARs will be reported 
as the DSUR to the competent authorities and the leading ethics 
committee, including all SUSARs.  
Withdrawal from further treatment shall be at the discretion of 
the investigator. 
Adverse Events of 
Special Interest (AESIs) 
For AESIs with immediate notification, GEICAM will be 
informed immediately (within 24 hours following knowledge 
of the event), as per the SAE notification instructions, even if 
not fulfilling a seriousness criterion. 
An overdose (accidental or intentional) with the study 
treatments is an event suspected by the investigator or 
spontaneously notified by the patient and defined as: 
 The intake of more than 23 capsules of palbociclib 
during a cycle (e.g. more than two capsules on more 
than two days of a cycle, more than two capsules during 


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the week of break) or more than 2 capsules on the same 
day.  
 The intake of more than two tablets of exemestane in 
the same day on more than three days of a cycle.  
 The intake of an amount of capecitabine that is 10% 
higher than is normally used for a given cycle.   
It has to be reported within one working day as an SAE on an 
SAE form.  
Reporting of AESIs 
without immediate 
notification 
A non-relevant overdose (accidental or intentional) with the 
study treatments is an event suspected by the investigator or 
spontaneously notified by the patient and defined as: 
 The intake of 22 or 23 capsules of palbociclib in the 
same cycle.  
 The intake of 29 or 30 capsules of exemestane in the 
same cycle when the next cycle has not been delayed.  
 The intake of an amount of capecitabine that is less than 
10% higher than is normally used for a given cycle.   
It is to be reported to the sponsor in the eCRF. 
Reporting of Potential 
Cases of Drug-Induced 
Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or 
alanine transaminase (ALT) concurrent with abnormal 
elevations in total bilirubin that meet the criteria outlined below 
in the absence of other causes of liver injury are considered 
potential cases of drug-induced liver injury (potential Hy’s Law 
cases) and should always be considered important medical 
events.  
The threshold of laboratory abnormalities for a potential case of 
drug-induced liver injury depends on the patient’s individual 
baseline values and underlying conditions. Patients who present 
with the following laboratory abnormalities should be 
evaluated further to definitively determine the etiology of the 
abnormal laboratory values:  
 Patients with AST or ALT and total bilirubin baseline 
values within the normal range who subsequently 
present with AST or ALT ≥ 3 X ULN concurrent with a 
total bilirubin ≥ 2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase ≤ 2 X ULN or 
not available.  
 For patients with preexisting ALT OR AST OR total 


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bilirubin values above the upper limit of normal, the 
following threshold values should be used in the 
definition mentioned above:  
 For patients with pre-existing AST or ALT 
baseline values above the normal range: AST or 
ALT ≥ 2 times the baseline values and ≥ 3 X 
ULN, or ≥ 8 X ULN (whichever is smaller).  
Concurrent with  
 For patients with pre-existing values of total 
bilirubin above the normal range: Total bilirubin 
increased by one time above the baseline value.  
The patient should return to the investigational site and be 
evaluated as soon as possible, preferably within 48 hours from 
awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical 
assessment. In addition to repeating AST and ALT, laboratory 
tests should include albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/INR, and alkaline phosphatase. A 
detailed history, including relevant information, such as review 
of ethanol, acetaminophen, recreational drug and supplement 
consumption, family history, occupational exposure, sexual 
history, travel history, history of contact with a jaundiced 
subject, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected. Further testing 
for acute hepatitis A, B, or C infection and liver imaging (eg, 
biliary tract) may be warranted. All cases confirmed on repeat 
testing as meeting the laboratory criteria defined above, with no 
other cause for LFT abnormalities identified at the time should 
be considered potential Hy’s Law cases irrespective of 
availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs. Such potential Hy’s 
Law cases should be reported as SAEs. 
Death on Study 
Any death occurring during the active treatment part of the 
study and within 30 days following the last treatment must be 
reported to GEICAM as the sponsor within 24 hours, regardless 
of the relation to study treatment(s), and has to be reported on 
the death report form section of the eCRF.  
The cause of death should be documented (cancer-related, 
treatment-related, cancer- and treatment-unrelated). Autopsy 


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reports should be collected whenever possible and sent to 
GEICAM.  
Deaths that occur due to tumor progression do not have to be 
reported as a SAE unless they occurred before end of treatment. 
Deaths after the end of study which are considered to be related 
to study treatment have to be reported as SAEs.  
To the extent feasible sufficient information including relevant 
laboratory values, ECG, scan, biopsy or autopsy results must be 
provided by the investigator in the SAE narrative (even if 
investigator determines the SAE is not related) so as to permit 
an independent causality assessment by a Competent Authority. 
6.2.5. 
Management, Timing and Assessment of SUSARs 
Expedited Notification of  
SUSAR to the Competent 
Authorities/IRB 
The Pharmacovigilance Department of GEICAM or its designee 
is responsible to notify to each of the competent authorities and 
IRBs of the participating countries, all the SUSARs collected in 
the study, following the procedures shown in the current 
legislation.   
Timing of notification  
The deadline for reporting a SUSAR shall be 15 calendar days 
from when GEICAM becomes aware of it. When suspected 
SUSAR caused the death of the patient or endangered her life, 
GEICAM will send the information within 7 calendar days from 
the date on which it becomes aware.  
Expedited reporting of 
other relevant safety 
information 
GEICAM will also notify, expeditiously, all the information 
that could modify the balance benefit/risk of the investigational 
product, or determine changes in its administration pattern or in 
the study performance, such as: 
o A qualitative change or an increase in the percentage of 
occurrence of the SAR expected, which are considered 
clinically significant. 
o The SUSAR occurring after completion of the study and 
are reported by the investigator to the sponsor.  
o New events related to the conduct of a trial or the 
development of an IMP likely to affect the safety of 
patients, such as: 
 SAE that could be related with the study 
procedure and could modify the conduct of the 


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trial. 
 A significant risk to patients such as lack of 
efficacy in a drug used to treat a life-threatening 
illness. 
 A major safety finding from a newly completed 
animal study (such as carcinogenicity). 
 A temporary halt of a trial for safety reasons if 
the 
trial 
is 
conducted 
with 
the 
same 
investigational medicinal products in another 
country and if this information is known by 
GEICAM. 
 Any recommendation of the IDMC that is 
relevant to the safety of patients (if applicable). 
This relevant information shall be notified as soon as possible 
and no later than 15 days after GEICAM becomes aware of it. 
Additional information will also be notified as quickly as 
possible.  
Development Safety 
Update Report (DSUR) 
The DSUR that includes the SAEs and SUSARs collected 
during the study will be sent by GEICAM or its designee to the 
Competent Authorities and EC/IRB at the time established by 
the current legislation. 
Notification to  
investigators 
GEICAM will communicate to the investigators any safety 
information that may affect the safety of trial patients, as soon 
as possible.  
Information on SUSAR occurred during the study will be sent 
quarterly, in aggregate, in a list along with a brief analysis of 
the data provided.  
They will be informed also, throughout the entire study, of any 
safety aspect that impacts the performance on the clinical trial 
or in the product development, including the interruption or 
modification in the development program of the protocol 
safety-related.  
6.3. 
Other Assessments  
6.3.1.   Pharmacokinetic Assessments 
These studies will be performed in patients randomized in the experimental arm (palbociclib 
plus exemestane) of Cohort 1 in selected sites and only in patients accepting to participate.  


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Enrollment of these patients were to be finalised at the completion of cohort 1 recruitment, 
samples from approximately 20 evaluable patients were to be collected.  
The potential for a clinically significant drug-drug interaction (DDI) between palbociclib and 
exemestane is considered to be very low. Exemestane is metabolized by cytochrome P 450 3A4 
(CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, 
including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. Therefore, exemestane is unlikely to affect 
palbociclib PK. Rifampin reduced exemestane exposure by ~50%. However, in a clinical 
pharmacokinetic study, coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has 
no significant effect on exemestane pharmacokinetics. Therefore, it is unlikely that palbociclib, 
which has been shown to be a weak time-dependent inhibitor of CYP3A, will have an effect on 
exemestane PK.   
All efforts are made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing. However, samples obtained within 10% of the nominal time AND collected 
prior to administration of the investigational product on that day will be considered protocol 
compliant (ie, a 24 hour post-dose trough sample taken within ± 2 hours 24 minutes of the 24 
hour nominal time will not represent a protocol deviation unless the sample was taken after that 
days dose of investigational product). Patients are instructed to withhold their daily dose of 
study treatments on PK sampling days until the pre-dose PK sample and safety assessments 
(ie hematology, blood chemistry) have been completed. The exact time of the sample collection 
and the most recent dosing time (the previous and the immediately following doses) will be 
recorded on the eCRF. The date of any missing doses should also be recorded in the eCRF.  
In patients within the PK sub-study, exemestane is dosed daily during a 7-day lead-in period 
(day minus-7 through day minus-1) immediately preceding cycle 1.  
Exemestane 24-hour PK trough samples are drawn pre-dose on day minus-1, cycle 1 day 1 
(back-to-back days), and on day 14 in cycles 1 and 2. Palbociclib 24-hour PK trough samples 
should be drawn pre-dose on day 14 in cycles 1 and 2. Trough samples should be taken 
approximately 24 hours after the last dose of study treatment. If any of the Day 14 Cycle 1 and 
2 pre-dose PK samples is not collected at the protocol-specified visit, then the collection of 
these samples is allowed to be “made-up” on Days 15 through 21 within the same cycle, or on 
Days 14 through 21 in a later cycle, provided that no doses of palbociclib or exemestane have 
been missed during that cycle and providing that the palbociclib dose has not been reduced in 
that patient. 
Additional blood samples may be requested from patients experiencing unexpected or serious 
adverse events, or adverse events that lead to discontinuation. 
These samples are being analyzed for palbociclib and exemestane. The palbociclib results will 
be compared to historical controls to assess for major differences in PK. Exemestane results 
will be compared within each patient for major differences in PK (due to large variability in 
historical reports). These data will be used to explore the DDI potential between exemestane 
and palbociclib.  


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Refer to the Sample Management Manual for detailed collection, processing and shipping 
procedures. 
6.3.2. 
Biomarker, Pharmacogenomic and Pharmacodynamic Assessments 
Detailed instructions for the collection, handling and shipment of samples are outlined in the 
Sample Management Manual.  
Whole Blood Biospecimens: A whole Blood sample (EDTA tubes for whole blood collection 
optimized for DNA analysis) will be collected whenever feasible (preferable at baseline or 
within 7 days prior to the first dose of treatment) to be retained for potential 
pharmacogenomic/biomarker analyses related to drug response or adverse drug reactions. 
Genomic and metabolomic variation may help to explain some of the variability in response 
seen with some drugs among different individuals. Comparing the DNA, RNA, protein, and 
metabolite patterns of patients who respond well and those who respond poorly to treatment 
may help to better define the most appropriate group of patients in which to target a given 
treatment. Collecting samples for pharmacogenomic analyses and retaining them makes it 
possible to seek explanations for differences in, for example, exposure, efficacy, tolerability, or 
safety not anticipated prior to the beginning of the study. For example, putative safety 
biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or genes thought to 
be related to the mechanism of drug action may be examined. 
Plasma Samples for ESR1 mutational status and exploratory biomarker analyses: Four blood 
samples (tubes optimized for plasma collection) will be collected from all patients at: 1) 
baseline (Cycle 1, Day 1 pre-dose or within the 7 days prior to the first dose of study 
treatment), 2) Cycle 1 Day 15 (± 3 days), 3) Cycle 2 Day 15 (± 3 days), and 4) at the end of 
treatment (approximate 30 days after last study dose but always before the initiation of any new 
anticancer therapy), unless prohibited by local regulations. The baseline sample must be drawn 
prior to the first dose of study treatment and the samples of Cycle 1 Day 15 (± 3 days) and 
Cycle 2 Day 15 (± 3 days) prior to the fulvestrant dose in patients included in arm A of Cohort 
2. For patients included in the PK sub-study, the baseline plasma sample is collected in cycle 1 
on day -7 predose or within 7 days prior to the first exemestane dose, because in these patients 
exemestane will be administered daily during a 7 day lead-in period (day minus 7 through day 
minus 1) immediately pre-ceding cycle 1. If a patient ends the study treatment due to a reason 
different than disease progression, every effort should be made to collect an additional sample 
upon progression (regardless of the administration of other treatment). 
In case that a blood/plasma sample is not drawn by mistake at the protocol scheduled timepoint, 
it should be asked the sponsor for the convenience of collecting the sample at a later timepoint.  
ESR1 mutational status will be determined in circulating free DNA (cDNA) obtained from 
baseline plasma samples and will be prospectively determined before the interims or final 
analyses. ESR1 mutational status will be blinded to the patients, investigators and study team. 
Most common ER-Ligand Binding Domain (ER-LBD) activating mutations (e.g. c.1138 G>C 


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(E380Q), c. 1607 T>G (L536R), c. 1610 A>G (Y537C), c. 1613 A>G (D538G), c. 1387 T>C 
(S463P), c. 1609 T>A (Y537N) and c. 1610 A>C (Y537S) (97) will be analyzed to determine 
ESR1 mutational status as positive or wild type.  
Correlative plasma samples will be collected for exploratory analyses of circulating free DNA 
or RNA and their relationship to resistance or sensitivity to treatment with palbociclib 
(mononuclear cell DNA obtained from whole blood samples will be used as a control). Plasma 
samples will also be analyzed to explore treatment effects on the expression of specific 
biomarkers.  
Tumor Tissue for Biomarker Assessments: For the purpose of eligibility, documentation of 
HR-positive and HER2-negative tumor will be performed based on local results utilizing an 
assay consistent with local standards. Most recent formalin fixed paraffin embedded (FFPE) 
tumor tissue will be collected for biomarker assessments. Samples will be sent to the sponsor 
designated central laboratories.  
Retrospectively, exploratory tumor tissue biomarkers, including DNA, RNA and protein 
analytes, will be analyzed to investigate possible associations with resistance/sensitivity to 
treatment with palbociclib. Biomarkers that will be analyzed will be selected based on their 
known relevance to mechanisms involved in cell cycle regulation or breast cancer 
development.  Examples of such biomarkers include CCND1 and CDKN2A gene copy number, 
CDK4 and CDK6 RNA expression, and Ki67, pRb, cyclin E and p16 protein expression. The 
relationship between centrally assessed biomarkers and resistance/sensitivity to treatment with 
palbociclib will be reported in an exploratory fashion.  
A single biomarker will be nominated as the primary biomarker for analysis using data 
external to the current study. The interaction between the primary biomarker and benefit from 
palbociclib in terms of prolongation of PFS will be examined in a prospective fashion. All other 
biomarkers will be examined in an exploratory fashion. 
6.3.3 
Patient Reported Outcomes 
Patient reported outcomes of health-related quality of life will be assessed using the EORTC 
QLQ-C30 and breast modules (QLQ-BR23) instruments and the EuroQol Health Utilities Index 
EQ-5D-3L instrument (see attachment 10). 
The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional 
subscales (physical, role, cognitive emotional, and social functioning), three multi-item 
symptom scales (fatigue, nausea/vomiting, and pain), a global health/quality of life (QOL) 
subscale, and six single items assessing other cancer-related symptoms (dyspnea, sleep 
disturbance, appetite, diarrhea, constipation, and the financial impact of cancer). The 
questionnaire employs 28 4-point Likert scales with responses from “not at all” to “very much” 
and two 7-point Likert scales for global health and overall QOL. For functional and global 
QOL scales, higher scores represent a better level of functioning and are converted to a 0 to 100 
scale. For symptom-oriented scales, a higher score represents more severe symptoms. 


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The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the 
EORTC-QLQ-C30 and consists of two functional scales (body image and sexuality); three 
symptom subscales (arm/hand, breast, and systemic side effects) and single items covering 
sexual enjoyment, distress at hair loss, and future perspective. 
The EuroQol-5D (EQ-5D) (version 3L) is a 6 item instrument designed to assess health status 
in terms of a single index value or utility score. It consists of 5 descriptors of current health 
state (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression); a patient is 
asked to rate each state on a three level scale (1=no problem, 2=some problem, and 3=extreme 
problem) with higher levels indicating greater severity/impairment. It also includes a visual 
analogue scale: the EQ VAS. The EQ VAS records the patient’s self-rated health on a scale 
from 0 (worst imaginable health state) to 100 (best imaginable health state). Published weights 
are available that allow for the creation of a single summary score. Overall scores range from 0 
to 1, with low scores representing a higher level of dysfunction and 1 as perfect health.  
Patients will complete each instrument within 28 days (±7 days) prior to the first treatment 
administration, pre-dose on Day 1 (-3 days) of every two cycles starting with Cycle 3 until Day 
1 (-3 days) of Cycle 7 (at cycles 3, 5 and 7), thereafter on Day 1 (-3 days) of every three cycles 
till the end of treatment (at cycles 10, 13, etc) and at the post-treatment visit (30 days ± 5days 
from the last study treatment dose and/or before the initiation of any new anticancer therapy). 
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically documented PD or initiate a new anticancer therapy will additionally complete these 
instruments after RECIST-defined disease progression. Completed questionnaires are always 
considered source document and must be filed accordingly. 
Patients must complete these instruments in clinic (cannot be taken home) and prior to having 
any tests and to any discussion of their progress with healthcare personnel at the site.  
Interviewer administration in clinic may be used under special circumstances (eg, patient forgot 
their glasses or feels too ill). The instruments will be given to the patient in the appropriate 
language for the site.  


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7. 
Data Quality Assurance 
To ensure accurate, complete and reliable data, GEICAM will do the following: 
 provide instructional material to the study sites, as appropriate 
 sponsor a start-up training session to instruct the investigators and study 
coordinators. This session will give instructions on the protocol, the completion 
of the eCRFs, and study procedures 
 make periodic visits to the study site to review study progress, investigator and 
patient compliance with the clinical trial protocol requirements and any 
emergent problems 
 be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
 review and evaluate eCRF data and use standard computer edits to detect errors 
in data collection 
 conduct a quality review of the database  
   verify the quality of the data 
To ensure the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide GEICAM, applicable regulatory agencies, and applicable ethical 
review boards with direct access to original source documents. 
7.1. 
Data Management and Registries file 
Data for this study will be recorded via an electronic data capture system using eCRFs. Data will 
be transcribed by the site from the paper source documents onto the eCRF. In no case the eCRF 
is to be considered as source data for this trial. The eCRFs must be completed in an electronic 
Data Base called ORACLE. That electronic Data Base carries out with the regulatory authorities 
requirements. It is the responsibility of the Investigator to maintain adequate and accurate 
eCRFs (according to the technology used) designed by GEICAM to record (according to 
GEICAM instructions) all observations and other data pertinent to the clinical investigation. All 
eCRFs should be completed in their entirety in a neat, to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to GEICAM as soon as they are entered in the eCRF. 
The computerized handling of the data by GEICAM when available in the eCRF may generate 
additional requests to which the Investigator is obliged to respond by confirming or modifying 
the data questioned. The requests with their responses will be managed through the eCRF. 
 


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8. 
Sample Size and Statistical Methods 
8.1. 
Determination of Sample Size 
8.1.1. 
Sample Size determination  
The primary objectives of this study are to demonstrate that the combination of palbociclib and 
fulvestrant is superior to capecitabine in prolonging PFS in postmenopausal women with 
HR+/HER2- metastatic breast cancer, whose tumors are resistant to prior aromatase inhibitors 
(Cohort 2) and to demonstrate that palbociclib in combination with endocrine therapy 
(exemestane or fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal 
women with HR positive/HER2 negative MBC whose disease was resistant to aromatase 
inhibitors and whose tumor had estrogen receptor (ESR1) mutational status as wild type at 
study entry (Cohort 1 + Cohort 2). All patients from Cohort 2 and patients with ESR1 
mutational status as wild type from Cohort 1 + Cohort 2 are eligible for the two primary 
inferential assessments of efficacy. 
Cohort 2 will have an 80% power to detect a difference between the control arm with a median 
PFS of 6 months and the experimental arm (palbociclib plus fulvestrant) with a median PFS of 
9 months, for a hazard ratio of 0.667, with a 5% significance level. Assuming a non-uniform 
accrual accomplished over a period of about 26 months, and a follow-up period for the final 
PFS analysis of about 28 months from the start of study randomization of Cohort 2, a total 
sample size of approximately 300 patients (150 in each treatment arm) will be required and the 
necessary number of events for the final PFS analysis is determined to be 193. 
Cohort 1 + Cohort 2 (ESR1 wild type) should have an approximately 80% power to detect a 
difference between the control arm with a median PFS of 6 months and the experimental arm 
(palbociclib plus fulvestrant or exemestane) with a median PFS of 9 months, for a hazard ratio 
of 0.667, with a 5% significance level in ESR1 mutation status as wild type patients. The 
sample size will be similar to Cohort 2. Approximately 308 patients and 193 PFS events will be 
accumulated if we assume 80% cDNA collection/detect rate and 70% of patients will have 
tumors with ESR1 mutational status as wild type at study entry (approximately 140 mutational 
status as wild type from 250 patients from Cohort 1 and 168 mutational status as wild type 
from 300 patients from Cohort 2). 
The sample size described above will also allow the assessment of differences in the secondary 
endpoint of overall survival (OS). The median OS for women with advanced or metastatic 
breast cancer treated with capecitabine is assumed to be 22 months. With an overall 
significance level of 10% and one interim analysis of OS (at the time of PFS final analysis), 
Cohort 2 will have approximately 80% power to detect a hazard ratio of 0.667 (representing a 
50% increase in median OS from 22 months to 33 months) when approximately 152 deaths 
have occurred after an approximate follow-up of 50 months from the start of study 
randomization.  Similar sample size determination also applies to Cohort 1 + Cohort 2 (ESR1 
wild type). 


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8.2. 
Statistical and Analytical Plans 
8.2.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of GEICAM. The interpretation of 
study results will be the responsibility of the principal investigator of the study.   
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained by 
GEICAM.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
8.2.1.1. 
Patient Populations 
Intent to treat population (ITT): The ITT population will include all patients who are 
randomized, with study treatment assignment designated according to initial randomization.   
ESR1 wild type population: The ESR1 wild type population will include all patients who are 
randomized, with study treatment assignment designated according to initial randomization and 
whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry.  
The ITT and ESR1 wild type populations will be the primary populations for evaluating patient 
characteristics and efficacy. 
Per-protocol population: a subset of the ITT population that received at least one dose of 
study treatment and completed the study without certain major protocol deviations according to 
the Appendix I of the Protocol Deviation Manual.  
Safety population: will include all patients randomized in the study who received at least one 
dose of treatment. This population is for the safety analysis.  
PK population: a subset of included patients with evaluable PK samples. 
Biomarker population: a subset of included patients with available biological samples and 
clinical data for Biomarker, Pharmacogenomic and/or Pharmacodynamic analysis. 
QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline 
and at least one more). 
8.2.2. 
Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
 summary of patients entered and  by site 
 total number of patients entered 
 total number of patients enrolled 
 summary of reasons for patients entered, but not enrolled 
 total number of patients treated 


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 summary of reasons for patients enrolled, but not treated. 
A detailed summary of reasons for patient discontinuation from study treatment will be 
provided. 
A summary of all identified important protocol deviations will be provided. 
8.2.3. 
Patient Characteristics 
Patient characteristics will include a summary of the following: 
 patient demographics 
 baseline disease characteristics 
 preexisting conditions/secondary conditions 
 prior therapy 
Other patient characteristics will be summarized as deemed appropriate. 
Standard descriptive statistics, such as the mean, median, range and proportion, will be used to 
summarize the patient sample and to estimate parameters of interest. Ninety-five percent 
confidence intervals will be provided for estimates of interest where possible.  
8.2.4. 
Concomitant Therapy  
A summary of concomitant therapies will be generated in the safety population.  
8.2.5. 
Treatment Compliance  
Treatment information will be collected at each dose administration. The estimate of percent 
compliance will be given by: 
    Percent Compliance =          Actual dose administered per week               x   100 
 
 
 
      Dose expected to be administered per week 
 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses. To 
be considered compliant patients should have received at least 80% of the planned number of 
doses.  Exploratory analysis of the impact of compliance on selected efficacy endpoints may be 
performed if deemed necessary. 
8.2.6. 
Efficacy Analyses 
All efficacy analysis will be based on the ITT and ESR1 wild type populations. Additional PFS 
and OS analyses will be performed on the per-protocol population. All analysis will be 
performed using the SAS Enterprise Guide 5.1 version. 
All primary and secondary endpoints based on radiological (and photographical where 
applicable) assessments of tumor burden (PFS, ORR, CBR and RD) will be derived using the 
local radiologist’s/investigator’s assessment.   


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8.2.6.1. 
Analyses of Primary Endpoint 
The primary endpoint is PFS which is defined as the time from the date of randomization to the 
date of the first documentation of objective progression of disease (PD) or death due to any 
cause in the absence of documented PD, whichever occurs first. PFS data will be censored on 
the date of the last tumor assessment on study for patients who do not have objective tumor 
progression and who do not die while on study. Patients lacking an evaluation of tumor 
response after randomization will have their PFS time censored on the date of randomization 
with 1 day duration. Additionally, patients who start a new anti-cancer therapy prior to 
documented PD will be censored at the date of the last tumor assessment prior to the start of the 
new therapy. 
A modification of Hochberg’s method (98) will be used for two primary treatment comparisons 
to provide control of experiment-wise Type 1 error at a 5% significance level. With this closed 
testing method, statistical significance applies to both p1 for Cohort 2 and p2 for Cohort 1+ 
Cohort 2 (ESR1 wild type) if p1<0.05 and p2<0.05; or it applies only to Cohort 2 if p1≤0.025 
when Cohort 1+ Cohort 2 (ESR1 wild type) has p2>0.05; or it applies to only Cohort 1+ Cohort 
2 (ESR1 wild type) if p2≤0.025 when Cohort 2 has p1>0.05 (assuming the analyses results 
represented by both p1 for Cohort 2 and p2 for Cohort 1+ Cohort 2 (ESR1 wild type) 
demonstrate that the combination of palbociclib and fulvestrant and palbociclib and endocrine 
therapy respectively are superior to capecitabine in prolonging PFS). 
The primary analyses of PFS will be performed in the ITT population for Cohort 2 and ESR1 
wild type population for Cohort 1 + Cohort 2. A stratified log-rank test will be used to compare 
PFS time between the 2 treatment arms at the interim and/or final analyses with the overall 
significance level preserved at 5%. The stratification factor(s) will be specified in the SAP. PFS 
time associated with each treatment arm will be summarized for the ITT/ESR1 wild type 
populations using the Kaplan-Meier method and displayed graphically where appropriate. 
Confidence intervals (CIs) for the 25th, 50th and 75th percentiles of the event-free time will be 
reported. The Cox Proportional hazards model will be fitted to compute the treatment hazard 
ratio and the corresponding 95% CI. Additionally a similar analysis will be also performed in 
the per-protocol population. 
The secondary analysis of PFS will be performed in the ITT population for Cohort 1 + Cohort 
2. Statistical methods for this analysis will be the same that outlined above. 
8.2.6.2. 
Analysis of Secondary Endpoints 
The secondary efficacy endpoints are: 
Overall Survival (OS): is defined as the time from date of randomization to date of death due 
to any cause. In the absence of confirmation of death, survival time will be censored to last date 
the patient is known to be alive.  
OS will be analyzed in the ITT population for Cohort 2, ESR1 wild type population for Cohort 
1 + Cohort 2 and ITT population for Cohort 1 + Cohort 2. A stratified log-rank test will be used 
to compare OS time between the 2 treatment arms at the interim and/or final analyses with the 
overall significance level preserved at 0.10. The stratification factor(s) will be the same as for 


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the PFS analysis. OS for the two arms will be assessed using Kaplan-Meier methods and 
displayed graphically where appropriate. The median event times and 95% CIs will be 
estimated. Cox regression models will be used to estimate the treatment hazard ratio and its 
95% confidence interval. Additionally a similar analysis will be also performed in the per-
protocol population. 
Objective Response (OR): objective response is defined as a complete response (CR) or 
partial response (PR) according to the Response Evaluation Criteria in Solid Tumors recorded 
from randomization until disease progression or death due to any cause.  
A patient will be considered to have achieved an OR if the patient has a sustained complete 
response (CR) or partial response (PR) according to RECIST v.1.1 definitions.  Otherwise, the 
patient will be considered as non-responders in the OR rate analysis. Additionally, patients with 
inadequate data for tumor assessment (eg, no baseline assessment or no follow-up assessments) 
will be considered as non-responders in the OR rate analysis.  
The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the 
number of patients with objective response (CR or PR) by the ITT/ESR1 wild type patients 
with measurable disease by treatment arm (“response rate”).  
 
Objective Response Rate =       _________Number of CRs + PRs________                       
     ITT or ESR1 wild type population with measurable disease 
 
The ORR will be reported, including a 95% confidence interval. ORR comparison between the 
two treatment arms will be assessed using Cochran-Mantel-Haenszel (CMH) test with the same 
stratification factors as for the PFS analysis. 
In addition, the best objective response for each patient will be summarized by treatment arm.   
Response Duration (RD): is defined as the time from the first documentation of objective 
tumor response (CR or PR) to the first documentation of objective tumor progression or death 
due to any cause, whichever occurs first.  RD data will be censored on the date of the last tumor 
assessment on study for patients who do not have objective tumor progression and who do not 
die due to any cause while on study. Additionally, patients who start a new anti-cancer therapy 
prior to documented PD will be censored at the date of the last tumor assessment prior to the 
start of the new therapy.  
RD will only be calculated for the subgroup of patients with an objective response. RD for the 
two treatment arms will be summarized using Kaplan-Meier methods and displayed 
graphically, where appropriate. The median event time and 95% CI for the median will be 
provided for each endpoint.  
Clinical Benefit (CB): clinical benefit is defined as complete response (CR), partial response 
(PR), or stable disease (SD) ≥24 weeks according to the RECIST version 1.1, recorded in the 
time period between randomization and disease progression or death of any cause.  


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Clinical benefit (CB) rate (CBR) on each randomized treatment arm will be estimated by 
dividing the number of patients with CR, PR, or SD ≥24 weeks by the ITT/ESR1 wild type 
populations by treatment arm. A 95% CI for the CBR will be provided. CBR comparison 
between the two treatment arms will be assessed using CMH test with the same stratification 
factors as for the PFS analysis.   
All of the above secondary analyses will be conducted at a two-sided 0.05 level of significance.  
Additional sensitivity analyses will be outlined in the SAP.  
8.2.7. 
Safety Analyses 
The toxicity and tolerability of study treatment will be evaluated in the safety population. 
Safety analyses will include summaries of the incidence of adverse events by maximum 
CTCAE grade (v4.0; NCI 2010) that occur during the study treatment period or within 30 days 
of the last dose of study treatment, regardless of causality and according to the relationship to 
study treatment as assessed by the investigator. Additionally, the following safety-related 
outcomes will be summarized: 
 study treatment discontinuations due to adverse events. 
 deaths 
 SAEs 
 hospitalizations and transfusions  
 use of key concomitant medications or growth factors. 
Analyses for data with discrete dates, for example, deaths, transfusions, and concomitant 
medications, will be done through 30 days after each patient’s last dose of study treatment.  
Adverse events will also be analyzed in this timeframe; that is, if an event starts within 30 days 
of discontinuation from study treatment, but after 30 days after the last dose of study treatment, 
it will not be included. 
Adverse events data and serious adverse events will be presented in frequency tables by grade. 
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters. The safety analysis will be performed in the safety population.  
An early safety review will be performed by the IDMC. In addition, the interim analyses for 
PFS will provide the potential to identify early any unexpected safety issues associated with the 
palbociclib combinations. 
8.2.8. 
Other Analyses 
8.2.8.1. 
Pharmacokinetic Analysis 
Within-patient average trough concentrations will be listed by patient by analyte. Summary 
statistics will be provided for palbociclib trough concentrations by study cycle and for within-
patient average trough concentrations. Summary statistics will be provided for exemestane 
trough concentrations by nominal collection time, for within-patient average trough 


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concentrations during the exemestane lead-in period, and for the within-patient average trough 
concentrations from Day 14 of Cycles 1 and 2.  
8.2.8.2. 
Biomarker, Pharmacogenomic and Pharmacodynamic Analysis 
For continuous endpoint data, descriptive statistics, including the mean, standard deviation, 
median, minimum, and maximum values, will be provided by treatment arm.  
For baseline categorical data, the number and percentage of patients in each category will be 
provided by treatment arm. In all possible cases, the 95% confidence intervals will be 
calculated. If appropriate, a chi-squared test will be used to test group differences for 
categorical variables. 
Appropriate statistical methods will be used to investigate any possible relationship of 
biomarker levels with palbociclib plus endocrine treatment anti-tumor efficacy.  
If applicable, parametric test (analysis of variance or t test) or non-parametric testing, such as 
Wilcoxon’s rank-sum test or Kruskal–Wallis test for continuous variables, and the Pearson χ2-
test or Fisher exact test for categorical variables will be used to test group differences. All test 
performed will be two-sided and carried out with a 5% α-error rate without correction for 
multiplicity. 
If applicable, the analysis described in this paragraph will be performed.The Kaplan-Meier 
limit-product method will be used to estimate the primary or secondary efficacy endpoints 
(PFS, OS, RD, etc.). The comparison of those endpoints between groups will be performed 
using the Log-Rank test. The Kaplan-Meier survival curves will be presented graphically. 
Median PFS, OS and RD with the 95% confidence interval will be reported. Cox regression 
models will be used to estimate unadjusted and adjusted hazard ratio and its 95% confidence 
interval. The Wald test will be used to establish the prognostic importance of each variable. If 
needed logistic regression models will be used to test the association of biomarkers with OR 
and CB and to estimate odds ratios and their 95% confidence intervals. If applicable, univariate 
and multivariate analyses will be carried out to explore the influence of the selected variables in 
PFS, OS, RD, ORR, CBR, etc. If appropriate, additional statistical analysis will be performed 
to investigate any possible relationship of biomarker levels with outcome and/or study 
treatment efficacy. Any additional sensitivity analyses will be outlined in specific SAPs. 
8.2.8.3.  Patient Reported Outcomes 
Breast cancer-specific quality of life scores and change from baseline scores will be compared 
between the treatment arms using a mixed model repeated measures approach adjusting for 
specified covariates. In addition, analyses will be performed to determine if the change from 
baseline scores achieve the appropriate minimally important difference (MID) cut-off for the 
scale being examined.   
In addition to the above analyses, an examination of the time to deterioration composite 
endpoint will be carried out using survival analysis methods. A composite definition for 


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deterioration based on death, tumor progression, and/or breast cancer-specific quality of life 
subscale MIDs may be used. 
8.2.9. 
Subgroup Analyses 
Exploratory subgroup analysis may be performed if deemed appropriate. 
8.2.10. Interim Analysis 
The study is designed to have two interim analyses and the final analysis based on the primary 
endpoint of PFS. The first interim analysis will be performed after approximately 150 patients 
have documented progressive disease or death in Cohort 1 and only patients randomized to 
Cohort 1 will be included. The enrollment of Cohort 2 will not be affected by the outcome of 
the first interim analysis. The purposes for the first interim analyses are to assess the safety of 
the patients and to potentially re-evaluate the assumption of the proportion of patients with 
ESR1 wild type randomized to the study which may affect the sample size determination for 
Cohort 1 + Cohort 2 (ESR1 wild type) analyses. The second interim analysis will be performed 
on Cohort 2 and Cohort 1 + Cohort 2 (ESR1 wild type) after approximately 116 patients have 
documented progressive disease or death in Cohort 2 (approximately 60% of the total events 
expected for Cohort 2). The purposes for the second interim analyses are to allow for early 
stopping of the study for efficacy, futility, to assess the safety of the combination regimens and 
to potentially re-estimate the sample size of the trial. The significance level will be allocated to 
the second interim and final analyses with a Bonferroni method, such as alpha=0.002 for the 
second interim analysis and alpha=0.048 for the final analysis. The same Hochberg method 
described above will be used for the second interim analysis.The rho spending function family 
(99) will be used for the futility boundary (rho=4, non-binding) for PFS at the second interim 
analysis. Non-binding for futility implies that the futility boundary will be constructed in such a 
way that it can be overruled if desired by the IDMC without inflating the Type I error rate. The 
total Type I error rate will be well preserved. The sample size of the study may be adjusted at 
the second interim analysis using the method outlined by Cui et al. (100) and applied to the 
time-to-event endpoint. Using the Cui method guarantees that the overall type I error will still 
be preserved after a sample size increase. Specific details regarding the efficacy and futility 
boundaries, and sample size re-adjustment will be described in the SAP. If the results of the 
interim analyses indicate serious safety concerns, the IDMC will alert the SC with the 
recommendation to stop the clinical trial for safety reasons. 
8.2.11. Data Monitoring Committees  
The study will use an IDMC. The IDMC membership and governance is outlined in a separate 
charter. 
The IDMC will be responsible for ongoing monitoring of the efficacy and safety data from 
patients in the study according to the Charter. The IDMC will make recommendation as to 
whether or not the trial should continue based on ongoing reviews of safety data. In addition, 


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the IDMC will also evaluate the interim efficacy data and make a recommendation regarding 
study continuation based on observed results of the study.  
In addition to the use of the IDMC, the safety of the trial will also be monitored by the SC. The 
recommendations made by the IDMC to alter the conduct of the study will be forwarded to the 
SC for final decision. GEICAM will designate a biostatistician not affiliated with the project to 
prepare data for IDMC review. Clinical sites will be restricted from access to study results until 
the conclusion of the study.  
8.2.12. Criteria for End of Study 
This study will be considered complete following the data cut-off date and datalock for the 
final analysis of OS. The data cut-off date for the final analysis will occur when approximately 
50% of enrolled patients in Cohort 2 (approximately 152 patients) have died.   
If further data are collected that are not included as part of the final locked database, the 
postlock data will eventually be combined with the locked database and stored in a data library 
separate from the locked database.   
Performing exploratory objectives will be independent of the date of the end of the study. 
 


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9. 
Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations 
9.1. 
Informed Consent 
The investigator is responsible for ensuring that the patient understands the risks and benefits of 
participating in the study, including answering any questions the patient may have throughout 
the study and sharing any new information that may be relevant to the patient's willingness to 
continue his or her participation in the trial in a timely manner. 
The informed consent document will be used to explain the risks and benefits of study 
participation to the patient in simple terms before the patient is entered into the study, and to 
document that the patient is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative. This includes obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study treatment.   
As used in this protocol, the term "informed consent" includes all consent and assent given by 
patients or their legal representatives. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. The Coordinating Investigator will 
assess if all patients (including those already being treated) should be informed of the new 
information, given a copy of the revised form and give their consent to continue in the study.  
9.2. 
Respect of Confidentiality 
The investigator will be responsible for preserving the suitable information about each patient 
(for example, name, address, telephone number, social security number and study identification) 
so that the competent authorities can have access to said information if necessary. These records 
must be confidentially preserved for the time indicated by the legislation. 
The investigators and GEICAM will maintain the confidentiality of all patients participating in 
the study, according to Good Clinical Practice, GCP and local legislation. 
This clinical trial will be held in accordance and in compliance with local current legislation.  
 
9.3. 
Responsibility Insurance 
GEICAM has signed an insurance policy to cover the responsibilities of the investigator and 
those of other parties participating in the study. 


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9.4. 
Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with good clinical practices and the 
applicable laws and regulations.  The investigator, head of the medical institution, or designee 
will promptly submit the protocol to applicable ethical review board(s). 
9.4.1. 
Investigator Information 
Physicians with a specialty in medical oncology will participate as investigators in this clinical 
trial. 
If investigators are added after the study has been approved by GEICAM, an EC/IRB, or a 
regulatory agency, these additions will not be considered changes to the protocol. 
9.4.2. 
Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to GEICAM. 


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10. Practical Considerations 
10.1.  Monitoring, Audit and Inspections 
The study will be monitored by means of regular visits of the patients. During the visits to the 
center, the monitor must review the original records of the patients, the records of medication 
stocks and document preservation. The monitor must also evaluate the study procedures and 
discuss the possible problems with the investigator. During the course of the study, audit visits 
can be carried out in the participating centers. The investigator will allow direct access to the 
source documents/data for the tasks of monitoring, audit, reviewed by the EC/IRB and the 
inspection by the Competent Authorities. 
10.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with 
GEICAM or designee (and IRB or EC, as required) to determine the appropriate course of 
action. There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
10.3.  Preservation of Study Documentation 
The copies of all the relevant information will be preserved by the investigator for a period of at 
least 25 years after the end of the study, according to current legislation. 
10.4.  Protocol Modification 
Once it has been authorized by the EC/IRB and the competent authority any protocol 
modification must be documented by writing, in the form of an amendment. 
The amendments must be duly identified, by its chronological order number, dated and signed 
by GEICAM and the Coordinating investigator. 
All the protocol amendments must be notified to the EC/IRBs involved in the trial and to the 
competent authority. If the modifications are relevant, the authorization of the involved 
EC/IRBs and/or the competent authority will be necessary before their application. 
After reading the protocol amendment and prior to the submission to the EC/IRB, each 
principal investigator will sign the protocol amendment signature page and send a copy of the 
signed page to GEICAM. 
10.5.  Use of the Information and Publication 
All the information concerning the study treatment provided by GEICAM in relation to this 
study, and not previously published, is considered to be confidential information with property 
right of GEICAM. This information comprises the basic information about the product, the 
clinical protocol, the work forms where appropriate, the e-CRFs, the assessment methods, the 
technical methodology and the basic scientific data. This confidential information will be the 


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property of GEICAM, it must not be disclosed to third parties without the prior written consent of 
GEICAM and it must not be used other than for the purposes of the study. 
The information developed during the practice of this clinical study is also considered to be 
confidential. This information can be disclosed to the extent considered necessary by GEICAM.  
To allow the use of the information derived from this study and to ensure the compliance with the 
current rules, the investigator is obliged to provide GEICAM with all the results of examinations 
and all the data developed in this study. Except in that required by law, the information obtained 
during the study can only be provided to the doctors and to the competent authorities by 
GEICAM. 
GEICAM commits to publish the results of the study and to present them in scientific meetings 
either if they are positive or negative. The different disclosures and author lists will be discussed 
and prepared by the SC.  
10.5.1 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and 
to comply with applicable laws, regulations and guidance, GEICAM will, at a minimum 
register interventional clinical trials sponsored by GEICAM anywhere in the world on 
ClinicalTrials.gov or other publicly accessible websites (European Union Clinical Trials 
Register and national clinical trials public website (if applicable)), as required by GEICAM 
policy and local health authorities.  
10.5.2 
Clinical Trial Results Disclosure 
GEICAM will post the results of clinical trials on ClinicalTrials.gov or other publicly 
accessible websites, as required by GEICAM Policy/Standard and applicable local laws and/or 
regulations. 
10.6.  Ethics Committees and/or IRBs 
GEICAM or its designee or the Investigator will supply relevant documents for submission to 
the respective EC/IRB for the protocol’s review and approval. This protocol, the Investigator’s 
Brochure/Summary of Product Characteristics [SmPC], a copy of the informed consent form, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, will be submitted to a central or local EC/IRB 
for approval. The EC/IRB’s written approval of the protocol and subject informed consent must 
be obtained and submitted to GEICAM or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied study treatment or study specific screening activity). 
GEICAM or its designee will notify the site once GEICAM or its designee has confirmed the 
adequacy of site regulatory documentation and, when applicable, GEICAM or its designee has 
received permission from competent authority to begin the trial. Until the site receives 
notification, no protocol activities, including screening, may occur. 


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As per applicable regulatory requirements, GEICAM or its designee or the Investigator will 
submit the required reports of the progress of the study to the EC/IRB and will communicate the 
possible SAE, the life-threatening adverse events and deaths. At the end of the study, GEICAM 
or its designee or the Investigator must inform the EC/IRB of trial closure. Al these notifications 
will be performed according to the applicable regulatory requirements. 
 
 


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receptor-positive,HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a 
randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35.   
88. Turner NC, Ro J, Andre F, et al, Palbociclib in Hormone-Receptor–Positive Advanced 
Breast Cancer. N Engl J Med. 2015 Oct 22;373(17):1672-3. 
89. Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in 
circulating tumor DNA demonstrate evolution during therapy for metastatic breast 
cancer. Sci Transl Med. 2015 Nov 11;7(313):313ra182. 
90. Chandarlapaty S, Sung P, Chen D, et al. cfDNA analysis from BOLERO-2 plasma 
samples identifies a high rate of ESR1 mutations: Exploratory analysis for prognostic 
and predictive correlation of mutations reveals different efficacy outcomes of endocrine 
therapy–based regimens 38th San Antonio Breast Cancer Symposium (SABCS) San 
Antonio, TX, USA December 8‒12, 2015, Abst.  S2-07  
91. Turner et al. Unpublished, ASCO 2016 abstract submission  
92. Krop I, Johnston S, Mayer IA, et al. The FERGI phase II study of the PI3K inhibitor 
pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, 
aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results. 
37th San Antonio Breast Cancer Symposium (SABCS) San Antonio, TX, USA 
December 9‒13, 2014. Abst. S2-02. 
93. Baselga J, Im S-A, Iwata H, et al. PIK3CA status in circulating tumor DNA (ctDNA) 
predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal 
women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results 
from the randomized, phase III BELLE-2 trial. 38th San Antonio Breast Cancer 
Symposium (SABCS) San Antonio, TX, USA December 8‒12, 2015. Abst. S6-01. 5. 
94. Johnston S, Kilburn LS, Ellis P, et al, Fulvestrant plus anastrozole or placebo versus 
exemestane alone after progression on non-steroid aromatase inhibitors in 
postmenopausal patients with hormonal –receptor-positive locally advanced or 
metastatic breast cancer (SoFEA): a composite, multicenter phase 3 randomized trial, 
Lancet Oncology 2013; 14: 989-98. 
95. Steven Dunn at Pfizer Research Unit (unpublished). 
96. Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD/SERM Hybrid-CDK4/6 
Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin 
Cancer Res. 2015;21(22):5121-30. 
97. Jeselsohn R, Buchwalter G, De Angelis C, et al, ESR1 mutations—a mechanism for 
acquired endocrine resistance in breast cancer. Nature Reviews-Clinical Oncology. 
2015; 12: 573-83 
98. Gary G. Koch & Todd A. Schwartz (2014) An Overview of Statistical Planning to 
Address Subgroups in Confirmatory Clinical Trials, Journal of Biopharmaceutical 
Statistics,24:1, 72-93. 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 123 of 142 
 
99. Kim K, DeMets DL. Confidence intervals following group sequential tests in clinical 
trials.  Biometrics 1987;43(4):857-64. 
100. Cui L, Hung HMJ, Wang S, et al. Modification of sample size in group-sequential clinical 
trials. Biometrics 1999; 55: 853-7. 
101. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast 
Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. 
102. Finn RS, Crown J, Lang I, et al. Overall survival results from the randomized phase II 
study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline 
treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18). J Clin Oncol 
35, 2017 (suppl; abstr 1001). 
103. Martin M, Hoffman J, Borrego MR, et al. Evaluation of the Drug Interaction Potential 
of Palbociclib and Exemestane – Results from the PEARL Pharmacokinetic Sub-Study 
[abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 
Dec. 5-9; San Antanio, TX: Abstract nr P5-21-23. 
104. Rugo HS, Finn RS, Dieras V, et al. Palbociclib (PAL) + letrozole (LET) as first-line 
therapy in estrogen receptor-positive (ER+)/ human epidermal growth factor receptor 2-
negative (HER2-) advanced breast cancer (ABC): Eficacy and safety updates with 
longer follow-up across patient subgroups [abstract]. In: Proceedings of the 2017 San 
Antonio Breast Cancer Symposium; 2017 Dec. 5-9; San Antonio, TX: Abstract nr P5-
21-03. 
105. H. S. Rugo, R. S. Finn, V. Diéras et al. Palbociclib plus letrozole as first-line therapy in 
estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced 
breast cancer with extended follow-up. Breast Cancer Res Treat. 2019; 174(3): 719–729. 
106. Nicholas C. Turner, Dennis J. Slamon, Jungsil Ro, et al. Overall Survival with Palbociclib 
and Fulvestrant in Advanced Breast Cancer. N Engl J Med 2018; 379:1926-1936. 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 124 of 142 
 
Protocol Attachment 1. Study Schedule 
Study Schedule of Events and Timelines. 
GEICAM/2013-02 
During Study Treatment. 
All visits ± 3 days of scheduled treatment day. 
Post-
treatment 
visit (30 
+/- 5 
days) 
from the 
last study 
treatment 
doset 
After study treatment 
termination 
 
Cycle 
Baseline 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
PFS  
Follow-up 
Period  
(12 weeks +/- 
14 days from 
last tumor 
assessment) 
OS Follow-
up Period 
(6 months 
± 14 days) 
from last 
tumor 
assessment
Day of cycle 
1 
1 
1 
1 
ICD for Entry (before any 
study specific tests)a 
X 
 
 
 
 
 
 
 
 
Procedure/Laboratory/  
Diagnostic Test 
Within 28 days 
(±7 days) 
RANDOMIZATION 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Medical and surgical history 
and demographicsb 
X 
 
 
 
 
 
 
 
Physical examinationc 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
 
Hematologyd 
X 
X 
Day 1f & 
14 (only Exp 
Arm) 
X 
Day 1 & 
14 
(only Exp 
Arm)
X 
X 
X 
 
 
Blood Chemistrye 
X 
Xf 
X 
X 
X 
X 
 
 
Standard 12-lead ECG 
X 
If clinically indicated 
 
QLQ-C30, QLQ-BR23 and 
EQ-5D questionnairesg 
X 
 
 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
AEs and SAEsh  
X 
X 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 125 of 142 
 
Study Schedule of Events and Timelines. 
GEICAM/2013-02 
During Study Treatment. 
All visits ± 3 days of scheduled treatment day. 
Post-
treatment 
visit (30 
+/- 5 
days) 
from the 
last study 
treatment 
doset 
After study treatment 
termination 
 
Cycle 
Baseline 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
PFS  
Follow-up 
Period  
(12 weeks +/- 
14 days from 
last tumor 
assessment) 
OS Follow-
up Period 
(6 months 
± 14 days) 
from last 
tumor 
assessment
Exemestane dosing 
 
 
Xi 
 
 
 
Palbociclib dosing 
 
Xj 
X 
X 
X 
 
 
 
Capecitabine dosing  
 
Xk 
X 
X 
X 
 
 
 
Fulvestrant dosing 
 
Xl 
X 
X 
X 
 
 
 
Tumor Assessmentm 
X 
Every 8 weeks (±7 days) from the start of treatment 
and every 12 weeks (±7 days) after 120 weeks of 
treatment. Patients with bone lesions identified at 
baseline will repeat the bone scans as clinically 
indicated or to confirm a complete response.  
 
Xn 
 
Date of death  
 
 
 
 
 
 
 
Xo 
Translational Research 
 
 
 
 
Blood samples for Exemestane 
PK studiesp 
 
X 
(Predose) 
Day minus-
1, Day 1 & 
14 
 
X 
(Predose)
Day 14 
 
 
 
 
 
 
Blood samples for Palbociclib 
PK studiesp 
 
X 
(Predose) 
Day 14 
 
X 
(Predose)
Day 14 
 
 
 
 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 126 of 142 
 
Study Schedule of Events and Timelines. 
GEICAM/2013-02 
During Study Treatment. 
All visits ± 3 days of scheduled treatment day. 
Post-
treatment 
visit (30 
+/- 5 
days) 
from the 
last study 
treatment 
doset 
After study treatment 
termination 
 
Cycle 
Baseline 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
Cycles 
PFS  
Follow-up 
Period  
(12 weeks +/- 
14 days from 
last tumor 
assessment) 
OS Follow-
up Period 
(6 months 
± 14 days) 
from last 
tumor 
assessment
Blood (Plasma) samples for 
Biomarker studiesq 
 
X 
Day 1 
(Predose) 
and Day  
15 (±3 
days)  
X 
Day 15 
(±3 days)
 
 
 
X 
 
 
Whole blood for 
Pharmacogenomics analysisr 
 
 
X (Day1) 
 
 
 
 
 
 
Tumor tissue for Biomarker 
analysiss 
X 
 
 
 
 
 
 
 
 
 
Study Schedule of Events and Timelines. Protocol GEICAM/2013-02 
a 
Signed, written informed consent (approved by ERB) obtained prior to any study specific procedure. 
b 
Includes local laboratory ER/PgR/HER2 expression levels and methods used to assess them, previous treatments. Sex, Race and Age  
c 
Physical examination includes measurements of height (BL only), weight, area surface body (BL only), blood pressure, pulse rate and body temperature. In 
arm B (capecitabine), the area surface body will be recalculated in the event that patients experience body weight variations greater than 10% during the 
treatment period. 
d 
Hemoglobin, WBC, absolute neutrophils, platelet count. In the experimental arm, the hematology will be performed every two weeks (±3days)  for the 
first two cycles and from cycle 3 onward, every four weeks (±3days).  
e 
At baseline visit: Fasting glucose, alkaline phosphatase, ALT, AST, total bilirubin, serum creatinine, sodium, potassium, magnesium, total calcium,. At 
treatment visit or safety visit: Fasting glucose, alkaline phosphatase, ALT, AST, total bilirubin, serum creatinine, total calcium 
f 
Not on cycle 1 if the assessments were performed within the 7 days prior to day 1 of treatment. The initiation of the treatment will be within 7 days after 
randomization   
g 
Patients will complete each instrument within 28 days (± 7 days) prior to the first treatment administration, pre-dose on Day 1 of every two cycles starting 
with Cycle 3 until Day 1 of Cycle 7 (at cycles 3, 5 and 7), thereafter on Day 1 of every three cycles till the end of treatment (at cycles 10, 13, etc) and at the 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 127 of 142 
 
post-treatment visit (30 days from the last study treatment dose or before initiation of new anticancer therapy). Patients who discontinue study treatment for 
reasons other than radiographically and/or clinically documented PD or initiate a new anticancer therapy, will additionally complete these instruments after 
RECIST-defined disease progression. 
h 
After informed consent form signature, but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. 
Adverse events to be monitored continuously during the treatment period. All AEs occurring during the study and until the treatment discontinuation visit 30 
days after the last study treatment to be recorded with grading according to NCI-CTCAE, thereafter all study treatment-related SAEs should continue to be 
collected.  
i 
Exemestane will be taken orally, daily, and continuously. In patients within the PK sub-study, exemestane will be administered daily during a 7-day lead-in 
period (day minus-7 through day minus-1) immediately preceding cycle 1. 
j 
Palbociclib will be taken orally, daily, and during 3 weeks (Day 1 to Day 21) followed by a 1 week rest period in 28-day cycles 
k 
Capecitabine will be taken orally, daily, and during 2 weeks (Day 1 to Day 14) followed by a 1 week rest period in 21 days cycles 
l 
Fulvestrant will be administered as two 5ml intramuscular injections, one in each buttock, on days 1 and 15 (±3 days) of Cycle 1, and then on Day 1 of each 
subsequent 28 day cycle (±3 days). Time windows extended to ±7 days after 24 weeks. 
m 
Disease assessment for all patients at baseline will include: 
 CT (or PET-CT) scan or MRI of the chest, abdomen and pelvis (CAP). 
 Bone scan (or PET scan) is mandatory if the patient has bone disease or if there is any suspicious of bone metastases.  Any suspicious abnormalities (ie, 
hotspots) identified on the bone scans or PET scan at baseline must be confirmed by X-ray (if there are other measurable lesions), CT (or PET-CT) scan 
with bone windows or MRI (if only bone disease is present).   
 Brain CT scan or MRI is mandatory if the patient has CNS metastases or if there is any suspicious of CNS metastases.   
 CT scan or MRI of any other sites of disease as clinically indicated.  
 Clinical assessment of superficial disease which will include photographs of all superficial metastatic lesions.    
All lesions, including bone lesions followed by X-ray (if there are other measurable lesions), CT (or PET-CT) scan with bone windows or MRI (if only bone 
disease is present), will be followed every 8 weeks (± 7 days) from the start of treatment and every 12 weeks (±7 days) after 120 weeks of treatment.. Bone 
scans (if applicable) will be repeated as clinically indicated (ie, patient describes new or worsening bone pain, or has increasing alkaline phosphatase level, or 
other signs and symptoms of new/progressing bone metastases) and to confirm a complete response. 
n 
Only to be performed post-study treatment if disease progression has not yet been confirmed and patients have not initiated a new therapy. Tumor assessments 
will be performed every 12 weeks (± 7 days)  from the last tumor assessment and bone scans (if applicable) as clinically indicated bone scan.   
o 
The patients will be followed for survival every 6 months (±14days) from last tumor assessment until death, loss to follow-up, withdrawal of consent or study 
termination by GEICAM. After progression, the tumor assessment will be performed according to the standard medical practice. The date of death and all 
treatments received by the patient after progression (according to the standard medical practice) will be collected in the eCRF.  
p 
Only to be performed in selected sites and in Arm A (Cohort 1) in patients accepting to participate. Exemestane PK samples should be collected pre-dose on 
day minus-1, cycle 1 day 1 (back-to-back days), and on day 14 in cycles 1 and 2. Palbociclib PK samples should be collected pre-dose on day 14 in cycles 1 
and 2. Additional blood samples may be requested from patients experiencing unexpected or serious adverse events, or adverse events that lead to 
discontinuation. Refer to the Sample Management Manual for detailed collection, processing and shipping procedures. 
q 
 
In arms A and B. 
Blood (Plasma) samples for ESR1 mutation analysis and exploratory biomarker analyses: Fourblood samples (tubes optimized for plasma collection) will be 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 128 of 142 
 
collected from all patients at: 1) baseline (Cycle 1, Day 1pre-dose or within the 7 days prior to the first dose of treatment), 2) Cycle 1 Day 15 (±3 days), 3) 
Cycle 2 Day 15 (±3 days) and 4) at the end of treatment (approximate 30 days after last study dose but always before the next anti-cancer therapy). If a patient 
ends the study treatment due to a reason different than disease progression, every effort should be made to collect an additional sample upon progression 
(regardless of the administration of other treatment) 
The baseline sample must be drawn prior to the first dose of any study treatment and the sample of Cycle 1 Day 15 (± 3 days)  prior to the fulvestrant dose in 
patients included in arm A of  Cohort 2. For patients included in the PK sub-study, the baseline plasma sample will be collected on day -7 predose or within 7 
days prior to the first exemestane dose, because in these patients exemestane will be administered daily during a 7 day lead-in period (day minus 7 through 
day minus 1) immediately pre-ceding cycle 1. 
r 
In arms A and B. 
Whole blood for Pharmacogenomics analysis:  A whole blood sample (K2 EDTA whole blood collection tubes optimized for DNA analysis) will be collected 
when feasible but preferable within 7 days prior to the first treatment dose to be retained for potential pharmacogenomic/biomarker analyses related to drug 
response or adverse drug reactions.  
s 
 
 
In arms A and B. 
Tumor Tissue for Biomarker Assessments: Formalin-fixed paraffin embedded (FFPE) tumor tissue, preferably from metastatic tumor, will be collected for 
retrospective biomarker assessments, Samples will be sent to the sponsor-designated central laboratories.  
t 
For safety reasons all patients will have a visit 30 (±5) days after finishing treatment with the study treatment. This post-treatment visit must be performed 
before initiation of any new anticancer therapy and may be advanced when a new anticancer therapy is scheduled before 30 (±5) days after finishing the study 
treatment. 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 129 of 142 
 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status 
ECOG Performance Status 
Grade 
Description 
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, e.g., 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 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5(6):649-65. 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 130 of 142 
 
Protocol Attachment 3. List of Drugs Known to Predispose to Torsade 
de Pointes 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone, Pacerone, 
Nexterone 
Antiarrhythmic 
Abnormal heart 
rhythm 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 
3 inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox 
Anticancer 
Cancer (leukemia) 
Astemizole  
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil  
Vascor 
Antianginal 
Angina Pectoris (heart 
pain) 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine, Largactil, 
Megaphen 
Antipsychotic / 
Antiemetic 
Schizophrenia, nausea, 
many others 
Cilostazol 
Pletal 
Phosphodiesterase 
3 inhibitor 
Intermittent 
claudication 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Bacterial infection 
Cisapride  
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, 
SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Abnormal heart 
rhythm 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Abnormal heart 
rhythm 
Domperidone 
Motilium, Motillium, 
Motinorm Costi, Nomit 
Antinausea 
Nausea, vomiting 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Dementia (Alzheimer's 
Disease) 
Dronedarone 
Multaq 
Antiarrhythmic 
Abnormal heart 
rhythm 
Droperidol 
Inapsine, Droleptan, Dridol, 
Xomolix 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), 
nausea 
Erythromycin 
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, 
Erythrocot, E-Base, 
Erythroped, Ilosone,  MY-E, 
Pediamycin, Zineryt, 
Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, 
Stiemycine, Acnasol, Tiloryth Antibiotic 
Bacterial infection, 
increase GI motility 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 131 of 142 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Escitalopram 
Cipralex, Lexapro, Nexito, 
Anxiset-E (India), Exodus 
(Brazil), Esto (Israel), 
Seroplex, Elicea, Lexamil, 
Lexam, Entact (Greece), 
Losita (Bangladesh), Reposil 
(Chile), Animaxen 
(Colombia), Esitalo 
(Australia), Lexamil (South 
Africa) 
Antidepressant, 
SSRI 
Depression (major), 
anxiety disorders 
Flecainide 
Tambocor, Almarytm, 
Apocard, Ecrinal, Flécaine 
Antiarrhythmic 
Abnormal heart 
rhythm 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
Gatifloxacin  
Tequin 
Antibiotic 
Bacterial infection 
Grepafloxacin  
Raxar 
Antibiotic 
Bacterial infection 
Halofantrine 
Halfan 
Antimalarial 
Malaria 
Haloperidol 
Haldol (US & UK), 
Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol 
(Germany), Einalon S, 
Eukystol, Halosten, Keselan, 
Linton, Peluces, Serenace, 
Serenase, Sigaperidol 
Antipsychotic 
Schizophrenia, 
agitation 
Ibogaine  
None 
Psychedelic 
Narcotic addiction, 
unproven 
Ibutilide 
Corvert 
Antiarrhythmic 
Abnormal heart 
rhythm 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Bacterial infection 
Levomepromazine 
Nosinan, Nozinan, 
Levoprome 
Antipsychotic 
Schizophrenia 
Levomethadyl 
acetate  
Orlaam 
Opioid agonist 
Narcotic dependence 
Levosulpiride  
Lesuride,  Levazeo,  Enliva 
(with rabeprazole) 
Antipsychotic 
Schizophrenia 
Mesoridazine 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadon 
Opioid agonist 
Narcotic dependence, 
pain 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran, Anset, Ondemet, 
Zuplenz, Emetron, Ondavell, 
Emeset, Ondisolv, Setronax 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Eloxatin 
Antineoplastic 
Agent 
Cancer 
Papaverine HCl 
(Intra-coronary) 
none 
Vasodilator, 
Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 132 of 142 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
pneumonia) 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
Probucol  
Lorelco 
Antilipemic 
Hypercholesterolemia 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Abnormal heart 
rhythm 
Propofol 
Diprivan,  Propoven 
Anesthetic, 
general 
Anesthesia 
Quinidine 
Quinaglute, Duraquin, 
Quinact, Quinidex, Cin-Quin, 
Quinora 
Antiarrhythmic 
Abnormal heart 
rhythm 
Roxithromycin  
Rulide, Xthrocin, Roxl-150, 
Roxo, Surlid, Rulide, Biaxsig, 
Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, 
Coroxin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, 
general 
Anesthesia 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Abnormal heart 
rhythm 
Sparfloxacin  
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride  
Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Sulpor 
Antipsychotic, 
atypical 
Schizophrenia 
Sultopride  
Barnetil,  Barnotil,  Topral 
Antipsychotic, 
atypical 
Schizophrenia 
Terfenadine  
Seldane 
Antihistamine 
Allergic rhinitis 
Terlipressin  
Teripress,  Glypressin,  
Terlipin,  Remestyp,  Tresil,  
Teriss and others 
Vasoconstrictor 
Septic shock 
Terodiline 
Micturin,  Mictrol (not 
bethanechol) 
Muscle relaxant 
Bladder spasm 
Thioridazine 
Mellaril, Novoridazine, 
Thioril 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa 
Anticancer 
Cancer (thyroid) 
Note: Medicines on this list are reviewed on an ongoing basis by the Scientific Review Board of the Arizona Center for Education 
and Research on Therapeutics (AzCERT) to assure that the available evidence supports their continued placement on this list. The 
list changes regularly and we recommend checking the website at crediblemeds.org for the most up-to-date information. There may 
be many additional brand names that are not listed on this form.          
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm 
 
                                            
 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 133 of 142 
 
Protocol Attachment 4. Capecitabine Dose Calculation According to 
Body Surface Area 
Standard and reduced dose calculations according to body surface area for a starting dose 
of capecitabine of 1,250mg/m2 
 
100% Dose Level = 2,500 mg/m2/day  
(twice daily 1,250 mg/m2) 
Number of tablets to be taken 
at each dose 
(morning and evening) 
Surface Area (m2) 
Total Daily 
Dose (mg)* 
Twice Daily 
dose (mg) 
150mg 
500mg 
< = 1.25 
3000 
1500 
– 
3 
1.26–1.37 
3300 
1650 
1 
3 
1.38–1.51 
3600 
1800 
2 
3 
1.52–1.65 
4000 
2000 
– 
4 
1.66–1.77 
4300 
2150 
1 
4 
1.78–1.91 
4600 
2300 
2 
4 
1.92–2.05 
5000 
2500 
– 
5 
2.06–2.17 
5300 
2650 
1 
5 
> = 2.18 
5600 
2800 
2 
5 
* Total Daily Dose calculated on mg/m2 for the median value, and rounded to  
the nearest 100mg. 
                             


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 134 of 142 
 
    
75% Dose Level = 1,900 mg/m2/day  
(twice daily 950 mg/m2) 
Number of tablets to be taken 
at each dose 
(morning and evening) 
Surface Area (m2) 
Total Daily 
Dose (mg)* 
Twice daily 
dose (mg) 
150mg 
500mg 
< = 1.14 
2000 
1000 
_ 
2 
1.15 – 1.30 
2300 
1150 
1 
2 
1.31 – 1.49 
2600 
1300 
2 
2 
1.50 – 1.67 
3000 
1500 
– 
3 
1.68 – 1.83 
3300 
1650 
1 
3 
1.84 – 2.02 
3600 
1800 
2 
3 
2.03 – 2.21 
4000 
2000 
– 
4 
> = 2.22 
4300 
2150 
1 
4 
* Total Daily Dose calculated on mg/m2 for the median value, and rounded to  
the nearest 100mg. 
 
50% Dose Level = 1,250 mg/m2/day  
(twice daily 625 mg/m2) 
Number of tablets to be taken 
at each dose 
(morning and evening) 
Surface Area (m2) 
Total Daily 
Dose (mg)* 
Twice daily 
dose (mg) 
150mg 
500mg 
1.16 – 1.43 
1600 
800 
2 
1 
1.44 – 1.71 
2000 
1000 
– 
2 
1.72 – 1.95 
2300 
1150 
1 
2 
1.96 – 2.23 
2600 
1300 
2 
2 
> = 2.24 
3000 
1500 
 
3 
* Total Daily Dose calculated on mg/m2 for the median value, and rounded to 
 the nearest 100mg. 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 135 of 142 
 
Standard and reduced dose calculations according to body surface area for a starting dose 
of capecitabine of 1,000mg/m2 
 
2,000mg/m2/day  
(twice daily 1,000mg/m2) 
 
Full dose 
2,000mg/m2 
Number of 150mg tablets 
and/or 500mg tablets per 
administration (each 
administration to be given 
morning and evening) 
Reduced dose 
(75%) 
1,500mg/m2 
Reduced dose 
(50%) 
1,000mg/m2 
Surface Area (m2)
Total Daily 
Dose (mg)* 
150mg 
500mg 
Total Daily Dose 
(mg)* 
Total Daily 
Dose (mg)* 
< = 1.26 
2,300 
1 
2 
1,600 
1,200 
1.27–1.38 
2,600 
2 
2 
2,000 
1,200 
1.39–1.52 
2,900 
3 
2 
2,200 
1,500 
1.53–1.66 
3,200 
4 
2 
2,400 
1,600 
1.67–1.78 
3,500 
5 
2 
2,600 
1,600 
1.79–1.92 
3,600 
2 
3 
2,800 
1,800 
1.93–2.06 
4,000 
- 
4 
3,000 
2,000 
2.07–2.18 
4,300 
1 
4 
3,200 
2,100 
> = 2.19 
4,600 
2 
4 
3,500 
2,200 
 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 136 of 142 
 
Protocol Attachment 5. Capecitabine Interruptions and Extended Rest 
Periods 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 137 of 142 
 
Protocol Attachment 6. Palbociclib/Fulvestrant Interruptions and 
Extended Rest Periods 
Cohort 2: PALBOCICLIB Dosing Interruption 
In the event of a toxicity requiring dosing delay of palbociclib, the administration of 
Fulvestrant should be continued as pre-planned schedule, though every effort should be 
made to re-synchronize the day 1 palbociclib administration and Fulvestrant injection 
using the allowed visit windows as defined in the study schedule 
 
 
 
 
 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 138 of 142 
 
 
Cohort 2: FULVESTRANT Dosing Interruption 
 
Fulvestrant can also be delayed by a maximum of 7 days, or longer if required for 
satisfactory recovery of the platelet count, as it should not be administered if the platelet 
count is< 50,000/mm3. 
 
 
A single Fulvestrant dose can be skipped a single time in case of a Fulvestrant related 
toxicity. 
 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 139 of 142 
 
Protocol Attachment 7. Palbociclib, Exemestane and Capecitabine 
Diaries 
In separate document. 
 
 
 
 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 140 of 142 
 
Protocol Attachment 8. Adverse event (AE) non defined in CTCAE 
CTC 
Grade 
Equivalent 
to: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily 
activity. 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although 
this could improve the overall well-being or symptoms of 
the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated in treatment 
or medical intervention is indicated in order to improve 
the overall well-being or symptoms; delaying the onset of 
treatment is not putting the survival of the patient at direct 
risk. 
Grade 4 
Life-
threatening / 
disabling 
An immediate threat to life or leading to a permanent 
mental or physical conditions that prevents work or 
performing daily 
activities; treatment or 
medical 
intervention is required in order to maintain survival.  
Stage 5 
Death 
AE resulting in death. 
 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 141 of 142 
 
Protocol Attachment 9. Adverse Events / Serious Adverse Events 
Assessment Guide 
Time 
After ICD 
Before Drug 
During Therapy 
30-Day  
Post-
discontinuation  
Follow-up Period 
Long-Term  
Follow-up Period 
Events to 
Collect  
AE/SAEs 
 
New/Ongoing AE/SAEs 
 
New/Ongoing SAEs 
 
 
Related to 
Procedures 
Regardless of Relatedness to 
Study Treatment or Procedures 
Related to Study 
Treatment or Procedures 
Abbreviations:  AE = adverse event, ICD = informed consent document, SAE = serious adverse event. 


GEICAM/2013-02                                                                   EudraCT number: 2013-003170-27  
 
Protocol version 8.0, 05 November 2019                                 Confidential                                           Page 142 of 142 
 
Protocol Attachment 10. QLQ-C30, QLQ-BR23 and EQ-5D 
Questionnaires 
In separate document.  

SAP_001.pdf: