A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy After Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer
Phase: PHASE3
Conditions: HER-2 Positive Breast Cancer, Estrogen Receptor Positive Breast Cancer
Sponsor: Alliance Foundation Trials, LLC.



 
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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety 
of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine 
Therapy after Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive 
Metastatic Breast Cancer 
 
 
Protocol Number: AFT-38 
IND Number: 132050 
EudraCT Number: 2017-000419-17 
 
 
 
 
US Sponsor Name: 
 
 
Alliance Foundation Trials (AFT), LLC 
 
 
 
 
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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Synopsis 
Study Title 
A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety 
of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 
Therapy + Endocrine Therapy after Induction Treatment for Hormone Receptor 
Positive (HR+)/HER2-Positive Metastatic Breast Cancer 
Study Number 
AFT-38 
Study Type/Phase 
International, multicenter, open-label, pivotal Phase III study 
Clinical Indication 
HER2+, HR+ Metastatic Breast Cancer 
ClinicalTrials.gov 
Identifier 
NCT02947685 
IND Number 
132050 
Number of Trial 
Patients 
496 
Estimated Duration 
of Trial 
9 Years 
End of Study 
The study will end approximately 5 years after the last patient is randomized. 
Rationale 
The current study is built on strong pre-clinical and clinical rationale 
demonstrating the benefits of palbociclib when given in combination with 
endocrine therapies and anti-HER2 therapies. We expect that the addition of 
palbociclib to the first-line treatment of HER2 disease will delay the onset of 
therapeutic resistance and ultimately prolong patient’s survival. The study is 
designed to treat the subset of HER2+ disease classified as hormone receptor 
positive. We expect that palbociclib will modulate the endocrine resistance in 
HER2+HR+ disease and also potentiate the benefits of anti-HER2 therapy. 
Lastly, the current study includes a comprehensive molecular characterization 
of the disease at the study entrance which will allow us to investigate the 
benefits of palbociclib in subsets of HER2+ disease such (e.g. PIK3CA mutant).  
Primary Objective 
The primary objective of this study is to demonstrate that the combination of 
palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-
HER2-based therapy plus endocrine therapy in prolonging PFS in participants 
with hormone receptor-positive, HER2+ metastatic breast cancer who have not 
received any prior treatment beyond induction treatment in this setting.   
 
 
Secondary 
Objectives  
1. To compare measures of tumor control (including OR, CBR, DOR) 
between the treatment arms  
2. To compare median overall survival and overall survival probabilities 
at 3-years and 5-years between the treatment groups  

 
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3. To compare safety and tolerability between the treatment arms  
4. To compare the incidence of CNS metastasis between the treatment 
arms  
5. To compare patient reported time to symptom progression as assessed 
by the FACT-B TOI-PFB   
6. To compare patient reported breast cancer specific health related 
quality of life (HRQOL) and general health status.  
 
Translational 
Science Objectives 
 
Principal:  
To compare progression-free survival based upon investigator assessment of 
progression between patients in the two treatment arms in the subset of patients 
with tumors bearing a PIK3CA mutation. PIK3CA genotype will be assessed in 
circulating tumor DNA (ctDNA)  
Exploratory: 
1. To evaluate PFS and OS in genomically-defined breast cancer 
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 anti-HER2 therapy plus 
endocrine therapy 
3. To evaluate tumor- and blood-based markers at time of disease 
recurrence for mechanisms of resistance to therapy  
4. To compare serial levels of circulating tumor DNA (ctDNA) in patients 
receiving anti-HER2 therapy plus endocrine therapy versus anti-HER2 
therapy plus endocrine therapy plus palbociclib  
5. To compare mutational profile/copy number variants obtained from 
tumor tissue to those measured in circulating tumor DNA (ctDNA) 
6. To use ctDNA sequencing to compare the inferred tumor transcriptome 
before and during treatment with anti-HER2 therapy and endocrine 
therapy with or without palbociclib 
7. To determine the trough concentrations of palbociclib when given in 
combination with trastuzumab plus endocrine therapy or trastuzumab 
plus pertuzumab plus endocrine therapy 
8. To determine trastuzumab and pertuzumab trough concentrations when 
given in combination with palbociclib plus endocrine therapy  
9. To explore correlations between palbociclib exposure and 
efficacy/safety findings in this patient population 
10. To compare the progression-free survival (PFS) outcomes assessed 
through either local and/or central imaging review with those evaluated 
using artificial intelligence-based imaging analysis 
 
Primary Endpoint 
Progression-free survival (PFS) as assessed by the Investigator 
Secondary 
Endpoints 
1. Overall Survival (OS) 
2. 3-year and 5-year survival probabilities  
3. Objective response (OR: CR or PR) 
4. Duration of response (DOR) 
5. Clinical Benefit Rate (CBR: CR or PR or SD ≥ 24 weeks) 
6. Incidence of CNS metastasis 

 
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7. Safety: Type, incidence, severity (as graded by the NCI CTCAE v. 4.0), 
seriousness and attribution to the study medications of AEs and any 
laboratory abnormalities 
8. Patient Reported Outcomes: Time to symptom progression (FACT-B 
PFB-TOI), breast cancer specific health treatment related quality of life 
and general health status 
Correlative 
Endpoints 
1. Trough plasma concentration of palbociclib, trastuzumab and 
pertuzumab in the subgroup of patients enrolled in the US 
2. PIK3CA genotype assessed in circulating tumor DNA (ctDNA) 
3. Tumor tissue biomarkers including genes, proteins, and RNA 
expression 
 
Inclusion Criteria 
Inclusion Criteria (Preliminary Screening) 
1. 
Signed Preliminary Screening Informed Consent Form obtained prior 
to any study specific assessments and procedures 
2. Age ≥18 years (or per national guidelines)  
3. Participants must have histologically confirmed invasive breast cancer 
that is metastatic or not amenable for resection or radiation therapy with 
curative intent. Histological documentation of metastatic/recurrent 
breast cancer is not required if there is unequivocal evidence for 
recurrence of the breast cancer.  
4. Patients must have histologically confirmed HER2+ and hormone 
receptor positive (ER+ and/or PR+), metastatic 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) 
guidelines.  
5. Patients must agree to provide a representative formalin-fixed paraffin-
embedded (FFPE) tumor tissue block (preferred) from primary breast or 
metastatic site (archival) OR at least 15 freshly cut unstained slides from 
such a block, along with a pathology report documenting HER2 
positivity and hormone receptor positivity. 
6. Patients should be willing to provide a representative tumor specimen 
obtained from recently biopsied metastatic disease if clinically feasible.  
This is recommended but optional tissue.   
Inclusion Criteria (Randomization Screening) 
7. Signed Main Informed Consent Form obtained prior to any study 
specific assessments and procedures 
8. Age ≥ 18 years (or per national guidelines) 
9. ECOG performance status 0-1  
10. Patients must be able and willing to swallow and retain oral medication 
without a condition that would interfere with enteric absorption. 
11. 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 

 
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patients randomized into the study must use adequate contraception for 
the duration of protocol treatment which is for 6 months after the last 
treatment with palbociclib if they are in Arm A and for 7 months after 
last treatment with trastuzumab if in either Arm A or Arm B. 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). 
12. Resolution of all acute toxic effects of prior induction anti-HER2-based 
chemotherapy regimen to NCI CTCAE version 4.0 Grade ≤1 (except 
alopecia or other toxicities not considered a safety risk for the patient at 
investigator's discretion) 12 weeks between last dose of chemotherapy–
anti-HER2therapy and randomization are allowed. Endocrine therapy 
could start before study randomization.  
13. Willingness and ability to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures 
Prior Treatment Specifics 
14. Patients may or may not have received neo/adjuvant therapy, but must 
have a disease-free interval from completion of anti-HER2 therapy to 
metastatic diagnosis ≥6 months.  
15. Patients must have received an acceptable, standard, chemotherapy 
containing anti-HER2 based induction therapy for the treatment of 
metastatic breast cancer prior to study enrollment. For this study, 
chemotherapy is limited to a taxane or vinorelbine (only for 
trastuzumab-based regimen). Eligible patients are expected to have 
completed 6 cycles of chemotherapy containing anti-HER2-therapy 
treatment. A minimum of 4 cycles of treatment is acceptable for patients 
experiencing significant toxicity associated with treatment as long as 
they are without evidence of disease progression (i.e. CR, PR or SD). 
The maximum number of cycles is 8. Patients can randomize 
immediately following completion of their induction therapy, or for 
those who have already completed induction, a gap of 12 weeks 
between their last infusion/dose of induction therapy and the C1D1 visit 
is permitted. Patients are eligible provided they are without evidence of 
disease progression by local assessment (i.e. CR, PR or SD).  
16. Patients with a history or presence of asymptomatic CNS metastases are 
eligible provided they meet all of the following criteria:  
x 
Disease outside the CNS is present. 
x 
No evidence of interim progression between the completion of 
induction therapy and the screening radiographic study  
x 
No history of intracranial hemorrhage or spinal cord 
hemorrhage  
x 
Not requiring anti-convulsants for symptomatic control 
x 
Minimum of 3 weeks between completion of CNS 
radiotherapy and Cycle 1 Day 1 and recovery from significant 
(Grade ≥ 3) acute toxicity with no ongoing requirement for 
corticosteroid 
 

 
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Baseline Body Function Specifics 
17. Absolute neutrophil count ≥ 1,000/mm3 
18. Platelets ≥ 100,000/mm3 
19. Hemoglobin ≥ 10g/dL 
20. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct 
bilirubin within normal range in patients with documented Gilbert’s 
Syndrome. 
21. Aspartate aminotransferase (AST or SGOT) and alanine 
aminotransferase (ALT or SGPT) ≤ 3 × institutional ULN (≤5 x ULN if 
liver metastases are present). 
22. Serum creatinine below the upper limit of normal (ULN) of the 
institutional normal range or creatinine clearance ≥ 60 mL/min/1.73 m2 
for patients with serum creatinine levels above institutional ULN. 
23. Left ventricular ejection fraction (LVEF) t 50% at baseline as 
determined by either ECHO or MUGA 
 
Exclusion Criteria 
Exclusion Criteria (Randomization) 
1. Concurrent therapy with other Investigational Products. 
2. Prior therapy with any CDK 4/6 inhibitor. 
3. History of allergic reactions attributed to compounds of chemical or 
biologic composition similar to palbociclib. 
4. Patients receiving any medications or substances that are strong 
inhibitors or inducers of CYP3A isoenzymes within 7 days of 
randomization (see Section 8.6.3 for list of strong inhibitors or inducers 
of CYP3A isoenzymes). 
5. Uncontrolled current 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. 
6. 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. 
7. Patients on combination antiretroviral therapy, i.e. those who are HIV-
positive, are ineligible because of the potential for pharmacokinetic 
interactions or increased immunosuppression with palbociclib. 
8. QTc interval >480 msec, Brugada syndrome or known history of QTc 
prolongation or Torsade de Pointes. 
9. Patients with clinically significant history of liver disease, including 
viral or other known hepatitis, current alcohol abuse, or cirrhosis  
 
 
 

 
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Study Schema 
 
 
* Anti-HER2 treatment options are Trastuzumab plus Pertuzumab or Trastuzumab only (limited to 20% 
of the study population). The same anti-HER2-regimen should be used before and post randomization.  
** Endocrine therapy options are either an Aromatase Inhibitor or Fulvestrant.  Premenopausal women must 
receive ovarian suppression with a LHRH agonist if the patients have not documented ovarian ablation or bilateral 
oophorectomy before randomization or during the conduct of the study.  
 
 
1. Introduction 
This is a randomized, open-label, multicenter, Phase III trial to assess the safety and efficacy of 
palbociclib plus anti-HER2 therapy and endocrine therapy vs. anti-HER2 therapy plus endocrine 
therapy for hormone receptor positive / HER2+ metastatic breast cancer.  
1.1 
Background and Rationale 
Breast cancer remains the most frequently diagnosed cancer in women and is the leading cause 
of cancer-related death worldwide. Despite significant improvements in the treatment of early-
stage breast cancer, approximately 30 percent of women experience metastatic disease relapse 
[1]. Surprisingly, data from the Surveillance, Epidemiology, and End Results (SEER) program 
show that the incidence of metastatic breast cancer has been stable since 1975. The lack of 
change in the incidence of metastatic disease supports the notion that breast cancer is a systemic 
disease [2]. This concept is supported by the fact that approximately 5% of women diagnosed 
with breast cancer have evidence of metastatic disease at the time of diagnosis (de novo 
presentation) despite the advances in screening techniques. In consonance with previous 
findings, data from SEER show no signs of decline in the incidence of de novo metastatic breast 
cancer over the past three decades. While metastatic breast cancer remains an incurable disease, 
it is important to stress that the development of novel therapies for the treatment of metastatic 
breast cancer should be considered a high priority.  

 
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In light of the evolving breast cancer classification, HER2+ breast cancer has emerged as a 
separate disease entity and the development of therapies targeting the HER2 receptor has 
dramatically improved patient outcomes. During the first decade of trastuzumab use for 
advanced HER2+ breast cancer, a significant improvement in the understanding of the biology of 
HER2+ disease led to the development and approval of novel anti-HER2 agents. Pertuzumab is a 
monoclonal antibody similar to trastuzumab with the ability to block HER2 function as a co-
receptor, thus inhibiting HER2 heterodimerization with other members of HER family (e.g., 
HER1, HER3). The efficacy of pertuzumab was evaluated in a Phase 3 study called 
CLEOPATRA (Clinical Evaluation Of Pertuzumab And Trastuzumab) [3, 4]. 
Despite significant improvements, HER2+ breast cancer is still a serious and life-threatening 
disease. Patients with distant disease recurrence after treatment of HER2+ disease, along with 
patients with metastasis at diagnosis, eventually progress and die of breast cancer despite the 
availability of chemotherapy, endocrine therapy and anti-HER2 therapy. Of the 450,000 global 
deaths from breast cancer each year [5] around 15% to 20% (60,000~90,000) are likely to be due 
to HER2+ disease. This translates to around 12,000 to 15,000 deaths per annum in Europe and 
6,000 to 8,000 deaths per annum in the US.  
In order to improve beyond the current standards, it is important to highlight the major 
limitations of available therapies: 1) Patients with advanced disease inevitably develop resistance 
to anti-HER2 therapies; 2) Tumor heterogeneity within HER2+ disease is now evident and can 
be divided into two major subtypes according to the expression of hormone receptor status; 3) 
Specific subsets of HER2+ disease (e.g. somatic PIK3CA mutation) have a particularly 
unfavorable outcome when treated with conventional chemotherapy. Taking together these 
factors point to the need for clinical studies dedicated to specific subsets of HER2+ disease.  
The current study is built on strong pre-clinical and clinical rationale demonstrating the benefits 
of palbociclib when given in combination with endocrine therapies and anti-HER2 therapies. We 
expect that the addition of palbociclib to the first-line treatment of HER2 disease will delay the 
onset of therapeutic resistance and ultimately prolong patient’s survival. The study is designed to 
treat the subset of HER2+ disease that also expresses hormone receptor status. We expect that 
palbociclib will modulate the endocrine resistance in HER2+ER+ disease and also potentiate the 
benefits of anti-HER2 therapy. Lastly, the current study includes a comprehensive molecular 
characterization of the disease at the study entrance which will allow us to investigate the 
benefits of palbociclib in subsets of HER2+ disease such (e.g. PIK3CA mutant).  
1.2 
Overview of Palbociclib 
1.2.1 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 CDK 4 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 brochure [6]. 
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 cyclins [7-9]. The CDK4/6/Cyclin 

 
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D1(CCND1)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 entry[9]. CDK activity and G1 progression is negatively regulated by Cip-Kip and INK4 
family, typified by p16[10-14]. Overexpression of p16 in cells with normal Rb inhibits both 
CDK4-and CDK6-associated kinase activity and Rb phosphorylation, with subsequent cell cycle 
arrest [15, 16]. 
1.2.2 Preclinical Rational for Use of Palbociclib in HER2+ER+Positive Breast 
Cancer 
It is known that CCND1 is downstream of HER2 and plays a critical role in HER2 
transformation [17-19]. In preclinical studies, the association between HER2 signaling and 
regulation of CCND1-CDK complexes has been established [17-19]. Relatively simple cellular 
models of HER2-mediated transformation showed that CCND1/CDK4-6 activity was essential 
for this process [20]. These findings were further expanded on with a transgenic mice model 
overexpressing HER2 in the mammary gland that develops HER2 driven breast cancer on a 
predictable schedule. Reducing retinoblastoma protein (Rb) phosphorylation through CDK4 
knock-out or p16 overexpression is sufficient to block development of tumorigenesis in this 
model [21, 22]. Studies conducted at Sicinski and Hinds laboratories further illustrated the 
relationship between elevation of CCND1 and HER2 amplification/overexpression in clinical 
specimens and refined the requirement of CCND1/CDK4 activity in HER2 driven breast cancer 
models [19, 23]. 
In preclinical studies, HER2+ cell lines, such as MDA-MB-361 and BT474 were sensitive to 
palbociclib. In addition, palbociclib has been shown to have synergistic antitumor activity when 
combined with trastuzumab [24]. Witkiewicz et al have demonstrated in preclinical HER2+ 
models that palbociclib had potent cell cycle inhibitory activity and specifically suppressed long-
term proliferation in cells resistant to anti-HER2 treatment [25]. The interaction between 
CDK4/6 inhibition and established HER2 inhibitors has been evaluated in this study, and the 
data indicated that CDK4/6 inhibition has a complementary effect to anti-HER2 targeted agents. 
In particular, the potent cytostatic activity and induction of senescence properties of palbociclib 
reduced the number of vital cells at limiting dose of anti-HER2 therapy. More recent work with a 
transgenic HER2 mouse model has described significant tumor growth inhibition when treated 
with palbociclib [26]. Finally, recently published work in Cancer Cell describes the role of 
CDK4/6 activity in driving resistance to HER2 targeted therapy [27]. In this context CDK4/6 
signaling relieves feedback inhibition on the mTOR pathway and progression through the cell 
cycle. Inhibition of CDK4/6 with abemaciclib suppresses phosphorylation of Rb and mTOR 
substrates when combined with HER2 inhibitors and sensitizes patient derived xenografts to this 
therapy while delaying tumor recurrence. 
Data from extensive preclinical work demonstrates that the CCND1/CDK4 complex mediates 
resistance to HER2-targeted therapies [27]. Using novel transgenic mouse models, cell-line 
based functional assays, and patient-derived xenografts (PDX), the authors demonstrated that 
CDK4/6 inhibition re-sensitizes resistant HER2+ breast cancers to anti-HER2 therapies. Indeed, 
PDX tumors derived from anti-HER2 refractory tumors show tumor regression when treated 
with CDK4/6 inhibition plus anti-HER2 therapy. This occurs because CDK4/6 inhibitors not 
only suppress Rb phosphorylation, but also relieve feedback inhibition of upstream receptor 
tyrosine kinases (including HER2 and HER3). This leads to a re-sensitization of tumor cells to 

 
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HER2-targeting such that combined treatment induces a maximal suppression of P70S6-kinase 
activity. Collectively, the suppression of both Rb and S6RP phosphorylation induces a 
pronounced G1 arrest in tumor cells.  
1.2.3 Palbociclib Pharmacokinetic (PK) Data in Humans 
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). PK data from 
Studies A5481001, A5481003, and A5481010 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 Study A5481010, 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 women with 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 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 data indicate that palbociclib has a low potential for inhibiting the activities of selected 
uridine diphosphate glucuronosyltransferase (UGT) enzymes (UGT1A1, UGT1A4, UGT1A6, 
UGT1A9, and UGT2B7) and transporters (P-gp [systemically], BCRP [systemically], 
OATP1B1, OATP1B3, BSEP, OAT1, OAT3, and OCT2) at clinically relevant concentrations. 
However, palbociclib has the potential to inhibit the intestinal efflux transporters P-gp and 
BCRP, and the hepatic uptake transporter OCT1. 
An itraconazole Drug-Drug Interaction (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 Area Under the Curve 
(AUC)inf 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 

 
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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 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 male subjects 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). Compared to palbociclib given 
under overnight fasted conditions, the AUCinf and Cmax of palbociclib increased by 21% and 
38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 
13% and 24% when moderate-fat food was given 1 hour before and 2 hours after palbociclib 
dosing. In addition, food intake significantly reduced the intersubject and intrasubject variability 
of palbociclib exposure. 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-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, 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. 

 
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Based on a population pharmacokinetic analysis that included 183 patients, 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), mild hepatic impairment had no effect on the exposure of palbociclib. 
The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe 
hepatic impairment (total bilirubin >1.5 × ULN and any AST), but are currently being 
investigated in Study A5481013 (ongoing). 
Based on a population pharmacokinetic analysis that included 183 patients, 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), mild and moderate renal impairment had no effect 
on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in 
patients with severe renal impairment but are currently being investigated in Study A5481013 
(ongoing). 
In a substudy from Study A5481008 that was conducted as the definitive QT interval 
prolongation evaluation for the palbociclib program, triplicate ECGs were collected at clock 
time-matched baselines and at 5 time points (pre-dose and at 2, 4, 6, and 8 hours postdose) after 
palbociclib had reached steady-state concentrations following a therapeutic dosing schedule 
(125 mg QD on Schedule 3/1 in combination with letrozole). A total of 77 patients were enrolled 
for intensive QTc assessment in the palbociclib plus letrozole arm within the QT interval 
prolongation substudy, and 76 patients provided post-dose ECG data. A random-effect analysis 
of the ECG data from this substudy demonstrated that the upper bounds of the 1-sided 95% CIs 
for the mean changes from clock time-matched baseline for QTcF, QTcS, and QTcB were <8 
msec at all 5 time points in the QTc assessment period. In addition, 
pharmacokinetic/pharmacodynamic analyses to evaluate the relationship between palbociclib 
exposure and ECG endpoints (RR and QTc intervals) were developed using the same ECG data 
along with the time-matched PK data. There was no significant relationship between palbociclib 
concentrations and RR interval, suggesting that palbociclib does not appear to have a 
concentration dependent effect on the heart rate. There was a slight positive linear relationship 
was observed between palbociclib concentration and QTcS. At the mean steady-state palbociclib 
Cmax, the mean QTcS increase was 4.04 msec, with the upper bound of the 1-sided 95% CIs 
falling below 10 msec. Similar results were obtained when QTcF and QTcB were used. Both of 
these analyses indicate that palbociclib, when added to letrozole, did not prolong QT interval to a 
clinically meaningful extent. 
The proposed study will evaluate treatment with palbociclib plus anti-HER2 therapy plus 
endocrine therapy compared with anti-HER2 therapy plus endocrine therapy. The anti-HER2 
therapies include 1) trastuzumab, and/or 2) pertuzumab. In the current study, the choices of 
endocrine therapy are either an aromatase inhibitor (AI), (i.e. anastrozole, letrozole or 
exemestane) or Fulvestrant.  
The potential for a clinically significant DDI between palbociclib and trastuzumab is considered 
to be low. In general, therapeutic proteins (including trastuzumab) are not expected to have a 
direct effect on the metabolic pathway or pharmacodynamics of concomitantly administered 
medications (and vice versa). The most well documented therapeutic protein-caused DDI is via 
indirect mechanism, involving cytokine-mediated changes in drug-metabolizing enzymes. This is 
due to suppression of cytochrome P450 enzyme levels by inflammatory cytokines; whereas, the 
anti-cytokine therapies can “normalize” P450 level and as a result, alter clearance of drugs which 
are metabolized by P450 enzymes. For example, cytokines such as IL-6 can produce 

 
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concentration-dependent inhibition on various CYP isoforms at the transcription level or by 
alteration of CYP enzyme stability in patients with infection or inflammation, and increase the 
plasma concentrations of specific CYP substrate drugs. In contrast, cytokine modulators such as 
tocilizumab (anti-IL-6 receptor antibody) may reverse the apparent “inhibition” effect of the 
cytokines on CYP substrates, resulting in a “normalization” of CYP activities. Trastuzumab was 
not known to be a cytokine modulator, thus the probability of trastuzumab to affect the clearance 
of palbociclib is low. 
For therapeutic proteins (TPs), clearance often undergoes an array of specific target-mediated, 
immunogenicity-mediated, and/or non-specific receptor-mediated endocytosis mechanisms. TPs 
typically do not undergo metabolism or transport as their clearance pathway, therefore the 
potential is limited for small molecule drugs to affect TPs through metabolism or transport 
pathways. However, a drug may affect the clearance of TPs through the drug’s effect on 
immunogenicity (e.g., methotrexate reduces the clearance of infliximab, possibly due to 
methotrexate’s effect on the antibodies formed against infliximab). Palbociclib has not shown to 
affect the host immune system, thus the probability of palbociclib to affect the PK of 
trastuzumab is low.  
1.2.4 Palbociclib and Endocrine Therapy Pharmacokinetics 
Results from the Phase I 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. 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 tamoxifen[6]. A two-way DDI assessment between 
palbociclib and tamoxifen in cancer patients has been incorporated into the ongoing 
PENELOPE-B Study (ClinicalTrials.gov NCT01864746). 

 
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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 PENELOPE-B Study 
(ClinicalTrials.gov NCT01864746). 
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 
Study (ClinicalTrials.gov NCT02028507).  
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 DDI studies have been performed and no confirmed interactions 
have been reported between goserelin and other drugs. A DDI assessment between palbociclib 
and goserelin has been included into two ongoing studies; A5481023 and the PENELOPE-B 
Study. 
1.2.5 Preclinical Data – Palbociclib 
1.2.5.1 Overview of Nonclinical Efficacy 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 showed 
antiproliferative effects (selective G1 arrest) on Rb-positive cancer cells in vitro and in vivo 
where palbociclib activity was associated with reduced Rb-phosphorylation and decreased 
expression of the cell proliferation marker Ki67.   
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 PM, 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 

 
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lines show the opposite characteristics.  Sensitive cell lines in this panel represent mostly the 
luminal ER-positive subtype.  
The combination of palbociclib with tamoxifen has been tested in vitro in ER-positive human 
breast cancer cell lines indicating a synergistic interaction and provided a biologic rationale for 
evaluating the combination of palbociclib with anti-hormonal therapy in the clinic.   
1.2.5.2 Overview of Nonclinical Safety Data 
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, and phototoxicity 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, kidney, and adipose tissue in rats only, and effects on 
bone and growing incisor tooth 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 hemato-lymphopoietic 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 chronic progressive neuropathy), 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.  Finally, palbociclib was determined to be an aneugen, for which a no effect exposure 
was identified.  Additional information may be found in the IB for palbociclib. 

 
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1.2.6 Clinical Data – Palbociclib 
1.2.6.1 Palbociclib Clinical Data in Breast Cancer 
Palbociclib has been tested in a Phase 1 dose escalation trial (Study A5481001) in 74 patients 
with advanced cancer. Two dosing schedules were evaluated: Schedule 3/1 (3 weeks on 
treatment followed by 1 week off treatment; n=41) at doses ranging from 25 to 150 mg and 
Schedule 2/1 (2 weeks on treatment followed by 1 week off treatment; n=33) at doses ranging 
from 100 to 225 mg. 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 (AEs) included fatigue, anemia, diarrhea, 
constipation, vomiting, and dyspnea, mostly mild to moderate severity. A greater proportion of 
patients on Schedule 2/1 had treatment-related AEs during and after Cycle 1 than patients on 
Schedule 3/1 although the proportion of patients with treatment-related neutropenia was similar 
with respect to the 2 dosing schedules, both during and after Cycle 1. A total of 13/37 patients on 
Schedule 3/1 evaluable for efficacy experienced stable disease (SD), including 6 patients with 
SD lasting 40 weeks or longer. Based on the relatively improved safety profile of Schedule 3/1 
and the efficacy results, Schedule 3/1 was selected for further clinical development and the 
Recommended Phase 2 Dose (RP2D) for this schedule was determined to be 125 mg/day.  
Palbociclib has been investigated in the following pivotal studies for the treatment of advanced 
breast cancer: A5481003 (Study 1003), A5481008 (Study 1008), and A5481023 (Study 1023).  
Study 1003 was a Phase 1/2, randomized, open-label study designed to assess the efficacy and 
safety of palbociclib (125 mg QD on Schedule 3/1) in combination with letrozole 2.5 mg QD 
versus letrozole 2.5 mg QD alone for the first-line treatment of post-menopausal women with 
ER-positive/HER2-negative advanced breast cancer. The results from the study demonstrated a 
statistically significant improvement in PFS for the palbociclib plus letrozole arm compared to 
the letrozole alone arm (20.2 vs. 10.2 months; HR=0.488 [95% CI: 0.319, 0.748]; p <0.001) [28]. 
The most common AEs reported for the palbociclib plus letrozole arm were hematologic events, 
mostly neutropenia and leukopenia that were reversible. Based on the results from this study, 
palbociclib was granted accelerated approval in the US in combination with letrozole for the 
treatment of post-menopausal women with ER-positive/HER-2 negative advanced breast cancer 
as initial endocrine-based therapy for their metastatic disease.  
Study 1008 was a Phase 3, randomized, double-blind, placebo-controlled study designed to 
assess the efficacy and safety of palbociclib (125 mg QD on Schedule 3/1) plus letrozole 2.5 mg 
QD versus placebo plus letrozole 2.5 mg QD for the first-line treatment of post-menopausal 
women with ER-positive/HER2-negative advanced breast cancer. The results from the study 
demonstrated a statistically significant improvement in PFS for the palbociclib plus letrozole arm 
compared to the placebo plus letrozole arm (24.8 vs. 14.5 months; HR=0.58 [95% CI: 0.46, 
0.72]; p <0.000001) [29] confirming the significant clinical benefit and safety of palbociclib plus 
letrozole in ER-positive/HER2-negative advanced breast cancer who had not received prior 
systemic therapy for their advanced disease observed in Study 1003 [28]. 
Study 1023 was a Phase 3, randomized, double-blind, placebo-controlled study designed to 
assess the efficacy and safety of palbociclib (125 mg QD on Schedule 3/1) plus fulvestrant 500 
mg versus placebo plus fulvestrant 500 mg for the treatment of women with HR-positive/HER2-
negative advanced breast cancer whose disease had progressed after prior endocrine therapy. The 

 
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results from the study indicated that the addition of palbociclib to fulvestrant significantly 
prolongs PFS with the median PFS of 9.5 months (95% CI: 9.2, 11.0) for the palbociclib plus 
fulvestrant arm and 4.6 months (95% CI: 3.5, 5.6) for the placebo plus fulvestrant arm 
(HR=0.461 [95% CI: 0.360, 0.591]; p <0.0001) [30]. The AEs observed in the study were 
consistent with the known safety profile of palbociclib. Overall, palbociclib was well tolerated 
with AEs managed by dosing interruptions, dose reductions, and/or standard medical care. Based 
on the results from this study, palbociclib was approved in the US in combination with 
fulvestrant for the treatment of women with HR-positive/HER2-negative advanced breast cancer 
with disease progression following endocrine therapy. 
1.2.6.2 Palbociclib Clinical Data in HER2+ Breast Cancer 
As mentioned above, in preclinical studies in HER2+ models, palbociclib has been shown to 
have synergistic antitumor activity when combined with trastuzumab and not only prevented 
proliferation, but also limited the invasive potential of cells [25]. In addition, a preclinical PDX 
model demonstrated that CDK4/6 inhibition re-sensitizes resistant HER2+ breast cancers to anti-
HER2 therapies [27]. Furthermore, the published data suggest that it is rare for HER2+ tumors to 
exhibit loss of Rb function [30]. The TCGA data also showed Rb mutation occurs at a much 
lower rate in ER+/HER2+ (at <5%) as compared to ER-negative/HER2+ (at 25%). These 
preclinical data provide the impetus to investigate palbociclib in HER2+ breast cancer.  
There are 4 ongoing independent Investigator Sponsored Phase Ib and Phase II clinical studies of 
palbociclib in HER2+ metastatic and early breast cancer (Table). As of the end of February 
2016, approximately 70 patients have been treated in 4 clinical trials with palbociclib in 
combination with various anti HER2 agents in patients with HER2+ early stage and metastatic 
breast cancer. This includes combination of palbociclib with trastuzumab with or without 
endocrine therapy (Studies NCT01037790 and NCT02448420), with T-DM1 (Study 
NCT01976169), and with trastuzumab plus pertuzumab plus endocrine therapy (Study 
NCT02530424).  
Interim information from palbociclib in combination with anti-HER2 therapy indicates 
encouraging signals of activity. Data to date on these 72 patients show the most commonly 
reported AEs were hematological toxicities, similar to the known safety profile of single agent 
palbociclib or palbociclib in combination with endocrine therapy in hormone receptor-positive, 
HER2-negative disease. No unexpected serious AE reports on anti-HER2- therapy have been 
received. 
Table 1. Ongoing Studies in HER2+ Breast Cancer 
Study Title  
(Tracking No) 
Country 
Treatment 
Setting 
Regimen 
Schedule/ 
Dosage 
Numbers of 
Patients 
Treated / 
Target 
Enrolment 
Phase II Trial of CDK 
Inhibitor PD 0332991 In 
Patients with Cancer (Solid 
tumors: Breast, colon, germ 
cell, etc.) – included HER2-
positive cohort  
(NCT01037790) 
 
US 
  
Recurrent or 
metastatic 
HER2-positive 
breast cancer 
RB-positive 
Palbociclib + 
trastuzumab 
Schedule 3/1 
Palbociclib 125 
mg QD + 
trastuzumab 
6mg/kg every 21 
days  
10/10 
 

 
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Table 1. Ongoing Studies in HER2+ Breast Cancer 
Study Title  
(Tracking No) 
Country 
Treatment 
Setting 
Regimen 
Schedule/ 
Dosage 
Numbers of 
Patients 
Treated / 
Target 
Enrolment 
Phase Ib Study of 
Palbociclib (PD-0332991) 
in Combination With T-
DM1(Trastuzumab-DM1) 
(NCT01976169) 
US 
  
Recurrent or 
metastatic 
HER2-positive 
breast cancer 
 
Must previously 
treated with 
trastuzumab 
Palbociclib + 
T-DM1 
Schedule 2/1 
Palbociclib 150 
mg-200 QD Day 
5-18 on a 21-
day cycle  
 
T-DM1 by 
intravenous 
infusion at 3.6 
mg/kg for 90 
minutes on day 
1 of each 21 day 
cycle 
9/17 
A Phase II study of 
palbociclib and trastuzumab 
with or without letrozole in 
pretreated HER2-positive 
metastatic breast cancer 
patients. 
(SOLTI-13-03; 
NCT02448420) 
Spain 
 
Recurrent or 
metastatic 
HER2-positive 
breast cancer 
Must previously 
treated with 
trastuzumab 
Palbociclib + 
Trastuzumab 
with or 
without 
endocrine 
therapy 
Schedule 2/1 
Palbociclib 150 
mg-200 QD  
Trastuzumab 
6mg/kg every 21 
day  
 
17/45 (Run-
in) 
107 
(expansion)  
Neo-Adjuvant Treatment 
with the CDK4,6 inhibitor 
Palbociclib in HER2-
positive and ER-positive 
breast cancer: effect on 
Ki67 and apoptosis before, 
during and after treatment  
EudraCT number 2014-
001984-11 
Acronym: NA-PHER2 
(NCT02530424) 
Italy 
  
ER+/HER2-
positive early 
stage breast 
cancer 
Trastuzumab+ 
pertuzumab+ 
palbociclib + 
fulvestrant 
Trastuzumab 6 
mg/kg IV q.3 
wks Pertuzumab 
840 mg 420 mg 
IV q. 3 wks 
Palbociclib 125 
mg po q.d. x 21 
q. 4 wks 
Fulvestrant 
500mg monthly 
intra-muscle at 
the dose of 500 
mg every 4 
weeks 
36/36 
1.2.7 Palbociclib Safety Profile 
A comprehensive description of Palbociclib Safety Profile is provided in the Palbociclib 
Investigational Brochure. Data from Phase III studies have demonstrated that palbociclib when 
given in combination with endocrine therapy is well-tolerated. The primary toxicity of 
palbociclib is asymptomatic neutropenia which can be effectively managed by dose reduction.  
The Safety Profile of Data from the Seminal Phase III studies evaluating the efficacy of 
palbociclib can be summarized as follows:  
The PALOMA-3 phase 3 study [30] enrolled 521 patients with 347 randomized to palbociclib 
plus fulvestrant and 147 to fulvestrant plus placebo. Neutropenia of all grades was more common 
in the palbociclib group (81%) than in the control group (3%). Grad 3 and 4 neutropenia were 
reported in 55% and 10% of patients treated with palbociclib, respectively. Febrile neutropenia 
was an uncommon event and reported in only 3 patients treated with palbociclib. Grade 3 and 4 

 
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leucopenia were reported in 27% and 1% of patients treated with palbociclib, respectively. The 
following AEs were observed more frequently among patients treated with palbociclib and 
reported as lower Grade AEs (i.e. Grade 1 or 2) for the majority of patients. Infection (Grade 1-2 
40%, Grade 3 2%, Grade 4 <1%); Fatigue (Grade 1-2 37%, Grade 3 2%), Nausea (Grade 1-2 
32%); Anemia (Grade 1-2 25%, Grade 3 3%); Thrombocytopenia (Grade 1-2 19%, Grade 3 2%, 
Grade 4 1%). Alopecia of any grade was reported in 17% of patients in the palbociclib arm. 
Serious AEs occurred in 13% of patients treated with fulvestrant plus palbociclib. No treatment-
related deaths occurred in the study.  
The PALOMA-2 phase 3 study [29] enrolled 666 patients with 444 randomized palbociclib plus 
letrozole and 222 to letrozole plus placebo. Neutropenia of all grades was more common in the 
palbociclib group (80%) than in the control group (6%). Grad 3 and 4 neutropenia were reported 
in 56% and 10% of patients treated with palbociclib, respectively. Febrile neutropenia was an 
uncommon event and reported in only 1.6% patients treated with palbociclib. Grade 3 and 4 
leucopenia were reported in 24% and 1% of patients treated with palbociclib, respectively. The 
following AEs were observed more frequently among patients treated with palbociclib and 
reported as lower Grade AEs (i.e. Grade 1 or 2) for the majority of patients. Fatigue (Any Grade 
37%, Grade 3 2%), Nausea (Any Grade 35%, Grade 3 <1%); Anemia (Any Grade 24%, Grade 3 
5%); Thrombocytopenia (Any Grade 16%, Grade 3 1%). Alopecia of any grade was reported in 
33% of patients in the palbociclib arm. Serious AEs occurred in 19.6% of patients treated with 
fulvestrant plus palbociclib. Death due to AEs was reported in 2.3% of patients in the palbociclib 
arm and 1.8% of patients in the placebo arm.  
1.3 
Overview of Anti-HER2 Therapies 
1.3.1 Trastuzumab 
Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain (ECD) 
of HER2, thereby inhibiting tumor cell growth and proliferation. The mechanism of action of 
trastuzumab includes inhibition of ligand-independent receptor dimerization and thereby of 
downstream signaling transduction pathways (e.g. PI3K signaling). In the advanced-stage 
setting, trastuzumab-based regimens have improved the survival of patients diagnosed with 
HER2+ breast cancer, and have favorably changed the dire natural history of advanced HER2+ 
disease. In the early-stage setting, the addition of trastuzumab to adjuvant chemotherapy has led 
to a striking reduction in the risk of relapse and death, by 50% and 30%, respectively. 
Refer to the Full Prescribing Information for trastuzumab for complete safety information: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.  
1.3.2 Pertuzumab 
Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular 
dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein 
(HER2), and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER 
family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-
initiated intracellular signaling through two major signal pathways, mitogen-activated protein 
(MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can 
result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates 
antibody-dependent cell-mediated cytotoxicity (ADCC).  

 
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While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of 
pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft 
models.  
1.4 
Overview of Endocrine Therapies 
1.4.1 Fulvestrant 
Fulvestrant is an ER antagonist approved for the treatment of patients with metastatic ER+ breast 
cancer. Fulvestrant binds to the ER disrupting the signaling pathway and leading to ER 
degradation. The recommended dose of fulvestrant is 500mg given by IM injections (two, 250 
mg IM injections) on days 1 and 15 of the first month and then monthly thereafter.  
Refer to Full Prescribing Information for Fulvestrant for complete safety and dosing information: 
https://medicalinformation.astrazeneca-us.com/home/prescribing-information/faslodex.html 
1.4.2 Aromatase Inhibitors 
Refer to Full Prescribing Information for Anastrozole, Letrozole or Exemestane for complete 
safety information: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. 
https://www.arimidex.com/prescribing-information.html 
2. Study Rationale 
Extensive pre-clinical data and initial results from clinical studies point to the added benefit of 
CDK4/6 inhibition when combined with anti-HER2 therapy (Refer to 1.2.2 and 1.2.6). Data from 
two randomized phase III studies provide robust evidence of benefit when palbociclib is given in 
combination with endocrine therapy among patients diagnosed with metastatic ER+ breast 
cancer.  
The current study is designed to evaluate the added benefit of palbociclib when given in 
combination with anti-HER2 therapy and endocrine therapy. We expect that palbociclib will 
modulate the endocrine resistance in HER2+ER+ disease and also potentiate the benefits of anti-
HER2 therapy.  
Cross-talk between HER2 and ER signaling contributes to resistance to endocrine therapy. 
Breast cancer cell lines that are once sensitive to anti-estrogen therapy become resistant once 
transfected with the HER2 gene, suggesting an association between HER-2 overexpression and 
estrogen independence.  
There is a strong link between the actions of estradiol and the G1-S phase transition, where the 
estradiol effector is the CCND1-CDK4/6-Rb complex. CCND1 is a direct transcriptional target 
of ER and inhibition of CCND1 halts estrogen-induced S phase entry. Endocrine resistance is 
associated with persistent CCND1 expression and Rb phosphorylation. Consistent with the 
notion that the main function of CCND1 is to activate CDK4/6, its oncogenic activity is 
dependent on CDK4/6-associated kinase activity and CDK4/6 inhibitors are most effective in 
tumors with gene amplification and overexpression of CCND1 which is common in ER+ breast 
cancer. A preclinical study evaluating the efficacy of palbociclib in a panel of cell lines showed 
that palbociclib was most effective for luminal ER+ breast cancer cells, including those that 
exhibited endocrine resistance [24]. 

 
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The cross-talk among HER2, steroid hormone signaling, and CDK4/6 role in cell cycle provides 
a biologic rationale for evaluating the combination of palbociclib with anti-HER2 therapy and 
anti-hormonal therapy in the clinic [24, 29]. 
3. Study Design Rationale 
3.1 
Rationale for Choice of Anti-HER2 and Endocrine Therapy 
Targeted anti-HER2 therapy has become the cornerstone of management for patients with 
advanced HER2-positive breast cancer. Currently, first-line therapy comprises a taxane given in 
conjunction with trastuzumab and pertuzumab (two anti-HER2 antibodies) [3, 4].  
While dual HER2 blockade should be the preferred first line option for the majority of patients, 
consensus recommendations consider less intense regimens (i.e. trastuzumab-based regimens) 
for the first-line treatment of HER2+ disease for highly selected patients. (ESO-ESMO 2nd 
ABC2, NCCN and ASCO guidelines) [31, 32]. Clinicians might consider less intense regimen(s) 
in the first-line setting particularly for patients with minimal disease burden. Furthermore, the 
ASCO guidelines also suggest trastuzumab given in combination with chemotherapy as an 
option for selected patients with HER2+ER+ metastatic breast cancer.  
Given the benefits of pertuzumab in the first-line setting, we expect that the majority of patients 
enrolled in the current study will be treated with a dual anti-HER2 blockade (trastuzumab and 
pertuzumab). In order to account for potential variability in patterns of use of pertuzumab across 
different geographic regions, the study allows a non-pertuzumab option (i.e. trastuzumab-based 
regimen). The non-pertuzumab treatment option is limited to up to 20% of the study population.  
In the current study, the choices of endocrine therapy are either an AI (i.e. anastrozole, letrozole 
or exemestane) or fulvestrant.  
Retrospective observations have pointed to the superiority of AI over tamoxifen among patients 
diagnosed with HER2+ER+ [33]. While the available literature does not provide conclusive 
evidence to this matter (AI vs. TAM in HER2+ER+) [34], tamoxifen is not considered an 
endocrine therapy option in the current study. Premenopausal women and men are allowed to 
participate in the study but premenopausal women must receive ovarian suppression with a 
LHRH agonist if the patients have not documented ovarian ablation or bilateral oophorectomy or 
orchiectomy before randomization or during the conduct of the study. 
Flexibility in choices of endocrine therapy was deemed critical for the purpose of this clinical 
study considering patients may have been treated with endocrine agents in the early-stage setting 
and physicians should be able to choose the endocrine agent deemed appropriate for patients 
enrolled in the study.  
3.2 
Rationale for Induction Therapy Prior to Randomization 
The current study will enroll patients after completion of pre-specified number of chemotherapy 
containing anti-HER2 therapy cycles for the treatment of metastatic breast cancer in the first-line 
setting. Eligible patients are expected to have completed 6 cycles of chemotherapy containing 
anti-HER2 regimen and a maximum of 8 eight cycles. A minimum of 4 cycles of treatment is 
acceptable for patients experiencing significant toxicity associated with treatment as long as they 
are without evidence of disease progression (i.e. CR, PR or SD) by local assessment.  

 
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In previous phase III studies (CLEOPATRA and MA 31 study) anti-HER2 blockade (i.e. single 
or dual anti-HER2 blockade) was given in combination with chemotherapy (i.e. median of six to 
eight cycles) followed by the continuation of trastuzumab and/or pertuzumab. This is also 
supported by published treatment guidelines. Based on the available literature, it is expected that 
the majority of the patients who enter into this study will receive 6-8 cycles of induction therapy.  
Eligible patients are expected to have received an optimal anti-HER2 regimen. Clinicians should 
recommend the combination of trastuzumab, pertuzumab and a taxane for the majority of 
patients. In order to account for variability in clinical practice and the need for less intense 
therapeutic regimens for a subset of patients diagnosed with HER2+ER+ disease, clinicians are 
allowed to recommend the combination of trastuzumab and chemotherapy (defined as a taxane 
or vinorelbine). The non-pertuzumab treatment option is limited to up to 20% of the study 
population.  
In a previous study, trastuzumab plus vinorelbine showed comparable efficacy to trastuzumab 
plus docetaxel but with a superior safety profile [35, 36]. The choice of vinorelbine in the current 
study is limited to the subset of patients treated with trastuzumab-based regimens.  
3.3 
Rationale for Correlative Science 
The pre-clinical and clinical data generated over the past two decades have shed light onto tumor 
heterogeneity within HER2+ disease. It is clear that HER2+ER+ disease has a unique genomic 
profile when compared to other disease subtypes. The current study builds upon previous 
observations and includes a comprehensive molecular characterization of HER2+ER+. This will 
allow us to answer important translational research questions. 
As part of the Primary Translational Research Question, we will compare PFS based upon 
investigator assessment of progression between patients in the two treatment arms in the subset 
of patients with tumors bearing a PIK3CA mutation. PIK3CA genotype will be assessed in 
circulating tumor DNA (ctDNA). 
Constitutive activation of PI3K signaling due to mutation(s) in the PIK3CA gene and/or loss of 
PTEN, occur in approximately one third of HER2+ breast cancers. Data from recent studies 
showed that the presence of PIK3CA mutation(s) was associated with worse clinical outcome in 
patients treated with regimens containing trastuzumab and pertuzumab or lapatinib. In the 
CLEOPATRA study, shorter median PFS was seen among patients with mutant PIK3CA tumors. 
In the control arm of CLEOPATRA, the median PFS arm was 8.6 months for PIK3CA mutants 
versus 13.8 for PIK3CA wild type. In the pertuzumab-containing arm of the study, the median 
PFS arm was 12.5 months for PIK3CA mutants versus 21.8 for PIK3CA wild type. The impact of 
PIK3CA mutations on patients’ outcome could not be attributed to specific mutation, or to 
mutation(s) in specific exons based on the available dataset.  
Data from a recent publication described synergy between HER2 and CDK4/6 inhibitors in cells 
lines that are either mutant or wild type for PIK3CA [27]. Interestingly, the synergistic 
interaction was strongest in cells with activating PIK3CA mutation(s). Furthermore, studies of 
resistance to endocrine therapy and estrogen-receptor biology suggest the cross talk between 
PI3K/mTOR/AKT pathway and estrogen pathway could confer the resistance to endocrine 
therapy. However, recently published data has shown that the degree of improvement of 
palbociclib in combined with fulvestrant over fulvestrant alone is independent of PI3KCA 
mutational status. There is no difference on PFS or OR between patients with or without 

 
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PI3KCA mutation when palbociclib is combined with endocrine therapy [30]. Thus, it is 
conceivable that PIK3CA mutant, HER2+ cancers will be especially susceptible to combined 
HER2-CDK4/6 blockade, as the increased dependence on the PI3K signaling pathway after 
CDK4/6 inhibition might be particularly enhanced. If true, this would be particularly important 
and the absolute benefit with the addition of palbociclib could be greater in the subset of patients 
with tumors bearing features of PIK3CA activation. 
In order to provide a detailed and reliable description of the landscape of the most common 
somatic mutations (i.e. beyond PIK3CA), the current study includes a genomic panel test the 
results of which may be shared with study investigators. The Oncopanel genomic assay surveys 
exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes including relevant 
genes for breast cancer (i.e. PIK3CA, HER2, ESRI) to detect somatic mutations, copy number 
variations and structural variants in tumor DNA extracted from fresh, frozen, or formalin-fixed 
paraffin-embedded samples. 
4. 
Objectives and Endpoints 
4.1 
Primary Objectives 
The primary objective of this study is to demonstrate that the combination of palbociclib with 
anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine 
therapy in prolonging PFS in participants with hormone receptor-positive, HER2+ metastatic 
breast cancer who have not received any prior treatment beyond induction treatment in this 
setting.  
4.2 
Secondary Objectives 
1. To compare measures of tumor control (including OR, CBR, DOR) between the 
treatment arms  
2. To compare median overall survival and overall survival probabilities at 3-years and 5-
years between the treatment groups  
3. To compare safety and tolerability between the treatment arms  
4. To compare the incidence of CNS metastasis between the treatment arms  
5. To compare patient reported time to symptom progression as assessed by the FACT-B 
TOI-PFB. 
6. To compare patient reported breast cancer specific health related quality of life 
(HRQOL) and general health status   
4.3 
Translational Science Principal Objectives 
To compare progression-free survival based upon investigator assessment of progression 
between patients in the two treatment arms in the subset of patients with tumors bearing a 
PIK3CA mutation. PIK3CA genotype will be assessed in circulating tumor DNA (ctDNA).  
4.4 
Exploratory Objectives 
1. To evaluate PFS and OS in genomically-defined breast cancer 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 anti-HER2 therapy plus endocrine therapy 
3. To evaluate tumor- and blood-based markers at time of disease recurrence for 
mechanisms of resistance to therapy  

 
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4. To compare serial levels of mutations of circulating tumor DNA (ctDNA) in patients 
receiving anti-HER2 therapy plus endocrine therapy versus anti-HER2 therapy plus 
endocrine therapy plus palbociclib  
5. To compare mutational profile/copy number variants obtained from tumor tissue to 
those measured in circulating tumor DNA (ctDNA)  
6. To use ctDNA sequencing to compare the inferred tumor transcriptome before and 
during treatment with anti-HER2 therapy and endocrine therapy with or without 
palbociclib 
7. To determine the trough concentrations of palbociclib when given in combination with 
trastuzumab plus endocrine therapy or trastuzumab plus pertuzumab plus endocrine 
therapy 
8. To determine trastuzumab and pertuzumab trough concentrations when given in 
combination with palbociclib plus endocrine therapy  
9. To explore correlations between palbociclib exposure and efficacy/safety findings in 
this patient population 
10. To compare the progression-free survival (PFS) outcomes assessed through either local 
and/or central imaging review with those evaluated using artificial intelligence-based 
imaging analysis 
4.5 
Endpoints 
4.5.1 
Primary 
1. Progression-free survival (PFS) as assessed by the Investigator 
4.5.2 
Secondary 
1. Overall Survival (OS) 
2. 3-year and 5-year survival probabilities 
3. Objective Response (OR: CR or PR) 
4. Duration of Response (DOR) 
5. Clinical Benefit Rate (CBR: CR or PR or SD ≥ 24 weeks) 
6. Incidence of CNS metastasis 
7. Safety: Type, incidence, severity (as graded by the NCI CTCAE v. 4.0), seriousness 
and attribution to the study medications of AEs and any laboratory abnormalities  
8. Patient-reported Outcomes: Time to symptom progression (as assessed by the FACT-
B TOI-PFB) breast cancer specific health treatment related quality of life and general 
health status  
4.5.3 
Correlative 
1. Trough plasma concentration of palbociclib, trastuzumab and pertuzumab in the            
subgroup of patients enrolled in the US. 
2. PIK3CA genotype assessed in circulating tumor DNA (ctDNA) 
3. Tumor tissue biomarkers including genes, proteins and RNA expression 

 
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4.6 
Future Biomedical Research 
All biospecimens collected for this study will be stored in the Alliance Foundation Biorepository 
(AFB) until biospecimen accrual and clinical follow up is sufficiently complete to allow for the 
design and execution of specific correlative analyses.  
Such research is for biomarker testing to address emergent questions not described elsewhere in 
the protocol and will only be conducted on specimens from appropriately consented patients. The 
objective of collecting specimens for future biomedical research is to explore and identify 
biomarkers that inform the scientific understanding of disease and/or their therapeutic treatments. 
Unless prohibited by local regulations, patients approached to participate in the current study 
(PATINA/AFT-38) will be asked to indicate on the informed consent forms (ICFs) whether 
remaining biospecimens and clinical data collected for the PATINA study can be shared with the 
Mastering Breast Cancer (MBC) Initiative.  
The Mastering Breast Cancer Initiative is a multi-institutional, collaborative project aimed at 
improving outcomes for women with metastatic breast cancer. The overarching purpose of the 
Mastering Breast Cancer Initiative is to create a mechanism for understanding the natural history 
of metastatic breast cancer by cataloguing longitudinally studied tumor-specific markers and 
treatment effects. No additional procedures are included for participants consenting to the 
Mastering Breast Cancer Initiative. Participation in the Mastering Breast Cancer Initiative allows 
hosting of limited study tissue and data in the Mastering Breast Cancer Initiative Data and Bio-
Repositories upon completion of the PATINA/AFT-38 study.  The MBC Data Repository is 
located at the Mayo Clinic Stats and Data Center and the MBC Biorepository is located at the 
Alliance Foundation Trials (AFT) Biorepository at Washington University.  Both of these 
repositories will serve as the PATINA study repositories.  At the end of the PATINA study, 
leftover specimens and specific study data will be transferred from the AFT Data and 
Biorepositories to the MBC Data and Biorepositories at these locations.  
The following specimens and study data collected as part of this study (AFT-38/PATINA) 
during the baseline screening phase from patients consenting to the MBC Initiative will be 
hosted in the MBC Data and Bio-Repositories:   
x Leftover tissue from the archival tissue sample and/or optional tissue from a biopsy of 
metastatic disease 
x Limited baseline clinico-pathologic characteristics, for example: age, disease-free 
interval, prior treatment for early-stage breast cancer (for complete list of baseline 
clinico-pathologic characteristics, please refer to Section 10.1) 
x Biomarker data (genomic data) from baseline tissue samples  
 
For any patient who consents to the MBC Initiative, this screening data will be available to the 
MBC Data and Bio-Repositories regardless of whether the patient randomizes into the study or 
not.  Therefore, both for MBC-consented patients who screen fail and for those who randomize, 
baseline tissue should be submitted to the AFT Biorepository and baseline eCRFs should be 
completed in the PATINA study database (Medidata RAVE).  
 

 
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In addition to the above baseline data, the following study data collected from the patients 
randomized to the comparator arm (Arm B) only who consent to the MBC Initiative will be 
hosted in the MBC Data and Bio-Repositories: 
x Any remaining blood/plasma from germ-line and circulating tumor DNA (ctDNA) 
collections during treatment phase 
x Any remaining tissue from the optional biopsy at disease progression 
x Survival data, ongoing treatments, subsequent disease progression data collected in the 
study database (Medidata RAVE) 
x Biomarker data (genomic and/or pathology-based) derived from tumor biospecimens 
collected from consenting patients at the time of disease progression  
5. 
Study Design 
AFT-38 is an international, multicenter, open-label, pivotal Phase III study. The primary 
objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 
therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy in 
prolonging progression-free survival. The study will enroll 496 patients from approximately 130 
sites worldwide.  
 
The study starts after completion of a pre-specified number of chemotherapy containing anti-
HER2 therapy cycles for the treatment of metastatic breast cancer in the first-line setting. For the 
purposes of this study, chemotherapy is defined as either a taxane or vinorelbine (only permitted 
in patients who receive trastuzumab-based regimen). Eligible participants are expected to have 
completed 6 cycles of chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 
cycles of treatment is acceptable for patients experiencing significant toxicity associated with 
treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). The 
maximum number of cycles is 8. Participants are eligible provided they are without evidence of 
disease progression by local assessment (i.e. CR, PR or SD).  
 
Eligible participants are expected to have received an optimal anti-HER2 regimen. Clinicians 
should recommend the combination of trastuzumab, pertuzumab and a taxane for the majority of 
patients. In order to account for variability in clinical practice and the need for less intense 
therapeutic regimens for a subset of patients diagnosed with HER2+ER+ disease, clinicians are 
allowed to recommend the combination of trastuzumab and chemotherapy (defined as a taxane 
or vinorelbine) prior to the study initiation. Clinicians might also choose a non-pertuzumab 
option for patients who had been previously treated with pertuzumab in the neo(adjuvant) 
setting. Eligible participants should continue on the same anti-HER2 regimen initiated prior to 
study randomization (i.e. trastuzumab and pertuzumab or trastuzumab alone) after 
randomization. The non-pertuzumab treatment option is limited to up to 20% of the study 
population.  For potentially eligible patients identified during screening who have completed the 
above required induction treatment, the C1D1 visit must occur within 12 weeks of their last dose 
of induction therapy.  
 
AFT-38 includes both a Preliminary Screening and a Randomization Screening Phase. 
Participants potentially eligible to participate on the clinical trial will be consented twice prior to 
the study randomization – once prior to or during induction therapy to allow for collection of 

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baseline tissue samples (Pre-Screening Consent) and again prior to randomization to allow for 
remaining screening tests and study procedures (Main Consent). See Section 10 for more details. 
Below lists the biospecimens collected during screening:
Mandatory:
x
A representative formalin-fixed paraffin embedded (FFPE) archival (primary breast or 
metastatic) tumor tissue block (preferred) or at least 15 unstained slides from such a 
block, along with a pathology report documenting HER2 positivity and hormone receptor 
positivity
Optional:
x
Research biopsy: A biospecimen from a metastatic site if clinically feasible or
x
Tissue sample from recently biopsied metastatic site 
Below lists the biospecimens collected during the study:
Mandatory:
x
Blood draw for germ-line DNA at two timepoints (C1D1 and C4D1)
x
Blood draw for circulating tumor DNA (ctDNA) at three timepoints (C1D1, C4D1 and 
end of treatment)
Optional:
x
Biopsy of metastatic site at disease progression or
x
Tissue sample from recently biopsied metastatic site at disease progression
For more details, please see PATINA (AFT-38) Correlative Science Manual (CSM), on the 
BioMS website, which is accessible via the AFT portal, https://alliancefoundationtrials.org
Figure 1. 
Study Schema
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, in addition to standard anti-HER2 therapy and standard endocrine therapy 

 
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Arm B: Standard anti-HER2 therapy and endocrine therapy  
Endocrine Therapy: AI of choice or Fulvestrant. Premenopausal women must receive ovarian suppression with a 
LHRH agonist if the patients have not documented ovarian ablation or bilateral oophorectomy before randomization 
or during the conduct of the study 
6. 
Patient Selection/Population 
AFT does not grant eligibility waivers. Investigators must carefully consider any condition that 
in the opinion of the investigator would interfere with participation in the study. Please contact 
the study chair for eligibility questions. 
6.1 
Inclusion Criteria (Preliminary Screening) 
1) Signed Preliminary Informed Consent Form obtained prior to any study specific 
assessments and procedures 
2)  Age ≥18 years (or per national guidelines)  
3) Participants must have histologically confirmed invasive breast cancer that is metastatic 
or not amenable for resection or radiation therapy with curative intent.  Histological 
documentation of metastatic/recurrent breast cancer is not required if there is unequivocal 
evidence for recurrence of the breast cancer. 
4) Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+ 
and/or PR+), metastatic 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) guidelines.  
5) Patients must agree to provide a representative formalin-fixed paraffin-embedded (FFPE) 
tumor tissue block (preferred) from primary breast or metastatic site (archival) OR at 
least 15 unstained slides from such a block, along with a pathology report documenting 
HER2 positivity and hormone receptor positivity.  
6) Patients should be willing to provide a representative tumor specimen obtained from 
recently biopsied metastatic disease if clinically feasible.  This is recommended but 
optional tissue.  
6.2 
Inclusion Criteria (Randomization Screening) 
7) Signed Main Informed Consent Form obtained prior to any study specific assessments 
and procedures 
8) Age ≥18 years (or per national guidelines) 
9) ECOG performance status 0-1  
10) Patients must be able and willing to swallow and retain oral medication without a 
condition that would interfere with enteric absorption. 
11) 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 the 
study must use adequate contraception for the duration of protocol treatment which is for 
6 months after the last treatment with palbociclib if they are in Arm A and for 7 months 

 
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after last treatment with trastuzumab if in either Arm A or Arm B. 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). 
12) Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy 
regimen to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not 
considered a safety risk for the patient at investigator's discretion) 12 weeks between last 
dose of chemotherapy–anti-HER2 therapy and randomization are allowed. Endocrine 
therapy could start before study randomization.  
13) Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures 
Prior Treatment Specifics 
14) Patients may or may not have received neo/adjuvant therapy, but must have a disease-free 
interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months.  
15) Patients must have received an acceptable, standard, chemotherapy containing anti-HER2 
based induction therapy for the treatment of metastatic breast cancer prior to study 
enrollment. For this study, chemotherapy is limited to a taxane or vinorelbine (only for 
trastuzumab-based regimen). Eligible patients are expected to have completed 6 cycles of 
chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 cycles of 
treatment is acceptable for patients experiencing significant toxicity associated with 
treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). 
The maximum number of cycles is 8. Patients can randomize immediately following 
completion of their induction therapy, or for those who have already completed 
induction, a gap of 12 weeks between their last infusion/dose of induction therapy and the 
C1D1 visit is permitted. Patients are eligible provided they are without evidence of 
disease progression by local assessment (i.e. CR, PR or SD).  
16) Patients with a history or presence of asymptomatic CNS metastases are eligible provided 
they meet all of the following criteria:  
x Disease outside the CNS is present. 
x No evidence of interim progression between the completion of induction 
therapy and the screening radiographic study  
x No history of intracranial hemorrhage or spinal cord hemorrhage  
x Not requiring anti-convulsants for symptomatic control 
x Minimum of 3 weeks between completion of CNS radiotherapy and 
Cycle 1 Day 1 and recovery from significant (Grade ≥ 3) acute toxicity 
with no ongoing requirement for corticosteroid 
 
Baseline Body Function Specifics 
17) Absolute neutrophil count ≥ 1,000/mm3 
18) Platelets ≥ 100,000/mm3 
19) Hemoglobin ≥ 10g/dL 
20) Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within 
normal range in patients with documented Gilbert’s Syndrome. 
21) Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or 
SGPT) ≤ 3 × institutional ULN (≤5 x ULN if liver metastases are present). 

 
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22) Serum creatinine below the upper limit of normal (ULN) of the institutional normal range 
or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels 
above institutional ULN. 
23) Left ventricular ejection fraction (LVEF) t 50% at baseline as determined by either 
ECHO or MUGA 
6.3 
Exclusion Criteria (Randomization) 
1) Concurrent therapy with other Investigational Products. 
2) Prior therapy with any CDK 4/6 inhibitor. 
3) History of allergic reactions attributed to compounds of chemical or biologic composition 
similar to palbociclib. 
4) Patients receiving any medications or substances that are strong inhibitors or inducers of 
CYP3A isoenzymes within 7 days of randomization (see Section 8.6.3 for list of strong 
inhibitors or inducers of CYP3A isoenzymes). 
5) Uncontrolled current 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. 
6) 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. 
7) Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are 
ineligible because of the potential for pharmacokinetic interactions or increased 
immunosuppression with palbociclib. 
8) QTc interval >480 msec, Brugada syndrome or known history of QTc prolongation or 
Torsade de Pointes. 
9) Patients with clinically significant history of liver disease, including viral or other known 
hepatitis, current alcohol abuse, or cirrhosis  
7. 
Method of Treatment Assignment  
7.1 
Site Enrollment/Randomization Requirements 
Site must submit all required essential documents including, but not limited to:  
x IRB/Regulatory Approval 
x Clinical Study Agreement 
x Investigator 1572 
x Institutional informed consent forms  
x System training and access for all required staff 
x Protocol and Good Clinical Practice training for all required staff 
x Documentation of Site Initiation Visit 

 
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Essential documents must be submitted to the AFT (IQVIA) electronic Trial Master File, 
accessible via the AFT portal: https://alliancefoundationtrials.org.  
7.2 
Patient Randomization and Allocation to Treatment: 
Patient randomization and enrollment into the study will be facilitated using the Oracle web-
based IRT (interactive response technology) system, accessible via the AFT portal: 
https://alliancefoundationtrials.org.   
Patients must sign informed consent prior to any screening or study-related testing, including 
submission of biospecimens. After the signed Preliminary Screening Informed Consent Form has 
been obtained, the study site will register the patient in the IRT system to obtain a unique patient 
identification number which will stay the same throughout the entire study. After the Main 
Informed Consent Form is signed, all eligibility requirements for enrollment have been met and 
the required tissue specimen has been submitted to the central biorepository/lab, patients may be 
enrolled/randomized in the IRT system.  The time window from signing the Main Consent to 
completion of all randomization assessments is 28 days.  Results of screening tests performed 
prior to obtaining Main Informed Consent and within 42 days of randomization may be used 
rather than repeating required tests. (This does not apply to the baseline tumor assessments 
which must be done within 28 days of randomization). 
Patients screened but not randomized for any reason must be registered as a Screening Failure in 
IRT. 
Following randomization, the IRT system will provide the site with a printable confirmation of 
enrollment and treatment randomization information. Please print this confirmation for your 
records.  The site will receive information regarding dispensation of drug and maintenance of 
adequate drug supply via IRT, upon randomization. 
7.3 
Stratification Factors 
Randomization will be stratified by pertuzumab use (yes vs. no), by prior anti-HER2 therapy in 
the (neo) adjuvant setting (yes vs. no), by type of endocrine therapy (AI or fulvestrant), and by 
best response to induction therapy (CR or PR vs. SD) determined by investigator assessment. 
Eligible participants should continue on the same anti-HER2 regimen initiated prior to study 
randomization (i.e. trastuzumab and pertuzumab or trastuzumab alone) after randomization. The 
non-pertuzumab treatment option is limited to up to 20% of the study population.  
 
7.4 
Treatment Assignment 
IP Treatment is comprised of palbociclib treatment for patients randomized into Arm A.  
Non-IP Treatment is comprised of standard anti-HER2 therapy (trastuzumab and/or 
pertuzumab) and endocrine therapy (AI or fulvestrant) 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. Endocrine therapy and anti-HER2 therapy will not be provided by the 
Sponsors and must be selected by the Investigator as part of a standard of care therapy. 

 
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8. 
Treatment Plan 
During this phase, patients randomized into Arm A will receive IP treatment (palbociclib) and 
Non-IP treatment (anti-HER2 therapy plus endocrine therapy) and patients randomized into Arm 
B will receive Non-IP treatment only (anti-HER2 therapy plus endocrine therapy).   
 
Cycle 1 Day 1 (C1D1) should occur within 14 days of randomizing the patient. Sites should try 
to schedule the C1D1 visit to coincide with the patient’s next anti-HER2 infusions which are 
administered on an every 3-week cycle, in order to reduce the burden to the patient of multiple 
visits.  
 
Patients will continue with the Treatment Phase until they meet the criteria for Clinical Follow-
up or Survival Follow-up as outlined below:  
 
1) Clinical Follow-up Phase: Patient begins this phase when/if IP therapy (Arm A) and 
Non-IP therapy is permanently discontinued due to non-PFS event reason. This phase 
includes all of the visits required by the Schedule of Assessments through disease 
progression. Types of delays or interruptions in IP dosing which will not trigger 
discontinuation of IP treatment are specified in Section 9.  
 
2) Survival Follow-up Phase: Patients who discontinue Study Treatment due to a disease 
progression will move to the Survival Follow-up Phase.  
 
3) Randomized patients on either Arm who are deemed ineligible prior to first dose, or 
refuse to start their initial treatment will move to the Survival Follow-up Phase. 
 
8.1 
Palbociclib – Investigational Product (IP) 
8.1.1 
Palbociclib Administration 
Palbociclib should be taken orally, once per day with food around the same time, starting at 
the 125-mg dose. Treatment is continuous daily for 21 days, followed by 7 days off, to complete 
a 28-day cycle.  
 
Expected toxicities and potential risks as well as allowable dose modifications are described in 
section 9. 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. On days when a patient 
is scheduled for a clinic visit (dispensing visit), the patient should take the scheduled palbociclib 
dose once the visit assessments for potential hematologic and non-hematologic toxicities (see 
Section 9.1.2) have been performed and are within acceptable range unless otherwise indicated. 
 
Missed doses of palbociclib (meaning doses that are missed for one day) should not be made up. 
For example, 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. If a dose 
is vomited at any time after taking palbociclib, a replacement dose should NOT be taken. 

 
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Patients who inadvertently take 1 extra dose during a day must skip the next day’s dose and 
notify his or her treating physician. If a 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.  
8.1.2 
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 Sponsor as capsules or 
tablets containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free base. Palbociclib 
capsules supplied to sites will be in High Density Polyethylene (HDPE) bottles containing 75 
mg, 100 mg, or 125 mg capsules and are labeled for clinical use. The capsules can be 
differentiated by their size and color (see below).  
 
 
Table 2: Palbociclib Capsule Characteristics 
Dosage 
Capsule color 
Capsule 
size 
75 mg 
Sunset Yellow 
2 
100 mg 
Caramel/Sunset Yellow 
1 
125 mg 
Caramel 
0 
Palbociclib tablets supplied to sites will be in foil/foil blisters containing 75 mg, 100 mg, or 125 
mg tablets and are labeled for clinical use. The tablets can be differentiated by their shape and 
color (see below). 
Table 3: Palbociclib Tablet Characteristics 
Dosage 
  Tablet color 
Tablet 
Shape 
75 mg 
Lavender 
round 
100 mg 
Light Green 
oval 
125 mg 
Lavender 
oval 
8.1.3 
Storage, Handling and Processing 
Palbociclib capsules and tablets should be stored at controlled and monitored room temperature 
specified on the product labels. Further storage and stability conditions are stated in the 
palbociclib IB. Investigators and site staff are requested to check storage temperatures daily 
(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.  

 
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Deviations from the storage requirements, including any actions taken, must be documented 
and reported to AFT. 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. 
8.1.4 
Dispensation and Accountability 
The study IRT 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 container 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 or tablet 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. 
 
To ensure adequate records and patient compliance monitoring, study medication will be 
accounted for by the site on a Drug Accountability Log. Hence, the site must maintain a 
careful record of the inventory and disposition of the agent. Accurate records of all IP 
received at, dispensed to, returned from, returned to, and disposed of by the study site should 
be recorded as instructed by the study sponsor. 
 
Patients will be instructed to return previously dispensed containers (including unused drug 
and/or empty bottles/blisters) 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 on the Drug Accountability Log 
and within the eCRF. Drug accountability for palbociclib will be performed at each study visit 
prior to dispensing drug supply for the next cycle(s). 
8.1.5 
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 study Sponsor. The site's method of IP destruction must be agreed to by the 
Sponsor in writing. Ideally, verification of drug accountability by the monitor should be 

 
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completed before any IP is destroyed at site. However, in instances when IP needs to be 
destroyed prior to a monitor visit (for example, due to limited storage capacity), instructions 
provided to all sites by the sponsor (Drug Destruction Prior to CRA Review) must be followed. 
In all cases, destruction or return of investigational product must be adequately documented. 
8.2 
Endocrine Therapy – Non-Investigational Product (Non-IP) 
Endocrine treatment may have already started before the patient enters the study.  
 
The following standard endocrine treatment agents (also referred to as background treatment) are 
allowed for Arm A and Arm B: 
 
x Non-steroidal AIs (anastrozole, letrozole) for postmenopausal women. 
x Steroidal AI (exemestane) for postmenopausal women. 
x Fulvestrant for postmenopausal women  
x LHRH agonists in combination with AI or fulvestrant for premenopausal women  
x Surgical or radiologic ablation of the ovaries is also allowed, but additional endocrine 
treatment has to be given to these patients.  
 
Locally obtained commercial supply of anastrozole, letrozole, exemestane, fulvestrant 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 regimens of oral endocrine therapy are: 
x Letrozole: 
2.5 mg orally, once a day 
x Anastrozole: 1 mg orally, once a day 
x Exemestane: 25 mg orally, once a day 
x Fulvestrant: 2 x 250mg injections on D1 and D15 of Cycle 1 and q 4 
weeks thereafter 
 
Injection of LHRH agonist is mandatory for premenopausal women. If a premenopausal woman 
is receiving LHRH agonist in combination with AI or fulvestrant, it is recommended that she 
receives monthly injections rather than every-3-month depot injections.  
 
Specific storage conditions, handling, dispensation and administration instructions have to be 
followed according to local regulations and in accordance with respective local package inserts 
and/ or for sites outside of the US, local Summary of Product Characteristics (SmPCs) 
information.  
 
Expected toxicities and potential risks can be obtained from respective local pack inserts and or 
local SmPCs.  
 

 
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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, palbociclib and 
anti-HER2 therapy must continue. If palbociclib is stopped for a patient on Arm A due to reasons 
other than PFS event, it is strongly recommended that the patient resume endocrine therapy once 
symptoms resolve, or change to alternative endocrine therapy. See Section 12 for the schedule of 
assessments and follow-up.  
 
8.3 
Trastuzumab – Non-Investigational Product (Non-IP) 
8.3.1 
Description, Form, and Prescription 
This study will use trastuzumab from commercial supply. If the patient has known 
hypersensitivity to benzyl alcohol, trastuzumab must be reconstituted with sterile water for 
injection (SWFI). Trastuzumab that has been reconstituted with SWFI must be used immediately 
and any unused portion discarded. Use of other reconstitution diluents should be avoided. 
Determine the dose of trastuzumab needed based upon guidance provided in the latest package 
insert for q3w dosing schedules. 
8.3.2 
Administration 
Trastuzumab infusion should be performed according to local guidelines.  
Dosing begins on Day 1 of Cycle 1 and continues at every three-week intervals throughout the 
study. 
 
Patients should continue on the same dose they were given during induction unless there was a 
break from last dose of induction therapy to the C1D1 visit date necessitating a re-loading dose 
(per protocol, a break of up to 12 weeks is permitted). Consult the latest package insert for 
guidance regarding re-loading dose requirements.   
 
The use of subcutaneous formulation of trastuzumab is optional where available.  If 
administered, local guidelines should be followed. 
 
8.3.3 
Ordering 
Trastuzumab is a commercially available agent and therefore ordering should be performed as 
standard policy at the investigational site. 
8.3.4 
Drug Supplies and Accountability 
Trastuzumab is a commercially available agent and therefore accountability should be performed 
as standard policy at the investigational site. 
 
Expected toxicities and potential risks can be obtained from respective local pack inserts and or 
local SmPCs.   

 
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8.4 
Pertuzumab – Non-Investigational Product (Non-IP) 
8.4.1 
Description, Form and Preparation  
This study will use pertuzumab from commercial supply. Pertuzumab drug product is provided 
as a single use formulation containing 30 mg/mL pertuzumab in 20 mM L-histidine acetate (pH 
6.0), 120 mM sucrose and 0.02% polysorbate 20. Each 20 mL vial contains 420 mg of 
pertuzumab (14.0 mL/vial). Dextrose 5% solution should not be used. The preparation of 
pertuzumab solution should follow the manufacturer recommendations. 
 
Expected toxicities and potential risks can be obtained from respective local pack inserts and or 
local SmPCs.   
8.4.2 
Administration 
Pertuzumab infusion should be performed according to local guidelines. Patients should be 
observed for fever and chills or other infusion-associated symptoms.  
 
Dosing should begin on Day 1 of Cycle 1 (C1D1) and continue at every three-week intervals 
throughout the study, following the dosing instructions provided in the latest pertuzumab 
package insert.  For patients who have experienced a gap between their last pertuzumab dose and 
the C1D1 visit, consult the latest pertuzumab package insert for re-loading dose requirements.   
 
The use of subcutaneous formulation of pertuzumab is optional where available.  If administered, 
local guidelines should be followed.   
8.4.3 
Ordering 
Pertuzumab is a commercially available agent and therefore ordering should be performed as 
standard policy at the investigational site. 
8.4.4 
Drug Supplies and Accountability 
Pertuzumab is a commercially available agent and therefore accountability should be performed 
as standard policy at the investigational site. 
 
Expected toxicities and potential risks can be obtained from respective local package inserts and 
or local SmPCs.   
8.5 
Pre-Treatment Criteria 
8.5.1 
Cycle 1 Day 1 
Patients must meet baseline body function specifics listed in Section 5.1 Inclusion Criteria 
above.  
8.5.2 
Subsequent Cycles 
Retreatment with palbociclib at the start of a new cycle that requires a clinic visit may not occur 
until all of the following parameters have been met: 
 
x Platelet count t 75,000/mm3; 

 
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x ANC t 1000/mm3 and no fever; 
x See Section 9.1 for additional retreatment information 
8.6 
Concomitant Medications 
All prior treatment or medication administered during the 30 days prior to randomization and any 
concomitant therapy administered to the patient throughout the study until 42 days after 
confirmation of disease progression/end of treatment must be recorded in the Medidata RAVE 
EDC system on the respective page of the eCRF. The generic or trade name of the drug must be 
specified along with the dose, the duration of treatment, relation to AE and indication for use. 
8.6.1 
Permitted Ancillary Medications 
Supportive care medications are allowed at any time on trial, as long as they are not included in 
the list of prohibited medications based on CYP induction (see Section 8.6.3). 
 
Specifically, the following agents are permitted: 
x Antiemetics 
x Antidiarrheal therapy 
x Antiallergic measures such as corticosteroids and antihistamines 
x Bisphosphonates 
x Denosumab  
x Agents to assist in management of endocrine therapy-induced side effects 
(Nonsteroidal anti-inflammatory drugs [NSAIDs], gabapentin, duloxetine, 
venlafaxine, etc.).  
x Diabetes management medication including metformin 
x Rank Ligand Inhibitors 
8.6.2 
Prohibited Concomitant Medications 
Growth factors, including Granulocyte Colony Stimulating Factor (G-CSF), are not allowed on 
this trial (with the exception of situations where a patient becomes clinically and medically 
unstable due to neutropenia).  
8.6.3 
CYP3A Inhibitors/Inducers 
Strong 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 strong 
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 and should be 
discontinued within 7 days prior to randomization: 
 
x Strong CYP3A inducers, including carbamazepine, phenytoin, primidone, rifampin, 
rifapentin, and St. John’s wort. 
x 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. 

 
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The following compounds are not allowed 7 days prior to the PK sampling days until the 
completion of the PK samples collection in each period: 
 
x Moderate CYP3A inhibitors including amprenavir, atazanavir, diltiazem, 
erythromycin, fosamprenavir, verapamil. 
x Moderate CYP3A inducers including felbamate, nevirapine, phenobarbital, rifabutin. 
8.6.4 
Anticancer Therapies 
No additional investigational or commercial anticancer agents such as chemotherapy, 
immunotherapy, targeted therapy, biological response modifiers, radiation therapy 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. 
8.6.5 
Antacid Agents 
The concomitant use of Proton-pump inhibitors (PPI) with palbociclib is prohibited 7 days prior 
to the PK sampling days until the completion of the PK samples collection in each period.  
8.6.6 
Medications Not Recommended 
The following treatments are not recommended throughout the duration of the Treatment Phase. 
Alternative therapies should be considered whenever possible: 
 
x 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 are allowed. 
x The use of herbal medicine is not recommended during the Treatment Phase. 
x 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. 
8.6.7 
Concomitant Radiotherapy or Surgery 
Any concurrent radiotherapy (except palliative radiotherapy as specified below) is prohibited 
throughout the duration of the active Treatment Phase of the study.   
Palliative radiotherapy is permitted for the treatment of painful bony lesions provided that the 
investigator clearly documents that the need for palliative radiotherapy is not indicative of 
disease progression. 
In view of the current lack of data about the interaction of palbociclib with radiotherapy, 
palbociclib treatment should be interrupted during palliative radiotherapy, stopping 1 day before 
and resuming 1 week after. For patients with bone involvement, it is suggested to institute 
palliative radiotherapy before study initiation if possible and clinically appropriate (e.g., lesions 
at risk for spontaneous micro-fractures or painful lesions). The dates on which palliative 
radiotherapy is administered should be recorded on the appropriate CRFs. Patients may continue 

 
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endocrine therapy and anti-HER2 therapy during the course of palliative radiotherapy at the 
discretion of the treating physician. 
 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and palbociclib required to minimize the risk of 
impaired wound healing and bleeding has not been determined. Based on the available 
pharmacokinetic data, stopping palbociclib is recommended at least 7 days prior to elective 
surgery. Postoperatively, the decision to reinitiate palbociclib treatment should be based on a 
clinical assessment of satisfactory wound healing and recovery from surgery. Patients can 
continue endocrine and/or anti-HER2 therapy if palbociclib is held for surgery.  
9. 
Dose Modifications/Toxicity Management 
Every effort should be made to administer study treatment on the planned dose and schedule. 
However, in the event of significant treatment-related toxicity, administration of palbociclib may 
need to be adjusted. No dose reduction for trastuzumab, pertuzumab and endocrine therapy is 
permitted, but dose interruptions are allowed.  
 
Incidence, nature, and severity of AEs triggering dose or study treatment modifications are to be 
assessed by the investigator and graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0) as AE related dose 
and treatment modification recommendations are based on this grading scale.  
9.1 
Palbociclib 
9.1.1 
Dose Modifications/Toxicity Management 
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 below. 
 
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed. Patients are to be instructed to notify Investigators at the first occurrence of any 
adverse sign or symptom. 
 
The start of a cycle is defined as the day when palbociclib administration begins, starting with 
the first palbociclib dose at baseline (Cycle 1, Day 1). In case of palbociclib dose delays, 
administration of endocrine therapy and anti-HER2 therapy will continue according to the pre-
planned schedule.  
 
The need for a dose reduction at the time of treatment resumption should be based on the criteria 
defined in the Dose Reductions Section (Section 9.1.4) 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. 
 

 
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9.1.2 
Palbociclib Dosing Interruptions/Delays 
In general, cycles should be 28 days long unless the start of a new cycle is delayed.  
 
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 AE 
requiring a dose hold has not returned to baseline or grade 2 level by Day 1 of the next planned 
cycle with the exception of alopecia.  
 
Patients experiencing one or more of the following AEs should have their palbociclib treatment 
interrupted/delayed until criteria for retreatment.   
 
The following AEs need to return to baseline or grade 2 level by Day 1 of the next cycle: 
 
x Uncomplicated Grade 3 or 4 neutropenia (Absolute Neutrophil Count (ANC) < 
1000/mm3) 
x Grade 3 or 4 neutropenia (ANC < 1000/mm3) associated with a documented infection 
or fever t 38.3qC, 101qF (febrile neutropenia)  
x Grade 3 or 4 thrombocytopenia (Platelet count < 50,000/mm3) 
x Grade t 3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment) 
 
The following needs to return to baseline or grade 1 level by Day 1 of the next cycle:  
x Grade 2 or 3 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 or AST and >2x ULN total bilirubin at any 
time during the trial, palbociclib will be permanently discontinued. 
 
It is also important to monitor patients for pulmonary symptoms indicative of interstitial lung 
disease (ILD)/pneumonitis (e.g. hypoxia, cough, dyspneoa). In patients who have new or 
worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, 
interrupt palbociclib immediately and evaluate the patient.  Permanently discontinue 
palbociclib in patients with severe ILD or pneumonitis. 
 
9.1.3 
Palbociclib Retreatment Criteria 
In the case of a treatment interruption or delay, retreatment with palbociclib may not occur until 
all of the following parameters have been met: 
 
x Platelet count t 75,000/mm3; 
x ANC t 1000/mm3 and no fever; 
 

 
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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. 
 
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.  
 
9.1.4 
Palbociclib Dose Reductions 
The palbociclib dose may need to be reduced, following a dose interruption or cycle delay when 
treatment is resumed. 
 
x 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. 
x 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 3) 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 generally be administered at that dose level, unless further 
dose reduction is required. Dose re-escalation of palbociclib from 100mg to 125 mg is 
not allowed. Cautious dose re-escalation from 75mg to 100mg can be considered per 
investigator discretion. Patients requiring more than 2 dose reductions will 
discontinue palbociclib treatment permanently. If the patient remains on anti-HER2 
and/or endocrine therapy(ies), they remain in the Treatment Phase.  If all study 
medications are discontinued (for reasons other than disease progression), the patient 
should switch to the Clinical Follow-up Phase (see Section 10.4.2).  
 
 
 
Table 3: Palbociclib Dose Levels and Dose Reduction Schedule 
 
 
 
 
 
 
 
 
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 

 
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9.1.5 
Dose Modifications/Toxicity Management – Endocrine Therapy 
Patients should not hold or discontinue endocrine therapy for side effects potentially or likely 
related to concomitant anti-HER2 therapy and/or palbociclib as per the investigator’s judgment. 
If a patient finds oneself not able to tolerate endocrine therapy, an attempt to change to an 
alternative endocrine therapy is a priority, while continuing treatment with anti-HER2 therapy 
and/or palbociclib. If a patient is considering stopping endocrine medication altogether, 
palbociclib and anti-HER2 therapy must continue.  
9.1.6 
Dose Modifications/Toxicity Management – Anti-HER2 Therapy 
In general, patients should not hold or discontinue anti-HER2 therapy for side effects potentially 
or likely related to concomitant palbociclib as per the investigator’s judgment. If anti-HER2 
therapy is discontinued, patients may continue on endocrine therapy and/or palbociclib as per the 
investigator’s judgment. Please see Table 4 for palbociclib-related AEs that may necessitate anti-
HER2 therapy holds/discontinuations (if determined by investigator to be also related to the anti-
HER2 therapies).   
 
All patients will undergo scheduled LVEF assessments by ECHO or MUGA scans. The results 
of the LVEF assessments will be used to determine if trastuzumab and pertuzumab 
administration can be continued. Refer to Figure 2 for the algorithm for continuation and 
discontinuation of study treatment on the basis of asymptomatic LVEF assessment. 
 
Diarrhea and rash are considered EGFR-related risks based on the mechanism of action of 
pertuzumab. To prevent dehydration, early treatment of diarrhea with anti-diarrheal medication 
should be considered, and patients should be treated with fluids and electrolyte replacement, as 
clinically indicated. Treatment recommendations for EGFR-associated rash include topical or 
oral antibiotics, topical pimecrolimus, and topical or (for severe reactions) systemic steroids. 
These agents may be used in patients experiencing pertuzumab-related rash, as clinically 
indicated.  
 
During study treatment, some toxicity may be attributable to palbociclib, trastuzumab, or 
pertuzumab. It is important to evaluate the possible cause of toxicity and weigh risk versus 
benefit for each agent to determine the schema of dose modifications (e.g., which agent to 
prioritize for maintaining dose level and the sequence of dose modifications).  
 
General guidelines are provided in the following subsections based on the known safety profile 
of study drugs. 
 
 

 
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Table 5: AE-triggered Dose Modifications and Treatment Management for Trastuzumab and/or 
Pertuzumab 
 
Event 
Grade 
Action to Be Taken  
Infusion-related 
reactions 
 
Infusion-related 
symptoms 
Grades 12.  
Decrease infusion rate by 50% or interrupt infusion for 
patients who experience any other infusion-related 
symptoms (e.g., chills, fever). 
 
When symptoms have completely resolved, infusion may 
be restarted at d 50% of prior rate and increased in 50% 
increments every 30 minutes as tolerated. Infusions may be 
restarted at the full rate at the next cycle, with appropriate 
monitoring. In the event of a true hypersensitivity reaction 
(in which the severity of reaction increases with 
subsequent infusions) to trastuzumab or pertuzumab 
treatment, the respective agent must be permanently 
discontinued.  
 
Supportive care with oxygen, E-agonists, antihistamines, 
antipyretics, or corticosteroids may be used as appropriate 
at the investigator's discretion. 
 
Premedication with corticosteroids, antihistamines, and 
antipyretics may be used before subsequent infusions at the 
investigator’s discretion. 
 
Patients should be monitored until complete resolution of 
symptoms. 
 
Grade t 3 
allergic/hypersensitivity 
reaction  
 
Stop infusion. 
 
Supportive care with oxygen, E-agonists, antihistamines, 
antipyretics, or corticosteroids may be used as appropriate 
at the investigator's discretion. 
 
Patients should be monitored until complete resolution of 
symptoms.  Retreatment at subsequent cycle per 
investigator discretion. 
Pneumonitis/ 
Interstitial Lung 
Disease 
Grade 1 or 2 
Discontinue pertuzumab regardless of attribution. 
Interrupt palbociclib as per instruction in Section 9.1.2 
Grade 3 or 4 
Discontinue pertuzumab regardless of attribution. 
Discontinue palbociclib as per instruction in Section 9.1.2 
Ejection fraction 
decreased 
Grade 3 or 4 
Discontinue trastuzumab and pertuzumab  
Heart Failure  
Grade 3 or 4 
Discontinue trastuzumab and pertuzumab  
Heart Failure 
Accompanied by 
LVEF <45% 
Grade 2-4 
Discontinue trastuzumab and pertuzumab  
Asymptomatic 
decrease in LVEF 
See Figure 2 on following page for dose modifications 
 
 

 
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Figure 2: 
HER2-Directed Therapy Management Based on LVEF Assessments 
 
LVEF   left ventricular ejection fraction; EF   ejection fraction % points 
Note: Baseline refers to the screening LVEF.  
 
Discontinuation of anti-HER2 therapy is recommended if LVEF recovery does not occur after 
three intermittent holds of study treatment but subsequent treatment is at investigator discretion 
on a case by case basis. 
10. Study Phases 
The study consists of 3 main phases which apply to both of Arms A and B: 
x Screening Phase:  
x Preliminary Screening begins with the signing of the Preliminary Screening 
Consent 
x Randomization Screening Phase begins with the signing of the Main Study 
Consent 
x Treatment Phase begins on the date of the C1D1 visit which is the start of study 
treatment and continues until patients stop treatment, enter one of the follow-up 
phases or complete the study. 

 
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x Follow-up Phase (Clinical Follow-up and Survival Follow-up) begins at the end of 
study treatment – meaning the end of all study treatments – palbociclib (if Arm A), 
endocrine therapy and anti-HER2 therapy, through end of study. 
10.1 
Screening 
10.1.1 Preliminary Screening (pre-screening) 
During the Pre-Screening Phase participants will be asked if they are willing to provide 
an archival tissue sample (mandatory), if they would like to participate in the MBC 
Initiative (optional), and if they would be willing to provide tissue from a biopsy of their 
metastatic disease site (optional). The Pre-Screening Consent will explain that 
participation in the MBC Initiative includes a provision that limited baseline clinico-
pathologic characteristics and biomarker results (e.g. Genomic panel results) will be 
hosted in the MBC independent clinical data repository. The Pre-Screening ICF outlines 
the major goals of the MBC initiative and explains that this feature is optional. 
 
x After signing the Pre-Screening Consent document, a formalin-fixed paraffin-
embedded (FFPE) archival (primary breast or metastatic site) tumor tissue block 
or representative slides from such a block must be shipped to the AFT 
biorepository.  
x An optional biopsy of metastatic disease (for patients with disease amenable to 
biopsy) should be performed preferably prior to the initiation of induction 
treatment. Tissue from a recently performed biopsy of metastatic disease is also 
acceptable. 
 
Patients whose tumor samples are considered to be of low quality will be asked to 
resubmit additional tissue. Further details will be provided in the PATINA (AFT-38) 
Correlative Science Manual (CSM) which will be provided to all sites at study start-up.  
 
Baseline clinico-pathologic features that will be collected during the screening phases of 
the study include (but are not limited to) the following: 
 
1. Demographic data (gender, ethnicity, race, country of origin) 
2. ECOG performance status 
3. Menopausal status  
4. Height, weight 
5. Date of primary tumor diagnosis 
6. Primary tumor characteristics at diagnosis 
7. Prior treatments (surgery, radiation, chemotherapy, hormonal therapy) 
8. Date of first known metastatic disease 
 
The same information will be hosted in the MBC data repository for participants who 
consent to participate in the MBC Initiative.  
 
Patients can sign the Pre-Screening Consent at any time during their induction therapy. 
Since 6-8 cycles of induction therapy are permitted (4 cycles if evidence of toxicity), the 

 
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time from signing the Pre-Screening Consent to the C1D1 visit could be up to 168 days. 
For patients who are early in their induction therapy, sites should wait before obtaining 
the Main Study Consent and beginning the eligibility assessments.   
10.1.2 Randomization Screening  
 
The Randomization Screening Phase begins after a patient provides written informed 
consent (Main Study Consent) to participate in the PATINA/AFT-38 research study. 
During this phase, all remaining Inclusion and Exclusion criteria will be assessed. 
Concomitant medications, medical history, physical examination/vital signs, ECOG 
performance status assessment, AEs, serious adverse events, laboratory measurements, 
pregnancy testing (if applicable), will be collected during this phase (see Study 
Assessment Table, Section 12).   
 
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.  
 
The patient has a maximum of 28 days from the date the Main Study Consent is signed to 
determine eligibility and randomize the patient.  Results of screening tests performed as 
standard of care prior to obtaining informed consent and within 42 days prior to 
randomization may be used rather than repeating required tests. (This does not apply to 
the baseline tumor assessments which must be done within 28 days of randomization). 
The actual date of randomization is the date the site randomizes the patient in the IRT 
system, which can occur up to 14 days prior to the C1D1 visit.  In addition, screening 
assessments that are collected within 7 days of the C1D1 visit may serve as the C1D1 
assessments and do not have to be repeated. 
 
Since several of the study visits are intended to align with the patient’s anti-HER2 
infusion visits (for example the Arm A C1D22 visit for safety labs and the PK 
assessments), it is important to schedule the C1D1 visit on the date of a patient’s anti-
HER2 infusion.  
 
In the Main Study Consent, patients will be asked to consent to an Optional Research 
biopsy or to provide tissue from a recently biopsied site of metastatic disease at disease 
progression. This is for future research associated with the MBC Initiative. Patients will 
be instructed that they can participate in the main study regardless of their decision to 
undergo this biopsy. 
 
10.1.3 Screening Failures 
Signed and dated ICFs for screened patients and for patients who are not subsequently 
enrolled or randomized in the study will be maintained at the study site. All screening 
evaluations must be completed and reviewed to confirm that patients meet all criteria 
before randomization. 
 
Patients who complete the informed consent process but do not meet one or more 
eligibility criteria and therefore are not randomized will be considered screen failures. 

 
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Baseline genomic and clinico-pathologic data collected from patients who consented to 
the MBC Initiative will be stored in the MBC Data Repository regardless of whether 
these patients meet final eligibility to participate in this clinical study. 
 
For all screen failures, clinical sites must enter minimal baseline information into the 
study EDC system using the appropriate CRFs.  
 
Screen failures are allowed to be re-screened a single time only. All patients who are re-
screened must be re-consented. 
10.2 
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 (anti-
HER2 therapy plus endocrine therapy).   
 
The Treatment Phase for patients on both Arms starts on Day 1 of Cycle 1 (C1D1), which should 
be on or shortly after the date the patient is randomized in the IRT system (within no more than 
14 days).  Arm A patients should begin IP treatment and both Arm A and Arm B should undergo 
an anti-HER2 infusion on this day.  
 
Patients will continue with the Treatment Phase or begin the subsequent phases under the 
following conditions: 
 
1) If any part of protocol treatment (IP or any part of Non-IP) is still being received, the 
patient will continue on the Treatment Phase. For example, if an Arm A patient 
discontinues palbociclib but remains on either or both of the other protocol-defined 
treatments (anti-HER2 and endocrine therapies), they would continue in the active 
Treatment Phase.  If an Arm B patient stops anti-HER2 therapy but remains on endocrine 
therapy they would continue in the active Treatment Phase. This includes all visits and 
assessments required by the Schedule of Assessments table (see section 12) for this 
phase.  Patients may remain on study treatment until they enter into one of the follow-up 
phases or reach End of Study. 
 
2) Patients who discontinue all Study Treatment (Arm A: palbociclib, anti-HER2 therapy 
and endocrine therapy; Arm B: anti-HER2 therapy and endocrine therapy) due to a 
reason other than disease progression will move to the Clinical Follow-up Phase. 
 
3) Patients who discontinue Study Treatment due to disease progression will move to the 
Survival Follow-up Phase.  
 
4) Randomized patients on either Arm who are deemed ineligible prior to first dose or 
refuse to start their initial treatment will move to the Survival Follow-up. 
 
Patients who are deemed ineligible after starting protocol therapy will be discontinued 
from study treatment and will enter the Survival Phase of the study. In the event the 
ineligibility of a patient is not identified prior to starting treatment, continuation on 

 
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treatment will be reviewed on a case-by-case basis to evaluate any safety risks to the 
patient. 
 
 
5) Withdrawal of consent for all study participation will end patient activity in the study and 
all follow up. 
10.3 
Treatment Discontinuation 
The term "interruption" refers to a patient stopping the protocol therapy during the course of the 
study, but then re-starting it at a later time in the study. The reason for dosing interruption will be 
collected on the appropriate CRF. 
 
The term "discontinuation" refers to a patient's withdrawal from the Treatment Phase, i.e., 
discontinues all IP and Non-IP therapy. The reason for discontinuation from treatment will be 
collected on the appropriate CRF. 
 
If a patient opts to discontinue from the Treatment Phase as a result of an unacceptable adverse 
drug reaction, "withdrawal of consent" should not be the reason for discontinuation. Instead, the 
reason for discontinuation from the active Treatment Phase must be recorded in the “Off 
Treatment” eCRF as “Adverse Event/Side Effects/Complications.”  The event should also be 
reported on the AE CRF with “Action Taken” recorded as discontinuation of treatment.  
 
At the end of the study, for any patients who are still deriving clinical benefit from study 
treatment, the Sponsor will work with the investigator to explore options for alternative source of 
treatment, in accordance with local regulations and requirements.  
10.4 
Follow-Up Phase 
10.4.1 
End of Treatment Follow-up 
Patients who discontinue treatment due to disease progression or who were deemed ineligible 
and removed from treatment will enter the Survival Follow-up Phase as discussed below.  For 
these patients, the End of Treatment assessments can be those conducted at the study visit during 
which disease progression was determined, as long as all assessments were conducted at that 
visit (PROs, ECHO/MUGA, tumor scans, limited physical exam, etc.).  If disease progression is 
determined in between study visits and the previous visit was more than 12 weeks prior, then an 
End of Treatment visit should be performed within 28 days of treatment discontinuation and all 
data collected.   
 
Patients who discontinue all treatment for reasons other than disease progression should go into 
Clinical Follow-up and continue study visits every 12 weeks per the Schedule of Assessments.  
 
The final sample for ctDNA should be collected at treatment discontinuation (+28 days). 
 
10.4.2 
Clinical Follow-up 
For patients who discontinue all protocol Study Treatment for reasons other than disease 
progression, the patient will enter the Clinical Follow-up Phase. Patients will be seen in clinic 
every 12 weeks for imaging and assessment of adverse events per the Schedule of 

 
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Assessments/Clinical Follow-up Phase (see section 12) until disease progression. Once the 
patient progresses or initiates subsequent anti-cancer therapy (in the absence of progression), 
they will move to Survival Follow-up. 
 
10.4.3 
Survival Follow-up 
For patients who progress during the Treatment Phase (or who were deemed ineligible and 
removed from treatment), the Clinical Follow-up Phase, or who are randomized but do not 
initiate protocol treatment, the patient will enter the Survival Follow-up Phase. When disease 
progression is confirmed the optional research biopsy or request for tissue from a recently 
biopsied metastatic site should be offered to patients who signed the Optional Research Biopsy 
question in the Main Study Informed Consent Form. 
 
Survival data, ongoing treatments and subsequent disease progression data will be collected 
during this phase of the study. Telephone contact is acceptable as well as medical record review. 
 
Follow-up will be discontinued early due to: 
x Patient Death 
x Patient Withdrawal of consent for all follow-up 
x Patient deemed lost to follow-up 
 
10.4.4 
Study Discontinuation 
 
Lost to Follow-up 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. If after two years of unsuccessful attempts to contact the patient, one of which is by 
registered letter, the patient cannot be reached, the patient should be considered “lost to follow-
up.” Steps taken to contact the patient (e.g., dates of telephone calls, registered letters, etc.) must 
be clearly documented in the patient’s source documents.  
 
Withdrawal of Consent 
In any circumstance, every effort should be made to document patient status. If the patient can be 
reached and requests withdrawal from the study, the investigator should inquire about the reason 
for withdrawal, request that the patient return all unused investigational product(s), request that 
the patient return for a final visit, if applicable, and follow-up with the patient regarding any 
unresolved AEs. 
 
Data to be collected for the end of study treatment/withdrawal are described in the Schedule of 
Assessments (Section 12). If the patient withdraws from the study, and also withdraws consent 
for disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
 

 
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The reason for treatment discontinuation must be entered into the appropriate eCRF. Patients 
who discontinue treatment will remain on study in the Follow-up Phase (either Clinical or 
Survival depending upon their disease status).  
 
10.5 End of Study 
The end of study will occur approximately 5 years after the last patient is randomized.  
11. 
Study Assessments and Procedures 
11.1   Medical History and Demographic Data 
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.  
 
Patients may be considered postmenopausal if one of the following criteria applies: 
x Prior bilateral oophorectomy OR 
x Age ≥ 60 years OR 
x Age < 60 years with intact uterus and amenorrhea for ≥ 12 consecutive months* prior 
to chemotherapy and/or endocrine therapy exposure OR 
x Age < 60 years hysterectomized and FSH and plasma estradiol 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 apply, 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. 
11.2 
Concomitant Medications 
Any concomitant medications and treatments that a patient is or has been taking from 30 days 
prior to randomization up to the end of the Treatment Phase should be recorded on the 
appropriate CRF at each study visit. Endocrine therapy is not considered concomitant medication 
and needs to be recorded separately on the appropriate eCRF. 

 
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11.3 
ECOG Performance Status 
The ECOG Performance Status should be assessed prior to randomization and on Day 1 of 
Cycles 1, 2, 3, and 4 and every 12 weeks thereafter, with the last assessment at the End of 
Treatment visit.  
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able 
to carry out work of a light or sedentary nature (e.g. light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead 
 
11.4 
Complete Physical Exam 
A complete physical exam should be conducted prior to randomization and should include an 
evaluation of head, eye, nose and throat, and cardiovascular, respiratory, gastrointestinal, and 
neurological systems as well as a measurement of weight and height.  
11.5 
Limited Physical Exam 
A limited physical exam should be conducted monthly on Day 1 of Cycles 1, 2, 3, and 4 and 
every 12 weeks thereafter. This examination is a limited, symptom-directed examination which 
should include any of the assessments conducted in the complete physical as clinically indicated. 
11.6 
Vital Signs 
Vital signs should be collected monthly on Day 1 of Cycles 1, 2, 3, and 4 and every 12 weeks 
thereafter. Measurements include respiratory rate, pulse, and systolic and diastolic pressure.  
11.7 
CBC and Platelets 
CBC includes hemoglobin, white blood cell count (WBC) with differential, ANC, and platelet 
count. CBC will be collected monthly on Day 1 of Cycles 1, 2, 3, and 4 and every 12 weeks 
thereafter, with additional assessments as clinically indicated. In addition, subjects randomized to 
Arm A will have these labs performed on Day 22 of Cycle 1. These labs will be assessed at each 
site’s local lab with results entered into the appropriate eCRF. It is strongly recommended that 
these assessments be performed at the research center lab. If this is not feasible, laboratory tests 
for individual patients should be performed at the same laboratory. 
11.8 
Blood Chemistry 
Blood chemistry will be collected monthly on Day 1 of Cycles 1, 2, 3, and 4 and every 12 weeks 
thereafter, with additional assessments as clinically indicated. Blood chemistry includes AST 
(SGOT)/ALT (SGPT), alkaline phosphatase, sodium, potassium, total calcium, total bilirubin, 
serum creatinine, total protein and albumin. Additional hematology/chemistry panels may be 
performed as clinically indicated. All blood chemistries will be assessed at each site’s local lab 
with results entered into the appropriate eCRF. It is strongly recommended that these 

 
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assessments be performed at the research center lab. If this is not feasible, laboratory tests for 
individual patients should be performed at the same laboratory. 
11.9 
Pregnancy Test 
A serum pregnancy test should be performed within 7 days of randomization for women of 
childbearing potential, including premenopausal women who have had a tubal ligation, and 
premenopausal women who have chemotherapy-induced amenorrhea (includes women with 
amenorrhea induced by chemotherapy during the Induction Phase prior to study randomization).  
Afterward, perform every 12 weeks (± 2 days) on urine or serum until disease progression. A 
positive urine pregnancy test must be confirmed with a serum pregnancy test.  
Note: 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. 
11.10 ECG - Electrocardiogram (12-Lead ECG) 
At screening, a single standard 12-lead resting ECG will be performed according to each site's 
standard of care process. 
ECGs will be analyzed locally at each site. Parameters including heart rate, rhythm, and RR, PR, 
QRS and QTc intervals should be assessed to determine eligibility into the study (see Exclusion 
Criteria 5 and 8).  
 
11.11 MUGA or Echocardiogram (ECHO) 
ECHO/MUGA should be performed prior to randomization and repeated on Day 1 of Cycle 4 
and every 12 weeks thereafter (±7 days), with additional examinations as clinically indicated. 
Left ventricular ejection fraction (LVEF) by ECHO is preferred. The same method should be 
used throughout the study for each patient and preferably performed and assessed by the same 
assessor. ECHO/MUGA should also be performed at Treatment Discontinuation if not done 
within the previous 12 weeks.  
11.12 Tumor Assessments 
The importance of timely and complete disease assessments in the study cannot be understated. 
Disease assessments must be performed as scheduled according to the study calendar to prevent 
the introduction of bias into the assessment of efficacy.  
Screening/baseline tumor assessment will be carried out within 28 days of randomization  
(unless otherwise as specified below). 
 

 
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11.12.1 
Imaging Assessment Collection Plan 
Disease assessment for patients at baseline will include: 
 
x CT or MRI scan of the chest, abdomen, and pelvis. 
 
x Bone scans or PET scan in order to detect bony sites of disease. Any suspicious 
abnormalities (i.e., hotspots) identified on the bone scans at baseline must be 
confirmed by X-ray, CT scan with bone windows or MRI.  
 
x Baseline brain CT or MRI are only required in case signs and symptoms suggest the 
presence of metastatic brain disease.  
 
x CT or MRI scan of any other sites of disease as clinically indicated. 
 
Post-baseline tumor assessments will be performed every 12 weeks (± 7 days) from C1D1 (to 
align with visit schedule) until disease progression with additional scans when clinically 
indicated. If a tumor assessment must be performed early or late, subsequent assessments should 
be conducted according to the original schedule. Radiologic tumor assessment must include CT 
and/or MRI of the chest, abdomen and pelvis. Additional imaging should be performed if 
clinically indicated. The same imaging modality used at screening must be used throughout the 
study.  
 
All scans throughout the study from baseline until disease progression will be uploaded to the 
Alliance Foundation Trials (AFT) Imaging Core Lab (ICL) at the Wright Center of Innovation in 
Biomedical Imaging (WCIBMI) at the Ohio State University. Complete imaging data sets in 
digital DICOM format will be collected and submitted electronically to the AFT ICL. Detailed 
instructions are provided in the AFT ICL Manual which will be provided to all sites during study 
start-up. 
 
Patients who are discontinued from study treatment for reasons other than disease progression 
(Clinical Follow-up) will be asked to continue to have tumor assessments every 12 weeks (± 7 
days) until disease progression or initiation of other anti-cancer therapies. 
 
An isotope bone scan (e.g., technetium) or PET scan should be repeated in the event of clinical 
suspicion of progression of existing bone lesions and/or the development of new bone lesions or 
for confirmation of complete response for all patients. For patients with bone-only disease not 
visible on the CT or MRI scans being performed as part of the tumor assessments, bone scans or 
PET scan should be repeated every 12 weeks (± 7 days) from the C1D1 visit until disease 
progression.  These scans will be submitted to the AFT ICL as well. 
11.13 Patient Reported Outcome (PRO) Assessments 
Patient reported outcomes of breast cancer specific health-related quality of life and health status 
will be assessed using validated questionnaires: The Functional Assessment of Cancer 
Therapy-Breast (FACT-B) and EuroQol-5D (EQ-5D) respectively [37, 38]. The FACT-B and 
EQ-5D will be given to the patient in the appropriate language for the site. 

 
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Patients will complete each instrument pre-dose on Day 1 of Cycles 1 and 4 and then Day 1 
every 12 weeks over the course of treatment until disease progression, or study treatment 
discontinuation and at end of treatment visit.  
Patients must complete these instruments in clinic (cannot be taken home) prior to having any 
tests and to any discussion of their progress with healthcare personnel at the site. Interviewer 
administration in clinic may be used under special circumstances (e.g. patient forgot their glasses 
or feels too ill). Completed questionnaires are always considered source documents and must be 
filed accordingly. 
Functional Assessment of Cancer Therapy (FACT-B) 
The FACT-B consists of the Functional Assessment of Cancer Therapy-General (FACT-G) (27-
items) and a breast-specific module: a 10-item instrument designed to assess patient concerns 
relating to BC. The FACT-G is a 27-item compilation of general questions divided into 4 
domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and 
Functional Well-Being. Patients are asked to respond to a Likert scale where 0=not at all, 1=a 
little bit, 2=somewhat, 3=quite a bit, and 4=very much. (Brady et al 1997) 
Euroqol-5D (EQ-5D) 
The EuroQol EQ-5D is designed to assess health status in terms of a single index value or utility 
score. It contains 5 descriptors of current health state (mobility, self-care, usual activities, pain or 
discomfort, and anxiety or depression) with each dimension having 5 levels of function (1=no 
problem, 2=slight problem, 3=moderate problem, 4=severe problem, and 5=unable/extreme). 
The scores on the 5 descriptors are summarized to create a single summary score. The EQ-5D 
also includes a visual analog scale (VAS), in which the patients self-rate their overall health 
status on a scale from 0 (worst imaginable) to 100 (best imaginable) [38]. 
11.14 IP Dispensing 
For palbociclib administration, please refer to Section 8.1. 
11.15 Trastuzumab and Pertuzumab 
The anti-HER2 therapies, trastuzumab and pertuzumab, should be administered every three 
weeks starting on Day 1 of Cycle 1.  For additional information, please refer to Section 12, Study 
Assessment Table and Sections 8.3 and 8.4.  
11.16 Survival Follow-up 
Following disease progression and the End of Treatment visit, survival data and follow-up 
information will be collected in all patients every 6 months (r 14 days) until the end of the study. 
In addition to survival information, the study will collect treatment information beyond disease 
progression and patterns of disease progression (i.e., sites of metastatic disease progression).  
11.17 Biomarker/Correlative Studies 
Please see the AFT-38 (PATINA) Correlative Science Manual (CSM) for further specifics 
regarding biospecimen collection, processing, and shipping.  The most current version of the 
AFT-38 CSM can be found on the AFT BioMS web site which is accessible via the AFT portal: 
(https://alliancefoundationtrials.org)  

 
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11.17.1 
Biomarker/Correlative Studies: Circulating Tumor DNA (ctDNA) 
and Germline DNA 
For assessment of germline DNA, one 10 mL lavender top (EDTA) tube of blood will be 
collected on Day 1 of Cycle 1 and Day 1 of Cycle 4.  
For assessment of circulating tumor (ctDNA), two 10mL Streck tubes of blood will be collected 
on Day 1 of Cycle 1, Day 1 of Cycle 4, and at treatment discontinuation (+28 days).  These tubes 
will be collected at each site’s local lab and then shipped to the study central lab (outside US 
sites) or AFT Biorepository (US sites) for processing, storage, and analyses.  
Collection of biospecimens is mandatory, unless specifically prohibited by local regulations.  
Specific instructions for the sample collection, preparation, storage, labeling, and shipment of 
biospecimens is provided in the Central Lab/Biorepository Manual of Procedures. Sample 
shipment to the respective central sample repository may only be performed following patient 
consent and allocation of the study specific patient identification number to each sample. 
11.17.2 
Primary Breast Tumor Tissue 
Submission of a representative archival (primary breast or metastatic site) formalin fixed and 
paraffin embedded (FFPE) tumor tissue sample is required from all patients prior to 
randomization. The archival tumor tissue specimen can be from a primary lesion, and may 
represent tissue obtained at the time of, or subsequent to, the initial diagnosis It would be 
preferable if the tumor tissue was collected within 6 months of enrollment into the trial to 
provide the most up-to-date information regarding the tumor and its microenvironment. Archived 
(primary breast or metastatic site) tumor tissue should be provided as ONE representative FFPE 
tumor tissue block containing sufficient tumor tissue to allow for sectioning of at least fifteen 
(15) slides each containing a 5-micron tissue section. All blocks will be returned at the end of the 
study or before, upon written request, if needed for specific patient clinical management. If a 
tissue block cannot be provided, sites should submit 15 freshly cut unstained slides, each 
containing a 5-micron tissue section cut serially from the same block.  
 
If existing FFPE tissue from a diagnostic or clinical procedure is not available, a new, ‘research 
only’ primary tumor biopsy sample must be obtained in accordance with local institutional 
practice for tumor biopsies. 
11.17.3 
 Biopsies of Metastatic Disease 
Screening Phase: In addition to archival tumor tissue, it is strongly encouraged to obtain a 
representative biopsy of a locally recurrent or metastatic tumor lesion. The biopsy may be 
performed any time after a patient is determined to be eligible for the Study and has signed the 
Consent to the Screening phase of the study. Biopsies of locally recurrent or metastatic lesions 
should be performed according to standard institutional procedures.  Providing tissue from a 
recently collected biopsy of the metastatic disease site is also permitted.  
 
Please see the PATINA (AFT-38) Correlative Science Manual (CSM) for further specifics 
regarding biospecimen collection, processing, and shipping.  The most current version of the 
PATINA CSM can be found on the AFT BioMS web site which is accessible via the AFT portal: 
(https://alliancefoundationtrials.org)     
 

 
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The recommendations described below for the amount of tissue to be obtained at the biopsy are 
not meant to replace clinical judgment at the time the procedure is performed. Less than the goal 
quantity of tissue is accepted for each type of biopsy and will be left to the clinical judgment of 
the physician performing the procedure.  Note that new biopsies of recurrent or metastatic 
disease submitted will be for ‘research purposes only.’  They will not be used to make or confirm 
a diagnosis of metastatic breast cancer.  Therefore, if required by clinical judgment, such 
biopsies should be submitted for local pathology diagnosis before or in addition to submission 
for correlative science studies.   
 
Core biopsies are preferred; punch biopsies may be done when necessary, but fine needle 
aspirates are not acceptable.  
 
x Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional 
guidelines for a diagnostic core biopsy of a breast mass 
x Skin/Chest wall: A goal of three 5-mm punch biopsies will be obtained 
x Lymph node/Soft tissue: A goal of 3-6 core biopsy specimens will be obtained using an 
18-gauge needle if possible. 
x Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle if 
possible. 
x Lung: Because of the risk of pneumothorax associated with core needle biopsies of lung 
nodules, no core biopsies of lung nodules are recommended on this protocol; unless they 
are clinically indicated. 
x Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively 
low, if a patient has another accessible site of disease (e.g., skin, lymph node, liver), that 
site should be biopsied preferentially. If bone is the only biopsy-accessible site, then a 
goal of 1-3 core biopsy specimens will be obtained using an 11 to 13-gauge needle if 
possible. 
x If ascites or pleural fluid is to be used as the investigational biopsy specimen, 
consideration should be given to confirming the malignant nature of the ascites or pleural 
fluid prior to study entry.  
 
Disease Progression: In addition, a recommended but optional de novo tumor biopsy or tissue 
from a recently biopsied metastatic site may also be obtained at disease progression. This biopsy 
may be performed on a locally recurrent or a metastatic lesion. 
 
Please refer to AFT-38 (PATINA) Correlative Science Manual (CSM) for a detailed description 
of collection, processing, and shipping procedures. The most current version of the PATINA 
(AFT-38) CSM can be found on the AFT.BioMS web site which is accessible via the AFT 
portal: (https://alliancefoundationtrials.org). 
11.17.4 
Pharmacokinetic (PK) Assessments 
PK samples will be collected for Arm A participants enrolled in the United States only. 
Palbociclib Pharmacokinetic (PK) Assessments 
Plasma PK samples for palbociclib determination will be collected on Cycle 1 Day 22, as 
described in the Study Assessment Table. Patients must have received at least 7 consecutive days 

 
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of palbociclib before PK assessments on Cycle 1 Day 22, and the prior infusion of trastuzumab 
(3 weeks earlier) administered as scheduled.  
Additional instructions for PK sampling include the following: 
x The palbociclib dose that is taken on C1D21 should be at least 20 hours from the time the 
PK sample is drawn on C1D22. Patients should record the time of their C1D21 
palbociclib dose in the patient diary. 
In the event PK sample cannot be collected (or is not collected) on C1D22, every effort should 
be made to collect makeup samples on any day from Day 8 to Day 22 of later cycles, using the 
same criteria. The exact time of the sample collection and the most recent dosing time before and 
after PK sample collection if applicable will be recorded on the eCRF. The date of missing dose 
should also be recorded in the eCRF.  
The actual times may change but the number of samples will remain the same. All efforts will be 
made to obtain the pharmacokinetic samples at the exact nominal time relative to dosing 
(predose samples are approximately 24 hours post the last dose). However, samples obtained 
within 10% of the nominal time (i.e., 2.4 hours) will not be captured as a protocol deviation, as 
long as the exact time of the sample collection is noted on the source document and data 
collection tool (e.g., CRF/DCT). 
During all study periods, blood samples (3 mL) to provide approximately 1 mL of plasma for 
pharmacokinetic analysis will be collected into appropriately labeled tubes containing 
dipotassium ethylenediaminetetraacetic acid (K2EDTA) at protocol-specified times.  
Please refer to the AFT-38 CSM for details on collection, processing and shipping procedures. 
The most current version of the PATINA (AFT-38) CSM can be found on the AFT BioMS web 
site which is accessible via the AFT portal (https://alliancefoundationtrials.org). 
Trastuzumab Pharmacokinetic (PK) Assessments 
Serum PK samples for trastuzumab determination will be collected prior to IV infusion (predose) 
on C4D1 as described in the Study Assessment Table. Patients must have received at least 3 
cycles of trastuzumab before PK assessments on C4D1 and the last trastuzumab dose prior to PK 
sampling administered as scheduled. 
In the event PK sample cannot be collected (or is not collected) on C4D1, every effort should be 
made to collect makeup samples on later trastuzumab administration days using the same 
criteria. The date of missing dose should also be recorded in the CRF. 
The actual times may change but the number of samples will remain the same. All efforts will be 
made to obtain the pharmacokinetic samples at the exact nominal time relative to dosing.  
During all study periods, blood samples (3 mL) to provide approximately 1 mL of serum for 
pharmacokinetic analysis will be collected into appropriately labeled tubes containing no 
additives at protocol-specified times.  
Please refer to the AFT-38 CSM for details on collection, processing and shipping procedures.  
The most current version of the PATINA (AFT-38) CSM can be found on the AFT.BioMS web 
site which is accessible via the AFT portal: (https://alliancefoundationtrials.org). 
 
 

 
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Pertuzumab Pharmacokinetic Assessments 
Serum PK samples for pertuzumab determination will be collected prior to IV infusion (predose) 
on C4D1 as described in the Study Assessment Table. Patients must have received at least 3 
cycles of pertuzumab before PK assessments on C4D1, and the last dose of pertuzumab prior to 
the PK sample collection administered as scheduled.  
In the event PK samples cannot be collected (or is not collected) on C4D1, every effort should be 
made to collect makeup samples on later pertuzumab administration days using the same criteria. 
The date of missing dose should also be recorded in the CRF.  
The actual times may change but the number of samples will remain the same. All efforts will be 
made to obtain the pharmacokinetic samples at the exact nominal time relative to dosing.  
During all study periods, blood samples (3 mL) to provide approximately 1 mL of serum for 
pharmacokinetic analysis will be collected into appropriately labeled tubes containing no 
additives at protocol-specified times. Samples will be kept in an ice bath prior to processing.  
Please refer to the AFT-38 CSM for details on collection, processing and shipping procedures. 
The most current version of the PATINA (AFT-38) CSM can be found on the AFT.BioMS web 
site which is accessible via the AFT portal: (https://alliancefoundationtrials.org). 
11.18 Treatment Adherence 
Drug Diaries will be maintained for all patients to capture adherence to palbociclib. Diaries will 
be completed by the patient and subsequently reviewed for accuracy with the patient at each 
visit. Patients will also be asked to bring in their pill containers at each visit, whether empty or 
still containing study medication. Pill counts of palbociclib will be performed and recorded at 
each study visit by research staff. 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 follow-up time point).   
 
Data from the Drug Diaries will be entered into the eCRF.  For each 28-day cycle, data regarding 
the number of days palbociclib was taken (start and stop dates per cycle along with any dose 
holds) will be entered into the eCRF. Adherence to study treatment will be determined by 
number of days taken / number of days drug should have been taken over various time points 
during the study. 
 
The frequency of assessments is provided in the Study Assessment Table (Section 12).  
 
 

 
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12. Study Assessment Table 
 
 
 
Treatment Phase (cycle = 28 days) 
 
 
 
 Preliminary 
Screening 
 a  
 
Screening/ 
Randomiz
ation a, b 
Cycle 1 
Cycle 2 
Cycles 3  
Cycle 4 + 
d 
Every 3 
Cycles (12 
wks) until 
disease 
progression 
End of Treatment 
bb 
Day 
 
 
D
1 
D
8 
D 
15 
D 
22 
c 
D
1 
D8 
D 
15  
D 
22 
D
1 
D8 
D 
15 
D 
22 
D1 
D
8 
D 
15 
D 
22 
 
D1 
Within 28 days after 
determination of 
disease progression 
and/or last dose 
(These assessments 
do not need to be 
repeated if collected 
within 12 weeks of 
determination of 
disease progression 
or end of treatment) 
(Window in 
days) 
Any time 
during 
induction 
 
-28 days 
 
+1
4 
 
 
± 2 
± 
2 
 
 
 
± 
2 
 
 
 
± 2 
 
 
 
 
± 2 
 
Informed 
Consent e 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclus
ion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications g 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
ECOG 
Performance 
Status h 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Complete 
physical exam i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited 
Physical Exam j 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital signs k 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 

 
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Treatment Phase (cycle = 28 days) 
 
 
 
 Preliminary 
Screening 
 a  
 
Screening/ 
Randomiz
ation a, b 
Cycle 1 
Cycle 2 
Cycles 3  
Cycle 4 + 
d 
Every 3 
Cycles (12 
wks) until 
disease 
progression 
End of Treatment 
bb 
Day 
 
 
D
1 
D
8 
D 
15 
D 
22 
c 
D
1 
D8 
D 
15  
D 
22 
D
1 
D8 
D 
15 
D 
22 
D1 
D
8 
D 
15 
D 
22 
 
D1 
Within 28 days after 
determination of 
disease progression 
and/or last dose 
(These assessments 
do not need to be 
repeated if collected 
within 12 weeks of 
determination of 
disease progression 
or end of treatment) 
(Window in 
days) 
Any time 
during 
induction 
 
-28 days 
 
+1
4 
 
 
± 2 
± 
2 
 
 
 
± 
2 
 
 
 
± 2 
 
 
 
 
± 2 
 
Adverse Events 
l 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
CBC and 
platelets m 
 
X 
X 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Blood chemistry 
n 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy test o 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
ECG p 
 
X 
 
 
 
MUGA or 
echocardiogram 
(ECHO) q 
 
 
 
X 
MUGA or ECHO (±7-day window) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Tumor 
assessments: CT 
and/or MRI of 
chest, abdomen, 
pelvis r 
 
 
 
 
X 
  
Tumor Assessments (±7-day window) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Tumor 
assessments: 
Bone or PET 
scan s 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Archival FFPE 
tumor tissue t 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Treatment Phase (cycle = 28 days) 
 
 
 
 Preliminary 
Screening 
 a  
 
Screening/ 
Randomiz
ation a, b 
Cycle 1 
Cycle 2 
Cycles 3  
Cycle 4 + 
d 
Every 3 
Cycles (12 
wks) until 
disease 
progression 
End of Treatment 
bb 
Day 
 
 
D
1 
D
8 
D 
15 
D 
22 
c 
D
1 
D8 
D 
15  
D 
22 
D
1 
D8 
D 
15 
D 
22 
D1 
D
8 
D 
15 
D 
22 
 
D1 
Within 28 days after 
determination of 
disease progression 
and/or last dose 
(These assessments 
do not need to be 
repeated if collected 
within 12 weeks of 
determination of 
disease progression 
or end of treatment) 
(Window in 
days) 
Any time 
during 
induction 
 
-28 days 
 
+1
4 
 
 
± 2 
± 
2 
 
 
 
± 
2 
 
 
 
± 2 
 
 
 
 
± 2 
 
Tissue from 
metastatic tumor 
biopsy u 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
One 10 mL 
lavender top 
(EDTA) tubes 
of blood v 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Two 10 mL 
Streck tubes of 
blood w  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
PK  
3 mL of blood 
for each PK 
assessment 
(palbociclib, 
trastuzumab, 
pertuzumab) x 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
PRO 
assessments y 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
IP (Palbociclib) 
Dispensing z 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 

 
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a. Preliminary Screening (pre-screening) Phase: Patients may be screened before or during induction treatment with anti-HER2 based therapy for 
the treatment of metastatic breast cancer prior to study randomization. If a patient is just starting induction, the time from signing the Pre-
Screening Consent to randomization could be up to 8 cycles or 168 days. If a patient has completed induction therapy, the time from their last 
infusion to C1D1 can be no longer than 12 weeks.  Following the pre-screening consent, an archival (primary breast or metastatic site) formalin-
fixed paraffin-embedded (FFPE) tumor tissue block or representative slides should be collected and submitted to the central biorepository. 
Optional research biopsy: representative tumor specimen from metastatic disease, is collected from consenting patients if clinically feasible.  
b. Randomization 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. All assessments should be complete and eligibility determined within 28 days 
of the patient signing the Main Consent Form. Results of screening tests performed as standard of care prior to obtaining informed consent and 
within 42 days prior to randomization may be used rather than repeating required tests. (This does not apply to the baseline tumor assessments 
which must be done within 28 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 and do not need to be repeated. Once all eligibility assessments are done and the patient is found to meet all 
eligibility criteria, the patient can be randomized in the IRT system.  The C1D1 visit should occur within 14 days of IRT randomization and must 
align with the patient’s anti-HER2 infusion schedule.  The visit at which disease progression is recorded can be used as the study drug 
discontinuation visit as long as tests required at the End of Treatment are performed. 
c. Patients in the palbociclib study arm only will have safety laboratory testing (i.e. CBC with differential and platelets) performed on Day 22 (± 2) 
of Cycle 1. Results can be checked by telephone contact only. Laboratory testing must be performed at the research center and telephone calls 
should occur after the laboratory testing is completed.  
 
 
 
Treatment Phase (cycle = 28 days) 
 
 
 
 Preliminary 
Screening 
 a  
 
Screening/ 
Randomiz
ation a, b 
Cycle 1 
Cycle 2 
Cycles 3  
Cycle 4 + 
d 
Every 3 
Cycles (12 
wks) until 
disease 
progression 
End of Treatment 
bb 
Day 
 
 
D
1 
D
8 
D 
15 
D 
22 
c 
D
1 
D8 
D 
15  
D 
22 
D
1 
D8 
D 
15 
D 
22 
D1 
D
8 
D 
15 
D 
22 
 
D1 
Within 28 days after 
determination of 
disease progression 
and/or last dose 
(These assessments 
do not need to be 
repeated if collected 
within 12 weeks of 
determination of 
disease progression 
or end of treatment) 
(Window in 
days) 
Any time 
during 
induction 
 
-28 days 
 
+1
4 
 
 
± 2 
± 
2 
 
 
 
± 
2 
 
 
 
± 2 
 
 
 
 
± 2 
 
Trastuzumab 
and/or 
Pertuzumab aa 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 

 
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d. Trastuzumab and/or Pertuzumab infusion will follow the three-week interval which does not necessarily match to Day 8 in a given treatment 
cycle.  
e. A Preliminary Screening Informed Consent Form will be provided to patients first to determine if they are willing to provide the mandatory 
archival tissue sample, an optional tissue sample from recent biopsy of metastatic disease, and optional participation in the Mastering Breast 
Cancer Initiative. It must be obtained before any of the above can occur. The Main Informed Consent Form must be obtained prior to any 
protocol required randomization screening assessments. which are 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, 
stratification factors, and self-reported race/ethnicity. 
g. Any concomitant medications and treatments will be recorded from 28 days prior to randomization and until 42 days following confirmation of 
disease progression.  
h. The ECOG Performance Status should be assessed prior to randomization and on Day 1 of Cycles 1-4 and every 12 weeks until disease 
progression.  
i. 
Complete physical examination should include the evaluation of head, eye, nose, and throat, and cardiovascular, respiratory, gastrointestinal, and 
neurological systems and measurement of weight and height. 
j. 
Limited physical examination should include a limited, symptom-directed examination or as clinically indicated. Limited physical examination 
will be performed on Day 1 of Cycles 1 to 4 and every 12 weeks thereafter, with additional examinations as clinically indicated. 
k. Vital signs include measurements of respiratory rate, pulse, and systolic and diastolic pressure. Vital signs will be checked Day 1 of Cycles 1 to 4 
and every 12 weeks thereafter, with additional examinations as clinically indicated. 
l. 
For all enrolled patients, AEs must be reported from the date of first treatment (C1D1) until 42 days following confirmation of disease 
progression.  SAEs need to be reported for 6 months following confirmation of disease progression. AEs that occur during the Screening Phase 
that are deemed to be related to any study specific procedure should be reported on the AE form in the clinical database. SAEs, including those 
fulfilling the criteria for expedited reporting must be reported within 24 hours of site awareness.  
m. CBC includes hemoglobin, white blood cell count (WBC) with differential, absolute neutrophils, platelet count. CBC will be performed on Day 1 
of Cycles 1 – 4 and every 12 weeks until disease progression, with additional examinations as clinically indicated. In addition, subjects in Arm A 
(palbociclib arm) will have these labs performed on Day 22 of Cycle 1 for safety testing. 
n. Blood chemistry includes AST (SGOT)/ALT (SGPT), alkaline phosphatase, sodium, potassium, total calcium, total bilirubin, serum creatinine, 
total protein and albumin. Chemistry will be performed Day 1 of Cycle 1 to 4 and every 12 weeks thereafter, with additional examinations as 
clinically indicated. Additional chemistry panels may be performed as clinically indicated. 
o. For women of childbearing potential, including premenopausal women who have had a tubal ligation, and premenopausal women who have 
chemotherapy-induced amenorrhea (i.e. amenorrhea induced by chemotherapy during the Induction Treatment Phase prior to study 
randomization). Screening assessment must be performed on serum or urine within 7 days prior to randomization. Afterward, perform every 12 
weeks (±2days) on urine or serum until disease progression. A positive urine test must be confirmed with a serum test.  
p. ECG (electrocardiogram). Single standard 12-lead digital ECGs will be performed at baseline as part of the screening assessments. 
q. LVEF assessment by ECHO is preferred. The same method should be used throughout the study for each patient and preferably performed and 
assessed by the same assessor. ECHO/MUGA should be done at baseline and repeated on Day 1 of Cycle 4 (±7 days) and every 12 weeks 
thereafter, with additional examinations as clinically indicated. ECHO/MUGA should also be performed at Treatment Discontinuation if not 
done within the previous 12 weeks.  

 
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r. 
Perform tumor assessment at screening (≤ 28 days prior to randomization), every 12 weeks (± 7 days) from C1D1 (to align with visit schedule 
until disease progression with additional scans when clinically indicated. If a tumor assessment must be performed early or late, subsequent 
assessments should be conducted according to the original schedule. Radiologic tumor assessment must include CT and/or MRI of the chest, 
abdomen and pelvis. Additional imaging should be performed if clinically indicated. The same imaging modality used at screening must be used 
throughout the study. Patients who are discontinued from study treatment for reasons other than disease progression will be asked to continue to 
have tumor assessments every 12 weeks (± 7 days) until disease progression or initiation of other anti-cancer therapies.  
s. An isotope bone scan (e.g., technetium) or PET scan will be performed at screening and should be repeated in the event of clinical suspicion of 
progression of existing bone lesions and/or the development of new bone lesions or for confirmation of complete response for all patients. For 
patients with bone-only disease not visible on the CT or MRI scans being performed as part of the tumor assessments, bone scans or PET scan 
should be repeated every 12 weeks (± 7 days) from C1D1 (to align with visit schedule) until disease progression. 
t. 
Archival (primary breast or metastatic site) tumor tissue blocks or a minimum of 15 freshly cut unstained slides from the most recent tumor 
tissue will be collected at screening for molecular characterization of the tumor tissue.  
u. Tissue from metastatic disease (optional): Tissue from recurrent / metastatic tumor biopsy collected at any time prior to screening for the purpose 
of molecular characterization (i.e. multigene panel).   Tissue from tumor biopsy collected at the time of disease progression is strongly 
recommended and will be collected for patients who consent to provide this optional tissue. 
v. Blood will be collected and banked in order to extract germline DNA to be used as normal DNA reference for tumor tissue-based studies. This 
will be collected on Day 1 of Cycle 1 and Day 1 of Cycle 4. 
w. Blood will be collected to assess circulating tumor DNA (ctDNA) on Day 1 of Cycle 1 and Day 1 of Cycle 4 and at end of treatment (+28 days). 
x. PK assessments for participants enrolled in the US only (Arm A only): A sample of 3 mL of blood for palbociclib PK determination will be 
collected on Day 22 of Cycle 1. Patients must have received at least 7 consecutive days of palbociclib before palbociclib PK sample collection 
and the last trastuzumab dose prior to the PK sampling administered as scheduled. A sample of 3 mL of blood for trastuzumab PK determination 
will be collected on Day 1 of Cycle 4 prior to IV infusion. Patients must have received at least 3 cycles of trastuzumab before trastuzumab PK 
sample collection on C4D1, and the last dose of trastuzumab prior to the PK sample collection administered as scheduled. A sample of 3 mL of 
blood for pertuzumab PK determination will be collected on Day 1 of Cycle 4 prior to IV infusion. Patients must have received at least 3 cycles 
of pertuzumab before pertuzumab PK sample collection on C4D1, and the last dose of pertuzumab prior to the PK sample collection 
administered as scheduled. 
y. Patient reported outcome (PRO) assessments (FACT-Breast and EQ-5D) will be completed by patients on Day 1 of Cycle 1 and Cycle 4 and then 
every 12 weeks until disease progression or end of study treatment. Final PROs at disease progression only need to be completed if not done 
within the previous 12 weeks.   
z. Patients will receive amount of IP in order to ensure sufficient supply until the next scheduled onsite visit (3 weeks of IP dispensed on Day 1 of 
Cycles 1, 2, and 3; 12 weeks of IP on Day 1 of Cycle 4 and every 12 weeks thereafter until end of treatment or disease progression). The visit 
window for all visits and hence IP dispensing is ± 2 days from each visit.  However, it is important for all Arm A patients to follow the 28-day 
cycle (21 days on IP, 7-day break) as outlined. If the visit is scheduled 2 days early (-2 days), the patient should be instructed to wait until the 7-
day break is completed before beginning their next 21-day cycle of IP.  Subsequent visits should be scheduled 28 days from the date the current 
cycle will have ended.  If the visit is scheduled 2 days late and the drug holiday is thus 9 days, the next visit should be scheduled 28 days from 
the actual visit date.  Any deviations from the protocol defined IP schedule need to be reported as protocol deviations.  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 

 
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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. 
aa. Trastuzumab and/or Pertuzumab will be administered every three weeks until end of treatment or disease progression. 
bb. An additional End of Treatment visit is required only if the last study visit occurred more than 12 weeks from the determination of disease 
progression.  In many cases, the assessments performed at the study visit during which disease progression was determined can be used as the 
End of Treatment assessments.  Patients who discontinue treatment for reasons other than disease progression will go into Clinical Follow-up and 
continue visits every 12 weeks.  The only exception is the final ctDNA sample which needs to be collected within 28 days after end of treatment. 
 
 

 
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Follow-up 
 
Clinical Follow-up 
(For patients who discontinue treatment for 
reasons other than disease progression) 
Survival Follow-up 
Day 
Every 12 weeks until disease progression or 
end of study 
Every 6 months until the end of the study 
(Window in days) 
± 2 daysc, d 
± 14 days 
Adverse Events a 
X 
X 
Serious Adverse Events b 
X 
X 
Tumor assessment c 
X 
 
Bone-scan or PET scan d 
X 
 
Tissue from metastatic tumor research biopsy e 
 
X 
Treatment beyond disease progression f 
 
X 
Survival follow-up assessment g 
 
X 

 
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a. AEs must be reported throughout the Clinical Follow-up period and Survival Follow-up period until 42 days following confirmation of 
disease progression.  
b. SAEs must be reported for 6 months after last treatment with palbociclib (Arm A patients) and for 7 months after last treatment with 
trastuzumab (Arm A and Arm B patients). SAEs deemed related to IP treatment must be reported throughout both Follow-up Phases as 
well. 
c. If a tumor assessment must be performed early or late, subsequent assessments should be conducted according to the original schedule. 
Radiologic tumor assessment must include CT and/or MRI of the chest, abdomen and pelvis. Additional imaging should be performed if 
clinically indicated. The same imaging modality used at screening must be used throughout the study. Patients who are discontinued from 
study treatment for reasons other than disease progression will be asked to continue to have tumor assessments every 12 weeks (±7 days) 
until disease progression or initiation of other anti-cancer therapies.  
d. An isotope bone scan (e.g., technetium) or PET scan will be performed in the event of clinical suspicion of progression of existing bone 
lesions and/or the development of new bone lesions or for confirmation of complete response for all patients. For patients with bone-only 
disease not visible on the CT or MRI scans being performed as part of the tumor assessments, bone scans or PET scan should be repeated 
every 12 weeks (±7 days) from C1D1 (to align with study visits until disease progression.  All scans should be uploaded to the Alliance 
Central Imaging Core Lab (ICL) at the Wright Center of Innovation in Biomedical Imaging at the Ohio State University according to the 
instructions provided in the ICL Manual. 
e. Tumor biopsy or tissue collection of recently biopsied site at the time of disease progression is strongly recommended and will be collected 
for patients who sign the Optional Research Informed Consent Form. 
f. 
Collection of treatment information beyond disease progression with a focus on anti-cancer agents for all patients who discontinue from the 
treatment phase unless the patient requests to be withdrawn from study survival follow-up . 
g. All patients who discontinue from the treatment phase will be followed for survival unless the patient requests to be withdrawn from study 
survival follow-up. For patients who discontinue study treatment due to objective disease progression, survival data (i.e., patient status along 
with start, stop and type of new anticancer therapy) will be collected every 6 months (r14 days), calculated from the last dose of study 
treatment until the end of the study.  Telephone contact is acceptable. 
 

 
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13. 
Adverse Events 
Palbociclib is currently approved in the US 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 are 
designed to ensure patient safety and will include specific eligibility criteria, safety reporting 
obligations and monitoring assessments as detailed below. 
13.1 
Adverse Events – General Overview 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution. An AE can therefore be any of the following: 
a. Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product or 
protocol-specified procedure whether or not considered related to the use of the 
medicinal product or protocol-specified procedure. 
b. Any worsening (i.e. any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of an 
investigational/medicinal product  
 
For each AE recorded on an AE eCRF page, the investigator will make an assessment of 
seriousness, severity, and causality as described below). 
13.1.1 
Adverse Events – Palbociclib 
The list of palbociclib associated AEs are summarized below. A detailed description of 
palbociclib associated AEs should be obtained from the palbociclib Investigator’s Brochure. 
Additional reference to safety information can be found in Section 1.2.7 of this document. 
 
Likely (greater than or equal to 50% chance that this will happen): 
x Neutropenia. A condition in which the number of white bloods cells called neutrophils is 
abnormally low. This increases the risk of infection, which may be serious or life 
threatening. You will be monitored closely for this risk.  
 
Frequent (between a 10 to 50% chance that this will happen):  
x Fatigue. Participants experiencing fatigue while taking palbociclib should exercise 
caution when driving or operating machinery.  
x Weakness 
x Low number of red blood cells that can causes tiredness and shortness of breath. May 
require a blood transfusion. (Anemia) 
x Diarrhea 
x Nausea 
x Low number of platelets, which may cause bleeding and bruising. Bleeding may be 
serious or life threatening and may require a blood transfusion. 
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x Constipation  
x Mouth blisters/sores 
x Infection of the sinus or lung 
x Vomiting 
x Loss of touch or sensation of pins and needles or numbness on the skin 
 
Occasional (Between a 1 to 10% chance that this will happen): 
x Rash 
x Bloating 
x Temporary hair loss  
x Swelling in extremities (hands and feet) 
x Headache 
x Nosebleed 
x Muscle spasm 
x Inflammation of the mucous membranes 
x Fever 
x Dry mouth  
x Fever with dangerously low white blood cell count 
x Abnormal taste 
 
Rare (Less than a 1 % chance that this will happen): 
x Abnormal electrical conduction within the heart which may lead to arrhythmias or 
irregular heartbeat 
x A blood clot that causes a sudden blockage in a lung blood vessel, usually due to a blood 
clot that traveled to the lung from the leg. A pulmonary embolism is a serious condition 
that can cause: permanent damage to part of your lung from lack of blood flow to lung 
tissue; low oxygen levels in your blood; damage to other organs in your body from not 
getting enough oxygen. If a clot is large, or if there are many clots, a pulmonary 
embolism can cause death.  
13.1.2 
Adverse Events – Endocrine Therapies 
The most common AEs experienced with use of AIs include hot flashes, arthralgia, and gradual 
loss of bone density. The most common AEs experienced with use of fulvestrant are injection-
site pain, nausea and bone pain.  
 
A detailed description of AEs of the 3 AIs (letrozole, anastrozole, exemestane), LHRH Agonist 
and fulvestrant should be obtained from the particular package inserts (SmPCs) of the locally 
obtained commercial supplies. 
 
 

 
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13.1.3 
Adverse Events – Anti-HER2 Therapies 
The most common adverse reactions in patients receiving trastuzumab in the adjuvant and 
metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, 
infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. 
Adverse reactions requiring interruption or discontinuation of trastuzumab treatment include 
congestive heart failure, significant decline in left ventricular cardiac function, severe infusion 
reactions, and pulmonary toxicity. 
The most common adverse reactions (! 30%) seen with pertuzumab in combination with 
trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and 
peripheral neuropathy.  
A detailed description of trastuzumab and pertuzumab should be obtained from the particular 
package inserts (SmPCs) of the locally obtained commercial supplies. 
13.2 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v 4.0) will be used for assessing 
AE severity. Table 8 will be used for assessing severity for AEs 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.  
 
Table 7: Adverse Event Severity Grading Scale 
 
Grade 
Severity 
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 Assessment of Severity of 
Adverse Events 
5 
Death related to adverse event d 

 
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NCI CTCAE National Cancer Institute Common Terminology Criteria for AEs. 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 SAE (see Section 13.8.1 
for reporting instructions), per the definition of SAE in Section 13.5. 
d Grade 4 (only if immediately life threatening) and Grade 5 events must be reported as SAEs (see Section 
13.8.1 for reporting instructions), per the definition of SAE in Section 13.5. 
 
13.3 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding the 
AE, and an evaluation of any potential alternative causes to determine whether or not an 
AE is considered to be related to the IP or Non-IP, indicating "yes" or "no" accordingly. The 
following guidance should be taken into consideration: 
x 
Temporal relationship of event onset to the initiation of study drug 
x 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
x 
Known association of the event with the study drug or with similar treatments 
x 
Known association of the event with the disease under study 
x 
Presence of risk factors in the patient or use of concomitant medications known 
to increase the occurrence of the event 
x 
Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event 
 
Table 8: Adverse Events - Causal Attribution Guidance 
 
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). 
 
 

 
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For patients receiving combination therapy, causality will be assessed individually for each of 
palbociclib, anti-HER2 and endocrine therapies. Investigator is responsible for reporting side 
effects of commercially available drugs to regulatory agency. 
13.4 
Adverse Event Reporting Period 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the study as well as those who will enroll in future 
studies using similar agents. During Screening, baseline AEs will be considered part of a 
patient’s underlying medical condition. If during Screening an AE occurs due to a required 
screening procedure (a blood draw, fresh tumor biopsy, or other protocol specified procedure or 
intervention), it should be reported on the AE form according to guidelines for standard AE 
reporting. 
Any new AEs or worsening of a documented preexisting condition from screening/history will 
be recorded as an AE from the time of the first treatment (Cycle 1, Day 1) through 42 days 
following confirmation of disease progression and cessation of treatment.  
All non-serious AEs are entered into the eCRF in RAVE EDC system within 7 days of the 
investigator’s awareness of the event. 
13.5 
Serious Adverse Events (SAEs) 
A SAE is any AE that at any dose: 
x Results in death 
x Is life threatening 
x Requires inpatient hospitalization or prolongation of existing hospitalization for ≥24 
hours 
x Results in persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
x Results in a congenital anomaly/birth defect 
x Is an Important Medical Event (ME) that may not result in death, be life threatening, 
or require hospitalization but, based upon the investigator’s judgement, may 
jeopardize the patient or may require medical/surgical intervention to prevent one of 
the outcomes listed above. 
 
SAEs have to be reported on the AE form and on the study specific SAE reporting form 
in the RAVE EDC system within 24 hours of the site investigator’s knowledge of this 
event. 
 
In line with the AE reporting guidelines, during Screening only SAEs deemed related to a 
specific protocol screening procedure need to be reported.  Once patients are randomized, 
the SAE reporting period starts at the time of the first treatment (Cycle 1, Day 1) through 6 
months after last treatment with palbociclib (Arm A patients) and 7 months after last 
treatment with trastuzumab (Arm A and B patients). SAEs deemed to be related to IP 
treatment must be reported throughout both Follow-up Phases as well. 

 
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13.6 
Adverse Events of Special Interest 
 
         Abnormal Liver Function Tests (LFTs) reported as Hy’s Law 
Investigators must report as a SAE the occurrence of either of the following: 
 
x 
Treatment-emergent ALT or AST (>3x ULN) in combination with total bilirubin 
(>2 x ULN) 
x 
Treatment-emergent ALT or AST (>3x ULN) in combination with clinical 
jaundice 
 
The finding of an elevated ALT or AST (>3x ULN) in combination with either an 
elevated total bilirubin (>2x 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 AE eCRF and reported to the AFT Safety 
Group immediately (no more than 24 hours after learning of the event) using the study 
specific SAE reporting way. 
13.7 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
x An adverse reaction that is both unexpected (not consistent with the applicable product 
information) and also meets the definition of a SAE/Reaction 
x Qualifies for expedited IND safety reporting to the FDA, Competent Authorities and 
other regulatory bodies by meeting all three definitions of suspected adverse reaction, 
serious, and unexpected. 
x Expected adverse reactions and related serious adverse reactions to palbociclib are listed 
in the Investigator Brochure (IB).  The AFT Safety group will evaluate all SAEs 
reported in the RAVE database for expectedness against the most recent Investigator 
Brochure (IB) and will determine if a reported SAE meets the criteria of a SUSAR. 
13.8 
Expedited Reporting Procedures 
13.8.1 
Serious Adverse Event Reporting Timelines 
All AEs need to be reported in the RAVE EDC system within 7 days of the investigator’s 
knowledge of the event.  
 
Certain events require immediate reporting. The following is a list of events that the 
investigator must report to the AFT Safety Group on the study specific SAE form within 
24 hours after learning of the event, regardless of the relationship to study drug: 
 
x 
Serious Adverse Events (SAEs), including: 
x 
Abnormal LFTs reported as Hy’s Law 
x 
SUSARs 
x 
Pregnancies 
x 
Lactation Exposure 

 
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The investigator must also report new significant follow-up information for these events 
on the study specific SAE form to the AFT Safety Group immediately (no more than 
24 hours after becoming aware of the information). 
 
New significant information includes the following: 
x 
New signs or symptoms or a change in the diagnosis 
x 
Significant new diagnostic test results 
x 
Change in causality based on new information 
x 
Change in the event’s outcome, including recovery 
x 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with requirements for reporting SAEs to the local 
IRBs/ECs and/or any other parties as locally required and if applicable. 
13.8.2 
Expedited Reporting to Regulatory Authorities 
The Safety Management group at AFT will complete and submit expedited regulatory safety 
reports (SUSARs) on the required MedWatch or CIOMS templates to the relevant 
regulatory/competent authorities within the required reporting timelines. In general, AFT is 
required to report all non-fatal or non-life threatening SUSARs to the FDA and regulatory 
authorities outside the US within 15 calendar days of investigator awareness of the event and 
all fatal or life-threatening SUSARs within 7 calendar days of investigator awareness.  
 
A comprehensive safety reporting process for this study is documented in the study Safety 
Management Plan. 
13.8.3 
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. 
 
The following hospitalization scenarios are not considered to be AEs: 
x Hospitalization for respite care 
x 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 AE 
x Hospitalization due solely to progression or recurrence of the underlying cancer 
x Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care 
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14. 
Data Collection and Management/ Data and Specimen Submission 
14.1 
Data Collection and Submission 
Data collection for this study will be done through the electronic Medidata RAVE clinical data 
management system. Access to the trial in RAVE is granted through the iMedidata application to 
all persons fulfilling Medidata RAVE training requirements and with the appropriate roles 
assigned in AFT’s Clinical Trial Management System (CTMS). Specific instructions are 
provided in the study Data Entry Guidelines. 
 
14.2 
Specimen Collection and Submission 
The following biospecimens will be collected during the study: 
At Screening: 
x Representative formalin-fixed paraffin-embedded (FFPE) archival (primary breast 
or metastatic site) tumor tissue block (preferred) or at least 15 unstained slides from 
such a block, along with a pathology report documenting HER2 positivity and 
hormone receptor positivity  
x Representative tumor specimen obtained from recently biopsied metastatic 
disease, if clinically feasible (optional)  
During Study: 
x Germ Line DNA (whole blood for isolation of white cell (constitutional) DNA): 
Day 1, Cycle 1 and Day 1, Cycle 4 
x Circulating tumor DNA (ctDNA): Day 1, Cycle 1; Day 1, Cycle 4, and end of 
treatment 
x Tumor specimen at disease progression, if patient consents 
 
For US sites, all biospecimen collection kits should be requested through the AFT.BioMS 
system which is accessible via the AFT portal (https://alliancefoundationtrials.org).  
Additional details for biospecimen collection, processing, and shipping can be found in 
the AFT-38 (PATINA) Correlative Science manual (CSM), which is also available on the 
AFT.BioMS web site via the AFT portal (https://alliancefoundationtrials.org).  
15. 
Measurement of Effect 
15.1 
Imaging Assessment Collection Plan  
Refer to section 11.11.1 about the collection of imaging assessments and submission to 
the Wright Center of Innovation in Biomedical Imaging at the Ohio State University (the 
Alliance central Imaging Core Lab). 
 
Post-baseline tumor assessments will be performed every 12 weeks (± 7 days) after the 
C1D1 visit (to align with study visits until disease progression with additional scans 
when clinically indicated.  
 
For patients having effusions or ascites, cases having cytological proof of malignancy 
should be recorded as non-target lesions on the tumor assessment CRFs. Effusions that 

 
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have not been evaluated using cytology or were found to be non-malignant should not be 
recorded on the non-target lesion CRF. 
 
Objective tumor response will be assessed using the Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1).  
 
Interpretation will be Progressive Disease if: 
 
x The malignant nature of one or more new lesions identified with bone scan is 
confirmed with X-ray, CT, or MRI scan. 
x Flare observed in bone scan is followed by confirmation of progression with other 
imaging modalities. 
x Clinical worsening of the disease is assessed by bone scan and disease 
progression (i.e. new lesion(s) is confirmed with other imaging modalities). 
x Unequivocal progression of existing bone lesions is observed.  
 
Interpretation will be SD if: 
 
x The malignant nature of all the new lesions identified with bone scan is not 
confirmed with X-ray, CT, or MRI scan. 
 
In the following cases, tumor assessment will be performed until documented PD, but it will 
be at the discretion of the investigator to discontinue the study treatment: 
 
1) on-study fracture.  
2) on-study management of pain (palliative radiation therapy, palliative surgery). 
3) clinical worsening not objectively confirmed with X-ray, CT, or MRI scan.  
 
It is suggested to institute palliative radiotherapy (e.g., lesions at risk for spontaneous micro-
fractures or painful lesions) before study initiation as well as palliative surgery if possible 
and clinically appropriate. 
16. 
Response Criteria in Solid Tumors (RECIST) 1.1 
16.1 
Definitions 
Evaluable for Target Disease response: Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response. These 
participants will have their response classified according to the definitions stated below. 
(Note: Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 

 
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considered evaluable for non-target disease. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
16.2 
Disease Parameters 
Measurable Disease  
Measurable disease  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 mm with 
CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
Non-measurable disease  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all considered non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
Target lesions  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to 

 
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further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions  
All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in 
rare cases unequivocal progression of each should be noted throughout follow up.  
16.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 

 
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FDG-PET  
While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
(b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
(c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
PET-CT 
 At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time. 
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.  
MIBG (meta-iodobenzylguanidine) 
The following is recommended, to assure high quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  

 
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I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred.  
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
Ultrasound  
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later data and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment 
to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure from 
CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy  
The utilization of these techniques for objective tumor evaluation is not advised. 
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  
Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a participant to be considered in complete 
clinical response  
 
Cytology, Histology  
These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). The cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
16.4 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
16.5 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase.  
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances.  
Evaluation of New Lesions 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
 

 
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16.6 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*     See RECIST 1.1 manuscript for further details on what is evidence of a   
       new lesion. 
*** In exceptional circumstances, unequivocal progression in non-target   
       lesions may be accepted as disease progression. 
 
Note: Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 
 

 
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For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
17. 
Statistical Considerations and Analysis Plan 
17.1 
Overview of Study Design 
This is a randomized, open-label, multicenter, Phase III trial to assess the safety and efficacy of 
palbociclib plus anti-HER2 therapy and endocrine therapy vs. anti-HER2 therapy plus endocrine 
therapy for hormone receptor positive / HER2+ metastatic breast cancer who are stable or 
responding after induction therapy. 
 
This study will use a permuted block randomization to allocate an equal number of patients to 
each of the treatment arms. This procedure will balance the marginal distributions of the 
stratification factors between the treatment arms. The stratification factors that will be used are: 
pertuzumab use (yes vs. no), prior anti-HER2 therapy in the neo (adjuvant) setting (yes vs. no), 
best response to induction therapy (CR or PR vs. SD) by investigator assessment and type of 
endocrine therapy (fulvestrant vs. AI).  
 
We will use an intention to treat (ITT) principle to define the population used for the analysis of 
the primary endpoint and secondary efficacy endpoints. The ITT Population will be comprised of 
all randomized patients, including those who do not start palbociclib, anti-HER2 therapy 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 to a treatment arm. 
17.2 
Sample Size, Accrual Time and Study Duration 
The sample size for this study is determined based on the results of a randomized Phase III trial 
CLEOPATRA [3] assessing trastuzumab and docetaxel with or without pertuzumab in HER2+ 
metastatic breast cancer in the first-line setting. The median PFS for the pertuzumab-containing 

 
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arm of the study was 18.5 months. Based upon these results and considering that the current 
clinical trial will enroll patients previously treated with approximately six to eight cycles of 
induction therapy (i.e. approximately 6 months), the median control arm in this study is assumed 
to be 13 months. Therefore, a risk reduction by 33% (a hazard ratio of 0.667) or an improvement 
by 50% to median PFS of 19.5 months with palbociclib plus anti-HER2 plus endocrine therapies 
is clinically significant. With one interim futility analysis planned at 50% (~135) of total PFS 
events and one interim efficacy analysis planned at 65% (~175) of total PFS events, a total of 
269 events are required in the two arms of the study based on a 1:1 randomization to have 90% 
power to detect a hazard ratio of 0.667 in favor of palbociclib plus anti-HER2 plus endocrine 
therapies using a 1-sided, log-rank test at a significance level of 0.025. Assuming a 15% drop-out 
rate on either treatment arm, a non-uniform accrual [0-6 months: 10 patients per month; 6-10 
months: 20 patients per month; ≥10 months: 25 patients per month] accomplished over a 24-
month period and follow-up for about 12 months after the last patient is enrolled, a total sample 
size of 496 participants is required. No crossover to experimental therapy is permitted in the 
control group within the current study design.  
 
The sample size described above will also allow the assessment of differences in the secondary 
endpoint of OS. The OS outcome for the pertuzumab contacting arm in the Phase 3 clinical trial 
(CLEOPATRA) of a similar patient population was approximately 56 months. Using similar 
argument as before where only 4.66% of the patients in the pertuzumab arm reported PD, 
allowing for ~6 months for induction treatment in the proposed trial, we assume that the median 
OS for the control arm in the proposed trial would be 50 months (~ 6 months less than what was 
reported in CLEOPATRA). Using this value as an assumption with a hypothesized 30% 
reduction risk (a hazard ratio of 0.70), ~10% improvement in 3 years OS probability (from 
60.71% to 70.515%), or 43% improvement in median OS (from 50 months to 71.429 months) in 
patients randomized to receive palbociclib plus anti-HER2 plus endocrine therapies, a total of 
247 events using a 1-sided, log-rank test is required for a significance level of 0.025 and power 
of 80% to detect the difference.  
 
17.3 
Statement for Primary Endpoint 
The primary endpoint is PFS which is defined as the time from the date of randomization to the 
date of the first documentation of objective progression of disease (PD), as defined by RECIST 
1.1 criteria, or death due to any cause in the absence of documented PD, whichever occurs first. 
PFS data will be censored on the date of the last tumor assessment on study for patients who do 
not have objective tumor progression and who do not die while on study. Patients lacking an 
evaluation of tumor response after randomization will have their PFS time censored on the date 
of randomization with the duration of one day. Additionally, patients who start a new anti-cancer 
therapy prior to documented PD will be censored at the date of the last tumor assessment prior to 
the start of the new therapy. Patients with documentation of PD after an unacceptably long 
interval (i.e., 2 or more incomplete or non-evaluable assessments) since the last tumor 
assessment will be censored at the time of last objective assessment that did not show PD for the 
primary analysis.  Patients who report symptomatic deterioration as the only cause of PD will be 
censored at the date of their last tumor assessment. A sensitivity analysis for PFS will be 
conducted counting as events those patients who report only symptomatic deterioration as PD 
and patients with documentation of PD after an unacceptably long interval. 

 
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17.4 
Interim Efficacy/Futility Analysis Plan 
The study is designed to have one interim futility analysis, one interim efficacy analysis, and the 
final analysis based on the primary PFS endpoint with the investigator assessment. The Lan-
DeMets/O’Brien-Fleming boundary (O’Brien et al 1979) will be used for the futility analysis. 
The Haybittle-Peto efficacy boundary (Haybittle 1971; Peto et al. 1976) for rejecting the null 
hypothesis will be used at the time of the interim efficacy analysis. To protect the integrity of the 
study and to preserve the type-1 error rate, a fraction of alpha (0.0002) for efficacy will be spent 
at the interim analysis and accounted for in the overall type I error rate. The overall significance 
level for the efficacy analysis of PFS will be preserved at 0.025 (1-sided test). The choice of a 
strict boundary (p≤0.0002) at the efficacy interim analysis was selected to provide a significant 
and meaningful improvement in favor of palbociclib of approximately 9 months at this point 
based on the assumptions. With one interim futility analysis planned at 50% (~135) of total PFS 
events and one interim efficacy analysis planned at 65% (~175) of total PFS events, a total of 
269 events are required in the two arms of the study based on a 1:1 randomization to have 90% 
power to detect a hazard ratio of 0.667 in favor of palbociclib plus anti-HER2 plus endocrine 
therapies using a 1-sided, log-rank test at a significance level of 0.025.  
17.5 
Analysis Plan for Primary Efficacy Endpoint 
A log-rank test (one-sided) will be used to compare PFS time between the 2 treatment arms at 
the interim and/or final analyses with the overall significance level preserved at 0.025 (one-
sided). PFS time associated with each treatment arm will be summarized using the Kaplan-Meier 
method and displayed graphically where appropriate. Median PFS time will be reported. 
Confidence intervals (CIs) for the PFS rate at 6 months, 1 year and 2 years will be generated. 
The Cox Proportional hazards model will be fit to compute the treatment hazard ratio and the 
corresponding 95% CI. A secondary stratified log-rank test accounting for the stratification 
factors will be performed and treatment hazard ratios and 95% CIs adjusted for the stratification 
factors will also be reported. 
This study will be designed as such that only at most 20% of patients enrolled will not have 
received pertuzumab. We assume that the median PFS will be the same as stated above in the 
pertuzumab treated subgroup (13 months for the non-palbociclib treatment arm and 19.5 months 
for the palbociclib treatment arm). PFS outcomes will be explored within the pertuzumab 
receiving cohort as part of the exploratory analysis outlined in Section 17.6.8. 
17.6 
Secondary Clinical Endpoints 
17.6.1 
Blinded Independent Central Review (BICR) of Progression-free 
Survival 
All patients who will be randomized in the study will be assessed by investigators for PFS. 
However, a third-party imaging core laboratory (Wright Center of Innovation in Biomedical 
Imaging at the University of Cincinnati) will perform BICR independent of investigator 
assessment on all patients. The independent third-party imaging core lab will assess clinical 
response and progression (determination of progression by RECIST 1.1 criteria) based on the 
review of scans for the study population. A sensitivity analysis for PFS using the BICR 

 
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assessments for PFS will be conducted to aid (or meet) Health Authorities requirements and 
regulatory submissions.  
  
17.6.2 
Adverse Events 
Per CTEP Version 4.0 of the NCI CTCAE, an AE is any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medical treatment or procedure that may or may not be considered related to the medical 
treatment or procedure. All grade 2, 3, 4 or 5 AEs will be documented and assigned an attribute 
by treating clinician as to its relationship to treatment. For a given AE, the proportion of patients 
on each treatment arm who report developing a grade 2-5 of this AE will be determined. 
17.6.3 
Overall Survival 
Overall survival (OS) is defined as the time from date of randomization to date of death due to 
any cause. In the absence of confirmation of death, survival time will be censored to last date the 
patient is known to be alive. 
 
All patients randomized will be considered evaluable for OS. OS will be hierarchically tested for 
significance at the time of PFS analysis, provided the primary PFS endpoint is statistically 
significant at the second interim and/or final analyses. If OS does not yield a significant result at 
the time of the second PFS interim analysis or at the time of the final PFS analysis, OS will be 
tested at the final OS analysis time point. The reporting of OS data will follow this procedure: 
OS data will not be reported until the final OS analysis unless the null hypothesis is rejected for 
OS at the interim testing. A log-rank test will be used to compare OS between the treatment 
arms. Overall type I error rate will be maintained at α=0.025 (1-sided) for the analyses of PFS 
and OS in this setting. 
 
OS for the two treatment arms will be assessed using Kaplan-Meier methods and displayed 
graphically where appropriate. The median event times and 95% CIs will be reported. Cox 
regression models will be used to estimate the treatment hazard ratio and its 95% CI. 
The 1-year, 2-year and 3-year survival probabilities and the corresponding 95% CIs will be 
estimated using the Kaplan-Meier method. 
 
A secondary stratified log-rank test accounting for the stratification factors will be performed 
and treatment hazard ratios and 95% CIs adjusted for the stratification factors will also be 
reported. 
17.6.4 
Objective Response 
Objective response (OR) is defined as a complete response (CR) or partial response (PR) 
according to RECIST v.1.1 recorded from randomization until disease progression or death due 
to any cause. 
 
A patient will be considered to have achieved an OR if the patient has a CR or PR according to 
RECIST v.1.1 definitions. Otherwise, the patient will be considered as non-responders in the OR 
rate analysis. Additionally, patients with inadequate data for tumor assessment (e.g., no baseline 

 
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assessment or no follow-up assessments) will be considered as non-responders in the OR rate 
analysis. 
 
The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the number 
of patients with OR (CR or PR) by the number of patients randomized to the respective treatment 
arm (“response rate”). An exact 95% binomial CI for the response rates will be provided. 
Response rate comparisons between the 2 treatment arms as randomized will be assessed using a 
chi-square test or Fisher’s exact test. Analyses of ORR will be performed on the ITT population 
based on the investigator’s assessment as well and also on the review of the blinded independent 
third-party core imaging laboratory. 
 
17.6.5 Incidence of CNS Metastases 
The incidence of CNS metastases will be compared between the treatment arms, which will 
include both the progression of existing brain metastases documented as target/non-target lesions 
at baseline as well as new brain metastases documented as new lesions at the time of progression 
on the disease assessment forms and/or patient status follow-up forms in the clinical database. 
 
17.6.6 
Duration of Response 
Duration of response (DR) is defined as the time from the first documentation of objective tumor 
response (CR or PR) to the first documentation of objective tumor progression or death due to 
any cause, whichever occurs first. DR data will be censored on the date of the last tumor 
assessment on study for patients who do not have objective tumor progression and who do not 
die due to any cause while on study. DR will only be calculated for the subgroup of patients with 
an OR. DR for the two treatment arms will be summarized using Kaplan-Meier methods and 
displayed graphically where appropriate. The median event time and 95% CI for the median will 
be provided for each endpoint. 
17.6.7 
Clinical Benefit Response 
Clinical benefit response (CBR) is defined as CR or PR or SD/Non-CR and Non-PD (for patients 
with non-measurable disease) ≥ 24 weeks according to the RECIST version 1.1 recorded in the 
time period between randomization and disease progression or death of any cause. 
 
The CBR rate on each randomized treatment arm will be estimated by dividing the number of 
patients with CR, PR, or SD/Non-CR and Non-PD (for patients with non-measurable disease)  ≥ 
24 weeks by the number of patients randomized to the treatment arm. A 95% CI for the CBR 
rates will be provided. CBR rate comparison between the two treatment arms as randomized will 
be assessed using chi-square or Fisher’s exact test.  
17.6.8 
Patient Reported Outcomes 
Patient reported outcomes of health-related quality of life and health status will be assessed using 
validated questionnaires, the Functional Assessment of Cancer Therapy-Breast (FACT-B) and 
EuroQol-5D (EQ-5D). The FACT-B and EQ-5D will be given to the patient in the appropriate 
language for the site. 
 

 
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Patients will complete each instrument every 12 weeks over the course of treatment until disease 
progression or discontinuation of the treatment and at the end of study treatment visit.  
 
The FACT-B consists of the FACT-G (27-items) and a breast cancer-specific scale (BCS) that 
consists of 10-items designed to assess patient concerns relating to breast cancer. The FACT-G is 
a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, 
Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. Patients are asked 
to respond to a Likert scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very 
much. 
 
The FACT-B TOI-PFB is a 23-items subset of the FACT-B that can be used as a summary measure 
of physical and functional well-being in patients with breast cancer (Brady et al, 1997). Scores 
range from 0 to 92 points; a higher score indicates a better well-being. A change of 5 points in the 
FACT-B TOI-PFB is considered to be clinically meaningful (Brady et al 1997, Yost et al, 2005). 
 
Change from baseline scores will also be compared between the treatment arms using a mixed 
model repeated measures approach adjusting for specified covariates.  
 
Time to symptom progression is defined as time from randomization to the first documentation of 
≥5-point decrease from baseline in the Trial Outcome Index-Physical/Functioning/Breast (TOI-
PFB) will be a key secondary endpoint that will be compared between the two arms using survival 
analyses methods.  
 
In addition, time to deterioration in breast cancer-specific (BCS) symptoms, defined by a decline 
in BCS from a baseline of ≥2 points will be compared between the two treatment arms as an 
exploratory endpoint. 
 
Breast cancer-specific quality of life, EQ-5D index and EQ-5D VAS scores and change from 
baseline scores will be compared between the treatment arms using a mixed model repeated 
measures approach adjusting for specified covariates, including baseline.  
17.6.9 
Analyses for the Exploratory Objectives 
In addition to the analyses specified above, PFS, OR, CBR, DR and OS will be analyzed based 
on the following factors: prior exposure to anti-HER2 therapy in the adjuvant/neoadjuvant 
setting (yes vs. no), pertuzumab use (yes vs. no); type of endocrine therapy (AI or fulvestrant) 
and response to induction therapy prior to study initiation (i.e. PR or CR vs. stable disease). 
Univariable and multivariable Cox proportional hazards models for time to event outcomes will 
be performed to look at the impact of baseline patient, tumor and disease characteristics. 
17.7 
Duration of Follow-up 
Refer to Section 10.6 for follow-up information.  
17.8 
Criteria for Taking a Patient Off Study 
Refer Section 10.5 for information on treatment discontinuation.  
 
 

 
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18. General Regulatory Considerations and Credentialing  
18.1 
Compliance with Trial Enrollment and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted 
will allow patients to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
18.2 
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/her personnel as well as the IRB. 
Study documents (protocols, investigator`s brochures, eCRFs, etc.) provided by the AFT will be 
stored in an appropriate manner in order to ensure confidentiality. The information provided to 
the investigator by AFT 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. 
 
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. 
 
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. 
 
18.3 
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).  
 

 
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In the case where the patient is unable to read, an impartial witness should be present during the 
entire informed consent discussion. After the patient has 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 comply with the ICH 
GCP guideline and regulatory requirements.  
18.4 
Responsibilities of the Investigator IRB/IEC/REB 
The regulatory requirements for the Investigator can be found in Subpart D of 
21CFR312(21CFR 312.60: General Responsibilities of Investigators) and in ICH E6 Section 4.  
 
Additional requirements are also outlined in the Statement of Investigator Responsibilities (Form 
FDA 1572) and the Site Services Agreement.  
AFT, LLC will supply the protocol and subsequent amendments.  
 
The Investigator is responsible for ensuring all patients and/or parents or legal guardian of each 
patient, if applicable, are informed about the study and that written consent is obtained prior to 
the conduct of any study related procedures.  
 
In addition, the Investigator is responsible for reviewing all health related information collected 
for each study patient in order to identify any safety related issues/AE or Infusion Associated 
Reactions (IAR). All SAEs and IARs are to be reported within 24 hours to AFT via the AFT 
Safety System of becoming aware of the event. If this is not reported within 24 hours, a Protocol 
Deviation will be documented.   
 
As specified in 21CFR 312.62 (Investigator Record Keeping and Record Retention) and ICH E6 
Sections 4.9 and 8, the Investigator is responsible for ensuring that their study staff maintains 
and retains all study related documentation, including but not limited to: signed Informed 
Consent forms, medical records that are applicable for this study and source documents, the 
AFT-38 protocol, Institutional Review Board (IRB) approvals, relevant IRB and Sponsor 
correspondence, and assorted regulatory documents. The Investigator is responsible for retaining 
and keeping safe all patient related documentation. In addition, the site staff will complete 
electronic case report forms (eCRFs) in a timely manner.  
18.5 
Financial Disclosures 
Investigators will provide AFT with adequate and accurate financial information in accordance 
with local regulations and laws in order to allow AFT 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. 
 

 
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18.6 
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 AFT and if locally applicable, to the respective IRB in accordance with 
local IRB policies and procedures.  
 
A deviation is a departure from the protocol. If deviations are discovered by the monitor or data 
manager, other member of study staff or otherwise, they will be discussed with the Investigator 
and study staff.  
 
AFT does not provide waivers for protocol deviations.  
18.7 
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, agreed by the investigator(s) and approved by relevant 
IRBs 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 must be provided to AFT 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, agreed by the investigator(s) and notified to the IRB.  
18.8 
Retention of Records (Study Documentation, Recordkeeping, and Retention of 
Records) 
Any records and documents relating to the conduct of this study and the distribution of 
investigational drug, including ICFs, eCRFs, PRO data, laboratory test results, and medication 
inventory records, must be retained by the study chair until notification by AFT, 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 AFT. Written notification should be provided to AFT 
prior to transferring any records to another party or moving them to another location. 
18.9 
Data Confidentiality 
Patient medical information, whether 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 generally not be provided to study investigators unless a request for research use is 
granted. The overall results of any research conducted using biologic specimens will be available 
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18.10 Database Management and Quality Control 
The Site Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. 
 
The Medidata RAVE EDC system will be used for this study. The study data will be transcribed 
by study-site personnel from the source documents onto an electronic case report form (eCRF), 
and transmitted in a secure manner to AFT within the timeframe agreed upon between the 
sponsor and the study site. The electronic file will be considered to be the eCRF.  The Clinical 
Research Coordinator (CRC) or designated study site personnel will complete the eCRFs in a 
timely manner after the information is collected, preferably within 3-5 business days after the 
study procedure has been performed. The Investigator will review and approve the completed 
eCRFs. Subjects will not be identified by name in the study database or on any study documents 
to be collected by the AFT (or designee), but will be identified by a unique patient number that 
will include a site number, subject number, and if the patient consented to participate in the MBC 
Initiative, a Master MBC identifier. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto eCRFs.  
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis.  
AFT will review eCRFs for accuracy and completeness at regular intervals and during on-site 
monitoring visits; any discrepancies will be resolved with the investigator or designee, as 
appropriate. Data entered into the clinical study database will be verified for accuracy and 
consistency with the data sources according to the study specific Monitoring Plan.  
Queries are entered, tracked, and resolved through the EDC system directly. The study database 
will be updated by the sites in accordance with the resolved queries. All changes to the study 
database will be documented. 
At critical junctures of the protocol (e.g., production of interim and final reports), data for 
analysis is locked and cleaned per established procedures. At study completion, when the 
database has been declared to be complete and accurate, the database will be locked. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), AFT should be prospectively notified. The study 
records must be transferred to a designee acceptable to AFT, such as another investigator, 
another institution, or to AFT itself. The Investigator must obtain AFT’s written permission 
before disposing of any records, even if retention requirements have been met. 
18.11 Site Monitoring 
Monitoring visits will be conducted by representatives of AFT according to the study specific 
Monitoring Plan and US CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). 
By signing this protocol, the Investigator grants permission to AFT (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate 
study documentation. 

 
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18.12 Data and Safety Monitoring Board (DSMB) 
The PATINA/AFT-38 study will utilize the AFT DSMB, an independent committee comprised 
of oncologists, at least one oncologist specializing in breast cancer, and an independent 
statistician to monitor safety and study conduct. A PATINA DSMB Charter will describe the 
DSMB process, including but not limited to role of the DSMB Chair, the meeting schedule, data 
for review during open and closed sessions, voting, and communication of recommendations.  
18.13 Regulatory Reporting 
SAEs meeting expedited reporting requirements (see Section 10) will be forwarded to FDA and 
OUS Competent Authorities by the IND Sponsor or designee within the required reporting 
timelines according to 21 CFR 312.32.  
 
It is the responsibility of the investigator and the research team to ensure that SAEs are reported 
according to the Code of Federal Regulations, Good Clinical Practices (GCP), the protocol 
guidelines, AFT’s guidelines, and Institutional Review Board (IRB) policy.  
18.14 Audits and Inspections 
To enable evaluations and/or audits from regulatory authorities or AFT, the Investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed informed consent forms, copies of 
all eCRFs, safety reporting forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports). The records should be retained by the Investigator according to 
ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever is longer, but 
at a minimum, all study documentation must be retained for 2 years after the last marketing 
application approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of AFT-38. 
 
To ensure compliance with the study protocol and all local, federal and/or international 
regulations, sites will be audited periodically according to the study specific Audit Plan.  
18.15  Early Discontinuation of the Study 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug in this patient population, 
e.g., study did not meet primary endpoint. 
18.16 Publication of Study Protocol and Results 
AFT, LLC prioritizes the timely presentation and publication of study results. Publications and 
any kind of presentations of results from the study shall be in accordance with accepted scientific 
practice, academic standards and customs and must be approved in writing by AFT as the 

 
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sponsor of this trial. No investigator may present or publish any portion of this trial without 
written approval from AFT. 
19. References 
1. 
Peto, R., et al., Comparisons between different polychemotherapy regimens for early breast 
cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. 
Lancet, 2011. 379(9814): p. 432-44. 
2. 
Welch, H.G., D.H. Gorski, and P.C. Albertsen, Trends in Metastatic Breast and Prostate Cancer-
-Lessons in Cancer Dynamics. N Engl J Med, 2015. 373(18): p. 1685-7. 
3. 
Baselga, J., et al., Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N 
Engl J Med, 2012. 366(2): p. 109-19. 
4. 
Swain, S.M., et al., Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast 
cancer. N Engl J Med, 2015. 372(8): p. 724-34. 
5. 
Ferlay, J., et al., Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 
2012. Eur J Cancer, 2013. 49(6): p. 1374-403. 
6. 
Palbociclib Investigator Brochure. 2015. 
7. 
Sherr, C.J. and J.M. Roberts, CDK inhibitors: positive and negative regulators of G1-phase 
progression. Genes & development, 1999. 13(12): p. 1501-12. 
8. 
van den Heuvel, S. and E. Harlow, Distinct roles for cyclin-dependent kinases in cell cycle 
control. Science, 1993. 262(5142): p. 2050-4. 
9. 
Weinberg, R.A., The retinoblastoma protein and cell cycle control. Cell, 1995. 81(3): p. 323-30. 
10. 
Harper, J.W., et al., The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-
dependent kinases. Cell, 1993. 75(4): p. 805-16. 
11. 
Koff, A., et al., Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent 
kinase by TGF-beta. Science, 1993. 260(5107): p. 536-9. 
12. 
Polyak, K., et al., p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and 
contact inhibition to cell cycle arrest. Genes & development, 1994. 8(1): p. 9-22. 
13. 
Sherr, C.J., D-type cyclins. Trends in biochemical sciences, 1995. 20(5): p. 187-90. 
14. 
Toyoshima, H. and T. Hunter, p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is 
related to p21. Cell, 1994. 78(1): p. 67-74. 
15. 
Lukas, J., et al., Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor 
p16. Nature, 1995. 375(6531): p. 503-6. 
16. 
Medema, R.H., et al., Growth suppression by p16ink4 requires functional retinoblastoma protein. 
Proceedings of the National Academy of Sciences of the United States of America, 1995. 92(14): 
p. 6289-93. 
17. 
Lee, R.J., et al., Cyclin D1 is required for transformation by activated Neu and is induced 
through an E2F-dependent signaling pathway. Mol Cell Biol, 2000. 20(2): p. 672-83. 
18. 
Lane, H.A., et al., ErbB2 potentiates breast tumor proliferation through modulation of 
p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth 
dependency. Mol Cell Biol, 2000. 20(9): p. 3210-23. 
19. 
Yu, Q., et al., Requirement for CDK4 kinase function in breast cancer. Cancer Cell, 2006. 9(1): p. 
23-32. 
20. 
Nahta, R., et al., Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy 
between herceptin and flavopiridol. Cancer Res, 2002. 62(8): p. 2267-71. 
21. 
Reddy, H.K., et al., Cyclin-dependent kinase 4 expression is essential for neu-induced breast 
tumorigenesis. Cancer Res, 2005. 65(22): p. 10174-8. 
22. 
Yang, C., et al., The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. 
Am J Pathol, 2004. 164(3): p. 1031-8. 

 
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23. 
Landis, M.W., et al., Cyclin D1-dependent kinase activity in murine development and mammary 
tumorigenesis. Cancer Cell, 2006. 9(1): p. 13-22. 
24. 
Finn, R.S., et al., PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits 
proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast 
Cancer Res, 2009. 11(5): p. R77. 
25. 
Witkiewicz, A.K., et al., The retinoblastoma tumor suppressor pathway modulates the 
invasiveness of ErbB2-positive breast cancer. Oncogene, 2014. 33(30): p. 3980-91. 
26. 
Roberts, P.J., et al., Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J 
Natl Cancer Inst, 2012. 104(6): p. 476-87. 
27. 
Goel, S., et al., Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with 
CDK4/6 Inhibitors. Cancer Cell, 2016. 29(3): p. 255-69. 
28. 
Finn, R.S., et al., The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with 
letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-
negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet 
Oncol, 2015. 16(1): p. 25-35. 
29. 
Finn, R.S., et al., PALOMA-2: Primary results from a phase III trial of palbociclib (P) with 
letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2- 
advanced breast cancer (ABC). ASCO Meeting Abstracts, 2016. 34(15_suppl): p. 507. 
30. 
Cristofanilli, M., et al., Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment 
of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on 
previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 
randomised controlled trial. Lancet Oncol, 2016. 17(4): p. 425-39. 
31. 
Ramakrishna, N., et al., Recommendations on disease management for patients with advanced 
human epidermal growth factor receptor 2-positive breast cancer and brain metastases: 
American Society of Clinical Oncology clinical practice guideline. J Clin Oncol, 2014. 32(19): p. 
2100-8. 
32. 
Cardoso, F., et al., ESO-ESMO 2nd international consensus guidelines for advanced breast 
cancer (ABC2)dagger. Ann Oncol, 2014. 25(10): p. 1871-88. 
33. 
Lipton, A., et al., Serum HER-2/neu and response to the aromatase inhibitor letrozole versus 
tamoxifen. J Clin Oncol, 2003. 21(10): p. 1967-72. 
34. 
Paridaens, R., et al., Mature results of a randomized phase II multicenter study of exemestane 
versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast 
cancer. Ann Oncol, 2003. 14(9): p. 1391-8. 
35. 
Burstein, H.J., et al., Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing 
metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum 
tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol, 2003. 
21(15): p. 2889-95. 
36. 
Chan, A., et al., Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-
positive metastatic breast cancer patients: an international phase II trial. Br J Cancer, 2006. 
95(7): p. 788-93. 
37. 
Brady, M.J., et al., Reliability and validity of the Functional Assessment of Cancer Therapy-
Breast quality-of-life instrument. J Clin Oncol, 1997. 15(3): p. 974-86. 
38. 
EuroQol, G., EuroQol--a new facility for the measurement of health-related quality of life. Health 
Policy, 1990. 16(3): p. 199-208. 
 
 
 

 
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20. Appendices 
Appendix I: ECOG Performance Status 
Appendix II: Investigator Responsibilities 
Appendix III: Abbreviations and Terms  
Appendix IV: QOL Forms 
 
 
20.1 
Appendix I: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* 
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
 
 
 
 
 
 

 
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20.2 
Appendix II: Investigator Responsibilities 
The regulatory requirements for the Investigator can be found in Subpart D of 
21CFR312(21CFR 312.60: General Responsibilities of Investigators) and in ICH E6 Section 4.  
Additional requirements are also outlined in the Statement of Investigator Responsibilities (Form 
FDA 1572) and the Site Services Agreement. AFT, LLC (AFT) will supply the protocol and 
subsequent amendments.  
The Investigator is responsible for ensuring all patients and/or parents or legal guardian of each 
patient, if applicable, are informed about the study and that written consent is obtained prior to 
the conduct of any study related procedures.  
In addition, the Investigator is responsible for reviewing all health related information collected 
for each study patient in order to identify any safety related issues/AE or Infusion Associated 
Reactions (IAR). All SAEs and IARs are to be reported to the AFT Safety Management Group 
within 24 hours of becoming aware of the event. If this is not reported within 24 hours, a 
Protocol Deviation will be documented.  
As specified in 21CFR 312.62 (Investigator Record Keeping and Record Retention) and ICH E6 
Sections 4.9 and 8, the Investigator is responsible for ensuring that their study staff maintains 
and retains all study related documentation, including but not limited to: signed Informed 
Consent forms, medical records that are applicable for this study and source documents, the AFT 
protocol, Institutional Review Board (IRB) approvals, relevant IRB and Sponsor 
correspondence, and assorted regulatory documents. The Investigator is responsible for retaining 
and keeping safe all patient related documentation. In order to do this, the site staff will complete 
electronic case report forms (eCRFs) in a timely manner.  
 
 
 
 
 
 
 
 
 
 

 
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20.3 
Appendix III – Abbreviations and Terms 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
AFT 
Alliance Foundation Trials  
ALT 
Alanine Aminotransferases  
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferases  
AUC 
Area Under the Curve 
AUCinf 
Area under the concentration-time curve from hour 
0 to infinity 
CAP 
College of American Pathologists  
CCND1 
Cyclin D1 
CDK 
Cyclin-Dependent Kinase 
ctDNA 
Circulating Tumor DNA 
C 
Cycle 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CSF 
Colony-Stimulating Factors 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
D 
Day 
DDI 
Drug-drug interaction 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
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 
GMP 
Good Manufacturing Practice 
GnRH 
Gonadotropin releasing hormone 
HDPE 
High Density Polyethylene 
HER2 
Human epidermal growth factor receptor 2 
HR+ 
Hormone receptor positive 
HRQL 
Health-related QOL 
IB 
Investigator’s Brochure 
IC50 
Concentration of 50% Inhibition  
ICF 
Informed Consent Form 
ICH 
 
International Conference on Harmonization of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use 

 
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IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IIR 
Investigator-Initiated Research 
IP 
Investigational Product; (Investigational Medicinal 
Product (IMP) can be used equally 
IP Treatment 
Palbociclib treatment within Arm A 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IxRS 
Interactive Voice and Web Response System 
ITT 
Intent-to-treat  
LFT 
Liver Function Test 
LHRH 
Luteinizing hormone-releasing hormone 
MBC 
Mastering Breast Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
OAT 
Organic anion transporter 
OATP 
Organic anion transporting polypeptide 
OCT 
Organic cation transporter 
OS 
Overall Survival 
Participant 
Participant enrolled in the study; terms participant 
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) 
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 
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 
RR 
The interval between an R wave and the next R 
wave 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

 
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SD 
Stable Disease or Standard Deviation (depending 
on context) 
SmPC 
Summary of Product Characteristics 
SULT 
Sulfotransferase 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tmax 
Time for Cmax 
ULN 
Upper Limit of Normal 
US 
United States 
USA 
United States of America 
Vz/F 
Apparent Volume of Distribution 
WBC 
White Blood Cells 
 
 
 

 
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20.4 
Appendix IV: Quality of Life Forms 
 
FACT-B (Version 4) 
 
 
 

 
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