PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Alliance Foundation Trials, LLC.

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ALLIANCE FOUNDATION TRIALS (AFT) 
AUSTRIAN BREAST & COLORECTAL CANCER GROUP (ABCSG) 
BREAST INTERNATIONAL GROUP (BIG) 
 
PROTOCOL NUMBER 
AFT – 05 
ABCSG 42 
BIG 14-03 
 
PALLAS: PALbociclib CoLlaborative Adjuvant Study: 
A randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus standard 
adjuvant endocrine therapy alone for hormone receptor positive (HR+) / human epidermal growth factor 
receptor 2 (HER2)-negative early breast cancer 
 
Protocol Version: 4.0 
Protocol Version Date: 23 Dec 2020 
 
Investigational Product: Palbociclib 
IND Sponsor: AFT 
IND#: 126003 
Non-US Sponsor: ABCSG GmbH 
EudraCT#: 2014-005181-30 
Investigational Product Supplier: Pfizer Inc. 
ClinicalTrials.gov Identifier: NCT02513394 
Erica L. Mayer, MD, MPH 
Susan F Smith Center for Women’s Cancers 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
Email address: 
 
Angela DeMichele MD MSCE 
Abramson Cancer Center 
University of Pennsylvania 
Email address: 
 
Michael Gnant MD 
Austrian Breast & Colorectal Cancer Study Group 
Medical University of Vienna 
Email address
 

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PROTOCOL SIGNATURE PAGE 
 
 
PALLAS Site ID: _ _ _ _ _ _ 
 
Protocol Title: PALLAS: PALbociclib CoLlaborative Adjuvant Study: 
A randomized phase III trial of Palbociclib with standard adjuvant endocrine therapy versus 
standard adjuvant endocrine therapy alone for hormone receptor positive (HR+) / human 
epidermal growth factor receptor 2 (HER2)-negative early breast cancer 
 
 
Protocol Number: 
AFT – 05, ABCSG 42, BIG 14-03 
EudraCT Number: 
2014-005181-30 
 
 
 
US Sponsor Name: 
Alliance Foundation Trials (AFT), LLC 
Non-US Sponsor Name: 
ABCSG GmbH 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the described 
trial in compliance with all stipulations of the protocol, all applicable regulations, ICH Good Clinical 
Practice (GCP) and Declaration of Helsinki. 
 
 
 
 
First Name, Last Name 
Date, Signature 

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I. 
Synopsis 
 
Study Title 
PALLAS: PALbociclib CoLlaborative Adjuvant Study: 
A randomized phase III trial of Palbociclib with standard adjuvant 
endocrine therapy versus standard adjuvant endocrine therapy alone for 
hormone receptor positive (HR+) / human epidermal growth factor 
receptor 2 (HER2)-negative early breast cancer 
Study Code 
AFT-05, ABCSG-42, BIG 14-03 
EudraCT Number 
2014-005181-30 
IND Number 
126003 
Sponsor 
AFT (US), ABCSG GmbH (Non-US Sites) 
Extended Academic Core Network 
BIG, GBG, NSABP, PrECOG 
Phase 
Phase III 
Rationale 
Although many patients with HR+/HER2- breast cancer may be cured 
of their disease with optimal local and systemic therapy, a significant 
number of patients with stage II and III disease will experience disease 
recurrence. Adjuvant endocrine therapy for breast cancer can be 
extremely effective, particularly with extension beyond 5 years, however 
disease recurrence can occur, with risk distributed over the decades 
following initial diagnosis. Methods to improve the efficacy of endocrine 
therapy, and delay the onset of resistance, are needed. 
HR+ breast cancer biologically may demonstrate features suggestive of 
sensitivity to CDK4/6 inhibition with agents such as palbociclib. Given 
the demonstrated activity and safety of palbociclib in the first-line 
treatment of metastatic HR+/ HER2- breast cancer, supporting FDA 
approval, there is interest in whether the benefits of CDK4/6 inhibition 
may translate into the adjuvant setting. The purpose of the PALLAS 
study is to determine whether the addition of palbociclib to adjuvant 
endocrine therapy will improve outcomes over endocrine therapy alone 
for HR+/HER2- early breast cancer. Assessment of a variety of 
correlative analysis, including evaluation of the effect of palbociclib in 
genomically defined tumor subgroups, is planned. 
Primary Objective 
To compare invasive disease-free survival (iDFS) for the combination 
of at least 5 years endocrine therapy and 2-year palbociclib treatment 
versus at least 5 years endocrine therapy alone in patients with 
histologically confirmed HR+/HER2- invasive early breast cancer 
(EBC). 

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Secondary Objectives 
To compare the following endpoints: iDFS excluding second primary 
invasive cancers of non-breast origin, distant recurrence-free survival 
(DRFS), locoregional recurrences-free survival (LRRFS), and overall 
survival (OS). 
To compare the safety of 2 years of palbociclib with adjuvant endocrine 
therapy versus adjuvant endocrine therapy alone. 
Translational Science Principal 
Objective 
To compare baseline tumor tissue to determine whether there is 
prognostic or predictive utility for defined genomic subtypes (luminal 
A, luminal B and non-luminal) with respect to iDFS and OS. 
Translational Science Additional 
Objectives 
To evaluate iDFS and OS in other genomically-defined breast cancer 
prognostic, theranostic or predicted subgroups based on pre-specified 
genomic assays. 
To evaluate baseline tumor and blood-based markers as predictors of 
benefit from the addition of palbociclib to endocrine therapy. 
To evaluate tumor and blood-based markers at time of disease recurrence 
for mechanisms of resistance to palbociclib and endocrine therapy. 
To perform exploratory analyses of serum and plasma samples over time 
to investigate the predictive and prognostic value of novel biomarkers in 
this specific trial setting related to efficacy or safety of the agent. 
To compare serial levels of circulating cell-free DNA (cfDNA) in 
patients receiving palbociclib and endocrine therapy versus endocrine 
therapy alone. 
To evaluate pharmacogenomic and pharmacogenetic predictors of 
toxicity and efficacy of palbociclib and endocrine therapy and to 
endocrine therapy alone. 
Clinical Science Objectives 
To evaluate adherence to oral therapy in patients receiving palbociclib 
and endocrine therapy. 
To determine the association of BMI with the efficacy of palbociclib 
and endocrine therapy. 
Patient Reported Outcome 
Objective 
To compare patient-reported quality of life, fatigue, arthralgia, alopecia, 
menstrual function, and endocrine symptoms of HR+/HER2- breast 
cancer patients randomized to receive palbociclib plus adjuvant standard 
endocrine therapy versus standard endocrine therapy alone overall and 
by subgroups defined by age at randomization (≤50 and 
>50) and initial endocrine therapy (tamoxifen and AI) at multiple pre- 
specified time points. 

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Trial Design and Schema 
This is a prospective, two arm, international, multicenter, randomized, 
open-label Phase III study evaluating the addition of 2 years of 
palbociclib to standard adjuvant endocrine therapy for patients with HR+ 
/ HER2- early breast cancer (EBC). 
Schema 
Randomized, open-label, Stage II or III EBC Patients (Stage IIA limited 
to 1000 patients). 
 
Figure 1: PALLAS Study Schema 
Endocrine adjuvant therapy may have started before randomization and 
be ongoing at the time of randomization. 
Eligible patients will be receiving standard adjuvant endocrine therapy 
for HR+/ HER 2- early breast cancer. A total of 5600 patients (revised 
target accrual) will be randomized in a 1:1 ratio to: 
Arm A: palbociclib at a dose of 125 mg orally once daily, Day 
1 to Day 21 followed by 7 days off treatment in a 28-day cycle 
for a total duration of 2 years, in addition to standard adjuvant 
endocrine therapy for a duration of at least 5 years. 
Arm B: standard adjuvant endocrine therapy for a duration of at 
least 5 years. 
Standard endocrine therapy (also referred to as background 
treatment) can be tamoxifen or aromatase inhibitor with or 
without LHRH agonist. 

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Patients will be randomized within strata defined by: 
• Anatomic stage (IIA vs IIB/III) assessed by pathologic staging, or 
by clinical staging if pre-operative therapy was given with the 
higher stage determining eligibility, 
• Neo/adjuvant chemotherapy (yes vs no), 
• Age (≤ 50 vs > 50 years), 
• Geographic region (North America vs Europe vs Other) 
Patients randomized into Arm A will receive protocol-assigned 
palbociclib therapy for the planned duration of 2 years or until diagnosis 
of an iDFS event, unacceptable toxicity, patient withdrawal of consent, 
or study termination by the Sponsor, whichever occurs first. 
Inclusion Criteria 
Please note that waivers to eligibility requirements are not allowed. 
Patients must meet the following criteria for study entry 
(1) 
Signed informed consent obtained prior to any study 
specific assessments and procedures. 
(2) 
Age ≥18 years (or per national guidelines). 
(3) 
Premenopausal and postmenopausal women or men 
with Stage II (Stage IIA limited to a maximum of 
1000 patients) or Stage III early invasive breast 
cancer per AJCC (American Joint Committee on 
Cancer) Breast Cancer Staging version 7 /UICC 
(Union for International Cancer Control)54. Baseline 
staging to document absence of metastatic disease is 
not 
required, 
however 
is 
recommended 
as 
determined by institutional practice (in patients 
where there may be a reasonable suspicion of 
advanced disease e.g., large tumors, clinically 
positive axillary lymph nodes, signs and symptoms). 
If performed, reports of these examinations must be 
available. Examination type for staging, i.e. X-ray, 
sonography, bone scan, CT, MRI, and/or PET-CT, is 
at the discretion of the investigator. 
If neoadjuvant systemic therapy was received 
(either chemotherapy or endocrine therapy or 
biologic 
therapy 
excluding 
'Anti-HER2 
treatment'), 
either 
initial 
clinical 
stage 
(determined by physical and/or radiologic 
examination) or post-operative 
pathologic 
stage can be used for eligibility purposes, with 
the higher stage determining eligibility. 
(4) 
Patients with multicentric and/or multifocal and/or 
bilateral early invasive breast cancer whose 
histopathologically examined tumors all meet 
pathologic criteria for ER+ and/or PR+ and HER2-. 
(5) 
Patients must have histologically confirmed 

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hormone receptor positive (ER+ and/or PR+), HER2-
, early invasive breast cancer. ER, PR and HER2 
measurements should be performed according to 
institutional guidelines, in a CLIA- approved setting 
in the US or certified laboratories for Non-US 
regions. Cut-off values for positive/negative staining 
should be in accordance with current ASCO/CAP 
(American Society of Clinical Oncology/College of 
American Pathologists) guidelines55, 95. Patients 
with equivocal HER2 in situ hybridization results 
according to current ASCO/CAP guidelines are 
eligible, as long as they have not received and are not 
scheduled to receive anti-HER2 treatment. Testing 
may occur on diagnostic core or surgical tumor 
tissue. 
(6) 
Patients must have undergone adequate (definitive) 
breast surgery for the current malignancy. For 
details please refer to Appendix D. 
(7) 
A formalin-fixed paraffin-embedded (FFPE) tumor 
tissue block must be transmitted to a central sample 
repository and confirmation of receipt must be 
available prior to randomization. For details please 
refer to Section 8.2 of the protocol. 
(8) 
ECOG performance status 0-1. 
(9) 
Patients must be able and willing to swallow and 
retain oral medication without a condition that would 
interfere with enteric absorption. 
(10) 
Serum or urine pregnancy test must be negative 
within 7 days of randomization in women of 
childbearing potential. Pregnancy testing does not 
need to be pursued in patients who are judged as 
postmenopausal 
before 
randomization, 
as 
determined by local practice, or who 
have 
undergone 
bilateral 
oophorectomy, 
total 
hysterectomy, or bilateral tubal ligation. Women of 
childbearing potential and male patients randomized 
into treatment Arm A or B must use adequate 
contraception for the duration of protocol treatment 
and for 6 months after the last treatment with 
palbociclib if they are in arm A. In addition, patients 
receiving standard adjuvant endocrine therapy (Arm 
A and Arm B) should use adequate contraception in 
accordance 
with 
the 
specific 
medication 
requirements 
(e.g. 
Summary 
of 
Product 
Characteristics). Adequate contraception is defined 
as one highly effective form (i.e. abstinence*, 
(fe)male sterilization) OR two effective forms (e.g. 
non-hormonal IUD and condom / occlusive cap with 
spermicidal foam / gel / film / cream / 
suppository). 

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*Abstinence is to be interpreted as “true abstinence” 
for heterosexual intercourse and therefore, “periodic 
abstinence” (e.g. calendar, symptothermal, post- 
ovulation 
methods) 
and 
withdrawal 
(coitus 
interruptus) are not considered highly effective. 
Prior Treatment Specifics 
(11) 
Patients may or may not have received neo/adjuvant 
therapy, but must be after last dose of chemotherapy 
and/or biologic therapy and must have sufficient 
resolution of side effects per physician assessment 
at the time of randomization. 
(12) 
Patients 
may 
or 
may 
not 
have 
received 
breast/axilla/post-mastectomy 
chest 
wall 
radiotherapy, but must be after last dose of 
radiotherapy and must have sufficient resolution of 
side effects per physician assessment at the time of 
randomization. 
(13) 
Patients must have sufficient resolution of any 
surgical side effects from the last surgery per 
physician assessment with no active wound healing 
complications at the time of randomization. 
(14) 
Patients must either be initiating or have already 
started adjuvant hormonal treatment. Patients 
may already have initiated endocrine therapy at the 
time of randomization, but randomization must take 
place within 12 months of date of histological 
diagnosis and within 6 months of initiating standard 
adjuvant endocrine therapy. Patients who received 
neoadjuvant endocrine therapy are eligible as 
long as they are randomized within 12 months of 
initial histological diagnosis and after completing no 
more than 6 months of adjuvant endocrine therapy. 
Patients may be receiving either tamoxifen or 
aromatase inhibitor (AI: letrozole, anastrozole, or 
exemestane). For premenopausal patients and men, 
concurrent LHRH agonist use is allowable and may 
also be ongoing at the time of randomization. If a 
LHRH agonist was used for ovarian protection 
during neo/adjuvant chemotherapy it is allowable 
and shall not be taken into account for calculations 
regarding the 6 months standard adjuvant endocrine 
therapy. 
Baseline Body Function Specifics 
(15) 
Absolute neutrophil count ≥ 1,500/mm3 
(16) 
Platelets ≥ 100,000/mm3 
(17) 
Hemoglobin ≥ 10g/dL 
(18) 
Total serum bilirubin ≤ ULN; or total bilirubin 

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≤ 3.0 × ULN with direct bilirubin within normal 
range in patients with documented Gilbert’s 
Syndrome. 
(19) 
Aspartate amino transferase (AST or SGOT) and 
alanine amino transferase (ALT or SGPT) ≤ 1.5 × 
institutional ULN. 
(20) 
Serum creatinine below the upper limit of the 
institutional normal range (ULN) or creatinine 
clearance (or glomerular filtration rate [GFR]) ≥ 60 
mL/min/1.73 m2 for patients with serum creatinine 
levels above institutional ULN. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from 
study entry: 
(1) 
Concurrent therapy with other Investigational 
Products. 
(2) 
Prior therapy with any CDK inhibitor. 
(3) 
Patients with Stage I or IV breast cancer are not 
eligible. Baseline staging to document absence of 
metastatic disease is not required, however is 
recommended as determined by 
institutional 
practice (in patients where there may be a reasonable 
suspicion of advanced disease e.g., large tumors, 
clinically positive axillary lymph nodes, signs and 
symptoms). 
If 
performed, 
reports 
of 
these 
examinations must be available. Examination type 
for staging, i.e. X-ray, sonography, bone scan, CT, 
MRI, and/or PET-CT, is at the discretion of the 
investigator. 
(4) 
History of allergic reactions attributed to compounds 
of chemical or biologic composition similar to 
palbociclib. 
(5) 
Patients receiving any medications or substances 
that are potent inhibitors or inducers of CYP3A 
isoenzymes within 7 days of randomization (see 
Section 9.5.2.1 of the protocol for list of CYP3A 
inhibitors and inducers). 
(6) 
Uncontrolled intercurrent illness including, but not 
limited to, ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, 
cardiac 
arrhythmia, 
diabetes, 
or 
psychiatric 
illness/social situations that would limit compliance 
with study requirements. Ability to comply with 
study requirements is to be assessed by each 
investigator at the time of screening for study 
participation. 
(7) 
Pregnant women, or women of childbearing potential 
without a negative pregnancy test (serum or urine) 
within 7 days prior to randomization, 

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irrespective of the method of contraception used, 
are excluded from this study because the effect of 
palbociclib on a developing fetus is unknown. 
Breastfeeding must be discontinued prior to study 
entry. 
(8) 
Patients with a history of any malignancy are 
ineligible except for the following circumstances: 
• 
Patients with a malignancy history other than 
invasive breast cancer are eligible if they have 
been disease-free for at least 5 years and are 
deemed by the investigator to be at low risk 
for recurrence of that malignancy. 
• 
Patients with the following cancers are eligible, 
even if diagnosed and treated within the past 5 
years: ductal carcinoma in situ of the breast, 
cervical cancer in situ, and non- metastatic non-
melanomatous skin cancer. 
(9) 
Patients are not eligible if they have previously 
received endocrine therapy within 5 years prior to 
diagnosis of the current malignancy. This includes 
use for prophylactic reasons, including treatment of 
osteoporosis or cancer prevention with tamoxifen, 
raloxifene or AI. Patients may concurrently receive 
bisphosphonates or rank ligand inhibitors while on 
this study if necessary for treatment or prevention of 
osteopenia or osteoporosis. 
(10) 
Patients on antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic 
interactions or increased immunosuppression with 
palbociclib. 
(11) 
Patients with clinically significant history of chronic 
liver disease, including chronic/active viral or other 
known hepatitis, current alcohol abuse, or cirrhosis, 
etc. 
(12) 
Patients receiving concurrent exogenous hormone 
therapy (hormone replacement therapy, oral or any 
other hormonal contraceptives such as hormonal 
contraceptive coil, etc.) are not eligible but topical 
vaginal estrogen therapy is allowable. 
Investigational Product and 
Formulation 
Palbociclib at a dose of 125 mg will be administered orally once a day, 
at the same time, for 21 days, followed by 7 days off treatment of every 
28-day cycle. Investigational medicinal product (IMP) will be 
administered with standard adjuvant endocrine therapy (Non- 
investigational product). 

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Non-investigational Treatment and 
Formulation 
Current treatment guidelines recommend adjuvant endocrine treatment 
for 5 to 10 years after surgery for patients with hormone-receptor- 
positive disease. Adjuvant endocrine treatment might have already 
started before the patient enters the study, however, initiation of standard 
adjuvant endocrine therapy must not be more than 6 months before 
randomization (please refer to inclusion criterion 14). 
The following endocrine therapies are allowed: 
• 
tamoxifen 
• 
non-steroidal aromatase-inhibitors (anastrozole, letrozole) 
• 
steroidal aromatase inhibitor (exemestane) 
• 
LHRH agonists in combination with tamoxifen or AI for 
premenopausal women and men 
Analysis Populations 
ITT Population: We will use intention to treat (ITT) principles to define 
the population used for the analysis of the primary endpoint and 
secondary efficacy endpoints. The ITT Population is comprised of all 
randomized patients, including those who do not start palbociclib or 
endocrine treatment. This population provides the basis for the main 
efficacy analyses. Patients will be analyzed according to the treatment 
group to which they were randomized. Randomized patients consist of 
all patients who have given their written informed consent and for whom 
there is confirmation of successful allocation of a randomization number 
through the IxRS (Interactive Voice and Web Response System). 
Safety Population (SP): For the purposes of evaluating and monitoring 
Adverse Events and all other patient safety, the Safety Population (SP) 
is defined as all randomized patients, excluding those who do not start 
palbociclib or endocrine treatment, i.e. as-treated. Patients will be 
analyzed according to treatment actually received. Randomized patients 
for whom it is unclear whether they took the palbociclib or endocrine 
treatment will be included in the safety population as randomized. 
Sample Size Calculation 
The revised total accrual is 5600 patients. A maximum of 1000 Stage IIA 
patients are to be enrolled. If the maximum is reached, the study will 
proceed to enroll only Stage IIB and III patients. 
Sample size is based on a target effect size on the hazard ratio (HR) scale 
for Arm A over Arm B of 0.75 as a clinically relevant level of 
improvement in iDFS. To have 85% power to detect this difference after 
accounting for interim analyses plans, the final analysis will occur when 
469 iDFS events are observed. 
Original assumptions: 
Total accrual is determined based on the assumed iDFS for patients on 
Arm B (standard adjuvant endocrine therapy; control) using results from 
ECOG 5103: Phase 3 randomized study of adjuvant therapy comprising  
doxorubicin    hydrochloride,    cyclophosphamide,    and 
paclitaxel with versus without bevacizumab in patients with lymph node-
positive or high-risk, lymph node-negative breast cancer48. In the 

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ER+ subset, the 5-year iDFS rate was 0.74, 0.82, and 0.92 for Stages 
III, IIB, and IIA, respectively. By simulation, it is anticipated that the 5- 
year iDFS rate will be 0.81 in Arm B for a mixed patient population with 
39% Stages III, 39% IIB and 22% IIA patients (capped). 
To define the total sample size, it is assumed that time to iDFS event and 
time to dropout follow an exponential distribution. The dropout rate is 
assumed to be 10% at 5 years. Assuming a quarterly step-wise increase 
in enrollment over the first year, and a constant rate of 153 patients per 
month thereafter, 4600 patients will be enrolled within 36 months. The 
final analysis at 469 iDFS events is anticipated to occur after 22 months 
of additional follow-up. 
Revised assumptions: 
The first patient was randomized in September 2015, and enrollment 
reached the cap of 1000 Stage IIA patients in September 2017 and closed 
to further accrual of this patient cohort. As of February 2018, over 3500 
patients have been enrolled into the study, with the rate of recruitment 
exceeding 250 during January 2018. The recruitment period is therefore 
anticipated to be shorter than originally projected. Further, contemporary 
trials investigating adjuvant treatment of hormone receptor-positive 
breast cancer have shown improved clinical outcomes and lower event 
rates. Specifically, in NSABP B-47 the 5-year iDFS rate was 0.896 and 
0.892 with and without the addition of trastuzumab to standard adjuvant 
therapy, respectively. In ABCSG-18, a randomized placebo-controlled 
study of the addition of denosumab to standard adjuvant AI therapy (n = 
3425), the 5-year iDFS rate was 0.78, 0.85, and 0.89 for Stages III, IIB, 
and IIA, respectively. In TEXT, premenopausal women received ovarian 
function suppression with anti- estrogen therapy and 5-year iDFS rate was 
0.77, 0.87, and 0.92 for Stages III, IIB, and IIA, respectively. Under an 
exponential model, the hazard ratio of iDFS in TEXT relative to the 
control arm of ECOG 5103 is 1.15, 1.42 and 1.0 for Stages III, IIB, and 
IIA, respectively, and supports an additional 1000 patients that are stage 
III or IIB, such that the study population is expected to be 41% Stages 
III, 41% IIB and 18% IIA patients (capped at 1000 patients). 
A revised total sample size of 5600 is anticipated to be enrolled within 
41 months. By simulation using (a) the actual accrual through 2017 and 
constant accrual thereafter, (b) the 5-year iDFS rates for stage IIB and 
III observed in TEXT, and (c) the original dropout rate of 10% at 5 years, 
the final analysis at 469 iDFS events is anticipated to occur after 24 
months of additional follow-up (65 months total ). 
Power is also calculated for the secondary endpoint: iDFS excluding 
second primary invasive cancers of non-breast origin as an event. Under 
the assumption that 12% of iDFS events will be second primary invasive 
cancers of non-breast origin, and time to event for this endpoint will 
follow an exponential distribution, there will be a 79.3% power to detect 
a HR = 0.75 for the secondary endpoint of iDFS 
excluding second primary invasive cancers of non-breast origin using a 

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one-sided alpha = 0.025. 
The expected study duration to primary analysis of iDFS is 5.4 years. 
Interim Monitoring and Interim 
Analysis 
Two interim efficacy analyses are planned for monitoring for futility and 
superiority, and are scheduled to occur when 33% and 67% of the total 
number of iDFS events are observed. 
The first interim analysis will take place after the first 157 iDFS events 
have occurred and the second interim analysis will take place after 
accrual is completed and 313 iDFS events have occurred. Under original 
assumptions: It is estimated that the 1st interim analysis will occur <3 
years and the 2nd interim analysis will occur <4 years after the first patient 
is randomized. Under revised assumptions: the 1st interim analysis is 
expected to occur <4 years and the 2nd interim analysis to occur <5 years 
after the first patient is randomized. 
The objective of the first interim efficacy analysis will be: 
• 
To assess safety. 
• 
To allow for early stopping of the trial due to futility. 
• 
To consider re-estimation of total sample size. 
The objective of the second interim efficacy analysis will be: 
• 
To assess safety. 
• 
To allow for early stopping of the trial due to futility. 
• 
To allow for early stopping of the trial due to overwhelming 
efficacy (superiority stopping boundary is crossed). 
• 
To consider re-estimation of total sample size. 
Although stopping the trial for overwhelming efficacy (superiority 
stopping boundary is crossed) is not considered as one of the objectives 
at the first interim analysis, the nominal alpha for the first interim analysis 
is still taken into account when calculating overall type I error. 
The following table summarizes the nominal significance level, 
corresponding hazard ratio, and 3-year and 5-year iDFS rates for each 
arm at the 2nd interim analysis and the final analysis when 67% of total 
events (313 events) or 100% of total events (469 events) are observed. 
The corresponding hazard ratio is estimated under the assumption of 
proportional hazards, and the corresponding 3-year / 5-year iDFS rates 
are estimated under the assumption of exponential distribution for iDFS. 

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Analysis 
Nominal 
α level 
(1- 
sided) 
Estimated 
Hazard 
ratio 
Estimated 
3-year 
iDFS rate for 
Estimated 
5-year 
iDFS rate for 
Control 
arm 
Palbo- 
ciclib 
arm 
Control 
arm 
Palbo- 
ciclib 
arm 
Original assumptions 
2nd 
interim 
analysis 
0.006 
0.753 
0.881 
0.909 
0.81 
0.853 
Final 
analysis 
0.0231 
0.832 
0.881 
0. 900 
0.81 
0.839 
Revised assumptions 
2nd 
interim 
analysis 
0.006 
0.753 
0.897 
0.923 
0.835 
0.876 
Final 
analysis 
0.0231 
0.832 
0.897 
0.915 
0.835 
0.863 
 
At each interim efficacy analysis, statistical hypothesis tests will be 
performed only for the primary efficacy endpoint, iDFS and the 
secondary endpoint, iDFS excluding second primary invasive cancer of 
non-breast origin. O’Brien – Fleming type stopping boundaries58 based 
on the Lan-DeMets spending function will be applied. Futility criteria 
will not be used to calculate the nominal alphas in order to control the 
overall Type I error (non-binding method). The Z-statistic from a one- 
sided, stratified logrank test will be calculated and compared to the 
stopping boundaries, and are defined on the Z-statistic scale for formal 
comparison to logrank test. In addition to the boundary and observed Z- 
statistics, the IDMC will be provided Kaplan-Meier product limit 
estimators to the survival functions for each arm, and estimated HRs 
and 95% CIs from the corresponding Cox proportional hazard models for 
iDFS. 
 
The IDMC will also be provided estimates (Kaplan-Meier, HR and 95% 
CI) for the secondary endpoint, iDFS excluding second primary invasive 
cancer of non-breast origin. 
Decision rules for sample size re-estimation at the first and second 
interim analyses will be based on the Cui, Hung and Wang61 method 
using conditional power based on the point estimate and standard error 
for the HR. Details on the sample size re-estimation and modifications 
to the stratified log-rank test to control the overall Type I error will be 
provided in the Statistical Analysis Plan (SAP). 

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II. 
Table of contents 
1. 
Background ......................................................................................................................................... 22 
1.1. 
Rationale for Patient Population: Hormone Receptor Positive Breast Cancer ........................... 22 
1.2. 
Palbociclib Mechanism of Action ............................................................................................... 22 
1.3. 
Palbociclib Preclinical Data ........................................................................................................ 23 
1.4. 
Palbociclib Pharmacokinetic (PK) Data in Humans ................................................................... 24 
1.5. 
Palbociclib Clinical Data ............................................................................................................ 29 
1.6. 
Clinical Safety Overview for Palbociclib ................................................................................... 31 
1.7. 
Palbociclib and Endocrine Therapy Pharmacokinetics ............................................................... 33 
1.8. 
Study Rationale ........................................................................................................................... 35 
2. 
Objectives ........................................................................................................................................... 39 
2.1. 
Primary Objective ....................................................................................................................... 39 
2.2. 
Secondary Objectives .................................................................................................................. 39 
2.3. 
Translational Science Principal Objective .................................................................................. 39 
2.4. 
Translational Science Additional Objectives .............................................................................. 40 
2.5. 
Clinical Science Objectives ........................................................................................................ 40 
2.6. 
Patient-Reported Outcomes Objective ........................................................................................ 40 
2.7. 
Endpoints .................................................................................................................................... 40 
3. 
Study Design ....................................................................................................................................... 41 
3.1. 
Overall Description of Study Design .......................................................................................... 41 
4. 
Patient Selection .................................................................................................................................. 43 
4.1. 
Inclusion Criteria ........................................................................................................................ 43 
4.2. 
Exclusion Criteria ....................................................................................................................... 45 
5. 
Method of Treatment Assignment/Patient Randomization ................................................................. 46 
5.1. 
Site Enrollment Requirements .................................................................................................... 46 
5.2. 
Patient Randomization Procedure ............................................................................................... 46 
5.3. 
Stratification Factors ................................................................................................................... 47 
6. 
Study Assessments and Procedures .................................................................................................... 47 
6.1. 
Study Phases ............................................................................................................................... 47 
6.2. 
Disease monitoring ..................................................................................................................... 51 
6.3. 
Informed Consent ........................................................................................................................ 51 
6.4. 
Medical History and Demographic Data ..................................................................................... 51 
6.5. 
Reporting of Concomitant Medication ........................................................................................ 52 

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6.6. 
Physical Examination and Vital Signs ........................................................................................ 52 
6.7. 
Laboratory Assessments ............................................................................................................. 53 
6.8. 
Adherence Measures ................................................................................................................... 53 
6.9. 
Patient Reported Outcome Measures .......................................................................................... 54 
6.10. 
Study measures implemented during COVID-19 Pandemic ................................................... 56 
7. 
Schedule of Assessments .................................................................................................................... 58 
8. 
Data and Specimen Submission .......................................................................................................... 61 
8.1. 
Data Collection and Submission ................................................................................................. 61 
8.2. 
Specimen Collection and Submission ......................................................................................... 62 
9. 
Study Treatment .................................................................................................................................. 64 
9.1. 
Study Treatment Overview/Terms and Descriptions .................................................................. 64 
9.2. 
Palbociclib - Investigational Product (IP) ................................................................................... 64 
9.3. 
Endocrine Therapy - Non-Investigational Product (Non-IP) ...................................................... 67 
9.4. 
Dose and Treatment Modifications ............................................................................................. 70 
9.5. 
Concomitant Medications ........................................................................................................... 77 
10. 
End of Treatment/End of Study Visits ............................................................................................ 79 
10.1. 
End of Treatment .................................................................................................................... 79 
10.2. 
End of Study ........................................................................................................................... 80 
11. 
Safety Instructions and Guidance ................................................................................................... 81 
11.1. 
Adverse Events – General Overview ...................................................................................... 81 
11.2. 
Adverse Events – Reporting Period ........................................................................................ 82 
11.3. 
Assessment of Severity of Adverse Events ............................................................................. 82 
11.4. 
Assessment of Causality of Adverse Events ........................................................................... 83 
11.5. 
Routine Adverse Event Reporting .......................................................................................... 84 
11.6. 
Expedited Adverse Event Reporting ....................................................................................... 85 
11.7. 
Expected Toxicities ................................................................................................................. 88 
11.8. 
SUSAR Reporting ................................................................................................................... 89 
12. 
Measurement of Effect .................................................................................................................... 89 
13. 
Statistical Considerations and Methodology ................................................................................... 90 
13.1. 
Overview of the Study Design ................................................................................................ 90 
13.2. 
Endpoints ................................................................................................................................ 91 
13.3. 
Analysis Populations ............................................................................................................... 92 
13.4. 
Analysis Plans for the Primary Endpoint ................................................................................ 92 
13.5. 
Sample Size, Accrual time, and Study Duration ..................................................................... 96 

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13.6. 
Study Operating Characteristics .............................................................................................. 98 
13.7. 
Analysis Plans for Secondary, Translational and PRO Endpoints .......................................... 99 
13.8. 
Correlative Science Objectives (TRANS-PALLAS) .............................................................. 99 
13.9. 
Independent Data Safety Monitoring the Study .................................................................... 100 
14. 
Correlative Sciences and Clinical Data Science ........................................................................... 100 
15. 
General Regulatory Considerations and Credentialing ................................................................. 101 
15.1. 
Regulatory and ethical compliance ....................................................................................... 101 
15.2. 
Ethics and Good Clinical Practice ......................................................................................... 101 
15.3. 
Confidentiality ...................................................................................................................... 101 
15.4. 
Protocol Amendments ........................................................................................................... 102 
15.5. 
Informed Consent .................................................................................................................. 102 
15.6. 
Financial Disclosure .............................................................................................................. 103 
15.7. 
Quality Control ..................................................................................................................... 103 
15.8. 
Protocol Deviations ............................................................................................................... 103 
15.9. 
Retention of Records ............................................................................................................. 104 
15.10. 
Trial Administrative Governance Structure .......................................................................... 104 
16. 
References ..................................................................................................................................... 106 
17. 
Appendices .................................................................................................................................... 112 
APPENDIX A: Eastern Cooperative Oncology Group (ECOG) Performance Status Criteria ....... 112 
APPENDIX B: PALLAS ~ Phases for Data Collection & Follow-Up ................................................ 113 
APPENDIX C: AJCC Cancer Staging from Edge S, Byrd DR, Compton CC, et al. AJCC cancer 
staging manual (7th ed). New York, NY: Springer; 2010 .................................................................... 114 
APPENDIX D: Recommendations on adequate local treatment for PALLAS trial candidates ...... 119 

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III. 
List of Tables 
 
Table 1 Adverse Events From 3 Randomized Studies in Patients With HR Positive, HER2 Negative 
Advanced or Metastatic Breast Cancer (N=872) 
32 
Table 2 Schedule of Assessments 
58 
Table 3 Tissue/Samples for TRANS-PALLAS translational research 
63 
Table 4 Palbociclib capsule characteristics 
64 
Table 5 Study treatment administration and dosing schedule for Arm A and Arm B 
69 
Table 6 Palbociclib Dose Levels and Dose Reduction Schedule 
74 
Table 7 AE triggered Dose Modifications and Treatment Management for Arm A 
75 
Table 8 Adverse Event Severity Grading Scale 
83 
Table 9 Adverse Events - Causal Attribution Guidance 
84 
IV. 
List of Figures 
Figure 1 PALLAS Schema 
42 
V. 
Abbreviations and Terms 
 
ABC 
Advanced Breast Cancer 
ABCSG 
ABCSG GmbH is the Austrian Breast and Colorectal Cancer Study Group (cooperative group 
sponsoring PALLAS outside the US) 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
AFT 
Alliance Foundation Trials USA (cooperative group sponsoring PALLAS in the US ) 
AJCC 
American Joint Committee On Cancer 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferases 
ALND 
Axillary lymph node dissection 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferases 
AUC 
Area Under the Curve 
AUC(0-24) 
Area under the concentration-time curve from time 0 to 24 hours after dosing 
AUCinf 
Area under the concentration-time curve from hour 0 to infinity 
BCPT 
Breast Cancer Prevention Trial Symptom Scale 
BCRP 
Breast cancer resistance protein 
BFI 
Brief Fatigue Inventory 

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BIG 
Breast International Group 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory 
BSEP 
Bile salt export pump 
CAP 
College of American Pathologists 
CCND1 
Cyclin D1 
CDK 
Cyclin-Dependent Kinase 
CDKN2A, p16Ink4A 
Cyclin-Dependent Kinase Inhibitor 2A 
cfDNA 
Circulating Cell-Free DNA 
C 
Cycle 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Plasma Concentration 
COVID-19 
Disease caused by SARS-CoV-2 infection, often synonymously used with such infection as 
well as “corona virus disease” 
CRF 
Case Report Form 
CSF 
Colony-Stimulating Factors 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
D 
Day 
DCIS 
Ductal Carcinoma In Situ 
DDFS 
Distant disease-free survival 
DDI 
Drug-drug interaction 
DFS 
Disease free survival 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DRFS 
Distant Recurrence-Free Survival 
EBC 
Early breast cancer 
EC 
Executive Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
ER 
Estrogen Receptor 
FACT 
Functional Assessment of Cancer Therapy 
FDA 
US Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GMP 
Good Manufacturing Practice 
GnRH 
Gonadotropin releasing hormone 
Hb 
Hemoglobin 
HDPE 
High Density Polyethylene 
HER 
Human Epidermal Growth Factor Receptor 
HER2 
Human epidermal growth factor receptor 2 

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HR 
Hazard ratio 
HR 
Hormone receptor 
HRQL 
Health-related QOL 
IB 
Investigator’s Brochure 
IC50 
Concentration of 50% Inhibition 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICSI 
Intracytoplasmic sperm injection 
iDFS 
Invasive disease-free survival 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IIR 
Investigator-Initiated Research 
IM 
Intramuscular 
IP 
Investigational Product; (Investigational Medicinal Product (IMP) can be used equally 
IP Treatment 
Adjuvant palbociclib treatment within Arm A 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IVF 
In-vitro fertilization 
IxRS 
Interactive Voice and Web Response System 
ITT 
Intent-to-treat 
LCIS 
Lobular Carcinoma In Situ 
LFT 
Liver Function Test 
LHRH 
Luteinizing hormone-releasing hormone 
LRRFS 
Locoregional recurrence-free survival 
LSLV 
Last Subject Last Visit 
MBC 
Metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAS-4 
Morisky Medication Adherence Scale 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
Non-IP Treatment 
(also referred to as 
Background 
Treatment) 
Standard adjuvant endocrine therapy within Arm A and B 
(according to the EU guidance document on the definition of Investigational Medicinal 
Products (IMPs) and Non Investigational Medicinal Products (NIMPs) 
[SANCO/C/8/SF/cg/a.5.001(2011)332855]) 
NSABP 
National Surgical Adjuvant Breast and Bowel Project 
OAT 
Organic anion transporter 
OATP 
Organic anion transporting polypeptide 
OCT 
Organic cation transporter 
OS 
Overall Survival 
PALLAS 
PALbociclib CoLlaborative Adjuvant Study 
Patient 
Patient participating in the study; terms patient and subject can be used equally 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
P-gp 
P-glycoprotein 
PI3K 
Phosphatidylinositol-3-kinase 
PK 
Pharmacokinetic 
PPI 
Proton Pump Inhibitor 
PR 
Partial Response or Progesterone Receptor (depending on context) 

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PR 
The PR interval is measured from the beginning of the P wave to the beginning of the QRS 
complex. 
pRB 
Retinoblastoma protein 
PRO 
Patient Reported Outcome 
Provider 
Anyone rendering medical care to the patient, including e.g., physicians, nurse practitioners, 
physician assistants, and others. 
PS 
Performance Status 
QD 
Quaque Die (once daily) 
QOL 
Quality Of Life 
QRS 
The QRS complex is a name for the combination of three of the graphical deflections seen on 
a typical electrocardiogram. 
The QRS complex reflects the rapid depolarization of the right and left ventricles. 
QT 
Time between the start of the Q wave and the end of the T wave in the heart's electrical cycle 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett's formula 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
QTcS 
QT interval corrected for heart rate according to a study-specific correction factor 
RB/Rb 
Retinoblastoma 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
RR 
The interval between an R wave and the next R wave 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SC 
Subcutaneous 
SC 
Steering Committee 
SD 
Stable Disease or Standard Deviation (depending on context) 
SmPC 
Summary of Product Characteristics 
SULT 
Sulfotransferase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time for Cmax 
TRC 
Translational Research Committee 
UICC 
Union for International Cancer Control 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
URTI 
Upper respiratory tract infection 
US 
United States 
USA 
United States of America 
Vz/F 
Apparent Volume of Distribution 
WBC 
White Blood Cells 

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1. Background 
 
1.1. Rationale for Patient Population: Hormone Receptor Positive Breast Cancer 
 
Hormone receptor positive (HR+) breast cancer is the most commonly diagnosed subset of 
breast cancer, and affects thousands of patients every year44. Endocrine therapy is highly 
effective for this subset of breast cancer. Standard adjuvant management for 
postmenopausal women with HR+ breast cancer involves adjuvant endocrine therapy for 
at least 5 years, including treatment with an aromatase inhibitor. Standard treatment for 
women with premenopausal HR+ breast cancer can include tamoxifen with or without 
ovarian suppression, or AI with ovarian suppression, and is recommended for at least 5 
years. Studies evaluating extended adjuvant endocrine therapy have suggested increased 
benefit when therapy is extended to up to 10 years. Despite this effective therapy, a 
percentage of patients will relapse with incurable metastatic disease, likely related to the 
development of resistance to endocrine therapy71. Therefore, improving the efficacy of 
adjuvant endocrine therapy would be of extraordinary benefit to a large number of breast 
cancer patients, and is an unmet medical need. 
 
A variety of novel agents targeting critical pathways in cellular growth and control are in 
development to improve the efficacy of endocrine therapy against HR+ breast cancer. Loss 
of control of the cell cycle, leading to unrestricted growth, is a classic hallmark of cancer1. 
Therefore, targeting cancers through the cyclin D1/CDK4/6 complex phosphorylates the 
retinoblastoma (pRb) protein, which leads to cell cycle activation. Results from several 
studies have indicated that CDK4 and CDK6 play an important role in estrogen stimulated 
proliferation of breast cancer cells in early to mid G1 phase84,85,86,87,88. Thus, CDK4 and 
CDK6 represent valuable therapeutic targets of HR- positive breast cancer2. 
 
1.2. Palbociclib Mechanism of Action 
 
Cell cycle inhibition is a target of choice for novel cancer therapeutics. Palbociclib (PD- 
0332991, Ibrance®), an orally active pyridopyrimidine, is a potent first-in-class, highly 
selective reversible inhibitor of CDK4 and CDK6 (IC50 = 11 nM; Ki = 2 nM) with a 
molecular weight of 447.53. Data from nonclinical studies indicate that palbociclib may 
have cytoreductive as well as cytostatic effects on tumor cells. A complete description of 
the activity and safety of palbociclib can be found in the Investigators Brochure3. 
 
The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle 
from G1 into the S phase, as demonstrated both in laboratory models and in early clinical 
trials. CDK4 and CDK6 control G1 to S phase transit by binding to D-type cyclins4-6. The 
CDK4/6/Cyclin D1 complex phosphorylates the retinoblastoma susceptibility (RB1) gene 
product (Rb), releasing the E2F and DP transcription factors that drive expression of genes 
required for S-phase entry6. CDK activity and G1 progression is negatively regulated by 
Cip-Kip and INK4 family, typified by p167-11. Overexpression of p16 in cells with normal 
Rb inhibits both CDK4-and CDK6-associated kinase activity and Rb phosphorylation, with 
subsequent cell cycle arrest12,13. 

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There is a strong link between the actions of estradiol and the G1-S phase transition, where 
the estradiol effector is the cyclin D1-CDK4/6-Rb complex14. Cyclin D1 is a direct 
transcriptional target of ER15-18 and microinjection of antibodies to cyclin D1 inhibits 
estrogen-induced S-phase entry19-23. In addition, anti-estrogen-induced growth arrest of 
ER+ breast cancer cells is accompanied by decreased cyclin D1 expression24 while 
endocrine resistance is associated with persistent cyclin D1 expression and Rb 
phosphorylation25. Consistent with the notion that the main function of cyclin D1 is to 
activate CDK4/6, its oncogenic activity is dependent on CDK4/6-associated kinase 
activity26 and CDK4/6 inhibitors may be most more effective in tumors with gene 
amplification and overexpression of cyclin D127-29, which is common in ER+ breast cancer. 
For example, palbociclib was most effective for ER+ breast cancer in a cell line panel30, 
including those that exhibited anti-estrogen resistance. Genetic aberrations leading to 
hyperactivation of cyclin D1-CDK4/6 is particularly common in ER+ breast cancer, 
consistent with its critical role in the tumorigenesis of this cancer subtype30, making 
CDK4/6 inhibitors particularly attractive agents for ER+ breast cancer. 
 
1.3. Palbociclib Preclinical Data 
 
Palbociclib preclinical data indicate that it may be expected to have direct effect on growth 
arrest as well as potential secondary cytoreductive activity. Single agent palbociclib has 
shown antiproliferative effects (selective G1 arrest) on Rb-positive cancer cells in vitro and 
in vivo28 where palbociclib activity was associated with reduced Rb- phosphorylation and 
decreased expression of the cell proliferation marker Ki67. Palbociclib showed no activity 
in Rb-negative tumor cell xenografts, consistent with CDK4/6 inhibition as the sole mode 
of action28. 
 
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. Of note for this study, ER+ 
breast cancer seems to be particularly appropriate for treatment with palbociclib; sensitive 
cell lines in this panel represent mostly the luminal ER+ subtype30. 
 
The combination of palbociclib with tamoxifen has been tested in vitro in ER+ human 
breast cancer cell lines indicating a synergistic interaction30 and provided a biologic 
rationale for evaluating the combination of palbociclib with anti-hormonal therapy in the 
clinic. Also, data in hormone resistant models (MCF7-CYP19) indicate a significant 
benefit from the combination of palbociclib and letrozole as well as palbociclib and 
fulvestrant over single agent letrozole and fulvestrant31. 

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The nonclinical safety profile of palbociclib has been well characterized through the 
conduct of single- and repeat-dose toxicity studies up to 39 weeks in duration, and safety 
pharmacology, genetic toxicity, reproductive and developmental toxicity, phototoxicity, 
and carcinogenicity studies. Consistent with the pharmacologic activity of palbociclib (cell 
cycle inhibition, CDK4/6 inhibition), the primary target organ findings included 
hematolymphopoietic (decreased cellularity of bone marrow and lymphoid organs) and 
male reproductive organ (seminiferous tubule degeneration, and secondary effects on the 
epididymis, prostate, and seminal vesicle) effects in rats and dogs, and altered glucose 
metabolism that was accompanied by effects on the pancreas and secondary changes in the 
eye, teeth, kidney, and adipose tissue in rats only, and effects on bone in rats only that were 
observed following single and/or repeat dosing at clinically relevant exposures. Altered 
glucose metabolism (hyperglycemia/glucosuria) correlated with pancreatic islet cell 
vacuolation that was determined to reflect a loss of beta cells with corresponding decreases 
in insulin and C-peptide. The reversibility of the effects on glucose homeostasis, pancreas, 
eye, kidney, and bone was not established following a 12-week non-dosing period; whereas 
partial to full reversal of effects on the hematolymphopoietic and male reproductive 
systems, teeth, and adipose tissue were observed. Additionally, a potential for QTc 
prolongation and hemodynamic effects were identified from safety pharmacology studies, 
and developmental toxicity was identified from embryo-fetal development studies in the 
rat and rabbit. Though gastrointestinal effects would be anticipated from a cell cycle 
inhibitor and while effects were observed in rats and dogs following single- and repeat-
dose studies up to 3 weeks in duration (emesis, fecal changes, and microscopic changes in 
stomach and intestines), the effects were of limited severity at clinically relevant doses. 
Gastrointestinal effects were not prominent in longer duration studies, limited to effects 
on the glandular stomach and rodent-specific effects on the non-glandular stomach in rats 
following 27 weeks of intermittent dosing that did not reverse during a 12-week non-dosing 
period. Additional palbociclib-related findings considered non-adverse at tolerated doses 
based on limited severity and/or absence of degenerative changes included cellular 
vacuolation in multiple tissues that was morphologically consistent with phospholipidosis; 
hepatic (increases in liver enzymes, hepatocellular hypertrophy/increased vacuolation), 
renal (increased CPN), adrenal (cortical cell hypertrophy), and respiratory (clinical signs, 
tracheal epithelial cell atrophy) effects; and prolonged coagulation times. Reversibility 
(partial or full) was established for these additional toxicities. Palbociclib was determined 
to be an aneugen. A palbocliclib-related neoplastic microscopic finding included an 
increased incidence of malignant microglial cell tumors in the central nervous system of 
male rats at exposures higher than clinically relevant exposures. The relevance of the 
neoplastic finding in male rats to humans is not known, however, no cases of microglial 
cell tumors were reported in humans as of the data‑lock point, 02 February 2018. 
 
1.4. Palbociclib Pharmacokinetic (PK) Data in Humans 
 
As of 31 August 2016, twenty-seven clinical studies have evaluated the PK of palbociclib. 
Eight of these trials were conducted in patients with advanced malignant disease. Nineteen 
Phase 1 clinical pharmacology and biopharmaceutic studies of 

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palbociclib were conducted in healthy subjects. Eleven of these 19 clinical trials were 
clinical pharmacology studies conducted to investigate the absorption, distribution, 
metabolism, and excretion of palbociclib as well as examine the potential for drug-drug 
interactions (DDIs) with palbociclib. The remaining 8 of the 19 clinical trials were 
biopharmaceutic studies conducted to examine the bioavailability, bioequivalence, and 
food effect of the palbociclib formulations. 
 
Pharmacokinetic (PK) data from patients with advanced cancer from Study A5481001 
indicate that the plasma pharmacokinetics of palbociclib are low to moderately variable 
with generally dose proportional exposures over the dose range evaluated (25 mg to 225 
mg) following single and multiple doses. PK data from Studies A5481001, A5481003, 
A5481010 and A541019 indicate that palbociclib is slowly absorbed with a median time 
of maximum concentration (Tmax) between 4 and 8 hours post-dose, and is slowly 
eliminated with an elimination half-life (t1/2) ranging from 23.2 hours to 28.8 hours. 
Palbociclib accumulates after repeated daily dosing (median Rac ranged from 1.9 to 2.4), 
which was consistent with its terminal t1/2. In both Studies A5481010 and A5481019, the 
median Rss (the predicted accumulation to estimate linearity) was 1.1, indicating that 
palbociclib clearance does not change over time. In Study A5481003, palbociclib was 
shown to achieve steady-state concentrations following 8 days of QD dosing. The 
palbociclib geometric mean volume of distribution (Vz/F) was 2583 L in patientswith 
advanced breast cancer (Study A5481003), which is significantly greater than total body 
water (42 L), indicating that palbociclib extensively distributes to peripheral tissues. 
 
In humans, metabolism is the major route of elimination of palbociclib. Following a 
single oral administration of [14C] palbociclib to healthy subjects (Study A5481011), the 
overall median recovery of the administered radioactivity in the excreta was 91.6% with a 
median of 17.5% recovered in urine and a median of 74.1% recovered in feces. Excretion 
of unchanged palbociclib in the feces and urine was 2.3% and 6.9% of dose, respectively, 
indicating that excretion plays a minor role in elimination of palbociclib. A study in healthy 
volunteers (A5481015) indicated that the absolute oral bioavailability of palbociclib was 
approximately 46%. 
 
In vitro data indicate that CYP3A and sulfotransferase (SULT) enzyme SULT2A1 are 
mainly involved in the metabolism of palbociclib. Palbociclib is a weak time-dependent 
inhibitor of CYP3A following daily 125 mg dosing to steady state in humans. In vitro, 
palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not 
an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations. 
 
In vitro evaluations indicated that palbociclib has a low potential to inhibit the activities 
of drug transporters P-glycoprotein (P-gp, systemically), breast cancer resistance protein 
(BCRP, systemically), organic anion transporter (OAT)1, OAT3, organic cation 
transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1, OATP1B3, and 
bile salt export pump (BSEP) at clinically relevant concentrations. In vitro, palbociclib 
has the potential to inhibit OCT1 at clinically relevant concentrations, as well as the 
potential to inhibit P-gp or BCRP in the gastrointestinal tract at the proposed clinical 
dose. Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the 
extent of oral absorption of palbociclib at therapeutical doses. 

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An itraconazole DDI study in healthy volunteers (Study A5481016) and a rifampin DDI 
study in healthy volunteers (Study A5481017) were conducted to evaluate the potential for 
strong CYP3A inhibitors and inducers, respectively, to alter the PK of palbociclib. Co-
administration of itraconazole and palbociclib increased palbociclib AUCinf and Cmax by 
approximately 87% and 34%, respectively, relative to those when palbociclib dose was 
given alone. Co-administration of rifampin and palbociclib decreased palbociclib AUCinf 
and Cmax by approximately 85% and 70%, respectively, relative to palbociclib given alone. 
Based on this data, the concurrent administration of strong CYP3A inhibitors and inducers 
with palbociclib should be avoided. 
 
A midazolam DDI study in healthy volunteers (Study A5481012) was conducted to 
evaluate the potential for palbociclib to act as a time-dependent inhibitor of CYP3A4/5 at 
steady-state. Plasma midazolam Cmax and AUCinf values increased 37% and 61%, 
respectively, when single oral doses of midazolam were co-administered with multiple 
doses of palbociclib as compared to its administration alone. This is consistent with weak 
time-dependent CYP3A4/5 inhibition mediated by palbociclib at steady-state following 
daily 125 mg dosing. 
 
PK data from the Phase 1 portion of Study A5481003 was analyzed to evaluate the potential 
for a drug-drug interaction (DDI) between palbociclib and letrozole at steady- state. These 
data indicate a lack of a potential for DDIs between palbociclib and letrozole when 
administered in combination. 
 
Data from a DDI study in healthy fasted subjects in Study A5481026 indicated that 
palbociclib exposures were comparable when a single dose of palbociclib was co- 
administered with multiple doses of tamoxifen and when palbociclib was given alone. 
 
The effect of food on the exposure of palbociclib, when administered as the commercial 
free base capsule, was evaluated in healthy subjects (A5481021). The study results indicate 
that palbociclib absorption and exposure were very low in approximately 13% of the 
population under the fasted condition. Food intake increased the palbociclib exposure in 
this small subset of the population, but did not alter palbociclib exposure in the rest of the 
population to a clinically relevant extent. Administration of palbociclib with or in between 
meals significantly reduced the intersubject variability (%CV). Based on these results, 
palbociclib commercial free base capsules should be taken with food. 
 
The solubility of the palbociclib free base is pH dependent—palbociclib is water soluble at 
low pH (2.1-4.5), while the solubility dramatically decreases as pH rises above 4.5. 
Concomitant administration of agents which increase gastric pH can alter the solubility and 
absorption of palbociclib free base formulations. 
 
In a drug interaction trial in healthy subjects (A5481038), co-administration of a single 125 
mg dose of commercial free base capsule with multiple doses of the proton pump inhibitors 
(PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited 
impact on AUCinf (13% decrease), when compared to a single dose of palbociclib 
administered alone. Given the reduced effect on gastric pH of H2-receptor antagonists and 
local antacids compared to PPIs, the effect of these classes of acid- 

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reducing agents on palbociclib exposure under fed conditions is expected to be minimal. 
Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, 
or local antacids on palbociclib exposure. In another healthy subject study (Study 
A5481018), co-administration of a single dose of commercial free base capsule with 
multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf 
and Cmax by 62% and 80%, respectively, when compared to a single dose of palbociclib 
administered alone. Collectively, these antacid DDI data further support the requirement 
that the free base capsule of palbociclib should be taken with food. 
 
Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 
133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 
123 kg), gender had no effect on the exposure of palbociclib, and age and body weight had 
no clinically important effect on the exposure of palbociclib. 
 
Based on a population pharmacokinetic analysis that included 183 advanced cancer patients 
from Studies A5481001, A5481002, and A5481003, where 40 patients had mild hepatic 
impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 
× ULN and any AST), and 1 patient had moderate hepatic impairment (total bilirubin 
>1.5 to 3.0 × ULN and any AST), indicated that there was no effect of mild hepatic 
impairment on the PKof palbociclib. The effect of moderate and severe hepatic impairment 
on the PK of palbociclib could not be evaluated as the pooled dataset included only 1 
patient with moderate hepatic impairment and no patients with severe hepatic impairment. 
 
PK analysis of the data from a separate hepatic impairment study (Study A5481013) in 
subjects with mild, moderate and severe hepatic impairment (as defined by Child-Pugh 
classification) was conducted to evaluate the impact of hepatic impairment on the PK of 
palbociclib. The mean fraction of unbound (fu) palbociclib in plasma increased 
incrementally with worsening hepatic function. Plasma palbociclib unbound exposure 
(AUCinf,u) decreased by approximately 17% in subjects with mild hepatic impairment 
(Child Pugh class A) and increased by approximately 34% and 77% in subjects with 
moderate (Child Pugh class B) and severe hepatic impairment (Child Pugh class C), 
respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound 
exposure (Cmax,u) increased by approximately 7%, 38% and 72% for mild, moderate and 
severe impairment, respectively, relative to subjects with normal hepatic function. Based 
on these data, no dose adjustment is required for patients with mild or moderate hepatic 
impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment 
(Child-Pugh class C), the recommended dose of palbociclib is 75 mg QD on Schedule 
3/1. 
 
Based on a population pharmacokinetic analysis that included 183 advanced cancer patients 
from Studies A5481001, A5481002, and A5481003, where 73 patients had mild renal 
impairment (60 mL/min ≤ CrCl < 90 mL/min) and 29 patients had moderate renal 
impairment (30 mL/min ≤ CrCl < 60 mL/min), and no patients with severe renal 
impairment (CrCl < 30 mL/min), indicated that there was no effect of mild or moderate 
renal impairment on the PK of palbociclib. 

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PK analysis of the data from a separate renal impairment study (Study A5481014) in 
subjects with mild, moderate and severe renal impairment was conducted to evaluate the 
impact of renal impairment on the PK of palbociclib. The observed fu in this study was 
consistent with the in vitro determined fu in human plasma, and there appeared to be no 
obvious trend in the mean fu with worsening renal function. Plasma palbociclib AUCinf 
increased modestly, ranging from 31% to 42% in subjects with mild, moderate, and severe 
renal impairment relative to subjects with normal renal function. Plasma palbociclib Cmax, 
increased by 17%, 12%, and 15% for mild, moderate, and severe impairment, respectively, 
relative to subjects with normal renal function. Based on these data, no dose adjustment is 
required for patients with mild, moderate or severe renal impairment. 
 
A pharmacokinetic/pharmacodynamic analysis to evaluate the relationship between 
palbociclib exposure and ECG variables (RR interval and QTc) was developed using data 
from postmenopausal women with ER-positive, HER2 negative advanced breast cancer 
enrolled in the QTc analysis subgroup included in Study A5481008 that was conducted 
as the definitive QT interval prolongation evaluation for the palbociclib program. A total 
of 125 patients were enrolled in this subgroup to evaluate the effect of palbociclib on the 
QT interval. Of these 125 patients, 77 were randomized to the palbociclib plus letrozole 
treatment arm and 48 were randomized to the placebo plus letrozole arm. A total of 2597 
recorded individual QT intervals and 322 palbociclib concentrations obtained from 77 
palbociclib plus letrozole-treated patients were included in the analysis dataset. The median 
(range) age and baseline body weight of patients in the analysis dataset was 62.0 (36-86) 
years and 72.3 (48.1-157) kg, respectively. Among the 77 patients, 70 patients provided a 
total of 320 matched PK-ECG pairs to evaluate the relationship between palbociclib 
exposure and ECG variables (RR interval and QTc). Following administration of a 
therapeutic regimen of 125mg palbociclib QD in combination with 
2.5 mg letrozole QD, the observed plasma concentrations of palbociclib had a median 
(range) of 88.0 (14.7-210) ng/mL in the PK-ECG matched data. The average heart rate, RR 
interval, QT interval, QT interval corrected for heart rate according to Bazett (QTcB), QT 
interval 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 PK-
ECG matched data were 76.0 beats per minute, 811 msec, 384 msec, 429 msec, 413 msec, 
and 415 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 predicted upper bound of the one- sided 95% CI 
for the increase in QTcS was less than 10 msec. Palbociclib, when added to letrozole, did 
not prolong the QT interval to a clinically relevant extent at the recommended dosing 
regimen according to the criteria described in the ICH guidance for Industry E14 (ICH 
E14). Similar results were obtained when QTcF and QTcB were used. 
 
An analysis to assess the relationship between palbociclib exposure and ECG endpoints 
(RR interval and QTc) was performed previously using pooled data from 3 clinical trials 

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in patients with advanced malignant disease (Studies A5481001, A5481002, and 
A5481003). Results from this analysis, which included data from palbociclib doses ranging 
from 25 mg to 225 mg QD and included a male population in addition to females, yielded 
the same overarching conclusion that palbociclib did not prolong the QT interval to a 
clinically meaningful extent at the recommended clinical dose (125 mg QD) according to 
the criteria described in the ICH guidance for Industry E14 (ICH E14). 
 
 
1.5. Palbociclib Clinical Data 
 
1.5.1. Phase I Palbociclib Monotherapy Studies 
 
Palbociclib has been tested in a Phase 1 dose escalation Study (A5481001) in 74 
patients with advanced cancer. Two dosing schedules were evaluated: Schedule 
3/1 (3 weeks on treatment/1 week off treatment) and Schedule 2/1 (2 weeks on 
treatment/1 week off treatment). All dose limiting toxicities (DLTs) observed in 
this study were related to myelosuppression and mainly consisted of Grade 3 
neutropenia lasting more than 7 days after the end of the treatment cycle. However, 
neutropenia was reversible and non-cumulative. The most common non-
hematological adverse events included fatigue, anemia, diarrhea, constipation, 
vomiting and dyspnea, all with mild to moderate severity. A greater proportion of 
patients on the 2/1 schedule had treatment emerged adverse events (TEAEs) during 
and after Cycle 1 than patients on the 3/1 schedule although the proportion of 
patients with treatment-related neutropenia was similar with respect to the 2 dosing 
schedules, both during and after Cycle 1. One partial response (PR) was reported 
in a patient with testicular cancer. A total of 13/37 patients treated with Schedule 
3/1 evaluable for efficacy experienced stable disease (SD), including 6 patients 
with SD lasting 40 weeks or longer. 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 has been selected for further clinical 
development and the RP2D for this schedule was determined to be 125 mg/day. 
This schedule and associated RP2D was further explored in combination with 
letrozole in the Phase I/II study in patients with advanced breast cancer described 
below. 
 
1.5.2. Phase II palbociclib monotherapy study in advanced breast cancer 
 
A phase II study evaluated single agent palbociclib in 37 women with advanced 
breast cancer35. Palbociclib was dosed at 125 mg orally, days 1- 21 of a 28-day 
cycle. The study population was 84% (HR)+/HER2-, 5% HR+/HER2+ and 11% 
HR-/HER2-, with a median of 2 prior cytotoxic regimens. Grade 3/4 toxicities were 
primarily hematologic including 51% with grade 3 neutropenia, and 51% requiring 
dose reduction for toxicity. Two patients experienced a PR, and 5 others had stable 
disease for at least 6 months, giving a clinical benefit rate of 

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19%, including 21% in HR+ and 29% in HR+/Her2- who had progressed through 
> 2 prior lines of hormonal therapy. Assessment of potential biomarkers of 
response, including Rb expression/localization, KI-67, p16 loss and CCND1 
amplification, did not identify a candidate tumor population. In conclusion, therapy 
with palbociclib monotherapy was considered well-tolerated, and demonstrates 
clinical benefit primarily in patients with HR+/HER2- breast cancer, including 
those with progression on prior hormonal- and chemotherapy. 
 
1.5.3. Phase I/II trial of palbociclib in combination with letrozole in advanced breast cancer 
 
A randomized, multicenter active-controlled Phase 1/2 Study (A5481003, 
PALOMA-1) was designed to assess the efficacy, safety and PK of letrozole 2.5 
mg QD (continuously) in combination with palbociclib 125 mg QD (schedule 
3/1) versus single agent letrozole 2.5 mg QD (continuously) for the first-line 
treatment of ER+/ HER2- advanced breast cancer in postmenopausal women36. 
Letrozole was selected as the active control based on its worldwide approval and 
use as standard of care for the first-line hormonal treatment of postmenopausal 
women with ER+ advanced breast cancer. 
 
Study A5481003 was comprised of a limited Phase 1 portion, aimed at confirming 
the safety and tolerability of the combination and excluding a PK interaction with 
the combination, and a randomized Phase 2 portion aimed at evaluating the 
efficacy and safety of letrozole in combination with palbociclib when compared to 
letrozole alone in the first-line treatment of postmenopausal patients with 
ER+/HER2- advanced breast cancer. The Phase 2 portion consisted of 2 parts. In 
Part 1, patient selection was based only on ER/HER2 status. In Part 2, patients 
were prospectively selected also taking into account potential biomarkers: tumor 
CCND1 amplification and/or p16 loss. A total of 177 patients were enrolled in the 
study. Twelve (12) were enrolled in the Phase 1 portion and 165 (66 and 99 in Part 
1 and 2, respectively) were enrolled in the Phase 2 portion. 
 
Results from the Phase 1 portion37 indicated no PK interaction between palbociclib 
and letrozole with mean AUC(0-24) of 2047 and 2021 ng•hr/mL (n=12) for 
palbociclib in the absence and presence of letrozole, respectively, and 2027 and 
1776 ng•hr/mL (n=11) for letrozole in the absence and presence of palbociclib, 
respectively. The RP2D was determined to be 125 mg QD on Schedule 3/1 (3 
weeks continuous treatment followed by 1 week off treatment) in combination with 
letrozole 2.5 mg QD continuously. PRs were reported for 3 (33%) out of 9 patients 
with measurable disease (3 had bone-only disease). Another 5 patients (42%) had 
stable disease for ≥ 6 months and the clinical benefit rate (PR + SD ≥ 6 months) 
was 67%. 
 
Final results of the Phase 2 portion of the study demonstrated an improvement in 
the primary endpoint point of progression-free survival (PFS) for the entire study 
population from 10.2 months with letrozole alone, to 20.2 months with the 
combination of letrozole and palbociclib (Hazard Ratio 0.488, p = 0.0004), and an 
increase in response rate from 33% to 43%36. Evaluation of Cohorts 1 and 2 

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found improvements in both groups with the addition of palbociclib, but no 
apparent correlation between presence of biomarker and improved outcomes 
(Cohort 1, PFS 5.7 vs 26.1 mo, Hazard Ratio 0.299, p<0.0001; Cohort 2 PFS 
11.1 vs 18.1 mo, Hazard Ratio 0.508, p = 0.0045). No statistically significant OS 
improvement in overall survival was observed in this small population (OS 33.3 
months letrozole vs 37.5 months letrozole and palbociclib, Hazard Ratio 0.813, p 
= 0.2105). 
 
The toxicity profile in PALOMA-1 was generally favorable and indicates that the 
combination of palbociclib with letrozole is well tolerated with a safety profile 
similar to that seen with either palbociclib or letrozole when administered alone. 
The most common toxicities observed with exposure to palbociclib included 
hematologic; 54% of patients receiving combination therapy experienced grade 3/4 
neutropenia, however infectious complications, including febrile neutropenia, were 
not observed. Serious adverse events that occurred in more than one patient 
included pulmonary embolism (4%), back pain (2%), and diarrhea (2%). About 
40% of patients required a delay or dose reduction due to toxicity; a total of 11 
patients in the combination arm discontinued therapy due to treatment-related 
toxicity versus 2 in the letrozole alone arm. Other observed all-grade toxicities 
included nausea (26%), vomiting (14%), diarrhea (19%), and alopecia (19%). At 
2 years of follow-up from this study, the cumulative incidence of neutropenia 
remained stable (75.8%), suggesting the hematologic toxicity of palbociclib occurs 
early in treatment and no data support long-term or cumulative hematologic 
toxicity after exposure to palbociclib. 
 
Multiple trials are ongoing in advanced breast cancer to better define the role of 
palbociclib in metastatic ER+/HER2- disease. This includes two global 
randomized Phase 3 studies have completed enrollment and are still ongoing: 
Study A5481008, a study of letrozole +/- palbociclib in front-line advanced breast 
cancer (ABC) and Study A5481023, a study of fulvestrant +/- palbociclib in 
recurrent ABC. 
 
In February 2015, based on the published data in PALOMA-1, the Food and Drug 
Administration granted accelerated approval to palbociclib, to be used in 
combination with letrozole for initial endocrine-based therapy for metastatic breast 
cancer in postmenopausal women with ER+/HER2- advanced breast cancer. 
 
1.6. Clinical Safety Overview for Palbociclib 
 
The overall safety profile of palbociclib is based on pooled data from 872 patients who 
received palbociclib in combination with endocrine therapy (N=527 in combination with 
letrozole; N=345 in combination with fulvestrant) in 3 randomized clinical trials in HR- 
positive, HER2-negative advanced or metastatic breast cancer. Table 1 presents adverse 
drug reactions of any grade reported in these 3 clinical trials. The most common AEs were 
neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, and 
diarrhea. The most common (≥ 2%) Grade ≥ 3 AEs were neutropenia, leukopenia, 

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anemia, fatigue, and infections. Dose reductions or dose modifications due to any AEs 
occurred in 34.4% of patients regardless of the combination. Permanent treatment 
discontinuation associated with AEs as occurred in 4.1% of patients. 
 
Table 1. 
Adverse Drug Reactions From 3 Randomized Studies in Patients With HR Positive, 
HER2 Negative Advanced or Metastatic Breast Cancer (N=872) 
System Organ Class 
Frequency 
Preferred Terma 
All Grades 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Infections and infestations 
Very common 
523 (60.0) 
53 (6.1) 
9 (1.0) 
Infectionsb 
Blood and lymphatic system disorders 
Very common 
Neutropeniac 
719 (82.5) 
499 (57.2) 
101 (11.6) 
Leukopeniad 
430 (49.3) 
260 (29.8) 
8 (0.9) 
Anemiae 
261 (29.9) 
48 (5.5) 
2 (0.2) 
Thrombocytopeniaf 
197 (22.6) 
17 (2.0) 
4 (0.5) 
Common 
Febrile neutropenia 
13 (1.5) 
11 (1.3) 
2 (0.2) 
Metabolism and nutrition disorders 
Very common 
160 (18.3) 
8 (0.9) 
0 (0.0) 
Decreased appetite 
Nervous system disorders 
81 (9.3) 
0 (0.0) 
0 (0.0) 
Common 
Dysgeusia 
Eye disorders 
Common 
Vision blurred 
49 (5.6) 
1 (0.1) 
0 (0.0) 
Lacrimation increased 
62 (7.1) 
1 (0.1) 
0 (0.0) 
Dry eye 
39 (4.5) 
0 (0.0) 
0 (0.0) 
Respiratory, thoracic and mediastinal disorders 
Common 
77 (8.8) 
12 (1.4) 
0 (0.0) 
1 (0.1) 
0 (0.0) 
0 (0.0) 
Epistaxis 
ILD/pneumonitisi (identified post-marketing)i 
Gastrointestinal disorders 
Very common 
Stomatitisg 
269 (30.8) 
8 (0.9) 
0 (0.0) 
Nausea 
317 (36.4) 
5 (0.6) 
0 (0.0) 
Diarrhoea 
243 (27.9) 
10 (1.1) 
0 (0.0) 
Vomiting 
167 (19.2) 
6 (0.7) 
0 (0.0) 
Skin and subcutaneous tissue disorders 
Very common 
Rashh 
164 (18.8) 
8 (0.9) 
0 (0.0) 
Alopecia 
235 (27.0) 
0 (0.0) 
0 (0.0) 
Dry skin 
96 (11.0) 
0 (0.0) 
0 (0.0) 
General disorders and administration site conditions 
Very common 
Fatigue 
366 (42.0) 
26 (3.0) 
2 (0.2) 
Asthenia 
120 (13.8) 
14 (1.6) 
0 (0.0) 

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Table 1. 
Adverse Drug Reactions From 3 Randomized Studies in Patients With HR Positive, 
HER2 Negative Advanced or Metastatic Breast Cancer (N=872) 
System Organ Class 
Frequency 
Preferred Terma 
All Grades 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Pyrexia 
121 (13.9) 
1 (0.1) 
0 (0.0) 
Investigations 
Very common 
Alanine aminotransferase increased 
96 (11.0) 
18 (2.1) 
2 (0.2) 
Aspartate aminotransferase Increased 
104 (11.9) 
22 (2.5) 
0 (0.0) 
N/n=number of patients 
a. Preferred terms (PTs) are listed according to Medical Dictionary for Regulatory Activities (MedDRA) 19.0, 
unless otherwise noted. 
b. INFECTIONS includes all PTs that are part of the System Organ Class Infections and infestations. 
c. 
NEUTROPENIA includes the following PTs: Neutropenia, Neutrophil count decreased. 
d. LEUKOPENIA includes the following PTs: Leukopenia, White blood cell count decreased. 
e. 
ANEMIA includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased. 
f. 
THROMBOCYTOPENIA includes the following PTs: Thrombocytopenia, Platelet count decreased. 
g. STOMATITIS includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth 
ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. 
h. RASH includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, 
Dermatitis, Dermatitis acneiform, Toxic skin eruption. 
i 
ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial lung 
disease (narrow). 
 
The adverse drug reaction table (Table 1) includes data from the studies A5481003, 
A5481008 and A5481023 with cut-off date 15 November 2018.. 
 
Overall, neutropenia of any grade was reported in 719 (82.5%) patients regardless of the 
endocrine therapy combination, with 499 (57.2 %) being Grade 3 and 101 (11.6%) being 
Grade 4 (Table ). Eleven (1.3%) patients permanently discontinued due to neutropenia. 
13(1.5%) patients experience febrile neutropenia, of which 11 (1.3 %) were Grade 3 and 
2 (0.2%) was Grade 4. 
 
 
1.7. Palbociclib and Endocrine Therapy Pharmacokinetics 
 
Results from the Phase 1 portion of PALOMA-1 indicated no PK interaction between 
palbociclib and letrozole with mean AUC (0-24) of 2002 and 2043 ng•hr/mL (n=11) for 
palbociclib in the absence and presence of letrozole. 
 
The potential for a DDI between palbociclib and tamoxifen is considered to be probable 
based on in vitro data. Multiple enzymes are responsible for the metabolism of tamoxifen 
and its active metabolites including CYP3A4, CYP2C9, and CYP2D6. In vitro evidence 
suggest that tamoxifen and one of its primary active metabolites, 4-hydroxy-tamoxifen, are 
inducers of CYP3A4 enzymes. In clinical trials, co-administration of tamoxifen with 
letrozole and anastrozole (both CYP3A4 substrates) has resulted in decreased exposures 
(AUC) of each by 37% and 27%, respectively. Palbociclib is a CYP3A4 substrate and 
CYP3A4 is thought to be the primary route of the oxidative metabolism of palbociclib. 

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Thus, the co-administration of tamoxifen and palbociclib may lead to lower circulating 
levels of palbociclib and require an upward dose adjustment in palbociclib if these two 
compounds are used in conjunction. Additionally, time-dependent inhibition of CYP3A4 
has been observed in preclinical studies of palbociclib. 
 
The effect of multiple dosing of tamoxifen (60 mg QD for 4 days followed by 20 mg QD 
for 23 days), on the single-dose PK of palbociclib (125 mg), was evaluated in 25 healthy 
fasted subjects in Study A5481026. Administration of palbociclib in the presence of 
tamoxifen and its metabolites (4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, and 4- 
hydroxy-N-desmethyl-tamoxifen) at steady state showed that palbociclib exposure was 
comparable with that when palbociclib was given alone. The ratios (90% CIs) of the 
adjusted geometric means of palbociclib AUCinf and Cmax were 108% (104%-111%) and 
116% (105%-129%), respectively, following administration of palbociclib with multiple 
doses of tamoxifen (Test) relative to palbociclib administered alone. These results indicate 
that it is not necessary to adjust palbociclib starting dose when co-administering with 
tamoxifen3. A two-way DDI assessment between palbociclib and tamoxifen in cancer 
patients has been incorporated into the ongoing PENELOPEB Study92,93. 
 
The potential for a clinically significant DDI between palbociclib and anastrozole is 
considered to be low. Anastrozole inhibited CYP1A2, 2C8, 2C9, and 3A4 in vitro with 
Ki values ~30-fold higher than the steady-state Cmax values observed following a 1mg daily 
dose. In vitro and in vivo assessments of oxidative metabolism have indicated the route of 
formation of the primary metabolite hydroxyanastrozole is predominantly through 
CYP3A4. Time dependent inhibition of CYP3A4 has been observed in in vitro studies of 
palbociclib, thus palbociclib has the potential to inhibit the primary clearance pathway of 
anastrozole. A two-way DDI assessment between palbociclib and anastrozole has been 
incorporated into the ongoing PENELOPEB Study 92. 
 
The potential for a clinically significant 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, co-administration of ketoconazole, a potent inhibitor of CYP 3A4, 
had no significant effect on exemestane pharmacokinetics. Therefore, it is unlikely that 
palbociclib, which is a weak time-dependent inhibitor of CYP34, will have an effect on 
exemestane PK. A two-way DDI assessment between palbociclib and exemestane has been 
incorporated into the ongoing PEARL Study92, 93. An interim analysis of the PK data from 
the PEARL Study indicated there is no clinically relevant DDI between palbociclib and 
exemestane when the 2 drugs are coadministered97. 
 
The potential for a clinically significant DDI between palbociclib and goserelin is 
considered to be very low. Goserelin is a synthetic decapeptide analogue of gonadotropin 
releasing hormone (GnRH) whose primary route of elimination is the cleavage of C- 
terminal amino acids followed by renal excretion. No formal drug-drug interaction studies 
have been performed and no confirmed interactions have been reported between 

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goserelin and other drugs. A DDI assessment between palbociclib and goserelin has been 
included into two ongoing studies; A5481023 and the PENELOPEB Study. 
 
1.8. Study Rationale 
 
Although many patients with HR+/HER2- breast cancer may be cured of their disease with 
optimal local and systemic therapy, a significant number of patients with stage II and III 
disease will experience disease recurrence. Adjuvant endocrine therapy for breast cancer 
can be extremely effective, particularly with extension beyond 5 years, however disease 
recurrence can occur, with risk distributed over the decades following initial diagnosis. 
Methods to improve the efficacy of endocrine therapy, and delay the onset of resistance, 
are needed. 
 
HR+ breast cancer biologically may demonstrate features suggestive of sensitivity to 
CDK4/6 inhibition with agents such as palbociclib. Given the demonstrated activity and 
safety of palbociclib in the first-line treatment of metastatic HR+/ HER2- breast cancer, 
supporting FDA approval, there is interest in whether the benefits of CDK4/6 inhibition 
may translate into the adjuvant setting. The purpose of the PALLAS study is to determine 
whether the addition of palbociclib to adjuvant endocrine therapy will improve outcomes 
over endocrine therapy alone for HR+/HER2- early breast cancer. Assessment of a variety 
of correlative analysis, including evaluation of the effect of palbociclib in genomically 
defined tumor subgroups, is planned. 
 
Complete information for palbociclib (PD-0332991 or Ibrance®) may be found in the 
Single Reference Safety Document for the compound, which for this study is the applicable 
current version of the Investigator's Brochure of palbociclib. The Single Reference Safety 
Document for the active comparator agents, letrozole, anastrozole, exemestane, tamoxifen 
and LHRH agonists will be the publicly available US Package inserts, or local equivalent 
depending on country-specific regulations. 
 
1.8.1. Rationale for the Duration of Palbociclib Treatment 
 
The specific elements of the rationale for evaluation of 2 years of treatment with 
palbociclib in the adjuvant treatment setting are outlined in detail throughout 
Section 1. These include risk of recurrence in the proposed population, mechanism 
of action of the drug, potential synergistic effects when given with hormonal 
therapy, information to date about the pattern of hematologic effects over time, and 
specific elements put in place to ensure optimal monitoring and iterative 
assessment of the safety profile. 
 
Given that the annual odds of the risk of disease recurrence in HR positive, HER2 
negative EBC are consistent and distributed quite evenly up to >20 years from the 
initial diagnosis, extending the length of endocrine therapy has been proven to be 
associated with increased benefits38,39. Similar to an anti-estrogen agent, 
palbociclib inhibits the proliferation of ER-positive breast cancer but is not known 
to cause apoptosis or cell death. 

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While senescence is an appealing mechanism of cell demise and is indeed observed 
in vitro after exposure of breast cancer cells and tumors to a combination of 
endocrine therapy and palbociclib89, the data in human trials are lacking about the 
degree of cell demise caused by combined palbociclib and anti- ER treatment. 
Moreover, in vitro data showed that, after removing palbociclib and/or the anti-ER 
agent, the cells can eventually re- start to divide90. Considering the synergistic 
mechanism of action with anti-hormonal agents and synergistic signaling through 
the same CDK4/6 dependent mechanism, it is likely that the anti-proliferative 
mechanism of action will require longer treatment for optimal antitumor effect. 
The benefit of increasing the length of treatment was clearly demonstrated for 
anti-hormonal agents when years of testing taught us that an enhanced benefit of 
tamoxifen in patients with EBC could be achieved by extending the length of 
therapy. Increased benefit with extending the length of therapy has also been 
demonstrated for other anticancer agents in other tumors (e.g. Gleevec® in 
gastrointestinal stromal tumor and chronic myelogenous leukemia). Thus, as 
predicted mechanistically, it is hypothesized that the longer a patient receives 
combined treatment with palbociclib and an antiestrogen, the more likely they may 
receive prolonged clinical benefit. 
 
It is therefore proposed to administer palbociclib for 2 years under close 
monitoring of emerging safety data both before PALLAS start and during the 
clinical trial. 
 
1.8.2. Rationale for the Collection of Tissue and Blood Samples 
 
The preclinical data cited above suggested specific tumor alterations as predictors 
of response based upon palbociclib’s mechanism of action. However, analyses of 
cell cycle biomarkers in the PALOMA-1 study and others did not identify a 
predictive marker beyond estrogen receptor (ER) 91. While ER is a strong positive 
predictor of response, not all ER+ patients will initially respond to the 
combination of endocrine therapy and palbociclib, and in others, resistance will 
emerge. Furthermore, no prospective evaluation of the predictive capacity of ER 
receptor as a biomarker is available in humans, and the limited number of 
patients with ER- disease treated with palbociclib precludes comparative 
analysis. Within the cohort of patients with ER + disease, ongoing efforts are 
needed to identify tumors and patients that will derive the greatest benefit from 
CDK4/6 inhibition, particularly in the curative setting. A robust biospecimen 
bank is essential to accomplishing this task; primary tumor tissue collection will 
be mandatory for all patients enrolled on the PALLAS trial. The resulting tumor 
bank will provide an invaluable resource to evaluate a large range of potential 
biomarkers, both through pre-specified analyses and exploratory investigations. 
Molecular analyses of breast cancer, pioneered by Perou and colleagues in 2000, 
have identified different subtypes of this disease, such as Luminal A, Luminal B, 
basal-like, HER2 type, etc.40. Each subtype of breast cancer has its distinct 
molecular features, and the disease prognosis for each subtype is different. In 
addition to clinical parameters, such as tumor size, grade, and node status, 
subtyping breast cancer may help in decisions about treatment options. 

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The preclinical development of palbociclib, demonstrated the greatest sensitivity 
(as evidenced by the lowest IC50) to palbociclib in tumors of the luminal 
subtype94. 
 
In PALLAS, molecular tests will be applied to the tumor samples from all patients 
enrolled in the study. This test will be performed retrospectively, and a 
prospectively defined analysis will be conducted to assess the response to 
palbociclib plus endocrine therapy in Luminal A and Luminal B patients and in the 
non-luminal subtype (further details in SAP). 
 
ER targeting and estrogen signaling blocking therapies, such as tamoxifen and AIs, 
have been proven to be effective treatments for ER-positive breast cancer. 
However, de novo and acquired resistance to anti-hormonal therapies may occur. 
Possible mechanisms of resistance include the presence of variant ER, ER 
mutations, the absence or loss of ER and altered expression of receptor- interacting 
proteins42,43. Those tumor features will be evaluated in PALLAS specimens as well 
as other potential factors influencing benefits of adding a CDK 4/6 inhibitor to 
standard endocrine therapy. Furthermore, collection of serum samples serially 
during PALLAS follow up will provide the opportunity to examine developing 
processes of tumor resistance and emergence from tumor dormancy. 
 
Additional planned analysis to identify predictors of therapeutic benefit by adding 
palbociclib to endocrine therapy include candidate gene approaches, such as 
examining genes, proteins, and RNAs relevant to cell cycle (e.g., CCND1 
amplification, CDKN2A loss), drug target (CDK4/6), and tumor sensitivity and/or 
resistance (Ki67, pRb, cyclin E, etc.). Global gene profiling such as whole exome 
sequencing may be applied to a subset of samples in this study, if patient tumor 
volume of samples allow. Planning and execution of these translational studies 
are overseen by the TRANS-PALLAS subcommittee. For details of translational 
analysis please refer to translational sub protocols and translational statistical 
analysis plan. 
 
1.8.3. Rationale for Patient Reported Outcome (PRO) Assessments 
 
Patient Reported Outcomes Questionnaires should be incorporated in order to 
evaluate the impact of adjuvant endocrine therapy with or without palbociclib on 
the quality of life (QOL) of HR+/HER2- breast cancer patients and provide a 
comprehensive risk benefit assessment that includes the patient perspective in 
addition to efficacy and safety. The questionnaires can evaluate the impact of 
treatment and related side effects on symptoms, functioning and global QOL. In 
addition to known side effects of tamoxifen therapy (e.g. hot flushes, weight 
gain, vaginal bleeding), AIs have a different toxicity profile with side effects, such 
as arthralgia, myalgia, joint pain, bone loss, cognitive dysfunction, increased risks 
of rash, nausea, diarrhea and vomiting. AIs, however, have been shown to have 
less vaginal bleeding and thromboembolic complication (i.e., 71% decreased risk 
of vaginal bleeding and 47% decreased risk of thromboembolic 

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events) than tamoxifen67,68. In addition, results of the ATAC study showed that 
patients treated with AIs have more symptoms of vaginal dryness, pain on 
intercourse and loss of sexual interest than patients receiving tamoxifen therapy. 
During that trial, some endocrine related symptoms (hot flushes, night sweats, 
gynaecological and sexual symptoms) improved during the study period, while 
other symptoms (reduced libido and vaginal dryness) persisted68,69. Similarly, 
patients treated with AI (letrozole) in the MA.17 study showed significant 
differences in night sweats, aching in muscles and joints, difficulty sleeping and 
vaginal dryness compared to the placebo group. Those patients had worse bodily 
pain domain scores assessed with the SF-36 and more vasomotor symptoms as 
assessed with the MENQOL instrument70. 
 
Application of targeted drugs (e.g., palbociclib) in the therapy of breast cancer 
has showed significant clinical benefit, but may introduce new side effects. In the 
Phase I/II trial (A5481003) of palbociclib in combination with letrozole in 
ER+/HER2-negative advanced breast cancer in postmenopausal women, the most 
frequently reported treatment-related adverse events included neutropenia, 
leukopenia, anemia, fatigue, nausea, hot flush, alopecia, arthralgia, diarrhea, 
decreased appetite, headache, dyspnea, asthenia, vomiting and cough36. The 
significance of these symptoms and impact on patient functioning and global QOL 
will be evaluated in PALLAS study. 
 
1.8.4. Benefit-Risk Assessment 
 
As described above, HR+ breast cancer is the most commonly diagnosed subset of 
breast cancer, and affects thousands of patients every year. Despite the efficacy of 
up to 10 years of adjuvant endocrine therapy, a percentage of patients will relapse 
with incurable metastatic disease, with risk extending for many years after initial 
diagnosis. Therefore, improving the efficacy of adjuvant endocrine therapy would 
be of extraordinary benefit to a large number of breast cancer patients, and is an 
unmet medical need. 
 
Data from PALOMA-1 has demonstrated a significant prolongation of median 
progression-free survival with the combination of palbociclib and letrozole 
compared with letrozole alone. The toxicity profile of palbociclib at the dose and 
schedule similar to the one that will be used in the PALLAS study was moderate, 
with neutropenia being the most frequent treatment related adverse event. The 
clinical picture of neutropenia seen with the palbociclib/letrozole combination in 
PALOMA-1 is notable for being quickly reversible, noncumulative and 
uncomplicated and managed without the use of growth stimulating factors. The 
data generated from PALOMA-1 has supported accelerated approval by FDA in 
the US of palbociclib in combination with letrozole for advanced HR+/HER2- 
breast cancer. 
 
In the PALLAS trial, all study participants are expected to have undergone 
adequate initial local treatment for their breast cancer including surgical resection, 
with or without adjuvant radiotherapy. For details, please refer to 

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Appendix D. Participants are also expected to have selected an appropriate 
systemic therapy plan, with or without chemotherapy and have decided to receive 
endocrine therapy. All patients, regardless of randomization arm, will receive 
standard adjuvant endocrine treatment according to institutional standards. It is not 
expected that toxicity of palbociclib will reduce compliance with endocrine 
treatment. 
 
As described before, there are no obvious differences in the clinical and laboratory 
safety profile between patients taking palbociclib for less than 12 months 
compared to those taking the drug for 12 months or longer based on data collected 
in clinical studies to date. It is concluded that the data available do not identify any 
safety concerns associated with long term administration of palbociclib. Given the 
increasing use of longer duration endocrine therapy and the known prolongation 
of cancer recurrence risk well beyond 5 years, palbociclib therefore will be 
administered for 2 years. 
 
In addition, participating patients in the current trial will have marginal additional 
burden due to investigations required for study participation (e.g. additional visits 
at the site, additional blood tests, and completion of questionnaires). However, 
the option to receive a treatment potentially significantly improving iDFS in this 
population is considered to balance uncertainties of the toxicity profile of 
palbociclib and the additional burden related to study investigations. 
 
2. Objectives 
 
2.1. Primary Objective 
 
To compare invasive disease-free survival (iDFS) for the combination of at least 5 years 
endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine 
therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast 
cancer (EBC). 
 
2.2. Secondary Objectives 
 
(1) 
To compare the following endpoints: iDFS excluding second primary invasive cancers 
of non-breast origin, distant recurrence-free survival (DRFS), locoregional 
recurrences-free survival (LRRFS), and overall survival (OS). 
(2) 
To compare the safety of 2 years of palbociclib with adjuvant endocrine therapy versus 
adjuvant endocrine therapy alone. 
 
 
 
2.3. Translational Science Principal Objective 

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(1) To compare baseline tumor tissue to determine whether there is prognostic or predictive 
utility for defined genomic subtypes (luminal A, luminal B and non- luminal) with 
respect to iDFS and OS. 
 
2.4. Translational Science Additional Objectives 
 
(1) 
To evaluate iDFS and OS in other genomically-defined breast cancer prognostic, 
theranostic, or predicted subgroups based on pre-specified genomic assays 
(2) 
To evaluate baseline tumor- and blood-based markers as predictors of benefit from 
the addition of palbociclib to endocrine therapy. 
(3) 
To evaluate tumor- and blood-based markers at time of disease recurrence for 
mechanisms of resistance to palbociclib and endocrine therapy. 
(4) 
To perform exploratory analyses of serum and plasma samples over time to investigate 
the predictive and prognostic value of novel biomarkers in this specific trial setting 
related to efficacy or safety of the agent. 
(5) 
To compare serial levels of circulating cell-free DNA (cfDNA) in patients receiving 
palbociclib and endocrine therapy versus endocrine therapy alone. 
(6) 
To evaluate pharmacogenomic and pharmacogenetic predictors of toxicity and 
efficacy of palbociclib and endocrine therapy and to endocrine therapy alone. 
 
2.5. Clinical Science Objectives 
 
(1) 
To evaluate adherence to oral therapy in patients receiving palbociclib and endocrine 
therapy. 
(2) 
To determine the association of BMI with the efficacy of palbociclib and endocrine 
therapy. 
 
2.6. Patient-Reported Outcomes Objective 
 
(1) To compare patient-reported quality of life, fatigue, arthralgia, alopecia, menstrual 
function, and endocrine symptoms of HR+/HER2- breast cancer patients randomized 
to receive palbociclib plus adjuvant standard endocrine therapy versus standard 
endocrine therapy alone overall and by subgroups defined by age at randomization 
(≤50 and >50) and initial endocrine therapy (tamoxifen and AI) at multiple pre- 
specified time points. 
 
2.7. Endpoints 
 
2.7.1. Primary Endpoint 
 
(1) 
Invasive disease-free survival (iDFS) defined according to STEEP criteria. 
 
2.7.2. Secondary Endpoints 

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(1) 
Invasive disease-free survival (iDFS) excluding second primary invasive cancers 
of non-breast origin as an event. 
(2) 
Overall Survival (OS) 
(3) 
Locoregional recurrences-free survival (LRRFS) defined as the composite of 
local/regional ipsilateral recurrence, contralateral invasive breast cancer or death 
from any cause 
(4) 
Distant recurrence free survival (DRFS) is defined according to STEEP criteria 
as the composite of distant recurrence or death from any cause. 
(5) 
Adverse Events 
 
2.7.3. 
Clinical Science Endpoints 
 
(1) 
Adherence measured by Drug Diary, Morisky Medication Adherence Scale, 
Medication Adherence and McHorney Brief Estimator questionnaires in a subset 
of patients. 
(2) 
Primary endpoint (iDFS) effected by baseline body mass index (BMI). 
 
2.7.4. Patient-Reported Outcomes Endpoint 
 
(1) 
Actual Scores and Change from baseline in functioning, symptoms, and global 
QOL 
 
2.7.5. Translational Science Principal Endpoint 
 
(1) 
Biomarker(s) reflective of or associated with breast cancer luminal subtypes 
 
3. Study Design 
 
3.1. Overall Description of Study Design 
 
This is a two-arm, randomized, open label, Phase III, multicenter study to evaluate the 
effect on iDFS of combining at least 5 years of adjuvant standard endocrine therapy and 2-
year adjuvant palbociclib treatment (Arm A) versus at least 5 years of adjuvant standard 
endocrine therapy alone (Arm B) in pre-and postmenopausal women and men with HR+ / 
HER2-, Stage II or III (Stage IIA limited to 1000 patients) early invasive breast cancer 
patients. 

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Figure 1: PALLAS Study Schema 
 
Endocrine adjuvant therapy may have started before randomization and be ongoing at 
that time. 
 
Approximately 5600 patients (revised target accrual) from approximately 500 global sites 
will be randomized into one of the two treatment arms with a 1:1 randomization ratio. The 
dosing schedule for both Arms, and potential dose reduction strategies, are given in section 
9: 
 
Arm A: palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 
days off treatment in a 28-day cycle for a total duration of 2 years (refer to 6.1.2 for details), 
in addition to standard adjuvant endocrine therapy for a duration of at least 5 years. 
 
Arm B: standard adjuvant endocrine therapy for a duration of at least 5 years 
 
Standard endocrine therapy (also referred to as background treatment) can be tamoxifen 
or aromatase inhibitor with or without LHRH agonist. 
 
In order to participate in the trial, a patient must fulfill all inclusion criteria and must not 
meet any of the exclusion criteria. Furthermore, a patient will need to consent for study 
participation and to the collection storage and analysis of his/her blood and tumor tissue 
samples for biomarker research as specified in section 14. Prior to randomization, a 

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representative tumor tissue block must be made available to the central sample 
repository. 
 
4. Patient Selection 
 
4.1. Inclusion Criteria 
Please note that waivers to eligibility requirements are not allowed. 
 
Patients must meet the following criteria for study entry: 
 
4.1.1. Patient/Disease Specifics 
 
(1) 
Signed informed consent obtained prior to any study specific assessments and 
procedures. 
(2) 
Age ≥18 years (or per national guidelines). 
(3) 
Premenopausal and postmenopausal women or men with Stage II (Stage IIA 
limited to a maximum of 1000 patients) or Stage III early invasive breast cancer 
per AJCC (American Joint Committee on Cancer) Breast Cancer Staging version 
7 / UICC (Union for International Cancer Control)54. Baseline staging to document 
absence of metastatic disease is not required, however is recommended as 
determined by institutional practice (in patients where there may be a reasonable 
suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph 
nodes, signs and symptoms). If performed, reports of these examinations must be 
available. Examination type for staging, i.e. X-ray, sonography, bone scan, CT, 
MRI, and/or PET-CT, is at the discretion of the investigator. 
If neoadjuvant systemic therapy was received (either chemotherapy or 
endocrine therapy or biologic therapy excluding 'Anti-HER2 treatment'), 
either initial clinical stage (determined by physical and/or radiologic 
examination) or post-operative pathologic stage can be used for eligibility 
purposes, with the higher stage determining eligibility. 
(4) 
Patients with multicentric and/or multifocal and/or bilateral early invasive breast 
cancer whose histopathologically examined tumors all meet pathologic criteria for 
ER+ and/or PR+ and HER2-. 
(5) 
Patients must have histologically confirmed hormone receptor positive (ER+ 
and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 
measurements should be performed according to institutional guidelines, in a 
CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-
off values for positive/negative staining should be in accordance with current 
ASCO/CAP (American Society of Clinical Oncology/College of American 
Pathologists) guidelines55, 95. Patients with equivocal HER2 in situ hybridization 
results according to current ASCO/CAP guidelines are eligible, as long as they 
have not received and are not scheduled to receive anti-HER2 treatment. Testing 
may occur on diagnostic core or surgical tumor tissue. 
(6) 
Patients must have undergone adequate (definitive) breast surgery for the current 
malignancy. For details please refer to Appendix D. 
(7) 
A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be 

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transmitted to a central sample repository and confirmation of receipt must be 
available prior to randomization. For details please refer to section 8.2. 
(8) 
ECOG performance status 0-1. 
(9) 
Patients must be able and willing to swallow and retain oral medication without a 
condition that would interfere with enteric absorption. 
(10) 
Serum or urine pregnancy test must be negative within 7 days of randomization, in 
women of childbearing potential. Pregnancy testing does not need to be pursued 
in patients who are judged as postmenopausal before randomization, as determined 
by local practice, or who have undergone bilateral oophorectomy, total 
hysterectomy, or bilateral tubal ligation. Women of childbearing potential and 
male patients randomized into treatment Arm A or B must use adequate 
contraception for the duration of protocol treatment and for 6 months after the last 
treatment with palbociclib if they are in arm A. In addition, patients receiving 
standard adjuvant endocrine therapy (Arm A and Arm B) should use adequate 
contraception in accordance with the specific medication requirements (e.g. 
Summary of Product Characteristics). Adequate contraception is defined as one 
highly effective form (i.e. abstinence*, (fe)male sterilization) OR two effective 
forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal 
foam / gel / film / cream / suppository). 
 
*Abstinence is to be interpreted as “true abstinence” for heterosexual intercourse 
and therefore, “periodic abstinence” (e.g. calendar, symptothermal, post- ovulation 
methods) and withdrawal (coitus interruptus) are not considered highly effective. 
 
 
4.1.2. Prior Treatment Specifics 
 
(11) 
Patients may or may not have received neo/adjuvant therapy, but must be after last 
dose of chemotherapy and/or biologic therapy and must have sufficient resolution 
of side effects per physician assessment at the time of randomization. 
(12) 
Patients may or may not have received breast/axilla/ post-mastectomy chest wall 
radiotherapy, but must be after last dose of radiotherapy and must have sufficient 
resolution of side effects per physician assessment at the time of randomization. 
(13) 
Patients must have sufficient resolution of any surgical side effects from the last 
surgery per physician assessment, with no active wound healing complications at 
the time of randomization. 
(14) 
Patients must either be initiating or have already started adjuvant hormonal 
treatment. Patients may already have initiated endocrine therapy at the time of 
randomization, but randomization must take place within 12 months of date of 
histological diagnosis and within 6 months of initiating standard adjuvant 
endocrine therapy. Patients who received neoadjuvant endocrine therapy are 
eligible as long as they are randomized within 12 months of initial histological 
diagnosis and after completing no more than 6 months of adjuvant endocrine 
therapy. Patients may be receiving either tamoxifen or aromatase inhibitor (AI: 
letrozole, anastrozole, or exemestane). For premenopausal patients and men, 
concurrent LHRH agonist use is allowable and may also be ongoing at the time 

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of randomization. If a LHRH agonist was used for ovarian protection during 
neo/adjuvant chemotherapy it is allowable and shall not be taken into account for 
calculations regarding the 6 months standard adjuvant endocrine therapy. 
 
4.1.3. Baseline Body Function Specifics 
 
(15) 
Absolute neutrophil count ≥ 1,500/mm3. 
(16) 
Platelets ≥ 100,000/mm3. 
(17) 
Hemoglobin ≥ 10g/dL. 
(18) 
Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin 
within normal range in patients with documented Gilbert’s Syndrome. 
(19) 
Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT 
or SGPT) ≤ 1.5 × institutional ULN. 
(20) 
Serum creatinine below the upper limit of the institutional normal range (ULN) 
or creatinine clearance (or glomerular filtration rate [GFR]) ≥ 60 mL/min/1.73 m2 
for patients with serum creatinine levels above institutional ULN. 
 
4.2. Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry: 
 
(1) 
Concurrent therapy with other Investigational Products. 
(2) 
Prior therapy with any CDK inhibitor. 
(3) 
Patients with Stage I or IV breast cancer are not eligible. Baseline staging to 
document absence of metastatic disease is not required, however is recommended 
as determined by institutional practice (in patients where there may be a reasonable 
suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph 
nodes, signs and symptoms). If performed, reports of these examinations must be 
available. Examination type for staging, i.e. X-ray, sonography, bone scan, CT, 
MRI, and/or PET-CT, is at the discretion of the investigator. 
(4) 
History of allergic reactions attributed to compounds of chemical or biologic 
composition similar to palbociclib. 
(5) 
Patients receiving any medications or substances that are potent inhibitors or 
inducers of CYP3A isoenzymes within 7 days of randomization (see Section 
9.5.2.1 for list of CYP3A inhibitors and inducers). 
(6) 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, diabetes, or psychiatric illness/social situations that would limit 
compliance with study requirements. Ability to comply with study requirements 
is to be assessed by each investigator at the time of screening for study 
participation. 
(7) 
Pregnant women, or women of childbearing potential without a negative 
pregnancy test (serum or urine) within 7 days prior to randomization, irrespective 
of the method of contraception used, are excluded from this study because the 
effect of palbociclib on a developing fetus is unknown. Breastfeeding must be 
discontinued prior to study entry. 

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(8) 
Patients with a history of any malignancy are ineligible except for the following 
circumstances: 
• 
Patients with a malignancy history other than invasive breast cancer are 
eligible if they have been disease-free for at least 5 years and are deemed by 
the investigator to be at low risk for recurrence of that malignancy. 
• 
Patients with the following cancers are eligible, even if diagnosed and treated 
within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer 
in situ, and non-metastatic non-melanomatous skin cancers. 
(9) 
Patients are not eligible if they have previously received endocrine therapy within 
5 years prior to diagnosis of the current malignancy. This includes use for 
prophylactic reasons, including treatment of osteoporosis or cancer prevention 
with tamoxifen, raloxifene or AI. Patients may concurrently receive 
bisphosphonates or rank ligand inhibitors while on this study if necessary for 
treatment or prevention of osteopenia or osteoporosis. 
(10) 
Patients on antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions or increased immunosuppression with palbociclib. 
(11) 
Patients with clinically significant history of chronic liver disease, including 
chronic/active viral or other known hepatitis, current alcohol abuse, or cirrhosis, 
etc. 
(12) 
Patients receiving concurrent exogenous hormone therapy (hormone replacement 
therapy, oral or any other hormonal contraceptives such as hormonal contraceptive 
coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable. 
 
5. Method of Treatment Assignment/Patient Randomization 
 
5.1. Site Enrollment Requirements 
 
Following regulatory and ethical approval for each participating site, it is the 
responsibilities of the respective Sponsor (AFT for US sites, ABCSG for non-US sites) to 
formally activate sites according to local obligations. Sites will only be able to enroll 
patients once formal site activation has been performed by the Sponsor. 
 
5.2. Patient Randomization Procedure 
 
After written informed consent has been obtained, the study site will obtain a unique patient 
number or unique patient identifier which will stay the same throughout the entire study 
covering all study periods (as described in section 6.1.) via an interactive voice and/or web-
based response system (IxRS). At this time point the patient is enrolled into the study. 
 
Once eligibility has been established and the patient specific tumor block has been 
confirmed as received at the central sample repository, the patient may be randomized, and 
the site will obtain the patient’s treatment assignment (Arm A or Arm B) from the IxRS. 
As this is an open label trial, treatment assignments will not be blinded. Patients enrolled 
but not randomized for any reason have to be registered as Screening Failure in IxRS. 

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5.3. Stratification Factors 
 
Patients will be randomized into one of the treatment arms in a 1:1 ratio. 
Stratification factors used at time of randomization include: 
• 
Anatomic stage (IIA vs IIB/III), assessed by pathologic staging or by clinical staging 
if pre-operative therapy was given with the higher stage determining eligibility, 
• 
Neo/adjuvant chemotherapy (yes vs no), 
• 
Age (≤ 50 vs > 50 years), 
• 
Geographic region (North America vs Europe vs Other) 
 
6. Study Assessments and Procedures 
 
6.1. Study Phases 
 
The study consists of 4 different phases which apply to both of Arms A and B: 
• 
Screening Phase 
• 
Treatment Phase 
• 
Follow-Up Phase I 
• 
Follow-Up Phase II 
 
See Appendix B for details as to how these phases correspond with the Schedule of 
Assessments calendar, Screening Phase, Treatment Phase and Follow-Up Phases I and II 
(please also refer to Sections 7, 9, and 10). 
 
6.1.1. Screening Phase 
 
The Screening Phase is the time between the date a patient provides written 
informed consent, and the time the patient completes randomization. Data 
collection and procedures during this time period include patient demographics, 
eligibility requirements, concomitant medications, type of endocrine therapy, 
medical history, physical examination/vital signs, ECOG performance status 
assessment, laboratory measurements, pregnancy testing (if applicable), 
biospecimens (blood and tissue samples), and PRO assessments (see sections 7). 
During the Screening Phase, only AEs deemed to be serious (SAEs) and related 
to protocol mandated and not routinely performed procedures have to be reported. 
 
During the Screening Phase, all laboratory assessments must be performed within 
14 days of randomization. If screening assessments occur within 7 days before 
Cycle 1 Day 1, then they may serve as the Cycle 1 Day 1 assessments also and do 
not need to be repeated. 
 
Male patients should be specifically informed about the fact that the effect of 
palbociclib on sperm production is not entirely clear. Therefore it is recommended 
for men who want to have children at a later time, to consider 

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sperm preservation prior to beginning therpay with palbociclib. Additionally men 
should not donate semen or father a child within treatment phase and 6 months 
thereafter. 
 
6.1.2. Treatment Phase 
 
During this phase, patients randomized into Arm A will receive IP treatment 
(palbociclib) and Non-IP treatment and patients randomized into Arm B will 
receive Non-IP treatment only (standard endocrine therapy). 
Treatment Phase for patients on both Arms can start at the day of randomization 
if both IP and Non-IP treatment are initiated on that day. However, patients will 
have the opportunity to start treatment within 7 days from randomization. For 
patients on Arm B, who have already started Non-IP treatment prior to 
randomization (maximum of 6 months adjuvant endocrine therapy) the date of 
randomization will be considered as start of the Treatment Phase as well as Cycle 
1 Day 1. 
 
As the intention is to administer at least 5 years of endocrine therapy alone (Arm 
B), or with 2 years of concurrent palbociclib (Arm A), 2 years will be used as the 
time period for this phase. IP treatment is to be given for 2 years, which is a total 
of twenty-six 28-days cycles (for patients without interruptions or delays) and the 
goal is not to administer a specific number of cycles, but to allow for completion 
of a cycle if it has started prior to two years from randomization. Patients will not 
be allowed to begin a new IP cycle once 2 years after start of IP treatment have 
elapsed. Therefore, the Treatment Phase is the time period between Day 1 of Cycle 
1 and the date of completion of 2 years of therapy, or the trigger date for early end 
of treatment phase (e.g. occurrence of an iDFS event), including the final 
assessment 30-42 days thereafter for AE/SAE safety reporting purposes. Study 
treatment with palbociclib and standard endocrine therapy (if not already started 
prior to randomization) must begin within 7 days after randomization. This phase 
is the time period applicable to more “intensive” data collection and required 
procedures, including physical examination/vital signs, ECOG performance status 
assessment, adverse events, serious adverse events, IP dispensation, concomitant 
medications, measurements of treatment adherence (see Section 6.8), laboratory 
measurements, biospecimens collection (including blood samples as well as 
samples of local/regional ipsilateral and/or distant metastatic recurrences and/or 
contralateral breast cancers, according to the respective guidelines or manuals), 
recurrence status determination (disease monitoring, see Section 6.2 for details), 
and PRO assessments (see sections 7 and 9). 
 
Patients will continue with the Treatment Phase or begin the subsequent phases 
under the following conditions: 
 
(1) Begin Follow-Up Phase I upon completion of 2 years of IP treatment in 
combination with Non-IP therapy (Arm A) or 2 years of Non-IP therapy 
(Arm B) following randomization. 

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(2) Continue in Treatment Phase if patient permanently discontinues IP therapy 
(Arm A) within 2 years of Day 1 of Cycle 1 due to non-iDFS event reasons, 
but continues Non-IP treatment (see section 10.1). This includes the visits 
required by the Schedule of Assessments through the completion of this phase. 
Types of delays or interruptions in IP dosing which will not trigger 
discontinuation of IP treatment are specified in Section 9.4.2.1. 
(3) Begin Follow-Up Phase I if both IP and Non-IP therapy are permanently 
discontinued within 2 years of Day 1 of Cycle 1 for non-iDFS event related 
reasons (Arm A). Types of delay in Non-IP therapy that will not trigger 
permanent discontinuation of Non-IP therapy are described in Section 9.4.1. 
(4) Begin Follow-Up Phase I if Non-IP therapy is permanently discontinued 
within 2 years of randomization for non-iDFS event related reasons (Arm B). 
Types of delay in Non-IP that will not trigger discontinuation of Non-IP are 
described in Section 9.4.1. 
(5) Discontinue IP therapy, perform an End of Treatment Phase Visit and begin 
Follow-Up Phase II if patient experiences an iDFS event at any time during 
Treatment Phase (Arm A). 
(6) Patients on Arm B experiencing an iDFS event at any time during Treatment 
Phase will perform an End of Treatment Phase Visit and begin Follow-Up 
Phase II. 
(7) Randomized patients on either Arm who are deemed ineligible to receive study 
treatment (IP and/or Non-IP treatment) prior to first dose, or refusing to start 
their initial treatment will move to Follow-Up Phase I. 
(8) Patients randomized to Arm A, who are deemed ineligible after starting IP 
therapy may be allowed to continue with IP therapy and remain in the 
Treatment Phase. However, this is a medical decision that will be made on a 
case by case basis upon approval after review by regionally assigned medical 
monitors and using the applicable process described in the Protocol Deviation 
Management Plan and/or Medical Monitoring Manual for the study. In case 
the medical monitor decides to stop IP treatment, the patient should begin 
Follow-Up Phase I. 
(9) Patients deemed ineligible after being randomized to Arm B will stop the 
Treatment Phase and enter into Follow-Up Phase I. However, this is a decision 
that will be made on a case by case basis upon approval after review by 
regionally assigned medical monitors and using the applicable process 
described in the Protocol Deviation Management Plan and/or Medical 
Monitoring Manual for the study. 
(10) 
Patients who are non-compliant or discontinue Study Treatment for non- 
iDFS event reasons, should be encouraged to complete an End of Treatment 
Phase Visit and continue participation for long term follow-up and move to 
Follow-Up Phase I. 
(11) 
Withdrawal of consent for all study participation will end patient activity 
in the study and clinical follow up. 
 
 
6.1.3. Follow-Up Phase I 

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Follow-Up Phase I covers years 3 through 5, after randomization and will begin 
for both treatment Arms upon completion of the Treatment Phase (e.g. at least 2 
years (refer to 6.1.2) after randomization/Cycle 1 Day 1, unless the Treatment 
Phase ends earlier for non-iDFS event reasons). During Follow-Up Phase I, patient 
visits should be performed every six months. Half year visits can be performed via 
phone calls from the site to the patient or provider or as in person visits; yearly 
visits should be in person. Expected visit dates are calculated based on the 
randomization date. For patients who terminate the Treatment Phase per protocol, 
the first Follow-Up visit (Follow-Up Phase I) will be 30 months after 
randomization (+/- 35 days) and subsequently every six months thereafter until 
patient completes 5 years after randomization or experiences an iDFS event (→ 
move to Follow-Up Phase II). For patients who are early end of Treatment Phase 
for non-iDFS event reasons, Follow-Up Phase I visits may occur at months 6, 12, 
18 and 24 after randomization (depending on the actual early end of Treatment 
Phase date) and until patient completes 5 years following randomization. 
Endocrine therapy (Non-IP) is allowed to continue in this phase. Patients will be 
followed even if endocrine therapy is permanently discontinued. Information 
collected during this Phase will include: serious adverse events (if related to 
palbociclib - IP therapy), recurrence status determination (disease monitoring, see 
Section 6.2 for details), PRO assessments, biospecimens (including samples of 
local/regional ipsilateral and/or distant recurrences and/or contralateral breast 
cancers, according to the respective guidelines or manuals), and limited 
information on all breast and/or non-breast anti-cancer related therapies have to be 
recorded (see section 7). 
 
Patients will continue with Follow-Up Phase I or begin the Follow-Up Phase II 
under the following conditions: 
 
(1) Once the patient has already entered Follow-Up Phase I, continue with Follow-
Up Phase I even if all Non-IP therapies are permanently discontinued for non-
iDFS event reasons. 
(2) Continue with Follow-Up Phase I if patient is deemed ineligible during this 
phase. 
(3) Begin Follow-Up Phase II upon reaching 5 years post randomization without 
occurrence of an iDFS event. 
(4) Begin Follow-Up Phase II if a patient experiences an iDFS event during 
Follow-Up Phase I. 
 
6.1.4. Follow-Up Phase II 
 
Follow-Up Phase II is the time period where information on extended adjuvant 
endocrine treatment (more than 5 years) and patient status will be collected 
annually by in person visits or phone contacts to the patient or provider until a 
maximum of 10 years after randomization. For patients who terminate the 
Treatment Phase and Follow-Up Phase I per protocol, the first regular Follow-Up 
Phase II visit will be 72 months after randomization (+/- 56 days) and subsequent 

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Follow-Up Phase II visits every 12 months thereafter until a maximum of 10 years 
after randomization have elapsed. 
For patients who are early end of Treatment Phase or early end of Follow Up Phase 
I for iDFS event reasons, Follow-Up Phase II visits may occur at months 12, 24, 
36, 48 and 60 after randomization (depending on the actual early end of Treatment 
Phase or Follow-Up Phase I date) and annually thereafter until patient completes a 
maximum of 10 years following randomization. Patients will be followed up even 
if endocrine (Non-IP) therapy is permanently discontinued. Information collected 
during this phase includes: serious adverse events (if related to palbociclib – IP 
treatment), recurrence status determination (disease monitoring, see Section 6.2 
for details), biospecimens (including tissue samples of local/regional ipsilateral 
and/or distant recurrences and/or contralateral breast cancers), and limited 
information on all breast and/or non-breast anti-cancer related therapies have to be 
recorded (see section 7). 
 
At the visits in year 7 and year 10 collection of additional blood samples is 
foreseen, to obtain circulating cfDNA as well as plasma samples from all available 
patients at those time points. 
 
Patients will continue with Follow-Up Phase II if patient experiences an iDFS 
event during Follow-Up Phase II. 
 
At the conclusion of this phase, or if a patient has withdrawn consent for further 
participation, patients will be considered to have reached their “End of Study Visit” 
(section 10) and all new data collection will cease. 
 
6.2. Disease monitoring 
 
All patients, including those who discontinue protocol therapy early, will be followed for 
oncological events (for details and definitions refer to section 12) and death per ASCO 
guidelines63 until the End of Study Visit (a maximum of 10 years after randomization for 
each single patient). 
 
6.3. Informed Consent 
 
Informed consent form (ICF) may be obtained greater than 30 days before randomization; 
however, it must be obtained prior to any protocol required assessment (i.e., Screening 
Phase) which is not performed as part of local routine care. 
 
Signed and dated ICFs for enrolled patients and for patients who are not subsequently 
screened or randomized will be maintained at the study site. All screening evaluations must 
be completed and reviewed to confirm that patients meet all eligibility criteria before 
randomization. 
 
6.4. Medical History and Demographic Data 
 
Medical history includes clinically significant diseases that are currently active or that 

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were active, including major surgeries, within the previous 5 years, any cancer history 
(including prior cancer therapies and procedures) and reproductive status. 
 
Patients may be considered postmenopausal in case that one of the following criteria 
applies: 
• 
prior bilateral ovariectomy/oophorectomy OR 
• 
Age ≥ 60 years OR 
• 
Age < 60 years with intact uterus and amenorrhoeic for ≥ 12 consecutive months* 
prior to chemotherapy and/or endocrine therapy exposure OR 
• 
Age < 60 years hysterectomized and FSH and plasma oestradiol levels in the post- 
menopausal range according to local policies prior to chemotherapy and/or 
endocrine therapy exposure 
*This criterion might not apply to patients younger than 60 years in case they were 
concurrently using hormone replacement therapy, oral or any other hormonal 
contraceptives (such as hormonal contraceptive coil etc.). 
 
If none of the above mentioned criteria fully applies, the patient may be judged 
premenopausal according to local policies. However, in case of any doubts, investigator’s 
judgment on menopausal status is desirable and has to be documented in patient’s notes 
and the eCRF. 
 
Previous type of neoadjuvant and/or adjuvant therapy (i.e. chemotherapy, radiation etc.) 
including start date and end date must be recorded on the electronic Case Report Form 
(eCRF) by the investigator or delegate at site. 
 
Demographic data will include age, sex, and self-reported race/ethnicity. 
 
6.5. Reporting of Concomitant Medication 
 
Any concomitant medications and treatments (with the exception of surgery related 
medication e.g. anesthetics) will be recorded from 30 days prior to randomization and up 
to the end of the Treatment Phase (refer to 6.1.2 for details). 
 
During the Follow-Up Phases I and II, limited information on all breast and/or non-breast 
anti-cancer related therapies must be recorded. 
 
6.6. Physical Examination and Vital Signs 
 
At screening, a physical examination including a palpation of breast/chest wall, axillae, 
supra- and infraclavicular region, height, weight, blood pressure and pulse rate is required. 
 
Symptom-directed physical examinations, blood pressure, weight and pulse rate will be 
performed at subsequent visits. 
All physical examinations and vital signs assessments should be performed by a physician 
or registered nurse or other qualified health care provider according to local regulations. 

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6.7. Laboratory Assessments 
 
It is strongly recommended that the following assessments be performed at the research 
center. If this is not feasible, laboratory tests for individual patients should be performed at 
the same laboratory. The frequency of assessments is provided in the schedule of 
assessments (section 7). All initial laboratory assessments during the screening period must 
be performed within 14 days of randomization. 
 
• 
Hematology: 
hemoglobin, white blood cell (WBC) count, absolute neutrophils and platelet count. 
 
• 
Blood chemistry with liver function tests: 
AST, ALT, alkaline phosphatase, sodium, potassium, total calcium, total bilirubin, 
serum creatinine, total protein and albumin. 
 
• 
Serum/urine pregnancy test, if required. 
 
Additional hematology/chemistry panels may be performed as clinically indicated. Local 
laboratory assessments will be performed whenever possible by the same laboratory 
(“site lab”). 
 
HbA1C measurements are mandatory at 5 different time points according to the schedule of 
assessments. In case of an abnormal value, please refer the patient to a diabetologist, 
diabetes nurse or locally equivalent medical qualified person for further diagnostic tests 
and to introduce medication if necessary. 
 
Serum or urine pregnancy test must be negative in women judged premenopausal within 
7 days of randomization, or in women with amenorrhea of less than 12 consecutive months 
at time of randomization. Pregnancy testing does not need to be pursued in patients who 
are judged as postmenopausal before randomization, as determined by local practice, or 
who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. 
 
6.8. 
Adherence Measures 
 
Drug Diaries will be maintained for all patients to capture adherence to both oral 
palbociclib as well as endocrine therapy. Diaries will be completed by the patient and 
subsequently reviewed for accuracy with the patient at each visit. Pill counts of palbociclib 
will also be performed and recorded at each study visit by research staff (pill counts for 
endocrine therapy cannot be performed due to the endocrine therapy being prescribed 
outside of the study trial). If the patient’s pill count of palbociclib is discrepant with the 
Drug Diary, the pill count will be used to determine adherence status. Patients found to be 
non-adherent with their medications may receive additional interventions by the treatment 
team to improve adherence (i.e. phone calls may be employed as a first-line intervention 
and extra study visits may be scheduled if non-adherence is still noted at the next three 
month follow-up timepoint). If a patient demonstrates persistent non-adherence 

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with endocrine therapy, the provider may stop IP therapy and the patient will be followed 
per section 6.1.2. 
 
Data from the Drug Diaries will be entered into the eCRF only for those patients who are 
part of the PRO sample. For each 28 day cycle, data regarding the number of days 
palbociclib and/or endocrine therapy were taken as well as number of days palbociclib 
and/or endocrine therapy should have been taken will be entered into the eCRF (adherence 
to study treatment will ultimately be determined by number of days taken / number of days 
drug should have been taken over various time points during study). 
 
Patient Self-Reported adherence to oral endocrine therapy and to palbociclib will be 
assessed separately in a subset of patients. 
For that purpose, the 4-item Morisky Medication Adherence scale (MMAS-4) 50,51 has been 
validated in English, Spanish and German and will be used in a subset of patients from 
countries with the unique official languages English, Spanish, and German. In addition to 
the four items of the MMAS-4, an additional question, “All things considered, did you 
actually take your {Palbociclib/ Anti-hormone pill} exactly as directed by your doctor?” 
will be asked and translated from English into Spanish and German for the respective 
Spanish-speaking and German-speaking cohorts. Each item has a Yes/No response format 
(Yes= zero and No= 1 or one point); scores from the five items will be added to create a 
composite score ranging from 0 to 5, with a score of 5 considered “most adherent” (the fifth 
question added to the MMAS-4 will be reverse-scored). 
 
The 3-item, 6-point Likert McHorney Brief Estimator will also be used to assess patient 
concerns and importance of adherence52,53. The McHorney Brief Estimator will be 
administered to English-speaking patients in US only. 
 
Both questionnaires (MMAS-4 and McHorney Brief Estimator) will be completed by 
willing patients within the above defined sub-groups via paper booklet or similar format 
during planned clinic visits before any procedures/tests are initiated at the site visit and 
prior to any discussion of their status with healthcare personnel at the site. Questionnaires 
will be collected at the following time points: on Day 1 of Cycles 2, 3, 6, 12, 18, and 24, 
as well as at the 36 months (from randomization) visit during Follow-Up Phase I. 
 
6.9. Patient Reported Outcome Measures 
 
In order to evaluate the impact of adjuvant endocrine therapy with or without palbociclib 
on the QOL of HR+/HER2- breast cancer patients and provide a comprehensive risk benefit 
assessment that includes the patient perspective in addition to efficacy and safety, below 
stated questionnaires will be used. These questionnaires were selected to evaluate the 
impact of treatment and related side effects on symptoms, functioning and global QOL. All 
questionnaires will be completed by a subgroup of willing patients via paper booklet or 
similar format during planned clinic visits before any procedures/tests are initiated at the 
site visit and prior to any discussion of their status with healthcare personnel at the site. 
Questionnaires will be collected at the following time points: on Day 1 of Cycles 1, 2, 3, 
6, 12, 18, and 24, as well as at the 36 months (from randomization) visit during Follow-
Up Phase I. At each administration time point, it is 

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anticipated that the questionnaires will take approximately 30-45 minutes for the patients 
to complete. Questionnaires will be used in a subset of patients from countries with the 
unique official languages English, Spanish, and German, except for the Breast Cancer 
Prevention Trial (BCPT) Symptom Scales. Patients may decline to complete a 
questionnaire at any time. The primary reason for any missed questionnaires will be 
collected on a case report form. 
 
EORTC QLQ-C30 plus one question from the EORTC QLQ-BR23: The EORTC QLQ- 
C30 is a well-validated cancer-specific measure73. It is comprised of six functional scales 
(physical, role, emotional, cognitive, social, and global health status/quality of life); three 
symptom scales (fatigue, pain, and nausea and vomiting); and six single items (appetite 
loss, constipation, diarrhea, dyspnea, sleep disturbance, and economic consequences of the 
disease and treatment). Functional and symptom scales/items are combined into a newly 
developed single health-related QOL (HRQL) summary measure81,82. The summary score 
and all scales and single items range from 0-100. A high score for the summary measure 
and all functional scales indicates a high/better level of QOL or functioning, whereas a high 
score on a symptom scale/item represents a higher level of symptoms/problems. The 
questionnaire has been designed for use in international clinical trials and has been 
developed in multicultural setting which facilitates cross study comparisons. It is available 
in more than 30 languages. In addition to the EORTC QLQ- C30, a single item measuring 
alopecia will be used from the EORTC QLQ-BR23. The BR23 is a rigorously developed 
and tested module commonly administered in patients receiving treatment for breast cancer 
in addition to the core C30 questionnaire. Like the C30 questionnaire, the BR23 is available 
in many languages. 
 
Brief Fatigue Inventory (BFI): This questionnaire measures the effect of cancer therapy 
and the disease itself on fatigue in cancer patients/survivor74. It assesses both the severity 
of fatigue, as well as its impact of daily functioning. It is comprised of 9 questions, and 
takes 1 minute or less to complete. Both severity and impact of fatigue scores are 
calculated, with higher scores indicating worse fatigue/impact on daily life. It is available 
in more than 30 languages. 
 
Brief Pain Inventory (BPI): To quantify arthralgia (joint pain) intensity and pain 
interference a modified Brief Pain Inventory (BPI) will be used. The BPI is one of the most 
widely used instruments to measure pain in cancer patients and has been demonstrated to 
be a reliable, valid, and responsive measure75. Since breast cancer patients can have pain 
other than arthralgia (e.g., post-mastectomy pain, neuropathy), the question will be 
modified by adding, “pain in and around your joints” to make the items more specific as 
also done in prior intervention trials76,77. To measure patient perception of joint pain due 
to hormonal therapies, a one-item question based on prior work has been developed78,79. 
Participants will be specifically asked to attribute their current joint pain to one or more 
of several listed factors included aging, aromatase inhibitors, other medical conditions, or 
medications. Patients who reported aromatase inhibitor (AI) as a cause of current arthralgia 
will be defined as having AI-associated arthralgia. The questionnaire is available in more 
than 30 languages. 

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Breast Cancer Prevention Trial (BCPT) Symptom Scales: Three subscales from the BCPT 
Symptom Scales will be used to assess symptoms related to hormone therapy: hot flashes 
(2 items), vaginal problems (2 items), and musculoskeletal pain (3 items). Respondents are 
asked to rate how bothersome these symptoms were in the past 4 weeks on a scale from 0 
(not at all), 1 (slightly), 2 (moderately), 3 (quite a bit), 4 (extremely). Single item scores 
are summed together to create the subscale scores. Higher scores indicate higher levels of 
bothersome symptoms80. The questionnaire will be administered to English-speaking 
patients in US only. 
 
Additional questions about menstrual function: Three questions are included to assess 
menstrual function. Specifically, female participants will be asked how often they had their 
menstrual period on average in the past 6 months (response options: approximately once 
every month; irregularly but at least once in the past 6 months; or no menstrual periods in 
the past 6 months). Female participants will also be asked if their menstrual periods have 
permanently stopped, and if so, the reason. Lastly, female participants will be asked if they 
have had surgical procedures involving the uterus and/or one or both ovaries. These 
questions are available in English, German and Spanish and will therefore not be required 
from any other study participants. 
 
6.10. 
Study measures implemented during COVID-19 Pandemic 
 
With the outbreak of the COVID-19 pandemic in 2019/2020, which subsequently affected 
all countries participating in the PALLAS trial, temporary alterations to study measures 
were implemented to minimize patient risk while safeguarding data documentation related 
to COVID-19 impact on the PALLAS trial. As communicated in a harmonized “Dear 
Investigator Letter” and a dedicated, harmonized “Sponsor Memo” the following measures 
were established during the COVID-19 pandemic: 
- 
Any patient visit described in the PALLAS Protocol, that does not require patients to 
be in clinic for study assessments, may be carried out remotely. 
- 
For active Arm A patients (receiving IP): 
o Patients should continue to receive routine safety lab and physical exam 
screenings to establish eligibility for retreatment as described in the PALLAS 
Protocol, if possible. 
o If hematology cannot be performed, yet the patient is 1) judged to be overall 
healthy, 2) less than 65 years old and 3) has no history of any Grade 3 
neutropenia for (at least) the last 4 Cycles, the onset of the next cycle may be 
delayed given the unavailability of hematology. Following this a renewed 
phone interview is to be conducted by investigator (or representative) on the 
day of delayed cycle start and IP treatment may be continued, if judged to be 
acceptable by the investigator. To supply patients unable or unwilling to attend 
visits on site with IP, exceptional site to patient shipments of IP were 
implemented (see below for details). 
o For any patient who does not fit the above criteria, hematology assessements 
should be available prior to IP dispensation. Palbociclib intake may be held for 
a maximum of 8 consecutive weeks considering the exceptional 
circumstances. 
- 
For Arm B patients and patients in Follow-Up: 

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o Visits may be restructured as remote visits as applicable and possible. 
- 
The use of local laboratories and medical centers to perform standard assessments 
(standard hematology and chemistry tests as well as physical examinations) is 
exceptionally permitted during the COVID-19 pandemic. Records of these tests must 
be sent to the treatment site for PI / Co-Investigator review in a timely manner. These 
assessments should be combined with telephone follow up for data collection and 
documentation in the eCRF. 
- 
Shipment of Study Drug and Questionnaires: 
o To enable continuous treatment of active Arm A Patients (see above), the 
controlled shipment of IP from the responsible site directly to the patient is 
permitted during the COVID-19 pandemic, if patient on site visits are not 
possible and the patient agrees with this process. 
o Study specific patient paper questionnaires are exceptionally permitted to be 
sent to patients via e-mail or mail. 
- 
Documentation of COVID-19 related study data: 
o A COVID-19 eForm was generated and implemented to document information 
on COVID-19 testing, early end of IP/non-IP or early end of study events 
related to COVID-19. This eForm is to be documented for any patients who 
are not early end of study by 01 Dec 2019 (time points of assessment are 
defined in section 7) 
o Any issues or protocol deviations occurring due to the COVID-19 pandemic 
are to be documented as a COVID-19 related protocol deviation, even if the 
issue is generally not defined as a protocol deviation. 
o Any remote patient contact or data acquired in such contacts is to be 
documented in the appropriate sections of the eCRF. 
- 
To maintain sponsor oversight, both sponsors implemented adequate measures and 
guidance documents on site monitoring processes in line with regulatory requirements. 
- 
All measurements are to be established in line with applicable local laws and 
regulations in the participating PALLAS countries. 

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7. Schedule of Assessments 
 
Screening 
Phasea 
Treatment Phaseb 
End of 
Treatment 
Phase Visit 
Follow-Up 
Phase I c, u 
Follow- 
Up 
Phase II 
c, u 
Patient Visit # 
0 
(baseline) 
1 
2v 
3 
4v 
5-12 
13 
Q 6 
months 
Q 12 
months 
Cycle (C) 
1 cycle = 28 Days 
0 
(baseline) 
C1 
C2 
C3, C6, C9,C12, 
C15,C18,C21,C24 
After C26 
or early 
termination 
Day (D) of Cycle 
-30 to 0 
D1d 
D14v 
D1 
D14v 
D1 
Time Window for 
Assessments (days) 
- Arm A 
-7 
+/-2 
-2n 
+/-2 
- 7n 
30-42 
+/- 35 
+/-56 
Time Window for 
Assessments (days) 
- Arm B 
+2/ -7 
+/-2 
+/-2n 
+/-2 
+/- 7n 
30-42 
+/-35 
+/-56 
Informed Consente 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History & 
Demographic Dataf 
X 
Concomitant 
Medicationsg 
X 
X 
X 
X 
X 
Xg 
Xg 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
Physical Exam/Vital 
Signsh 
X 
X 
X 
X 
X 
IP Dispensing; IP 
and Non-IP Drug 
Compliancei 
X 
X 
X 
Xx 
Adverse Event 
Reportingj 
X 
X 
Xv 
X 
Xv 
X 
X 
Xw 
Xw 
Hematologyk 
X 
X 
Xv 
X 
Xv 
X 
X 
Blood Chemistry, 
with Liver Function 
Testsk 
X 
X 
X 
X 
X 
Serum/Urine 
Pregnancy Testl 
X 
m 
HbA1C 
X 
Xm (C6, C12, C18) 
X 
Circulating cfDNAo 
X 
X (C6) 
X 
X (5y) 
X (7y, 
10y) 
Disease Monitoringp 
X 
Patients will be followed per ASCO Guidelines throughout the course of the study. 
Whole Blood 
(Pharmacogenomic 
X 
(X) 

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Screening 
Phasea 
Treatment Phaseb 
End of 
Treatment 
Phase Visit 
Follow-Up 
Phase I c, u 
Follow- 
Up 
Phase II 
c, u 
Patient Visit # 
0 
(baseline) 
1 
2v 
3 
4v 
5-12 
13 
Q 6 
months 
Q 12 
months 
Cycle (C) 
1 cycle = 28 Days 
0 
(baseline) 
C1 
C2 
C3, C6, C9,C12, 
C15,C18,C21,C24 
After C26 
or early 
termination 
Day (D) of Cycle 
-30 to 0 
D1d 
D14v 
D1 
D14v 
D1 
Time Window for 
Assessments (days) 
- Arm A 
-7 
+/-2 
-2n 
+/-2 
- 7n 
30-42 
+/- 35 
+/-56 
Time Window for 
Assessments (days) 
- Arm B 
+2/ -7 
+/-2 
+/-2n 
+/-2 
+/- 7n 
30-42 
+/-35 
+/-56 
Sample)q 
Serum 
X 
Plasmao 
X 
X (C6) 
X 
X (5y) 
X (7y, 
10y) 
Tumor Tissuer 
X 
In case of local/regional ipsilateral and/or distant disease recurrences and/or contralateral 
breast cancers, biopsies of these lesions are strongly encouraged. 
PRO 
Questionnairess 
X 
X 
X (C3, C6, C12, 
C18, C24) 
Xs 
Adherence 
Questionnairest 
X 
X (C3, C6, C12, 
C18, C24) 
Xt 
COVID-19 related 
assessment 
Xy 
Xy 
Xy 
Table 2: Schedule of Assessments 
a) 
Screening Phase: All screening evaluations must be completed and reviewed to confirm that patients meet all inclusion criteria and do 
not meet any of the exclusion criteria before randomization. 
b) 
Treatment Phase: Non-IP (if not already started) and IP therapy must start within 7 days after randomization. All assessments should 
be performed prior to dosing with IP (palbociclib) or Non-IP (endocrine therapy) on the visit day, unless otherwise indicated. The 
Schedule of Assessments during this planned 2 year period (including a visit at 30-42 days after completion of 2 years of therapy or 
after trigger date for early end of treatment phase for a final safety assessment) applies to both arms. IP treatment is to be given for 2 
years, which is a total of twenty-six 28-days cycles (for patients without interruptions or delays). The goal is not to administer a specific 
number of cycles, but to allow for completion of a cycle if it started prior two years from randomization. Patients will not be allowed to 
begin a new IP cycle once 2 years after start of IP treatment have elapsed. 
c) 
Follow-Up Phases I & II: Half year visits can be performed via phone calls from the site to the patient or the provider, or as in person 
visits; yearly visits should be in person during Follow-Up Phase I. During Follow-Up Phase II, annual patient contacts shall be performed 
by in person visits, or phone contacts to the patient or the provider (except FU II Visit year 7 and 10 where blood samples should be 
collected). See section 6.1 to make determinations how the patient will move through the Follow-Up I and Follow-Up II phases of the 
study for assessments, data collection, and follow-up for the study. Appendix B further describes these phases. 
d) 
If screening assessments occur within 7 days before Cycle 1 Day 1, then they may serve as the Cycle 1 Day 1 assessments also and do 
not need to be repeated. 
e) 
Informed consent form may be obtained greater than 30 days before randomization; it must, however, be obtained prior to any protocol 
required assessment (i.e., Screening Phase) which is not performed as part of local routine care. 
f) 
Medical history includes clinically significant diseases that are currently active or that were active, including major surgeries, within the 
previous 5 years, any cancer history (including prior cancer therapies and procedures) and reproductive status. Demographic data 
includes age, sex and self-reported race/ethnicity. In addition, stratification factors will be assessed. 
g) 
Any concomitant medications and treatments will be recorded from 30 days prior to randomization and up the end of the Treatment 
Phase (refer to section 6.1). During the Follow-Up Phase I and II, only limited information on breast and/or non-breast anti-cancer 
related therapies have to be recorded. Endocrine therapy is not considered concomitant medication and has to be recorded separately 
with detailed data capture during the Treatment Phase. 

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h) 
At screening, a physical examination including a palpation of breast/chest wall, axillae, supra- and infraclavicular region, height, weight, 
blood pressure and pulse rate is required. Symptom-directed physical examinations, blood pressure, weight and pulse rate will be 
performed at subsequent visits. 
i) 
IP dispensation (palbociclib) will take place at each Cycle Day 1 onsite visit. Patients will receive amount of IP in order to ensure 
sufficient supply until the next scheduled Cycle Day 1 onsite visit. Drug Compliance for IP will be assessed by drug accountability 
(patients are requested to return any used and unused bottles of IP at their next scheduled onsite visit). Furthermore, patients are requested 
to complete IP Drug Diaries, which also have to be returned at each onsite visit. At each visit, prior to IP dispensation, an AE and 
laboratory based assessment has to be performed by the investigator for evaluation of potential dose reduction obligations according to 
the protocol. There will be no drug accountability for Non-IP. However, compliance will be assessed at each patient onsite visit via 
Non-IP Drug Diaries completed by the patients. Patients are requested to bring Drug Diaries back to the site at each visit. IP Drug Diaries 
and/or Non-IP Drug Diaries should be collected during the treatment phase of the study. 
j) 
AEs/SAEs must be reported from the date of signature of informed consent form for all enrolled patients, until the last visit of the 
Treatment Phase (see section 6.1.1 and section 10.1). During the Screening Phase, only Adverse Events deemed to be serious (SAEs) 
and related to any study mandated and not routinely performed procedures must be reported to the appropriate study Sponsor. SAEs 
must be reported within 24 hours of site awareness (see section 11.6. for further instructions). AEs fulfilling the criteria for expedited 
reporting have to be treated according to the reporting procedures described in section 11 including a submission to the respective 
Sponsor within 24 hours of awareness. 
k) 
Hematology includes hemoglobin, white blood cell count (WBC), absolute neutrophils, platelet count. Blood chemistry includes AST 
(SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, total calcium, total bilirubin, serum creatinine, total protein and 
albumin. Additional hematology/chemistries panels may be performed as clinically indicated. It is strongly recommended that all 
assessments will be performed at the research center. If this is not feasible, laboratory tests for individual patients should be performed 
at the same laboratory. During the Screening Phase, all laboratory assessments must be performed within 14 days of randomization. 
l) 
Serum or urine pregnancy test must be performed and negative for women of childbearing potential (≤ 7 days prior randomization). 
Testing may be repeated on a regular schedule as per request of IRB/IECs or if required by local regulations. 
m) HbA1c will be measured at Screening, Day 1 of Cycles 6, 12, and 18 and at the End of Treatment Phase Visit. In case of an abnormal 
value, please refer the patient to a diabetologist or a diabetes nurse for further diagnostic tests and to introduce medication if necessary. 
n) 
Time window does not apply to patients experiencing AE induced dose delays at the start of a cycle. 
o) 
Blood samples for the assessment of circulating Cell-Free DNA and Plasma samples will be collected from all patients, at Cycle 1 Day 
1, Cycle 6 Day 1, at the end of Treatment Phase Visit, at 5 years after randomization and at the time of ipsilateral local/regional and/or 
distant recurrence and/or contralateral breast cancer, unless prohibited by local regulations. For details refer to table 3. 
p) 
Information will be collected on date and site of all recurrences, all endocrine, all cytotoxic (+/- targeted) treatment, date and cause of 
deaths as well as date and diagnosis of secondary malignancies. 
q) 
Whole blood sample for pharmacogenomic research should be either collected at C1D1 or C2D1. Only applicable for patients who 
agreed (prior to sample collection) to donate blood samples for the purpose of pharmacogenomic analyses, if required according to local 
regulations. 
r) 
Representative tumor tissue FFPE block from surgery or from diagnostic core biopsy is to be collected. Receipt of FFPE tumor tissue 
block at the central sample repository is required for patient randomization (see section 8.2.1). Tissue banking will be required for 
translational endpoint analyses. Local ER+ and/or PR+ as well as HER2- results will be used for the purpose of eligibility (according 
to local standards; Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society 
of Clinical Oncology/College of American Pathologists) guidelines). Patients with equivocal HER2 in situ hybridization results 
according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 
treatment. If a patient develops local/regional ipsilateral recurrences and/or distant recurrences and/or contralateral breast cancer, every 
effort should be made to collect a tumor sample from the sites of these oncological events. Details on preparation of these samples 
including processing, storage, and shipment will be provided in separate guidance documents. 
s) 
Following PRO measures will be used: EORTC QLQ–C30 plus one question from the EORTC QLQ-BR23, Brief Fatigue Inventory 
(BFI), Brief Pain Inventory (BPI), Breast Cancer Prevention Trial (BCPT) symptom scale, and additional questions about menstrual 
status; these will be collected on Day 1 of Cycles 1, 2, 3, 6, 12, 18, and 24, as well as at the 36 month visit (i.e., visit that is approximately 
36 months after randomization) during Follow-Up Phase I. Questionnaires will be used in a subset of patients from countries with the 
unique official languages English, Spanish, and German except for the BCPT symptom scale which will be administered to English-
speaking patients in US only. 
t) 
Two questionnaires for Adherence will be collected on day one of cycles 2, 3, 6, 12, 18 and 24, as well as at the 36 month visit (i.e., 
visit that is approximately 36 months after randomization) during follow up phase I. The McHorney Brief Estimator will be administered 
to English-speaking patients in US only. The Morisky Scale will be used in a subset of patients from countries with the unique official 
languages English, Spanish, and German. 
u) 
In Follow-Up I and II, extended adjuvant endocrine treatment (more than 5 years) is allowed and limited information should be 
documented within the medical records for subsequent data submission via Case Report Forms. 
v) 
Visits 2 and 4 (C1D14 and C2D14) can be telephone contacts for all patients, and can occur +/- 2 days around Day 14. All patients in 
both arms should have AEs collected on the calls. Patients in Arm A only will have safety laboratory testing performed for these Visits; 
laboratory testing must be performed at the research center, and the Visit 2 and 4 telephone calls should occur after the laboratory testing 
is resulted. Laboratory testing for Arm B is at the discretion of the provider. 
w) 
During Follow-Up Phases I and II only newly occurred serious adverse reactions (SARs) related to palbociclib have to be documented 
on the SAE form and have to be submitted to the respective Sponsor within 24 hours of site awareness. Serious adverse events occurring 
to a patient after the Treatment Phase has ended (i.e., during the Follow-Up Phases I & II) should be reported to the 

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respective Sponsors if the investigator becomes aware of them; at a minimum, all serious adverse events that the investigator believes 
to have at least a reasonable possibility of being related to palbociclib are to be reported to the respective Sponsor. 
x) 
No IP will be dispensed at this visit but only drug diaries collected. 
y) 
A COVID-19 related assessement (including data on COVID-19 testing, early end of IP/non-IP and early end of study) is to be 
perfomed and documented in the appropriate eForm for any patient who was not early end of study by 01 Dec 2019. 
 
8. Data and Specimen Submission 
 
For COVID-19 related measures implemented regarding data collection, please refer to section 6.10. 
 
8.1. Data Collection and Submission 
 
The site will be supplied with the following data collection tool: a web browser address for 
an Electronic Data Capture (EDC) system database that has been fully validated and 
conforms to 21 CFR Part 11 and the Guidance for Industry on Computerized Systems Used 
in Clinical Trials requirements. The EDC system databases will be maintained by Alliance 
Foundation Trials (AFT) for the US and by ABCSG for the Non-US sites. Periodically 
throughout the duration of the trial and at the completion of the trial, the US and Non-US 
sites databases will be merged to facilitate analysis of the complete trial dataset. 
 
The trained Investigator site staff will enter the data required by the protocol into the eCRFs 
from source documents (e.g., medical records and study-specific data capture forms as 
needed) into the EDC system. All information on the eCRFs must be traceable to these 
source documents. Data recorded directly on the eCRFs will be defined before study start. 
eCRFs will be completed for all subjects randomized to study treatment. eCRFs for subjects 
who are randomized but not treated will be completed with all data collected at the time of 
subject study discontinuation. A Clinical Monitor will review the eCRFs entered by 
investigational staff for completeness and accuracy according to respective trial monitoring 
plan. 
 
Automatic validation programs or manual checks for data discrepancies in the eCRFs may 
result in electronic queries generated for resolution by the investigational site. Designated 
investigator site staff is required to respond to these queries and make any necessary 
changes to the data. 
 
During the Screening Phase, only AEs deemed to be serious (SAEs) and related to protocol 
mandated and not routinely performed procedures have to be reported. 
All treatment-emergent AEs (events occurring from the first dose of study medication 
during the Treatment Phase until the end of safety reporting period (30 to 42 days after 
completion of 2 years of therapy or after trigger date for early end of treatment phase)) will 
be recorded. AEs will be coded using the MedDRA dictionary. Concomitant medications 
will be coded using a standard dictionary (e.g. WHODrug). 
 
Audits for quality assurance of the database may be performed according to relevant 
Standard Operating Procedures within the respective Sponsor. 

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8.2. 
Specimen Collection and Submission 
 
Table 3 summarizes the biospecimens that are to be collected from participants, with 
reference to specific study time points. All biospecimen collections are mandatory, unless 
otherwise specified and/or specifically prohibited by local regulations or patient refusal. 
Specific instructions for the collection, on-site processing, and shipment of biospecimens 
is provided in the TRANS-PALLAS Investigator Manual of Procedures and the sample 
management guidelines and/or manuals. 
 
Location of central tissue and blood specimen repositories, as well as logistical pathways 
for on-site processing and shipping of biospecimens will be different for US and Non-US 
sites. Details and instructions will be provided to the sites by the respective study Sponsor 
via separate sample management guidelines and/or manuals, including the TRANS- 
PALLAS Investigator Manual of Procedures. Following site request, the submitted FFPE 
tumor tissue block will be returned to the site. 
 
8.2.1. Tumor and Blood Specimen 
 
An archival, formalin-fixed paraffin-embedded (FFPE) tumor tissue BLOCK must 
be available and received at the central sample repository for EACH patient PRIOR 
TO RANDOMIZATION. Sample shipment to the respective central sample 
repository may only be performed following patient consent and allocation of the 
study specific patient identification number via IxRS. 
 
An FFPE block containing representative tumor tissue from a surgical specimen 
is requested from patients who have completed surgery prior to adjuvant systemic 
therapy. For patients who received preoperative/neoadjuvant systemic therapy, 
both pre-treatment diagnostic core biopsy samples and post-treatment surgical 
specimen are requested. If only one sample can be sent, then the pre- treatment 
tissue remains the first priority – to be consistent with the samples from the 
adjuvant setting – but post-treatment tumor tissue is acceptable as a second 
priority. 
 
Details on block selection, preparation, and shipment are found in the TRANS- 
PALLAS Investigator Manual of Procedures and the sample management 
guidelines and/or manuals. 
 
Once patient eligibility has been established and after receipt of adequate tissue 
at the central sample repository, the site will be authorized to randomize the 
respective patient into the study. Patients who have passed eligibility screening, 
but for whom no adequate FFPE tissue block has been received by the central 
sample repository, may not be randomized into the study. Sites will have the 
possibility to re-send a replacement specimen, in order to randomize the patient to 
the study. 
 
Although confirmed receipt of tumor tissue (without any quality check prior to 
randomization) at the central sample biorepository is sufficient to enable patient 

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randomization, site will be requested to re-send a further sample if the initial 
sample is inadequate. Patients who have passed eligibility screening and submitted 
an FFPE block to the central sample repository, but for whom the FFPE tissue 
block was found to be not adequate prior to randomization, may be randomized 
into the study. However, in this situation, sites are requested to send a replacement 
specimen to ensure that adequate tissue is available. The randomization will not be 
delayed by the shipment of this additional sample. 
 
Central confirmatory immunohistochemical review (e.g. ER, PR or HER2 testing) 
of the tumor block will not be performed. 
If available, a baseline sample of fresh or frozen tumor tissue may be provided as 
well. This sample is optional, and does not replace or substitute for the required 
FFPE tissue sample. Details on sample selection, preparation, and shipment are 
found in the TRANS-PALLAS Investigator Manual of Procedures and the sample 
management guidelines and/or manuals. 
 
 
 
Table 3: Tissue/Samples for TRANS-PALLAS translational research 
 
* 
See TRANS-PALLAS Investigator Manual of Procedures for further details on tube selection and 
specimen shipping. 
** Not required if patient experienced prior local/regional ipsilateral and/or distant recurrences and/or 
contralateral breast cancers and related blood draws have occurred (at the earliest possible 
occasion). 
*** Tissue sampling at the time of local/regional ipsilateral and/or distant recurrences and/or contralateral 
breast cancers is strongly encouraged not only to confirm disease, but also to provide a sample for 
the biorepository. It does not necessarily need to be a FFPE sample but can be other sample type as 
described in the TRANS-PALLAS Investigator Manual of Procedures. 
**** Whole blood sample for pharmacogenomic research should be either collected at C1D1 or C2D1. 
***** Optional samples, to be sent only if available. 

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9. Study Treatment 
 
9.1. Study Treatment Overview/Terms and Descriptions 
 
IP Treatment is comprised of palbociclib treatment for 2 years (refer to 6.1.2) for patients 
randomized into Arm A. 
 
Non-IP Treatment is comprised of standard endocrine therapy for at least 5 years for 
patients randomized into Arm A and B. 
 
Palbociclib is the only investigational product (IP) of this trial and will be provided free of 
charge by the Sponsors. 
 
Protocol approved adjuvant endocrine therapy regimens (also referred to as background 
treatment) are considered Non-IP as they represent routine or standard of care treatment 
for the respective patient population. Endocrine therapy will not be provided by the 
Sponsors and must be selected by the Investigator as part of a standard of care therapy. 
 
9.2. Palbociclib - Investigational Product (IP) 
 
9.2.1. Palbociclib – Formulation, Packaging and Labeling 
 
Palbociclib Drug Substance and Drug Product are manufactured, labelled and 
packed according to current Good Manufacturing Practice (GMP) and Good 
Clinical Practice (GCP) guidelines for use in the clinical studies. Each lot of 
palbociclib for clinical studies is subjected to a series of quality control tests to 
confirm its identity, purity, potency, and quality. 
 
Palbociclib will be manufactured by Pfizer and provided by the study Sponsors 
as capsules containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free 
base. Palbociclib will be supplied to sites in High Density Polyethylene (HDPE) 
bottles containing 75 mg, 100 mg, or 125 mg capsules and are labelled for clinical 
use. The capsules can be differentiated by their size and color (see below). 
 
Dosage 
Capsule color 
Capsule 
size 
75 mg 
Sunset Yellow 
2 
100 mg 
Caramel/Sunset Yellow 
1 
125 mg 
Caramel 
0 
 
Table 4: Palbociclib capsule characteristics 
 
9.2.2. Palbociclib – Storage, Handling and Processing 

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Palbociclib capsules should be stored at controlled and monitored room 
temperature (15-30°C, 59-86°F) in their original container. Further storage and 
stability conditions are stated in the palbociclib IB. Investigators and site staff are 
requested to check storage temperatures on working days (i.e. manually or by using 
alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products. 
 
Deviations from the storage requirements, including any actions taken, must be 
documented and reported to the respective study Sponsor – to AFT for US sites 
and to ABCSG for Non-US Sites. Once a deviation is identified, palbociclib must 
be quarantined and not used until receipt of documentation of permission to use 
the investigational product. 
 
Medication should be kept in a secured locked area at the study site in accordance 
with applicable regulatory requirements. Medication which has been returned by 
the patients should be stored separately from medication that needs to be dispensed. 
 
9.2.3. Palbociclib – Dosing and Administration 
 
Palbociclib should be taken orally, once per day with food. Treatment is 
continuous daily for 21 days, followed by 7 days off, to complete a 28 day cycle. 
Details can be found in table 5. 
 
Expected toxicities and potential risks as well as allowable dose modifications are 
described in section 9.4. No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the 
participant’s malignancy within the treatment phase. 
 
Administration is performed on an outpatient, self-administration basis. At the 
beginning of the new cycle, the patient should not take scheduled palbociclib dose 
before all visit assessments have been performed (and are within acceptable range) 
unless otherwise indicated. 
 
Missed doses of palbociclib should not be made up. For example, if a dose is 
vomited any time after taking palbociclib, a replacement dose should NOT be 
taken. If a dose is entirely missed for one day, dose should be skipped and 
NOT retaken the next day; patients should resume regular dosing as prescribed the 
following day. Patients who inadvertently take 1 extra dose during a day must 
skip the next day’s dose. If patient takes more than two doses of palbociclib in a 
day, the patient should bring this to the attention of his or her treating physician. 
 
Patients should be instructed to record daily administration of the study drugs in 
a drug or medication diary. 
 
9.2.4. Palbociclib – Dispensation and Accountability 

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The study IxRS system will be used by clinical sites to acknowledge receipt of 
study drug. Damaged shipments will be replaced. 
 
The patient number should be recorded on the bottle label in the spaces provided 
by site personnel at the time of assignment to patient. Site personnel must ensure 
that patients clearly understand the directions for self-medication. Patients should 
be given a sufficient supply to last until their next study visit and should further be 
instructed to keep their medication in the bottles provided and not transfer it to any 
other container. Due to possible unknown hazards associated with topical and 
environmental exposure to experimental agents, capsules must not be opened 
and/or emptied into any vehicle for oral ingestion; capsules must be swallowed 
intact. 
 
Only a single capsule strength will be dispensed to the patient at each dispensing 
visit. In the event of dose modification, request should be made of the patient to 
return all previously received and unused medication to the site and new capsules 
will be dispensed. 
 
For COVID-19 related measures implemented regarding IP dispensation, please 
refer to 6.10. 
 
 
To ensure adequate records and patient compliance monitoring, palbociclib 
capsules will be accounted for by the site as instructed by the respective study 
Sponsor. Hence, the site must maintain a careful record of the inventory and 
disposition of the agent. Accurate records of all IPs received at, dispensed to, 
returned from, returned to, and disposed of by the study site should be recorded 
as instructed by the respective study Sponsor. 
 
Patients will be instructed to return previously dispensed bottles (including unused 
drug and/or empty bottles) as well as their completed palbociclib Drug Diary to 
the clinic at each visit for accountability purposes even if they will not be issued 
with new medication at that visit. Unused returned medication MUST NOT be re-
dispensed to patients. The number of remaining capsules/tablets will be 
documented and recorded within the eCRF. Drug accountability for palbociclib 
will be performed at each study visit prior to dispensing drug supply for the next 
cycle(s). 
 
9.2.5. Palbociclib – Destruction and Return 
 
Sites will have to destroy or return unused investigational product(s). The site's 
principal investigator must ensure that any materials are destroyed or returned in 
compliance with applicable environmental local regulations, institutional policy, 
and any special instructions provided by the respective study Sponsor. The site's 
method of IP destruction must be agreed to by the Sponsor in writing. Verification 
of drug accountability by the monitor has to be completed before 

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any IP is destroyed at site. Destruction or return of investigational product must 
be adequately documented. 
 
9.3. Endocrine Therapy - Non-Investigational Product (Non-IP) 
 
Current treatment guidelines recommend adjuvant standard endocrine treatment for 5 to 10 
years for patients with HR+ breast cancer. Adjuvant endocrine treatment might have 
already started before the patient enters the study. However, initiation of standard adjuvant 
endocrine therapy must not be more than 6 months before randomization (for details please 
refer to the inclusion / exclusion section 4). 
 
The following Standard Endocrine Treatment agents (also referred to as background 
treatment) are allowed for Arm A and Arm B: 
 
• 
Tamoxifen for pre- and postmenopausal women, as well as men. 
• 
Non-steroidal aromatase-inhibitors (anastrozole, letrozole) for postmenopausal 
women. 
• 
Steroidal aromatase inhibitor (exemestane) for postmenopausal women. 
• 
LHRH agonists in combination with tamoxifen or AI for premenopausal women 
and men. 
• 
Surgical or radiologic ablation of the ovaries is also allowed, but additional 
endocrine treatment has to be given to these patients. Radiologic ablation of the 
ovaries cannot substitute for LHRH agonist if AI is being used in a premenopausal 
patient. 
 
Locally obtained commercial supply of tamoxifen, anastrozole, letrozole, exemestane or 
LHRH agonists will be administered to the patients at the discretion of the principal 
investigator (or his/her designee) as well as according to standard institutional or regional 
practice. Generics are allowed, if locally available. 
 
Administration is performed on an outpatient, self-administration basis according to local 
requirements and local standard practice. 
 
Recommended dosing regimes of oral endocrine therapy are: 
 
• 
Letrozole: 
2.5 mg orally, once a day 
• 
Anastrozole: 
1 mg orally, once a day 
• 
Exemestane: 
25 mg orally, once a day 
• 
Tamoxifen: 
20 mg orally, once a day 
 
Injection of LHRH agonist is allowable on study. If a premenopausal woman or a male 
patient is receiving LHRH agonist and AI, it is recommended that she/he receives monthly 
injections rather than every-3-month depot injections. Details for dosing regimes for Arm 
A and B can be found in table 5 below. 

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Specific storage conditions, handling dispensation and administration instructions have to 
be locally followed according to local regulations and in accordance with respective 
local package inserts and/or local SmPCs. 
 
Expected toxicities and potential risks can be obtained from respective local pack inserts 
and/or local SmPCs. Allowable dose modifications are described in section 9.4.1. 
 
Missed doses of endocrine therapy should not be made up. 
 
If a patient encounters difficulty tolerating endocrine therapy, the treating provider should 
make all possible efforts to continue the patient on adjuvant endocrine therapy, including 
the use of short drug holidays and rotation among endocrine agents, while continuing 
treatment with palbociclib. If the patient is on Arm A and despite best efforts is unable 
to tolerate endocrine medication altogether, the patient must then stop palbociclib 
treatment. If palbociclib is stopped for a patient on Arm A due to reasons other than iDFS 
events, it is strongly recommended that the patient resumes endocrine therapy once 
symptoms resolve, or changes to alternative endocrine therapy. See section 6.1 and 7.0 
for the schedule of assessments and follow-up. Rotation of AI therapy among the three 
approved agents is also allowed, as is change to AI from tamoxifen or change to tamoxifen 
from AI. 
 
Patient adherence to protocol therapy is described in section 6.8. 
 
One treatment cycle = 28 days for data collection purposes. If the patient does not 
discontinue the Treatment Phase early, a total of 26 cycles of IP and/or Non-IP treatment 
should be given in the first 2 years (refer to 6.1.2) of study participation. However, missed 
cycles will not be made up and all palbociclib intake will cease at approximately 2 years. 
Endocrine therapy should continue per standard of care. 

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treatment year) for endocrine therapy-related toxicities or personal reasons are 
allowed as per the investigator’s best medical judgment. 
 
However, no more than 6 cumulative weeks off endocrine therapy is recommended 
per treatment year on study. Subjects missing more than 6 cumulative weeks of 
endocrine therapy (per treatment year) during the treatment phase of the study will 
be removed from active treatment phase of the study and will stop IP treatment. 
Patients who discontinue study treatment (i.e. palbociclib and endocrine therapy 
for Arm A or endocrine therapy for Arm B) will continue to be followed according 
to post treatment follow up as defined in Schedule of Assessments (section 7), 
section 6.1 and Appendix B. 
 
Rotation of AI therapy among the three approved agents is also allowed, as is 
change to AI from tamoxifen or change to tamoxifen from AI. 
 
If a patient encounters difficulty tolerating endocrine therapy, the treating provider 
should make all possible efforts to continue the patient on adjuvant endocrine 
therapy, including the use of short drug holidays (as described above) and rotation 
among endocrine agents, while continuing treatment with palbociclib. If the 
patient is on Arm A and despite best efforts is unable to tolerate endocrine 
medication altogether (meaning permanent discontinuation of endocrine 
treatment), the patient must then stop palbociclib treatment. If palbociclib is 
stopped for a patient on Arm A, it is strongly recommended that the patient 
resumes endocrine therapy once symptoms resolve, or change to alternative 
endocrine therapy. 
 
Patients who discontinue study treatment (i.e. palbociclib and endocrine therapy 
for Arm A or endocrine therapy for Arm B) will continue to be followed according 
to post treatment follow up as defined in Schedule of Assessments (i.e., also see 
Follow-Up Phases in section 6.1). 
 
9.4.2. Dose Modifications / Toxicity management – Palbociclib 
 
Dose or treatment modifications for palbociclib are allowable and may occur as 
dose interruptions (within a cycle), dose delays (between cycles) or dose 
reductions. 
 
In the event of significant palbociclib treatment-related toxicity, palbociclib dosing 
may be interrupted or delayed or reduced as described within this section and 
according to table 7. 
 
In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed. Patients are to be instructed to notify Investigators at the first 
occurrence of any adverse sign or symptom. 
 
The need for a dose reduction at the time of treatment resumption should be based 
on the criteria defined in Dose Reductions Section (see section 9.4.2.3) 

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unless expressly agreed otherwise following discussion between the investigator 
and the sponsor. If a dose reduction is applied, the patient may need to return to 
the clinic to receive new drug supply. 
 
9.4.2.1. 
Palbociclib Dosing Interruptions/Delays 
 
In general, cycles should be 28 days long unless the start of a new cycle 
is delayed and palbociclib intake may not be interrupted/delayed for more 
than 4 consecutive weeks due to reasons other than surgery (refer to 
section 9.5.1) or IP-related adverse event (refer to section 9.4.2.2). 
 
Doses missed within a cycle (meaning dose interruptions) are not made 
up. If, e.g. the AE resolves before the end of the cycle, then the patient can 
resume taking the palbociclib for the remainder of the cycle but should 
still stop on Day 21 to maintain the 7- day break. 
 
The start of a new cycle should be delayed according to guidelines within 
this section, if an adverse event requiring a dose hold has not resolved by 
Day 1 of the next planned cycle. 
 
Patients on Arm A, experiencing one or more of the following adverse 
events should have their palbociclib treatment interrupted/delayed until 
criteria for retreatment are met: 
 
• 
Uncomplicated Grade 3 or 4 neutropenia (ANC < 1000/mm3). 
• 
Grade 3 or 4 neutropenia (ANC < 1000/mm3) associated with a 
documented infection or fever >38.3 C (101 F) or a sustained 
temperature of ≥ 38 C (100.4 F) for more than one hour. 
• 
Grade 3 or 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 2 non-hematologic toxicity persisting despite optimal medical 
treatment, lasting more than 3 weeks, and unacceptable to patient 
and/or provider. 
• 
In case of concurrent occurrence of > 3x ULN ALT and 2x ULN Total 
Bilirubin, at any time during the trial, palbociclib will be permanently 
discontinued. 
 
Patients should not hold or discontinue palbociclib for side effects 
potentially or likely related to concomitant standard endocrine therapy 
(e.g., grade 3 or long lasting grade 2 joint pain) as per the investigator’s 
judgment. 
Follow up assessments according to investigator’s decision should be 
performed until adequate recovery occurs as assessed by the Investigator. 
If a patient finds oneself not able to tolerate endocrine therapy, an attempt 
to change to an alternative endocrine therapy is a priority, while 

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continuing treatment with Palbociclib, if on Arm A with the alternative 
endocrine therapy. If patient is considering stopping endocrine medication 
altogether, if on Arm A the patient must stop palbociclib treatment. For a 
patient who chooses to stop palbociclib, it is strongly recommended to 
encourage the patient to resume endocrine therapy once symptoms resolve, 
or change to alternative endocrine therapy. Patients who discontinue study 
treatment (i.e. palbociclib and endocrine therapy for Arm A or endocrine 
therapy for Arm B) will continue to be followed according to post 
treatment follow up as defined in Schedule of Assessments (section 7), 
section 6.1 and in the Appendix B. 
 
9.4.2.2. 
Palbociclib Retreatment Criteria 
 
Retreatment with palbociclib following treatment interruption or delay for 
treatment related toxicity at the start of a new cycle that requires a clinic 
visit (day 1 of cycles 2, 3, 6, 9, 12, 15, 18, 21, 24) may not occur until all 
of the following parameters have been met: 
 
• 
Platelet count ≥ 75,000/mm3; 
• 
ANC ≥ 1000/mm3 and no fever; 
• 
Any persistent grade 2, grade 3 or higher treatment-related non-
hematologic AEs considered related to palbociclib have recovered to 
Grade ≤ 1 or baseline, or Grade ≤ 2 (if not considered a safety risk for 
the patient) 
 
The start of new cycles that do not require a clinic visit may begin without 
receiving laboratory results for additional laboratory tests. Study site 
should contact the patient when the laboratory results are available to 
instruct the patient to modify treatment if abnormal laboratory results 
requiring treatment hold are noted. Laboratory results must be available 
by Day 3 of each cycle where required. Whenever retreatment after dose 
delay occurs, the first palbociclib dosing day would count as Day 1 of the 
cycle. 
 
If a treatment delay results from decline in hematologic parameters, the 
frequency of blood count assessments should be adjusted as clinically 
indicated. 
 
If the retreatment parameters are met within 4 weeks of treatment 
interruption or cycle delay, palbociclib may be resumed. Please refer to 
Dose Reductions Section 9.4.2.3 for adverse events requiring dose 
reduction at the time of treatment resumption. Please note that if a cycle 
is delayed for more than 27 days, it is seen as a missed cycle and must be 
documented as not started. 

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If these parameters have not been met after 4 weeks of dose interruption 
(including the scheduled 1 week off treatment) or cycle delay, the patient 
should permanently discontinue palbociclib treatment. 
 
9.4.2.3. 
Palbociclib Dose Reductions 
 
• 
The palbociclib dose may need to be reduced, following a dose interruption 
or cycle delay when treatment is resumed. 
• 
No specific dose adjustments are recommended for Grade 1 or short lasting 
Grade 2 (< 4 weeks) treatment-related toxicity. However, investigators should 
always manage their patients according to their medical judgment based on the 
particular clinical circumstances and document the changes in the CRF. 
• 
For palbociclib related, Grade 2 toxicity lasting for ≥ 4 weeks (excluding 
alopecia) or for palbociclib related Grade 3 toxicities (despite maximum 
supportive care as judged by the investigator), palbociclib dose reduction is 
recommended for all subsequent cycles. Taking palbociclib according to 
recommendation (i.e., with food) should be reinforced and confirmed. Dose 
reduction of palbociclib by one dose level, and, if needed, by two dose levels 
(Table 6) may be required depending on type and severity of the toxicity 
encountered. 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-escalations are not allowed. Patients requiring more than 2 
dose reductions will discontinue palbociclib treatment and should stay in 
treatment phase as long as endocrine treatment is not discontinued (per section 
6.1.2). 
 
 
Dose Level 
Palbociclib once daily on days 
1-21, followed by 7 days off 
Starting dose 
125 mg/d 
Level -1 (first dose reduction) 
100 mg/d 
Level -2 (second dose reduction) 
75 mg/d 
Discontinue palbociclib treatment 
 
Table 6: Palbociclib Dose Levels and Dose Reduction Schedule 

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• 
Diabetes management medication including metformin 
 
Surgery is allowed during protocol therapy, however it is suggested to avoid 
surgery until the first 12 weeks of protocol therapy have been completed and to 
avoid nadir of counts at time of surgery. Patients pursuing surgery must hold 
palbociclib therapy 7 days before the surgery and up to 4 weeks after surgery. 
Patients undergoing free flap (i.e. Deep Inferior Epigastric Perforator (DIEP) 
reconstruction) breast reconstruction may hold palbociclib up to 5 weeks after 
surgery. Patients may resume palbociclib therapy once satisfactory wound healing 
and recovery have occurred. Patients should continue endocrine therapy if 
palbociclib is held for surgery. 
 
9.5.2. Prohibited Concomitant Medications 
 
Growth factors, including Granulocyte Colony Stimulating Factor (G-CSF), are 
not allowed on trial (with the exception of situations where a patient becomes 
clinically and medically unstable due to neutropenia). Growth factors are, in 
addition, not allowed in the course of elective surgical procedures. The use of 
concurrent investigational or other antitumor therapies, other than endocrine 
therapy, is not permitted for study patients. If a subject must take one of the 
following medications during the study, and there is no alternative, the subject 
needs to discontinue palbociclib. 
 
9.5.2.1. 
CYP3A Inhibitors/Inducers 
 
Potent (Strong/Moderate) CYP3A inhibitors/inducers: Palbociclib is 
metabolized to multiple metabolites in a qualitatively similar manner in 
rat, dog and human liver microsomes. In vitro, palbociclib is primarily 
metabolized by CYP3A4 enzymes. Co-administration with drugs that are 
potent CYP3A inhibitors and inducers may change the plasma 
concentrations of palbociclib in humans. The concurrent use of the 
following compounds is not allowed in the study: 
 
• Strong CYP3A inducers, including carbamazepine, phenytoin, 
primidone, rifampin, rifapentin, and St. John’s wort. 
• Strong CYP3A inhibitors, including, boceprevir, clarithromycin, 
conivaptan, delavirdine, indinavir, itraconazole, ketoconazole, 
lopinavir, 
mibefradil, 
miconazole, 
nefazodone, 
nelfinavir, 
posaconazole, 
ritonavir, 
saquinavir, 
suboxone, 
telaprevir, 
telithromycin, voriconazole, and grapefruit, grapefruit juice or any 
product containing grapefruit. 
• Moderate CYP3A inhibitors including amprenavir, atazanavir, 
diltiazem, erythromycin, fosamprenavir, verapamil. 
• Moderate CYP3A 
inducers including felbamate, nevirapine, 
phenobarbital, rifabutin. 
 
9.5.2.2. 
Anticancer Therapies 

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No additional investigational or commercial anticancer agents such as 
chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy other than those allowed in the protocol 
will be permitted during the active treatment phase. In general, any drugs 
containing “for the treatment of breast cancer” on the product label are not 
permitted during Treatment Phase of the study. 
 
Radiation therapy is not allowed during the active treatment phase of the 
study. 
 
9.5.2.3. 
Hormone replacement therapy, hormonal stimulation of the ovaries (i.e. oocyte 
cryopreservation, IVF or ICSI), topical estrogens (but not intra-vaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators e.g. raloxifene, with the 
exception of tamoxifen are prohibited during the active treatment phase with IP and/or 
Non-IP. 
 
9.5.3. Medications Not Recommended 
 
The following treatments are not recommended throughout the duration of the 
Treatment Phase. Alternative therapies should be considered whenever possible: 
 
• 
The concurrent use of dexamethasone is not recommended. 
 
• 
Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids. Steroids given for physiological replacement, as anti-emetics 
or inhaled as well as short course of oral/topical steroids given for allergic 
reactions or asthma flares are allowed. 
 
• 
The use of herbal medicine is not recommended during the Treatment Phase. 
 
• 
CYP3A Substrates with a Narrow Therapeutic Index: The dose of the sensitive 
CYP3A4 substrate with a narrow therapeutic index (e.g., alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, 
quinidine, sirolimus and tacrolimus) may need to be reduced when given 
concurrently with palbociclib as palbociclib may increase their exposure. 
 
10. End of Treatment/End of Study Visits 
 
10.1. 
End of Treatment 
 
Total duration of IP treatment (palbociclib, Arm A) is expected to be approximately 2 
years, beginning up to 7 days from the date of randomization (i.e., Treatment Phase). 
Unless a patient discontinues treatment early or experiences treatment delays, this would 
result in 26 cycles of treatment administered to the patient. Any premature, 

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permanent termination of IP treatment is referred to as “Early End of IP-treatment”. “End 
of IP treatment per protocol” means the IP treatment termination after 2 years (refer to 
6.1.2) of palbociclib treatment, post randomization. Section 6.1 describes the phase into 
which the patient will proceed, after permanently discontinuing IP treatment. 
 
Any one of the following criteria will be reason to stop IP-treatment before 2 years: 
 
• 
Development of an iDFS event by clinical and/or pathological evaluation. Pathological 
confirmation of iDFS events is strongly recommended. 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator (Endocrine 
treatment may continue; the decision is at the discretion of the investigator). 
• 
Unacceptable toxicity of, or unacceptable adherence to, either palbociclib or endocrine 
therapy. Patients who have unacceptable toxicity from palbociclib should continue 
endocrine therapy wherever possible. Patients, who have unacceptable toxicity to 
endocrine therapy, necessitating discontinuation of endocrine therapy, must also 
discontinue palbociclib. 
• 
Patient withdraws consent 
• 
If patient becomes pregnant. 
 
Patients who permanently discontinue IP treatment AND discontinue Non-IP treatment for 
non-iDFS event reasons will be followed according to Follow-Up Phase I (see section 
6.1.2) and the Schedule of Assessments (section 7). 
 
‘Early End of Non-IP Treatment’ means permanent discontinuation of Non-IP Treatment at 
any time prior to completion of 5 years standard endocrine therapy (i.e. considering possible 
standard endocrine treatment up to 6 month prior randomisation this means any 
discontinuation between 4,5 years and 5 years after randomisation). 
 
‘End of Non-IP Treatment, per protocol’ means permanent discontinuation of Non-IP 
Treatment at any time after at least 5 years of standard endocrine therapy. 
 
Following the results of the second Interim Analysis, the IDMC recommended on May 26th, 
2020 to prematurely end the Treatment Phase of the PALLAS trial due to futility of the 
analysed data, while no new safety concerns were observed that influenced that 
recommendation. The SC thereafter decided on May 29th, 2020 that all active PALLAS 
patients are to discontinue IP treatment and are to be moved to the Follow-Up Phase of the 
study. The Follow-Up Phase, including visit and assessment schedule, is to be conducted as 
defined by the study protocol. 
 
 
10.2. 
End of Study 
 
10.2.1. 
End of Study Visit 

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Patient’s end of study visit is the last formal study visit (including Follow-Up 
Phases I and II), or last formal contact or an unscheduled study visit in case of early 
withdrawal from all Phases of the study for treatment and follow-up. This 
coincides with the end of the Follow-Up Phase II (see Section 6.1.4). 
 
10.2.2. 
End of Study 
 
End of study is the date when the last patient has completed their end of study visit, 
all data have been collected, and all queries have been resolved. 
 
10.2.3. 
Managing Randomized Patients Who Never Received Protocol Treatment 
 
Patients who are randomized to the trial but never receive study treatment will be 
followed for efficacy endpoints (see section 6.1). 
 
10.2.4. 
Patients Lost to Follow Up 
 
During the duration of the study, sites will be expected to continue efforts to 
contact all randomized patients as well as regularly consult publicly available 
information to ascertain vital status of the patient if permissible per local 
regulation. In cases, where sites cannot successfully contact a patient and is not 
able to receive appropriate publicly available information for greater than two 
years (calculated from the last contact), the patient will be noted as lost to follow 
up. 
 
11. Safety Instructions and Guidance 
 
Palbociclib is currently approved in the US and other countries for metastatic breast cancer and is 
currently in clinical development. Therefore, the entire safety profile is not known at this time 
and human experience is currently limited. Currently available information is based on results from 
ongoing clinical studies. The following safety instructions and guidance for this study is designed 
to ensure patient safety and will include specific eligibility criteria, safety reporting obligations and 
monitoring assessments as detailed below. 
 
11.1. 
Adverse Events – General Overview 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore be 
any of the following: 
 
a. Any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product 

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b. Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 11.5.1. 
c. Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
d. Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) 
that is associated with symptoms requires additional diagnostic testing or 
medical/surgical intervention, leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug or is considered to be 
an AE by the Investigator. 
e. Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment. 
 
The investigator is responsible for ensuring that all adverse events (as defined above) are 
recorded on the respective Adverse Event eCRF page (Rave for US sites or MACRO for 
Non-US sites) and additionally reported to the respective safety departments (AFT for US 
sites or ABCSG for Non-US sites) in case the AE fulfills the criteria for expedited reporting 
in accordance with instructions provided in this section and in Section 11.6. 
For each adverse event recorded on an Adverse Event eCRF page, the investigator will 
make an assessment of seriousness (see Section 11.6.2 for seriousness criteria), severity 
(see section 11.3), and causality (see Section 11.4). 
 
The prompt reporting of adverse events is the responsibility of each investigator engaged 
in clinical research, as required by applicable regulations. Adverse events must be 
described and graded using the terminology and grading categories as defined by NCI’s 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
 
11.2. 
Adverse Events – Reporting Period 
 
Adverse event (Safety) reporting is mandatory from the date of informed consent form 
signature (i.e., screening phase) until the end of safety reporting period (30 to 42 days after 
completion of 2 years of therapy or after trigger date for early end of treatment phase, see 
section 10.1). During the Screening Phase, only AEs deemed to be serious (SAEs) and 
related to protocol mandated and not routinely performed procedures have to be reported. 
 
11.3. 
Assessment of Severity of Adverse Events 
 
The adverse event severity grading scale for the NCI CTCAE (v 4.0) will be used for 
assessing adverse event severity. Table 8 will be used for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
Grade 
Severity 

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1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
Table 8: Adverse Event Severity Grading Scale 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v 4.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who 
are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event (see Section 11.6.2 for reporting instructions), per the definition of serious adverse 
event in Section 11.6.2. 
d Grade 4 (only if immediately life threatening) and 5 events must be reported as serious adverse 
events (see Section 11.6 for reporting instructions), per the definition of serious adverse event 
in Section 11.6.2. 
 
11.4. 
Assessment of Causality of Adverse Events 
 
Investigators should use their knowledge of the patient, the circumstances surrounding the 
adverse event, and an evaluation of any potential alternative causes to determine whether 
or not an adverse event is considered to be related to the IP or Non-IP, indicating "yes" or 
"no" accordingly. The following guidance should be taken into consideration (see also 
Table 9): 
 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
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Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
Adverse events will be considered related, unless they fulfill the criteria as specified 
below. 
Evidence exists that the adverse event has an etiology other than the study drug (e.g. 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the adverse event has no plausible temporal relationship to 
administration of the study drug (e.g., cancer diagnosed 2 days after first dose of study 
drug). 
 
Table 9: Adverse Events - Causal Attribution Guidance 
 
For patients receiving combination therapy, causality will be assessed individually for each 
of palbociclib and endocrine therapy. Investigator is responsible for reporting side effects 
of commercially available drugs to regulatory agency. 
 
11.5. 
Routine Adverse Event Reporting 
 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the schedule of assessments in Section 7. Adverse events will be collected in 
a cumulative manner, with duration (start and stop) dates and using CTCAE v4.0 Adverse Event 
Severity Grading Scale. 
For this trial, eCRFs are used for routine AE reporting in Rave (US sites) and MACRO (Non- 
US sites). 
 
Note: All AEs during the defined AE Reporting Period require reporting regardless of 
causality. Attribution to treatment or other cause should be provided. 
 
11.5.1. 
Adverse Event Reporting Exceptions 
 
Recurrence or progression of the underlying malignancy is reportable only if the 
patient dies due to disease recurrence or progression within the reporting period. 
Hospitalization solely due to the recurrence or progression of the underlying 
malignancy should not be reported as an SAE. Clinical symptoms of recurrence or 
progression may be reported as AEs if the symptom cannot be determined as 
exclusively due to the recurrence or progression of the underlying malignancy, or 
does not fit the expected pattern of recurrence or progression for the disease under 
study. If there is any uncertainty about an AE being due to the disease under study, 
it should be reported as an AE or SAE as appropriate. 

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The following hospitalization scenarios are not considered to be adverse events: 
 
• 
Hospitalization for respite care 
• 
Hospitalization without underlying adverse event (e.g. solely for cosmetic 
surgery or due to patient´s wish) 
• 
Hospitalization for a preexisting condition provided that all of the following 
criteria are met: 
o The hospitalization was planned prior to the study 
o The patient has not suffered an adverse event 
• 
Hospitalization due solely to progression or recurrence of the underlying 
cancer 
• 
Hospitalization for outpatient care outside of normal clinic operating hours 
that is required per protocol or per local standard of care 
• 
Hospitalization for protocol mandated biopsies 
 
11.6. 
Expedited Adverse Event Reporting 
 
11.6.1. 
General Information 
 
Certain events require immediate reporting. The investigator must report such 
events either to the safety department of AFT (US sites) or ABCSG (Non-US sites) 
immediately. 
 
The following is a list of events that the investigator must report to the respective 
safety department within 24 hours after learning of the event, regardless of the 
relationship to study drug: 
 
• 
Serious adverse events 
• 
Abnormal Liver Function Tests reported as Hy’s Law 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these 
events to the respective safety department immediately (i.e., no more than 24 hours 
after becoming aware of the information). 
 
New significant information includes the following: 
 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 

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Investigators must also comply with local requirements for reporting serious 
adverse events to the local health authority and/or IRBs/ECs and/or any other 
parties as locally required and if applicable. 
 
11.6.2. 
Serious Adverse Events (Immediately Reportable During Treatment Phase) 
 
A Serious Adverse Event is any adverse event that meets any of the following 
criteria: 
 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
Life threatening (i.e., the adverse event, in the view of the investigator, places 
the patient at immediate risk of death). This does not include any adverse 
event that had it occurred in a more severe form or was allowed to continue 
might have caused death. 
• 
Requires or prolongs inpatient hospitalization (at least one overnight stay) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
Serious Adverse Events have to be reported on the study specific SAE reporting 
form to the safety department of AFT (US sites) or ABCSG (Non-US sites) and 
additionally be documented on the eCRF Adverse Event section in Rave (US sites) 
or MACRO (Non-US sites) during the adverse event reporting period (see section 
11.2). 
 
The Serious Adverse Event reporting period starts at the date of informed consent 
form signature and lasts until 30 to 42 days after completion of 2 years of therapy 
or after trigger date for early end of treatment phase. This would be approximately 
2 years post-randomization, plus an additional 30-42 days. During the Screening 
Phase, only AEs deemed to be serious (SAEs) and related to protocol mandated 
and not routinely performed procedures have to be reported. SAEs deemed to be 
related to IP treatment must be reported throughout both Follow-Up Phases (I and 
II) as well. 
 
11.6.3. 
Pregnancies 
 
Pregnancies have to be reported on the study specific pregnancy reporting form to 
the safety department of AFT (US sites) or ABCSG (Non-US sites), respectively. 
 
All pregnancies reported during the study should be followed until pregnancy 
outcome. 

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11.6.4. 
Abnormal Liver Function Tests reported as Hy´s Law 
 
Investigators must report as a serious adverse event the occurrence of either of 
the following: 
 
• 
Treatment-emergent ALT or AST (>3 x ULN) in combination with total 
bilirubin (>2 x ULN) 
• 
Treatment-emergent ALT or AST (>3 x ULN) in combination with 
clinical jaundice 
 
The finding of an elevated ALT or AST (>3 x ULN) in combination with either an 
elevated total bilirubin (>2 x ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator 
of severe liver injury. 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the 
abnormal laboratory values should be recorded on the Adverse Event eCRF and 
reported to the safety department of AFT (US sites) or ABCSG (Non-US sites) 
immediately (i.e., no more than 24 hours after learning of the event) using the study 
specific SAE reporting way. 
 
11.6.5. 
Expedited Reporting Procedures US Sites 
 
For reports of Serious Adverse Events, Abnormal Liver Function Tests reported as 
Hy’s Law and pregnancies, investigators should record all case details that can be 
gathered immediately (i.e., within 24 hours) within the AFT Safety Management 
System. In addition, the event should be captured on the Adverse Event eCRF page 
within the Rave EDC system during the adverse event reporting period (see 
section 11.2). 
All relevant follow-up information should be submitted through the safety 
management portal as soon as it becomes available. 
 
11.6.6. 
Expedited Reporting Procedures Non-US Sites 
 
For reports of Serious Adverse Events, Abnormal Liver Function Tests reported as 
Hy’s Law and pregnancies, investigators should record all case details that can be 
gathered immediately (i.e. within 24 hours) on the study specific paper Serious 
Adverse Event reporting form or Pregnancy reporting form and transmit to 
ABCSG safety department using the study specific reporting way. In addition the 
serious adverse event information will be captured on the Adverse Event eCRF 
page in the EDC system MACRO during the adverse event reporting period (see 
section 11.2). 
 
Relevant follow-up information should be submitted to ABCSG safety department 
as soon as it becomes available and/or upon request. 

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11.6.7. 
Post – Treatment Follow up (Follow-Up Phases I & II) 
 
Following the active safety reporting period, newly occurred serious adverse 
reactions (SARs) related to palbociclib, have to be documented on the SAE form 
and have to be submitted to the Sponsor within 24 h after becoming aware of the 
event. Serious adverse events occurring to a patient after the Treatment Phase has 
ended (i.e., during the Follow-Up Phases I & II) should be reported to the Sponsors 
if the investigator becomes aware of them; at a minimum, all serious adverse events 
that the investigator believes have at least a reasonable possibility of being related 
to study drug are to be reported to the Sponsor. 
 
11.7. 
Expected Toxicities 
 
11.7.1. 
Adverse Event List(s) for Palbociclib 
 
The primary anticipated toxicity of palbociclib is neutropenia. In the phase I, dose- 
escalation trial of palbociclib alone in advanced cancers43, neutropenia was the only dose- 
limiting toxicity (DLT). Grade 3 neutropenia during cycle 1 was observed in 3/22 patients 
receiving palbociclib 125 mg PO daily, with no grade 4 neutropenic events observed. Based 
on this result, 125 mg PO daily became the recommended phase 2 dose (RP2D). Other 
hematologic AEs of grade 3 or greater during cycle 1 were anemia and leukopenia, 
occurring in 1 and 4 of 41 patients, respectively. The most common non- hematologic AEs 
of grade 3 or greater during cycle 1 were fatigue, nausea, and abdominal pain (each 
occurring in 2 of 41 patients). Of note, there were no complicated hematologic AEs 
documented, and all hematologic AEs resolved during the off-drug period of a 3 week on/1 
week off schedule, and were non-cumulative. 
 
In a phase II trial of palbociclib alone for advanced breast cancer, the only toxicities > 
grade 3 observed were transient neutropenia (50%) and thrombocytopenia (21%)35. In a 
phase II trial of palbociclib plus letrozole for first-line therapy of hormone receptor positive 
breast cancer, the most common AEs reported were neutropenia, leukopenia, and 
fatigue37,45. The median time to first treatment delay for neutropenia was 58 days, and the 
median duration of treatment delay until recovery was 5 days (range 1-16 days, Pfizer 
internal data). In general, hematologic abnormalities were adequately managed with 
standard supportive care, were not complicated, and resolved during the drug hold with 
no cumulative toxicity noted. 
 
The Single Reference Safety Document for Palbociclib is the Investigator’s 
Brochure for the compound. Reference safety information can be found in section 
7.8 of this document. 
 
11.7.2. 
Adverse Event List(s) for Commercial Agent(s) – AIs (letrozole, anastrozole, 
exemestane), LHRH Agonist and Tamoxifen 
 
The most common adverse events experienced with use of AIs include hot flashes, 
arthralgias, and gradual loss of bone density. The most common adverse events 

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experienced with use of tamoxifen include hot flashes, night sweats, and vaginal 
discharge. Venous thromboembolic disease and endometrial cancer are rare risks 
of tamoxifen. 
 
For detailed description of AEs of the 3 AIs, LHRH Agonist and tamoxifen should 
be obtained from the particular package inserts (SmPCs) of the locally obtained 
commercial supplies. 
 
11.8. 
SUSAR Reporting 
 
Expected adverse reactions and related serious adverse reactions to palbociclib are 
listed in the Investigator Brochure (IB). All serious unexpected adverse events 
judged by either the investigator or the sponsor (AFT for US sites and ABCSG for 
Non-US sites) will be reported in accordance with applicable local regulations. 
 
12. Measurement of Effect 
 
Disease will be monitored according to ASCO-guidelines63 and is further detailed in section 7.0 
and Appendix B. Data for all types of oncological events will be captured for this study and 
histologic confirmation of diagnosis is strongly recommended. Biospecimens should be collected 
at the time of recurrence (see sections 7.0 and 8.2.1). In particular, tumor samples of local/regional 
ipsilateral and/or distant recurrences and/or contralateral breast cancers are desired, if obtainable 
(see section 8). Patients who discontinue study treatment for any reason should continue to pursue 
disease monitoring according to ASCO guidelines (see sections 6 and 7) up to a maximum of 10 
years after randomization. After the occurrence of an iDFS event, patients should continue in 
Follow-Up Phase II (ref. section 6.1.2 to 6.1.4). 
 
Following the last visit within the Treatment Phase (section 6.1.2. to 6.1.4 and 10.1), survival and 
disease status will be collected in all patients during Follow-Up Phase I every 6 months (alternating 
between annually, in person, with clinical staff and half yearly updates by telephone follow up) 
until year 5 after randomization. During Follow-Up Phase II survival update and disease monitoring 
will be performed annually by in-patient visits or telephone contacts with the patient or the provider 
until a maximum of 10 years after randomization. Imaging tests should be performed according to 
ASCO guidelines for follow up care. Information will be collected on date and site of non-invasive 
local recurrence (DCIS), invasive local recurrence, contralateral DCIS, contralateral invasive breast 
recurrence and, regional recurrence as well as distant recurrence. Limited information will be 
collected on any breast and/or non-breast anti-cancer related therapies as well as date and cause of 
deaths and date and diagnosis of secondary malignancies. 
 
The diagnosis of each type of oncologic event can be made only when the cytological, histological 
or radiological evidence of disease is confirmed as defined below. For all confirmed oncologic 
events, the time to event will be based on the earliest date of diagnostic evidence. Initial diagnosis 
of the event should not be a first occurrence of symptoms, but must be based on a clinical 
assessment with objective findings, whether by physical exam or radiological determination that is 
subsequently confirmed as described below. The date of “clinical diagnosis 

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of an oncological event” will be accepted if it has a close temporal relationship (less than 6 months) 
to further actions taken in order to achieve definite confirmation of event (i.e. radiologic imaging, 
cytological or histopathological confirmation) or in order to treat the oncological event. In case 
more than 6 months elapse between clinical diagnosis and confirmation (as described below), 
adjudication by a medical reviewer has to be performed. 
 
 
 
 
The following definitions are being used for confirmation of oncological events: 
 
Local recurrence 
Local recurrence is defined as the cytological or histological evidence of invasive breast cancer in 
the ipsilateral breast, or chest wall. 
 
Regional recurrence 
Regional recurrence is defined as the cytological or histological and/or radiological evidence of 
disease in the ipsilateral internal mammary, ipsilateral supraclavicular, ipsilateral infraclavicular 
and/or ipsilateral axillary nodes or soft tissue of the ipsilateral axilla. 
 
Distant recurrence 
Distant recurrence is defined as the cytological, histological and/or radiological evidence of disease 
recurrence in locations other than local or regional metastasis, for example the subcutaneous tissue, 
lymph nodes (not regional), lung, bone marrow, liver metastasis, etc. 
 
Second primary invasive breast cancer 
Second primary invasive breast cancer is defined as the histological evidence of invasive breast 
cancer in the contralateral breast, or chest wall. 
 
Second primary invasive cancer (non-breast) 
Second primary invasive cancer (non-breast) is defined as the cytological, histological and/or 
radiological evidence of any second primary invasive cancer of non-breast origin other than any 
new in situ carcinomas of any site or non-metastatic non- melanomatous skin cancers. 
 
Ductal carcinoma in situ ipsilateral breast 
Any histological evidence of ductal in situ carcinoma of the ipsilateral breast. 
 
Ductal carcinoma in situ contralateral breast 
Any histological evidence of ductal in situ carcinoma of the contralateral breast. 
 
13. Statistical Considerations and Methodology 
 
13.1. 
Overview of the Study Design 
 
This is a two arm Phase III study in patients with histologically confirmed HR- 
positive/HER2-negative early breast cancer (EBC). The primary objective is to compare 

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invasive disease-free survival (iDFS) for the combination of at least 5 years endocrine 
therapy and 2-year palbociclib treatment (Arm A) versus at least 5 years endocrine therapy 
alone (Arm B). Patients will be randomized between Arm A and Arm B with equal 
allocation (1:1) within strata defined by: Anatomic stage (IIA vs IIB/III), assessed by 
pathologic staging, or by clinical staging if pre-operative therapy was given with the higher 
stage determining eligibility, Neo/adjuvant chemotherapy (yes vs no), Age (≤ 50 vs > 50 
years) and Geographic region (North America versus Europe versus Other). 
 
The revised target accrual is 5600 patients, with a maximum of 1000 Stage IIA patients 
enrolled. Two interim analyses are planned to allow for early stopping due to futility (1st 
and 2nd) and superiority (2nd only). Potential sample size re-estimation at the first and 
second interim analyses will be based on the Cui, Hung and Wang61 method. Sample size 
and study operating characteristics were computed using East version v5.4.2 (Cytel Inc, 
Cambridge MA). 
 
13.2. 
Endpoints 
 
Primary Endpoint: The primary endpoint is invasive disease-free survival (iDFS) using 
STEEP criteria62 defined as the time from randomization to the date of the first event: 
local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, distant 
recurrence, second primary invasive* cancer of non-breast origin or death from any cause. 
Surviving patients who are event-free will be censored at: the date of last disease 
assessment, or withdrawal of consent to be followed, whichever occurs first. 
 
*Second non-breast primary cancers also include e.g. leukemia, myelodysplasia, 
plasmocytoma but do not include any new in situ carcinomas of any site or non- metastatic 
non-melanomatous skin cancers. 
 
 
Secondary Endpoints: 
Invasive disease-free survival (iDFS) excluding second primary invasive cancers of non-
breast origin defined as the time from randomization to the date of the first event: 
local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, distant 
recurrence, or death from any cause. Second primary invasive cancers of non-breast origin 
will not be considered as events for this endpoint. Surviving patients who are event-free 
will be censored at: the date of last disease assessment, or withdrawal of consent to be 
followed, whichever occurs first. 
 
Overall survival (OS), defined as the time period between randomization and death. 
Surviving patients classified as lost-to-follow up or having withdrawn consent to be 
followed will be censored at their date of last contact or withdrawal of consent to be 
followed, whichever occurs first. 
 
Locoregional recurrences-free survival (LRRFS), defined as the time from 
randomization to the date of the first event: local/regional invasive ipsilateral recurrence, 
contralateral invasive breast cancer, or death from any cause. Patients with second 

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primary invasive cancers of non-breast origin or distant recurrence will be censored at the 
date of diagnosis. Surviving patients who are event-free will be censored at: the date of last 
disease assessment, or withdrawal of consent to be followed, whichever occurs first. 
 
Distant recurrence free survival (DRFS) is defined according to STEEP62 criteria as 
the time from randomization to the date of the first event: distant recurrence or death from 
any cause. Patients with a locoregional recurrence will continue to be followed for DRFS. 
Surviving patients who are event-free will be censored at: the date of last disease 
assessment, or withdrawal of consent to be followed, whichever occurs first. 
 
Adverse Events will be collected according to the NCI CTCAE version v4.0. 
 
Clinical Science Endpoints: Adherence measured by Drug Diary, Morisky Medication 
Adherence Scale, Medication Adherence and McHorney Brief Estimator questionnaires 
in a subset of patients and primary endpoint (iDFS) effected by baseline body mass index 
(BMI). See separate document(s) for details regarding clinical science endpoints. 
 
PRO Endpoint: Average score for pre-specified PRO scales over the pre-specified time 
points during the initial 2-year treatment phase, adjusting for the baseline score. See 
separate document(s) for details regarding PRO endpoints. 
 
13.3. 
Analysis Populations 
 
ITT Population: We will use intention to treat (ITT) principles to define the population 
used for the analysis of the primary endpoint and secondary efficacy endpoints. The ITT 
Population is comprised of all randomized patients, including those who do not start 
palbociclib or endocrine treatment. This population provides the basis for the main efficacy 
analyses. Patients will be analyzed according to the treatment group to which they were 
randomized. Randomized patients consist of all patients who have given their written 
informed consent and for whom there is confirmation of successful allocation of a 
randomization number through the IxRS (Interactive Voice and Web Response System). 
 
Safety Population (SP): For the purposes of evaluating and monitoring Adverse Events 
and all other patient safety, the Safety Population (SP) is defined as all randomized patients, 
excluding those who do not start palbociclib or endocrine treatment, i.e. as- treated. Patients 
will be analyzed according to treatment actually received. Randomized patients for whom 
it is unclear whether they took the palbociclib or endocrine treatment will be included in 
the safety population as randomized. 
 
13.4. 
Analysis Plans for the Primary Endpoint 
 
The primary analysis of the study will be the comparison of iDFS between Arm A and Arm 
B using stratified logrank test and group sequential methods to control the overall one-
sided Type I error rate at 0.025. Stratified log-rank test will use the following subset of 
factors used in randomization: Neo/adjuvant chemotherapy (yes vs no), Age (≤ 50 vs > 50 
years). 

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The null and alternative hypotheses to be tested are defined using the hazard ratio (HR) of 
Arm A to Arm B as: 
 
H0: HR ≥ 1 
H1: HR < 1 
 
In addition to stratified log-rank test, survival functions will also be summarized using 
the Kaplan-Meier method according to randomized treatment assignment, and 
multivariable Cox proportional hazard model with study stratification factors and other 
known prognostic factors for EBC. 
 
13.4.1. 
Interim Analysis Decision Rules 
 
Two interim efficacy analyses are planned for monitoring for futility and superiority, 
and are scheduled to occur when 33% and 67% of the total number of iDFS events 
are observed. 
 
The first interim analysis will take place after the first 157 iDFS events have 
occurred and the second interim analysis will take place after accrual has completed 
and 313 iDFS events have occurred. Under original assumption: It is estimated that 
the 1st interim analysis will occur < 3 years and the 2nd interim analysis will occur 
<4 years after the first patient is randomized. Under revised assumptions: the 1st 
interim analysis is expected to occur <4 years and the 2nd interim analysis to occur 
<5 years after the first patient is randomized. 
 
The objective of the first interim efficacy analysis will be: 
• 
To assess safety. 
• 
To allow for early stopping of the trial due to futility. 
• 
To consider re-estimation of total sample size. 
 
The objective of the second interim efficacy analysis will be: 
• 
To assess safety. 
• 
To allow for early stopping of the trial due to futility. 
• 
To allow for early stopping of the trial due to overwhelming efficacy 
(superiority stopping boundary is crossed). 
• 
To consider re-estimation of total sample size. 
 
Although stopping the trial for overwhelming efficacy (superiority stopping 
boundary is crossed) is not considered as one of the objectives at the first interim 
analysis, the nominal alpha for the first interim analysis is still taken into account 
when calculating overall type I error. 
 
The following table summarizes the nominal significance level, corresponding 
hazard ratio, and 3-year and 5-year iDFS rates for each arm at the 2nd interim analysis 
and the final analysis when 67% of total events (313 events) or 100% of total events 
(469 events) are observed. The corresponding hazard ratio is estimated 

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under the assumption of proportional hazards, and the corresponding 3-year / 5- year 
iDFS rates are estimated under the assumption of exponential distribution for iDFS. 
 
Analysis 
Nominal α 
level (1-sided) 
Estimated 
Hazard ratio 
Estimated 3-year iDFS rate for Estimated 5-year iDFS rate for 
Control arm Palbociclib arm Control arm Palbociclib arm 
Original assumptions *: 
2nd interim 
analysis 
0.006 
0.753 
0.881 
0.909 
0.81 
0.853 
Final analysis 
0.0231 
0.832 
0.881 
0. 900 
0.81 
0.839 
Revised assumptions *: 
2nd interim 
analysis 
0.006 
0.753 
0.897 
0.923 
0.835 
0.876 
Final analysis 
0.0231 
0.832 
0.897 
0.915 
0.835 
0.863 
 
* Original and revised assumptions given in 13.5.1 
 
At each interim efficacy analysis, statistical hypothesis tests will be performed only 
for the primary efficacy endpoint, iDFS and the secondary endpoint, iDFS 
excluding second primary invasive cancers of non-breast origin. O’Brien – 
Fleming type stopping boundaries58 based on the Lan-DeMets spending function 
will be applied. Futility criteria will not be used to calculate the nominal alphas 
in order to control the overall Type I error (non-binding method). The Z-statistic 
from a one-sided, stratified logrank test will be calculated and compared to the 
stopping boundaries, and are defined on the Z-statistic scale for formal comparison 
to logrank test. In addition to the boundary and observed Z-statistics, the IDMC 
will be provided Kaplan-Meier product limit estimators to the survival functions 
for each arm, and estimated HRs and 95% CIs from the corresponding Cox 
proportional hazard models for iDFS. 
 
The IDMC will also be provided estimates (Kaplan-Meier, HR and 95% CI) for 
the secondary endpoint, iDFS excluding second primary invasive cancer of non- 
breast origin. 
 
See Section 13.9 for further details as to Safety Monitoring and the IDMC. 
 
Decision rules for sample size re-estimation at the first and second interim analyses 
will be based on the Cui, Hung and Wang61 method using conditional power based 
on the point estimate and standard error for the HR. Details on the sample size re-
estimation and modifications to the stratified log-rank test to control the overall 
Type I error will be provided in the Statistical Analysis Plan (SAP). 
 
13.4.2. 
Final Analysis Decision Rules 
 
The primary analysis of iDFS will occur when 469 iDFS events are observed if no 
changes are made based on sample size re-estimation during interim analyses. 

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In that case, results of the hypothesis test will be based on the Z-statistic and p- 
value from the stratified logrank test in the ITT population. 
 
The actual nominal α levels for the interim analyses and for the final analysis will 
depend on the fraction of total events occurred at the time of interim analysis, and 
at final analysis is noted to be 0.0231 (one-sided) under exact equal spacing in 
information time. 
 
First Interim 
Second Interim 
Final Analysis 
iDFS Events (%) 
157 (33%) 
313 (67%) 
469 (100%) 
Expected number of patients accrued 
(under H1 and original assumptions **) 
3996 
4600 
4600 
Approximate time after study 
Activation (under H1 and original 
assumptions **) 
32 months 
45 months 
58 months 
Expected number of patients accrued 
(under H1 and revised assumptions) ** 
5235 
5600 
5600 
Approximate time after study 
Activation (under H1 and revised 
assumptions) ** 
39 months 
52 months 
65 months 
Superiority Bound: critical Z 
3.710 * 
2.511 
1.993 
Nominal Alpha 
0.0001 
0.0060 
0.0231 
Accumulated Alpha 
0.0001 
0.0061 
0.0250 
 
* 
Stopping for superiority is not considered in the 1st interim. 
** 
Original and revised assumptions given in 13.5.1 
 
13.4.3. 
A pre-defined iDFS event rate in Stage IIA breast cancer patients of the control 
arm 
 
Considering that the iDFS event rate for Stage IIA breast cancer patients may be 
lower than in the other patient segments in this trial, it may be required to pre- 
define an event rate that must be observed in Stage IIA breast cancer patients of 
the control arm in order to make a reliable estimate of the treatment effect in this 
subgroup of patients. 
 
There were 2 registrational trials comprised of patients with Stage IIA breast 
cancer. In the ATAC trial (2002)59, the disease free survival (DFS) event rate was 
10% for anastrozole arm and 12% for tamoxifen arm. In the BIG 1-98 trial 
(2005)60, the DFS event rate was 8.8% for letrozole arm and 11% for tamoxifen 
arm. The DFS event rate in Stage IIA breast cancer patients observed in PALLAS 
could be lower than the event rate observed in these two trials. It is therefore 
assumed that an 8% iDFS event rate in Stage IIA breast cancer patients 

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of the control arm in the PALLAS study can be considered acceptable in order to 
reliably estimate the treatment effect. 
 
13.4.4. 
Update Analysis for Stage IIA breast cancer patients 
 
An update analysis will be conducted after 8% iDFS event rate in Stage IIA breast 
cancer patients of the control arm is observed. 
 
The update analysis is a subgroup analysis for Stage IIA breast cancer patients to 
estimate treatment effect on iDFS. The purpose of the update analysis is to make 
a reliable estimate of the treatment effect on iDFS with sufficient number of events 
in Stage IIA breast cancer patients. There will be no hypothesis testing in the 
update analysis. 
 
Assuming that 1000 Stage IIA breast cancer patients will be enrolled within 1 year 
of study start, it is estimated that the update analysis, if needed, will occur around 
6.3 years after study start and 1.5 years after the final analysis. 
 
13.4.5. Analysis at End of Study 
 
At End of Study, exploratory analyses of the secondary time-to-event endpoint 
OS, as well as other endpoints as requested will be conducted. 
 
13.4.6. Impact of COVID-19 Pandemic 
 
If, due to the COVID-19 pandemic, it becomes apparent that additional 
sensitivity analyses are necessary, specific statistical analyses will be 
documented in the statistical analysis plan (SAP) or additional documents. 
 
 
13.5. 
Sample Size, Accrual time, and Study Duration 
 
13.5.1. 
Sample Size 
 
The revised total accrual is 5600 patients. A maximum of 1000 Stage IIA patients 
are to be enrolled. If the maximum is reached, the study will proceed to enroll only 
Stage IIB and III patients. 
 
Sample size is based on a target effect size on the hazard ratio (HR) scale for 
Arm A over Arm B of 0.75 as a clinically relevant level of improvement in iDFS. 
To have 85% power to detect this difference after accounting for interim analysis 
plans, the final analysis will occur when 469 iDFS events are observed. 

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Original assumptions: 
Total accrual is determined based on the assumed iDFS for patients on Arm B 
(control) using results from ECOG 5103: Phase 3 randomized study of adjuvant 
therapy comprising doxorubicin hydrochloride, cyclophosphamide, and paclitaxel 
with versus without bevacizumab in patients with lymph node-positive or high-
risk, lymph node-negative breast cancer.48 In the ER+ subset, the 5-year iDFS rate 
was 0.74, 0.82, and 0.92 for Stages III, IIB, and IIA, respectively. By simulation, 
it is anticipated that the 5-year iDFS rate will be 0.81 in Arm B for a mixed patient 
population with 39% Stages III, 39% IIB and 22% IIA patients (capped). The 
alternative hypothesis is a 25% risk reduction with Arm A which equates to a 5-
year iDFS rate of 0.854 (absolute difference of 4.4%). 
 
To define the total sample size, it is assumed that time to iDFS event and time to 
dropout follow an exponential distribution. The dropout rate is assumed to be 10% 
at 5 years. Assuming a quarterly step-wise increase in enrollment over the first 
year, and a constant rate of 153 patients per month thereafter, 4600 patients will be 
enrolled within 36 months. The final analysis at 469 iDFS events is anticipated to 
occur after 22 months of additional follow-up. 
 
Revised assumptions: 
The first patient was randomized in September 2015, and enrollment reached the 
cap of 1000 Stage IIA patients in September 2017 and closed to further accrual of 
this patient cohort. As of February 2018, over 3500 patients have been enrolled 
into the study, with the rate of recruitment exceeding 250 during January 2018. 
The recruitment period is therefore anticipated to be shorter than originally 
projected. Further, contemporary trials investigating adjuvant treatment of 
hormone receptor-positive breast cancer have shown improved clinical outcomes 
and lower event rates. Specifically, in NSABP B-47 the 5-year iDFS rate was 0.896 
and 0.892 with and without the addition of trastuzumab to standard adjuvant 
therapy, respectively. In ABCSG-18, a randomized placebo-controlled study of the 
addition of denosumab to standard adjuvant AI therapy (n = 3425), the 5-year iDFS 
rate was 0.78, 0.85, and 0.89 for Stages III, IIB, and IIA, respectively. In TEXT, 
premenopausal women received ovarian function suppression with anti-estrogen 
therapy and 5-year iDFS rate was 0.77, 0.87, and 
0.92 for Stages III, IIB, and IIA, respectively. Under an exponential model, the 
hazard ratio of iDFS in TEXT relative to the control arm of ECOG 5103 is 1.15, 
1.42 and 1.0 for Stages III, IIB, and IIA, respectively, and supports an additional 
1000 patients that are stage III or IIB, such that the study population is expected to 
be 41% Stages III, 41% IIB and 18% IIA patients (capped at 1000 patients). 
 
A revised total sample size of 5600 is anticipated to be enrolled within 41 months. 
By simulation using (a) the actual accrual through 2017 and constant accrual 
thereafter, (b) the 5-year iDFS rates for stage IIB and III observed in TEXT, and 
(c) the original dropout rate of 10% at 5 years, the final analysis at 469 iDFS events 
is anticipated to occur after 24 months of additional follow-up (65 months total ). 

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Power is also calculated for the secondary endpoint: iDFS excluding second 
primary invasive cancers of non-breast origin as an event. Under the assumption 
that 12% of iDFS events will be second primary invasive cancers of non-breast 
origin, and time to event for this endpoint will follow an exponential distribution, 
there will be a 79.3% power to detect a HR = 0.75 for the secondary endpoint of 
iDFS excluding second primary invasive cancers of non-breast origin using a one-
sided alpha = 0.025. 
 
The expected study duration to primary analysis of iDFS is 5.4 years. 
 
Power is also calculated for the secondary endpoint: Invasive disease-free survival 
(iDFS) excluding second primary invasive cancers of non-breast origin as an 
event. Under the assumption that 12% of iDFS events will be second primary 
invasive cancers of non-breast origin, and time to event for this endpoint will 
follow an exponential distribution, there will be 79.3% power to detect a HR 
= 0.75 for the secondary endpoint of iDFS excluding second primary invasive 
cancers of non-breast origin using a one-sided alpha = 0.025. 
 
The expected study duration to primary analysis of iDFS is 5.4 years. 
 
13.5.2. 
Accrual Rate and Accrual Duration 
 
Under original assumptions: Accrual is expected to reach a rate of approximately 
153 patients per month after the first year of enrollment and have a total duration 
of 36 months. Enrollment will not be suspended for interim analysis. With 
quarterly step-wise increases to the maximum rate over the first year of enrollment, 
the target sample size is 4600 patients. 
 
It is also assumed that the cap of 1000 Stage IIA breast cancer patients will be 
reached within 1 year of study start. 
 
A revised total sample size of 5600 is anticipated to be enrolled within 41 months. 
 
13.5.3. 
Primary Endpoint Completion Date for ClinicalTrials.gov Reporting 
 
For purpose of ClinicalTrial.gov reporting, the Primary Endpoint Completion Date 
(PECD) for this study will be the date of awareness of the 469th event and is 
expected to occur at least 5 years from the first patient randomized. 
 
13.6. 
Study Operating Characteristics 
 
Under the interim and final analysis plan for efficacy and futility, there will be 85% 
power to detect the target HR = 0.75 in the comparison of Arm A to Arm B without 
consideration of sample size re-estimation. The following table provides 

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the probabilities of declaring the experimental intervention to be superior under 
other effect sizes. 
 
Hazard ratio 
(Arm A to B) 
Power 
0.700 
96.0% 
0.725 
91.7% 
0.750 
85.0% 
0.775 
75.6% 
0.800 
64.1% 
 
13.7. 
Analysis Plans for Secondary, Translational and PRO Endpoints 
 
For the time-to-event efficacy endpoints (iDFS excluding second primary invasive cancers 
of non-breast origin, DRFS, LRRFS and OS), analyses will be done comparing Arm A vs 
Arm B. In addition to stratified log-rank test, survival functions will also be summarized 
using the Kaplan-Meier method according to randomized treatment assignment. 
Multivariable Cox proportional hazard model with study stratification factors and known 
prognostic factors for EBC will be used to calculate adjusted hazard ratios and 95% 
confidence intervals. 
 
Toxicities will be summarized by maximum grade for all-causality adverse events (AEs) 
during protocol treatment. Serious adverse events (SAEs) will be analyzed using the 
previously defined safety population. Rates will be reported with 95% binomial exact 
confidence intervals. Actual laboratory values (vs. CTCAE grades) may additionally be 
summarized using graphical techniques, and summary statistics (e.g., means, median, 
standard deviations, ranges). 
 
All statistical inferences for secondary efficacy and patient safety will use two-sided 
alpha = 0.05. 
 
Further analysis details will be described in the statistical analysis plan (SAP). Details 
including how to evaluate iDFS and OS in genomically defined breast cancer subgroups 
based on a pre-specified genomic assay and how to compare quality of life by treatment 
arm through patient reported outcomes as well as adherence in a subgroup of patients, etc. 
will be described in a separate SAP. 
 
13.8. 
Correlative Science Objectives (TRANS-PALLAS) 
 
The Statistical Analysis Plan for all correlative science objectives (also known as “TRANS-
PALLAS”) will be contained within a separate document. Of note, the Primary 
Translational Objective will not be considered in controlling the family-wise error rate of 
the primary and secondary clinical objectives of the study. 

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13.9. 
Independent Data Safety Monitoring the Study 
 
Interim monitoring of data and safety will be reported to an Independent Data Monitoring 
Committee (IDMC). IDMC will review the safety data on at least a semi-annual basis, in 
conjunction with the results of any interim and final analyses and come up with 
recommendations to the SC in special consideration of any identified potential safety risks. 
Based on the recommendations of the IDMC, the SC will decide to either, proceed with the 
trial as planned, amend the protocol accordingly or prematurely terminate the trial. Once 
all patients are in follow-up, no further IDMC meetings take place. 
 
A preplanned safety analysis will occur when the first patient enrolled has completed one 
year of protocol therapy,and is estimated to occur when approximately 1/3 of patients are 
enrolled to the study. In addition to the data from the PALLAS study, the IDMC will also 
evaluate the safety data available in the Pfizer safety data base from ongoing or completed 
studies of palbociclib and endocrine therapy in the adjuvant and MBC (metastatic breast 
cancer) settings, with a goal to assess safety of the combination of palbociclib and 
endocrine therapy, as well as confirm the appropriateness to continue the treatment into the 
second year of palbociclib exposure. 
 
14. Correlative Sciences and Clinical Data Science 
 
Described protocol objectives as well as future research proposals can be generally categorized into 
projects requiring access to study data only versus requiring access to study data and surplus 
samples. 
´Clinical Study Data Projects´ (not involving (surplus) study samples) may be reviewed separately 
from ´Translational Research Projects´ (involving study data and (surplus) study samples and 
handled by TRANS-PALLAS working groups and TRC, as defined in respective charters). 
´Adherence/PRO´ research (requiring access to specific study data only) may be viewed as a further 
sub-group of ´Clinical Study Data Projects´. 
Multiple tissue- and liquid-based translational research studies are scheduled throughout the course 
of the PALLAS trial to evaluate potential markers of response and/or resistance in patients receiving 
endocrine therapy with palbociclib versus endocrine therapy alone. The companion TRANS-
PALLAS Investigator Manual of Procedures will be developed by the TRANS-PALLAS scientific 
steering committee. 
Additionally, examination of patient-reported outcomes (PRO)/quality of life in a sub-group of 
patients as well as adherence to oral therapy, and interaction of metabolic state and response to 
palbociclib will occur. 
Clinical Data Projects will be based on scientific research proposals brought to the attention of the 
study leadership after the primary analysis. 
Detailed analyses will be described in separate document(s). 

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15. General Regulatory Considerations and Credentialing 
 
15.1. 
Regulatory and ethical compliance 
 
By signing the Protocol, the investigator agrees to treat all of the information that is 
provided with the strictest confidentiality and to require the same of his personnel as well 
as the IRB/IEC. Study documents (protocols, investigator`s brochures, eCRFs, etc.) 
provided by the AFT/ABCSG will be stored in an appropriate manner in order to ensure 
confidentiality. The information provided to the investigator by AFT/ABCSG or Pfizer 
must not be made available to other parties without a direct written authorization by the 
aforesaid parties, with the exception of the extent to which disclosure is necessary in order 
to obtain informed consent from the patients who wish to participate in the study. 
 
15.2. 
Ethics and Good Clinical Practice 
 
This study will be conducted in compliance with the study protocol, subsequent 
amendment(s) and with the study-specific manuals/guidelines, if applicable. These 
documents ensure that the ICH E6 guideline for Good Clinical Practice is maintained as 
well as compliance with the principles of the Declaration of Helsinki (World Medical 
Association), or the laws and regulations of the country in which the research is conducted, 
whichever afford the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting). 
 
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. FDA regulation and applicable local, state and federal 
laws. 
 
Studies conducted in the European Union/European Economic Area will comply with the 
E.U. Clinical Trial Directive (2001/20/EC including 2005/28/EC) until the E.U. Directive 
2001/20/EC will be repealed and the E.U. regulation 536/2014 will enter into force by the 
publication of E.U. or EMA. 
 
By signing the study protocol the investigator agrees to comply with the instructions and 
procedures described therein and thus to adhere to the principles of good clinical practice, 
which these instructions and procedures reflect. 
 
15.3. 
Confidentiality 
 
Patient medical information both, associated with biologic specimens or not, is confidential 
and may only be disclosed to third parties as permitted by the ICF (or separate authorization 
for use and disclosure of personal health information) which has been signed by the patient, 
unless permitted or required by law. Data derived from biologic specimen analysis on 
individual patients will in generally not be provided to study investigators unless a request 
for research use is granted. The overall results of any 

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research conducted using biologic specimens will be available in accordance with the 
effective Translational Research Committee policy on study data publication. 
 
15.4. 
Protocol Amendments 
 
Any modifications to the protocol or the Informed Consent Form which may impact on the 
conduct of the study, potential benefit of the study, or may affect patient safety, including 
changes of study objectives, study design, patient population, sample sizes, study 
procedures, or significant administrative aspects will require a formal amendment to the 
protocol. Such amendment will be released by AFT/ABCSG, agreed by the investigator(s) 
and approved by relevant IRBs/IECs and health authorities according to local requirements 
prior to implementation. A signed and dated statement that the protocol, any subsequent 
relevant amended documents and the Informed Consent Form have been approved by 
relevant IRBs/IECs and/or health authorities must be provided to AFT/ABCSG before the 
study is initiated. 
Administrative changes of the protocol are minor corrections and/or clarifications that have 
no effect on the way the study is to be conducted. These administrative changes will be 
released by the AFT/ABCSG, agreed by the investigator(s) and notified to the IRB/IEC(s) 
and/or health authorities according to local requirements. 
Each change in the protocol should be reported to Pfizer who supplies the Investigational 
Product prior to submission to the involved IRB/IEC(s) and/or health authorities. 
 
15.5. 
Informed Consent 
 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations), to obtain written Informed Consent from each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. This information must be provided to the 
patient prior to undertaking any trial-related procedure which is not part of the routine 
clinical management of the patient (i.e. would not be indicated outside the study). 
 
For patients not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the patients and 
his/her legally acceptable representative are unable to read, an impartial witness should be 
present during the entire informed consent discussion. After the patient and representative 
have orally consented to participation in the trial, the witness’ signature on the form will 
attest that the information in the consent form was accurately explained and understood. 
The Investigator or designee must also explain that the patients are completely free to 
refuse to enter the study or to withdraw from it at any time, for any reason. 
 
Furthermore, it is the investigator’s responsibility to obtain the signed Informed Consent 
Form, and a signature from the person conducting the informed consent discussion, prior 
to undertaking any trial-related procedure. The proposed Informed Consent Form must 
accomplish with the ICH GCP guideline and regulatory requirements. 
The eCRF for this study contains a section for documenting patient’s Informed Consent(s), 
and this must be completed appropriately. 

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If new palbociclib safety information results in significant changes in the risk/benefit 
assessment, the Informed Consent Form should be reviewed and updated if necessary. All 
patients who may be directly affected (including those already being treated) should be 
informed of the new information, given a revised form and give their consent to continue 
in the study. 
 
15.6. 
Financial Disclosure 
Investigators will provide the respective study Sponsor with adequate and accurate 
financial information in accordance with local regulations and laws in order to allow the 
Sponsor to submit complete and accurate financial certification or disclosure statements to 
the appropriate health authorities. Investigators are responsible for providing updated 
information on financial interests during the course of the study as well as for 1 year after 
completion of the study. 
 
15.7. 
Quality Control 
 
The study will be monitored according to GCP by regular site visits and calls. The 
responsible and adequately trained monitor (Clinical Research Associate, CRA) or his/her 
designee will contact and visit the study sites as defined in the study specific Monitoring 
Plan. The monitor will be permitted to inspect the various records of the study patients 
(e.g. source documents) on request provided that the patient confidentiality is maintained 
in accordance with local regulations. 
The monitor is responsible for eCRF inspection on a regular basis throughout the study 
according to the study specific Monitoring Plan in order to verify adherence to the study 
protocol and in order to verify completeness, consistency and accuracy of the entered data. 
Furthermore, the monitor follows the progress of patient enrollment and ensures that IP is 
stored, dispensed and accounted for according to defined specifications. The monitor will 
access laboratory test reports and other patient records needed for verification of eCRF 
entries. The investigator or his/her designee agrees to cooperate with the monitor to 
ensure resolution of problems and other issues identified during study monitoring. 
Details will be outlined in the study specific Monitoring Plan. 
The investigational site must also allow inspections by applicable health authorities and 
audits by the respective study Sponsor. 
 
15.8. 
Protocol Deviations 
 
The investigator is responsible to document and explain any deviations from the approved 
protocol. The investigator should promptly report any deviations that might impact patient 
safety and data integrity to the respective Sponsor and if locally applicable, to the 
respective IRB/EC in accordance with local IRB/EC policies and procedures. Specific 
procedures and reporting requirements for the PALLAS study are defined in the common 
Protocol Deviation Management Plan for the study. 

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For COVID-19 related measures implemented for recording and defining protocol 
deviations, please refer to 6.10. 
 
 
15.9. 
Retention of Records 
 
Any records and documents relating to the conduct of this study and the distribution of 
IP, including ICFs, eCRFs, PRO data, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for a minimum of 15 years after 
completion or discontinuation of the study, or for the length of time required by relevant 
national or local health authorities, whichever is longer. After that period of time, the 
documents may be destroyed, subject to local regulations. No records may be disposed of 
without the written approval of the Sponsor. Written notification should be provided to the 
Sponsor prior to transferring any records to another party or moving them to another 
location. 
 
 
15.10. 
Trial Administrative Governance Structure 
 
15.10.1. Structure Co-Sponsorship (AFT, ABCSG GmbH) 
 
The PALLAS study is legally governed by two different study Sponsors: 
 
• 
Alliance Foundation Trials (AFT), LLC is the official and legal Sponsor 
for the area of United States of America and in this function responsible for 
US-sites, US operations, US regulatory and safety affairs etc. 
 
US Sites belong to AFT as study Sponsor and will hence have to report to this 
organization and should follow US instructions and US procedures as 
described within this protocol and any other study related US guidelines, 
unless otherwise indicated. 
• 
Austrian Breast and Colorectal Cancer Study Group (ABCSG GmbH) is 
the official and legal Sponsor for all area outside of the United States of 
America and in this function responsible for Non-US sites, Non-US 
operations, Non-US regulatory and safety affairs etc. 
 
Non-US Sites belong to ABCSG as study Sponsor and will hence have to 
report to this organization and should follow Non-US instructions and Non- 
US procedures as described within this protocol and any other study related 
Non-US guidelines, unless otherwise indicated. 
 
Among the scope of this study, ABCSG collaborates with the Breast 
International Group (BIG) as co-Lead partners, and with a number of different 
BIG Groups. 

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15.10.2. Steering Committee (SC) 
 
The Steering Committee is composed of and working according to the study related 
SC Charter. The SC is responsible for top-level trial design and management 
decisions, also in consideration of any IDMC recommendations. 
 
15.10.3. Executive Committee (EC) 
 
The EC is composed of and working according to the study specific EC Charter. It 
represents a subcommittee of the SC and serves as a rapid decision making body, 
when necessary. 
 
15.10.4. Independent Data Monitoring Committee (IDMC) 
 
The Independent Data Monitoring Committee (IDMC) is composed of and 
working according to the study specific IDMC Charter. This committee will 
independently monitor the safety of the patients enrolled into the study as well as 
data integrity and provide recommendations to the SC. 
 
15.10.5. Translational Research Committee (TRC) 
 
The Translational Research Committee is composed of and working according to 
the study related TRC charter. This committee will review all research project 
proposals requesting access to study data, biological samples collected during the 
conduct of the Study, make recommendations to the Steering Committee (SC) in 
line with the Policy for Access to Study Data and Biological Samples. 
 
15.10.6. Publication and Presentation Policy 
 
Publications and presentations resulting from the PALLAS trial will comply with 
recognized ethical standards concerning publications and authorship, including 
Uniform Requirements for Manuscripts Submitted to Biomedical Journals, 
established by the International Committee of Medical Journal Editors. 
Furthermore, publications and any kind of presentations of any results from the 
study shall be in accordance with accepted scientific practice, academic standards 
and customs and in accordance with the specific policy developed for this study. 
The detailed “Publication and Presentation Policy” shall be approved by the 
Study Steering Committee and made available to all investigators, sites and groups 
participating in the study. 

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16. References 
 
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measure of medication adherence. Med Care. 1986 Jan;24(1):67–74. 

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51 
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with endocrine therapy in breast cancer survivors recruited from an online research 
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to adhere to prescription medications for chronic disease. Current Medical Research and 
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McHorney C, Spain C, Alexander C, Simmons J: Validity of the Adherence Estimator in 
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Miller K, O'Neill AM, Dang CT, et al: Bevacizumab (Bv) in the adjuvant treatment of 
HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group 
E5103. ASCO Meeting Abstracts 32:500, 2014 
57 
Lan KKG, Demets DL: Discrete Sequential Boundaries for Clinical-Trials. Biometrika 
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O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 
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the PALOMA-1/TRIO-18 trial. Ann Oncol. 2014;25(suppl 4): iv122 Abstract no. 368P. 
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87 
van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle 
control. Science. 1993;262:2050-4 
88 
Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323-30. 
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Lee NV, Yuan J, Eisele K, et al. Mechanistic exploration of combined CDK4/6 and ER 
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Phase III Study Evaluating Palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 
4/6 Inhibitor in Patients With Hormone-receptor-positive, HER2-normal Primary Breast 
Cancer With High Relapse Risk After Neoadjuvant Chemotherapy "PENELOPEB” 
(NCT01864746) 
93 
Phase III Study of Palbociclib (PD-0332991) in Combination With Exemestane Versus 
Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative 
Metastatic Breast Cancer (MBC) Patients With Resistance to Non-steroidal Aromatase 
Inhibitors (PEARL) (NCT02028507) 
94 
Finn et al (Finn, Breast Cancer Research, 2009) 
95 
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Recommendations for Immunohistochemical Testing of Estrogen and Progesterone 
Receptors in Breast Cancer. Journal of Clinical Oncology; Volume 28, Number 16, 2010: 
2784-2795 
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Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical 
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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. 

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17. Appendices 
 
APPENDIX A: Eastern Cooperative Oncology Group (ECOG) Performance Status Criteria 
 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without 
restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature, i.e., light 
house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours. 
2 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
4 
Dead 
5 
 
 
Please refer to http://oncologypro.esmo.org/Oncology-in-Practice/Practice-Tools/Performance-Scales for 
conversion instructions between Karnofsky Scale and ECOG Status. 

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APPENDIX C: AJCC Cancer Staging from Edge S, Byrd DR, Compton CC, et al. AJCC 
cancer staging manual (7th ed). New York, NY: Springer; 2010 
ANATOMIC STAGE/PROGNOSTIC GROUPS 
 
Stage 
T 
N 
M 
0 
Tis 
N0 
M0 
IA 
T1* 
N0 
M0 
IB 
T0 
N1mi 
M0 
T1* 
N1mi 
M0 
IIA 
T0 
N1** 
M0 
T1* 
N1** 
M0 
T2 
N0 
M0 
IIB 
T2 
N1 
M0 
T3 
N0 
M0 
IIIA 
T0 
N2 
M0 
T1* 
N2 
M0 
T2 
N2 
M0 
T3 
N1 
M0 
T3 
N2 
M0 
IIIB 
T4 
N0 
M0 
T4 
N1 
M0 
T4 
N2 
M0 
IIIC 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
Notes 
* T1 includes T1mi. 
** T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB. 
• M0 includes M0(i+) 
• The designation pM0 is not valid; any M0 should be clinical. 
• If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and 
remains Stage IV regardless of response to neoadjuvant therapy. 
• Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, 
provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression 
and provided that the patient has not received neoadjuvant therapy. 
• Postneoadjuvant therapy is designated with “yc” or “yp” prefix. Of note, no stage group is assigned if there 
is a complete pathologic response (CR) to neoadjuvant therapy, for example, ypT0ypN0cM0. 

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Tumor (T) 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (LCIS) 
Lobular carcinoma in situ 
Tis (Paget`s) 
Paget’s disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ 
(DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast 
parenchyma associated with Paget’s disease are categorized based on the size and 
characteristics of the parenchymal disease, although the presence of Paget’s disease should still 
be noted. 
T1 
Tumor ≤ 20 mm in greatest dimension 
T1mi 
Tumor ≤ 1 mm in greatest dimension 
T1a 
Tumor >1 mm but ≤ 5 mm in greatest dimension 
T1b 
Tumor > 5 mm but ≤ 10 mm in greatest dimension 
T1c 
Tumor > 10 mm but ≤ 20 mm in greatest dimension 
T2 
Tumor >20 mm but ≤ 50 mm in greatest dimension 
T3 
Tumor > 50 mm in greatest dimension 
T4 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin 
nodules) 
Note: Invasion of the dermis alone does not qualify as T4 
T4a 
Extension to the chest wall, not including only pectoralis muscle adherence/invasion 
T4b 
Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the 
skin, which do not meet the criteria for inflammatory carcinoma 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma (see “Rules for Classification”) 

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Distant Metastases (M) 
 
M0 
No clinical or radiographic evidence of distant metastases 
cM0(i+) 
No clinical or radiographic evidence of distant metastases, but deposits of molecularly or 
microscopically detected tumor cells in circulating blood, bone marrow, or other non-regional 
nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases 
M1 
Distant detectable metastases as determined by classic clinical and radiographic means and/or 
histologically proven larger than 0.2 mm 
 
Regional Lymph Nodes (N) 
 
Clinical 
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastases 
N1 
Metastases to movable ipsilateral level I, II axillary lymph node(s) 
N2 
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically 
detected* ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node 
metastases 
N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other 
structures 
N2b Metastases only in clinically detected* ipsilateral internal mammary nodes and in the absence of 
clinically evident level I, II axillary lymph node metastases 
N3 
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary 
lymph node involvement; or in clinically detected* ipsilateral internal mammary lymph node(s) with 
clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular 
lymph node(s) with or without axillary or internal mammary lymph node involvement 
N3a Metastases in ipsilateral infraclavicular lymph node(s) 
N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c Metastases in ipsilateral supraclavicular lymph node(s) 
 
Notes 
* “Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical 
examination and having characteristics highly suspicious for malignancy or a presumed pathologic 
macrometastasis based on fine needle aspiration biopsy with cytologic examination. Confirmation of 
clinically detected metastatic disease by fine needle aspiration without excision biopsy is designated with 
an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the 
absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the 
confirmation of the nodal status will be designated in site-specific factors as clinical, fine needle aspiration, 
core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel 
lymph node biopsy only in conjunction with a pathologic T assignment. 

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Regional Lymph Nodes (N) 
 
Pathologic (PN)* 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for 
pathologic study) 
pN0 
No regional lymph node metastasis identified histologically 
Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 
mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. 
ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes 
containing only ITCs are excluded from the total positive node count for purposes of N 
classification but should be included in the total number of nodes evaluated. 
pN0(i–) 
No regional lymph node metastases histologically, negative IHC 
pN0(i+) 
Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC 
including ITC) 
pN0(mol–) 
No regional lymph node metastases histologically, negative molecular findings (RT-PCR) 
pN0(mol+) Positive molecular findings (RT-PCR)**, but no regional lymph node metastases detected by 
histology or IHC 
pN1 
Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in internal mammary nodes 
with metastases detected by sentinel lymph node biopsy but not clinically detected*** 
pN1mi 
Micrometastases (greater than 0.2 mm and/or more than 200 cells but none greater than 2.0 mm) 
pN1a 
Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2.0 mm 
pN1b 
Metastases in internal mammary nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected*** 
pN1c 
Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with 
micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically 
detected 
pN2 
Metastases in 4–9 axillary lymph nodes; or in clinically detected**** internal mammary lymph 
nodes in the absence of axillary lymph node metastases 
pN2a 
Metastases in 4–9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm) 
pN2b 
Metastases in clinically detected**** internal mammary lymph nodes in the absence of axillary 
lymph node metastases 
pN3 
Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph 
nodes; or in clinically detected**** ipsilateral internal mammary lymph nodes in the presence of 
one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes 
and in internal mammary lymph nodes with micrometastases or macrometastases detected by 
sentinel lymph node biopsy but not clinically detected****, or in ipsilateral supraclavicular lymph 
nodes. 
pN3a 
Metastases in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); 
or metastases to the infraclavicular (level III axillary lymph) nodes 
pN3b 
Metastases in clinically detected**** ipsilateral internal mammary lymph nodes in the presence of 

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one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in 
internal mammary lymph nodes with micrometastases of macrometastases detected by sentinel 
lymph node biopsy but not clinically detected*** 
pN3c 
Metastases in ipsilateral supraclavicular lymph nodes 
 
Notes 
* 
Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. 
Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection 
is designated (sn) for “sentinel node”, for example, pN0(sn). 
** RT-PCR: reverse transcriptase/polymerase chain reaction. 
***    “Not clinically detected” is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not 
detected by clinical examination. 
****   “Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical 
examination and having characteristics highly suspicious for malignancy or a presumed pathologic 
macrometastasis based on fine needle aspiration biopsy with cytologic examination. 

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APPENDIX D: Recommendations on adequate local treatment for PALLAS trial candidates 
 
In the PALLAS trial, all study participants are required to have undergone adequate initial local 
treatment for their breast cancer including surgical resection, with or without radiotherapy. Guidance on 
the definition of adequately treated patients prior to randomization is provided below: 
 
Positive Sentinel Node 
Based on the 2016 ASCO Guidelines on sentinel lymph node biopsy for patients with early-stage 
breast cancer96 a patient who has a limited positive sentinel lymph node biopsy and will be receiving 
adjuvant radiotherapy after breast conservation does not require a completion axillary lymph node 
dissection (ALND). Such patients are eligible for enrollment onto the PALLAS trial. However, it is 
strongly recommended that candidates for PALLAS who underwent breast‐conserving surgery and 
had 1‐2 sentinel lymph node metastases without ALND subsequently undergo conventionally 
fractionated whole-breast radiotherapy. 
PALLAS candidates who had a mastectomy and positive sentinel lymph node biopsy may have had a 
completion ALND. If mastectomy was performed and no ALND pursued, adjuvant radiotherapy is 
strongly recommended. 
 
Surgical Resection Margins 
Invasive breast cancer should have been excised to the best of local surgical ability. Patient’s surgical 
treatment is considered complete as long as there is no gross residual disease. The inked margins of 
breast conservation surgery or mastectomy should ideally be histologically free of invasive breast cancer 
and ductal carcinoma in situ, with the exception of the posterior margin if this margin is the pectoralis 
major fascia or the anterior margin if this is the dermis. Patients with resection margins positive for 
lobular carcinoma in situ are eligible. In patients who undergo a nipple sparing mastectomy (NSM), 
retro‐areolar tissue should have been excised and analyzed intraoperatively. If the retro-areolar margin 
is positive for DCIS or invasive cancer, the nipple areolar complex (NAC) should be removed.