Clinical trial NCT03691493
Conditions: Anatomic Stage IV Breast Cancer AJCC v8 Estrogen Receptor Positive HER2/Neu Negative Metastatic Breast Carcinoma Metastatic Malignant Neoplasm in the Bone Progesterone Receptor Positive Prognostic Stage IV Breast Cancer AJCC v8
Sponsor: Emory University
Start date: 2019-02-08; Completion date: 2022-10-13
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well radiation therapy given with standard care palbociclib and hormone therapy work in treating patients with breast cancer that has spread from one part of the body to the bone. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Antihormone therapy, such as fulvestrant, letrozole, anastrozole, exemestane, or tamoxifen, may lessen the amount of estrogen made by the body. Giving radiation therapy, palbociclib, and hormone therapy may work better in treating breast cancer patients with bone metastasis.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the response rate three months post-conventionally fractionated radiotherapy, relative to baseline, for bone metastases in breast cancer patients receiving concurrent palbociclib and hormone therapy treatment.

SECONDARY OBJECTIVES:

I. To determine whether conventionally fractionated radiotherapy in combination with palbociclib and hormone therapy in breast cancer patients with bone metastases adversely increases the frequency and severity of palbociclib toxicities including grade 3 neutropenia.

II. To determine whether radiotherapy in combination with palbociclib in breast cancer patients with bone metastases adversely increases the frequency and severity of radiotherapy toxicities including neurological and bone injury.

III. To assess fatigue, quality of life, and depression before and after radiotherapy for bone metastases in metastatic breast cancer patients treated with palbociclib.

IV. To determine progression free survival (PFS) and overall survival (OS) in breast cancer patients treated with palbociclib and concurrent radiotherapy to bone metastases.

V. To evaluate the relationship between volume of irradiated bone and side effects of treatment, including leukopenia and neutropenia.

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To collect, store, and analyze circulating tumor-derived deoxyribonucleic acid (ctDNA) in metastatic breast cancer patients treated with palbociclib and radiotherapy to bone metastases and to determine the relationship between ctDNA and responders versus non-responders, PFS, and OS.

II. To collect, store, and analyze plasma for inflammatory cytokine measurements and determine their relationship with fatigue, depression, and quality of life before and after radiotherapy for bone metastases in metastatic breast cancer patients treated with palbociclib.

III. To collect, store, and analyze ribonucleic acid (RNA) for gene expression to identify functional biology processes over-represented in genes differentially regulated among patients who develop toxicities versus those who do not and those who are responders versus those who are not and to identify transcriptional regulatory pathways driving observed differences in gene expression.

OUTLINE:

Patients undergo conventional radiation therapy over 5-10 days and receive palbociclib orally (PO) once daily (QD) on days 1-21. At the discretion of treating physician, patients also receive letrozole, anastrozole, exemestane, or tamoxifen PO QD on days 1-28, or fulvestrant intramuscularly (IM) on days 1 and 15 of cycles 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 and 3 months.

Arms: arm 1: Patients undergo radiation therapy over 5-10 days and receive palbociclib PO QD on days 1-21. At the discretion of treating physician, patients also receive letrozole, anastrozole, exemestane, or tamoxifen PO QD on days 1-28, or fulvestrant IM on days 1 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Anastrozole intervention 2: Exemestane intervention 3: Fulvestrant intervention 4: Letrozole intervention 5: Palbociclib intervention 6: Radiation Therapy intervention 7: Tamoxifen
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given IM intervention 4: Given PO intervention 5: Given PO intervention 6: Undergo radiation therapy intervention 7: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
Bone Metastasis in Breast Cancer Patients
Protocol version date 08/23/2022
1
Winship Protocol #: Winship 4472-18
Title:  A Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone 
Therapy for Treatment of Bone Metastasis in Breast Cancer Patients
PI: Mylin A. Torres, MD, Director, Emory Glenn Family Breast Center, Winship Cancer Institute
Key Personnel
Radiation Oncology:
Mylin A. Torres, MD  (PI)
Director, Glenn Family Breast Center
Louise and Rand Glenn Family Chair in 
Breast Cancer Research
Winship Cancer Institute
Associate Professor
Department of Radiation Oncology
Emory University School of Medicine
1365 Clifton Road NE
Atlanta, GA 30322
Email:  matorre@emory.edu
Matthew Cheney, MD, PhD 
Director of Research
Spectrum Radiation Oncology
Maine Medical Center
MaineHealth
Portland, ME
Email: 
Matthew.Cheney@spectrummg.com 
Adam W. Nowlan, MD, MPH
NRG Oncology Principal Investigator
Piedmont Healthcare
Medical Director
Radiation Oncology
Medical Oncology:
Manali, Bhave MD
Assistant Professor
Department of Hematology and Medical 
Oncology
Winship Cancer Institute
Emory University SOM.
Email: manali.ajay.bhave@emory.edu
Andrew Pippas, MD
Medical Director
John B. Amos Cancer Center
Piedmont Columbus Regional
Columbus, GA
Email: 
Andrew.Pippas@columbusregional.com 
Grant Lewis, MD
Medical Oncologist
Summit Cancer Care, P.C. at the Lewis 
Cancer & Research Pavilion
Savannah, GA 
Email: Glewis@summitcancercare.com 


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
Bone Metastasis in Breast Cancer Patients
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Piedmont Atlanta Hospital
Atlanta, GA
Email: adam.nowlan@piedmont.org
Nancy Wiggers, MD
Northside 
Radiation 
Oncology 
Consultants
Northside Hospital Cancer Institute
Atlanta, GA
Email: Nancy.Wiggers@northside.com 
Catherine Ferguson, MD
Associate Professor
Georgia Cancer Center at Augusta 
University
Department of Radiation Oncology
Georgia Radiation Therapy Center
821 St. Sebastian Way
Augusta, GA 30912 
Email: cferguson@augusta.edu
Translational Sciences:
Inflammatory Markers
Andrew Miller, MD
Professor, Psychiatry and Behavioral 
Sciences
Director, 
Behavioral 
Immunology 
Program
Emory University
Atlanta, GA
Email: amill02@emory.edu 
Gene Expression
Jennifer C. Felger, PhD
Assistant Professor
Department of Psychiatry and Behavioral 
Sciences
Emory Integrated Genomics Core
Emory University
Atlanta, GA
Email: jfelger@emory.edu 
ctDNA
Aditya Bardia, MD, MPH
Assistant Professor, Medicine, Harvard 
Medical School 
Circulating Tumor Cell Center
Massachusetts General Hospital
Radiology:
David Schuster, MD
Director
Division of Nuclear Medicine and Molecular 
Imaging
Associate Professor
Department of Radiology and Imaging 
Sciences
Emory University
Atlanta, GA  
Email: dschust@emory.edu 


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
Bone Metastasis in Breast Cancer Patients
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Harvard University
Boston, MA
Email: Bardia.Aditya@mgh.harvard.edu 
Statistician and Bioinformatics:
Jeffrey Switchenko, Ph.D
Biostatistics & Bioinformatics Shared 
Resource at Winship Cancer Institute 
Department of Biostatistics & 
Bioinformatics
Emory University
Atlanta, GA 
Email: jswitch@emory.edu 
Coordinating Institution: 
Emory Glenn Family Breast Center
Winship Cancer Institute
Emory University
1365 Clifton Rd.
Atlanta, GA 30322


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
Bone Metastasis in Breast Cancer Patients
Protocol version date 08/23/2022
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Contact Information:
For detailed information on the regulatory and monitoring procedures:  Contact Monica Goings, 
CCRC, MA, Multi-Site Coordinator, Emory University, 404-778-5747, monica.s.goings@emory.edu 
For patient enrollments: Contact India Green, india.eunhye.green@emory.edu; 404-778-1738
For study data submission: Contact India Green, india.eunhye.green@emory.edu; 404-778-1738 
for patient data submission unrelated to imaging or radiotherapy data submissions.  Contact Edi 
Schreibmann, eschre2@emory.edu, 404-778-5667, for imaging and radiotherapy DICOM data 
submissions.  
For biospecimen submission: Contact Evanthia Wommack, evi.christo@emory.edu   
For patient eligibility or treatment-related questions: Contact Dr. Mylin Torres, Study PI, 
matorre@emory.edu


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
Bone Metastasis in Breast Cancer Patients
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TABLE OF CONTENTS
1.
Objectives……………………………………………………………………………………….
7
2.
Background and Rationale………………………………………………………………......
8
3.
Patient Selection, Eligibility, & Ineligibility Criteria……………………………………..
15
4.
Response/Failure Definitions………………………………………………………………..
18
5.
Treatment Planning/Regimen Description………………………………………………..
18
6.
Biospecimen Collection and Submission…………………………………………………
28
7.
Compliance Criteria…………………………………………………………………………...
30
8.
Disease Monitoring……………………………………………………………………………
33
9.
Supportive Care Guidelines and General Concomitant Medication Use……………
34
10. Treatment Modifications/Management…………………………………………………….
35
11. Adverse Events………………………………………………………………………………..
37
12. Registration, Study Entry, Data Collection, and Withdrawal Procedures…………..
41
13. Drug Information………………………………………………………………………………
46
14. Special Studies………………………………………………………………………………...
46
15. Modality Reviews………………………………………………………………………………
46
16. Statistical Considerations……………………………………………………………………
46
17. Gender/Race/Ethnicity Distribution………………………………………………………..
48
18. Study Timeline………………………………………………………………………………….
50
19. References………………………………………………………………………………………
52
B
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STUDY SCHEMA
Overall Description:  This is a Phase II multi-institutional study to evaluate the efficacy and safety of 
palbociclib and hormone therapy during conventionally fractionated radiotherapy for bone metastases 
in hormone receptor positive, her2/neu negative breast cancer patients.  
         
Figure 1. Study Schema
Met-metastasis; ctDNA – circulating tumor DNA; CBC with diff – complete blood count with 
differential; CMP – complete metabolic panel; MFI – Multidimensional fatigue Inventory; QOL – 
Quality of Life; EORTC QLQ-BM22 – European Organization for Research and Treatment of Cancer 
Metastases Module; EORTC QLQ-C15-PAL - EORTC Quality of Life Questionnaire Core 15 for 
Palliative Care; HADS – Hospital and Anxiety Depression Scale; XRT- radiotherapy
Palbociclib (75 or 100 or 125 mg PO daily x 21 days, then 1 week off) and hormone therapy (at 
standard doses) must have started at least 28 days before radiotherapy is administered.  Standard 
hormone therapy can be tamoxifen, faslodex, or an aromatase inhibitor with or without LHRH agonist.  
To participate on this study, patients must fulfill all eligibility criteria and must not meet any exclusion 
criteria, as well as consent to blood draws and resulting biospecimen collection and analysis.   


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Protocol version date 08/23/2022
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1.0 OBJECTIVES
1.1 Primary Objective
To evaluate the response rate three months post conventionally fractionated radiotherapy, relative to 
baseline, for bone metastases in breast cancer patients receiving concurrent palbociclib and hormone 
therapy treatment
1.2 Secondary objectives
a) To determine whether conventionally fractionated radiotherapy in combination with palbociclib 
and hormone therapy in breast cancer patients with bone metastases adversely increases the 
frequency and severity of palbociclib toxicities including Grade 3 neutropenia
b) To determine whether radiotherapy in combination with palbociclib in breast cancer patients 
with bone metastases adversely increases the frequency and severity of radiotherapy toxicities 
including neurological and bone injury 
c) To assess fatigue, quality of life, and depression before and after radiotherapy for bone 
metastases in metastatic breast cancer patients treated with palbociclib
d) To determine progression free survival (PFS) and overall survival (OS) in breast cancer 
patients treated with palbociclib and concurrent radiotherapy to bone metastases
e) To evaluate the relationship between volume of irradiated bone and side effects of treatment, 
including leukopenia and neutropenia
      Translational Research Objectives
a) To collect, store, and analyze ctDNA in metastatic breast cancer patients treated with 
palbociclib and radiotherapy to bone metastases and to determine the relationship between 
ctDNA and responders versus non-responders, PFS, and OS 
b) To collect, store, and analyze plasma for inflammatory cytokine measurements and determine 
their relationship with fatigue, depression, and quality of life before and after radiotherapy for 
bone metastases in metastatic breast cancer patients treated with palbociclib
c) To collect, store, and analyze RNA for gene expression to identify functional biology processes 
over-represented in genes differentially regulated among patients who develop toxicities 
versus those who do not and those who are responders versus those who are not and to 
identify transcriptional regulatory pathways driving observed differences in gene expression.


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2.0 Background and Rationale: 
Approximately two-thirds of breast cancer patients have tumors that are hormone receptor (i.e. 
estrogen and/or progesterone receptor) positive.  Among hormone receptor positive, her2/neu 
negative breast cancer patients, as many as 6% will present with metastatic disease at diagnosis, 
and up to a third will go on to develop metastatic disease after definitive treatment.(1)  As metastatic 
hormone receptor positive breast cancer is a highly prevalent and incurable problem, developing 
novel therapeutics is imperative.  For many years, scientists have become increasingly intrigued by 
cell cycle inhibition as a strategy for developing novel cancer treatments, and preclinical studies have 
shown that palbociclib, a highly effective and selective reversible inhibitor of CDK4 and CDK6, is both 
cytostatic and cytoreductive in hormone receptor positive breast cancer cell lines.  These studies also 
showed that the likelihood of clinically significant drug-drug interactions between palbociclib and all 
forms of hormone therapy is low.  
Subsequently, randomized trials found that palbociclib in combination with hormone therapy (i.e. 
fulvestrant and letrozole) more than doubled median progression free survival compared with 
hormone therapy alone in the first or second line setting after progression on endocrine therapy in 
patients with hormone receptor positive, Her2/neu negative metastatic breast cancer.(2-4)  Studies of 
other cdk 4/6 inhibitors have indicated that additional hormone therapies (i.e. tamoxifen, anastrozole) 
in combination with a cdk 4/6 inhibitor lead to significant improvements in disease free survival in 
metastatic breast cancer patients with hormone receptor positive disease.(5)  Furthermore, all 
patients with this disease appear to benefit from this combination of therapies regardless of 
menopausal status.(3, 5, 6)  Although concurrent palbociclib and hormone therapy have led to more 
patients living longer without disease progression, one of the most common side effects of palbociclib 
is grade 3-4 neutropenia, impacting approximately two-thirds of women for more than 7 days after the 
end of a treatment cycle.(3, 4)  When neutropenia does occur, it tends to occur early, frequently after 
the first cycle (each cycle is 28 days, 3 weeks of palbociclib, 1 week off).  However, the neutropenia is 
non-cumulative, reversible, and infectious complications, including febrile neutropenia, are 
exceedingly rare. (2-4)   Fatigue, anemia, and GI distress in the form of diarrhea, constipation or 
vomiting, and dyspnea are the most common non-hematologic effects of palbociclib.  In the Phase II 
1003 study, patients treated with palbociclib and letrozole versus (vs.) those who received letrozole 
alone had significantly higher rates neutropenia (75% vs. 5%, respectively), leukopenia (43% vs. 3%, 
respectively), fatigue (41% vs. 23%, respectively), anemia (34.9% vs. 6.5%, respectively), nausea 
(28% vs. 13%, respectively), hot flashes (23% vs. 12%, respectively), alopecia (22% vs. 3%, 
respectively) and diarrhea (21% vs. 10%, respectively).  In PALOMA-1, although 40% of patients 
required a dose reduction or delay due to palbociclib-related toxicities, these patients still benefitted 
from the CDK4/6 inhibitor.(6)  Given the efficacy and acceptable toxicity profile of palbociclib and 
hormone therapy, the Federal Drug Administration approved its use in metastatic hormone receptor 
positive breast cancer patients in 2015.  Collectively, these data indicate that there is no evidence 
that palbociclib and hormone therapy is associated with any clinically significant long-term or 
cumulative toxicity.  The United States Package inserts of both palbociclib and hormone therapy, 
including letrozole, anastrozole, tamoxifen, fulvestrant, and exemestane provide publicly available 
and complete information which serve as the Single Reference Safety Documents for these 
compounds.    
Given the improvements in DFS with palbociclib and hormone therapy among metastatic breast 
cancer patients, clinicians are increasingly challenged by the best way to integrate palliative 
radiotherapy with palbociclib when patient’s progress and/or are symptomatic from their metastases.  


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Bone Metastasis in Breast Cancer Patients
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Bone is the most common site of metastatic disease among hormone receptor positive, her2/neu 
negative breast cancer patients.  These metastases are often painful and may put patients at risk for 
fracture and cord compression, particularly if these lesions are located in weight bearing regions or 
the spine.  Radiotherapy is a mainstay treatment for bone metastases, as it has been shown to 
alleviate pain, stabilize bone, and/or prevent fracture.(7, 8)  However, known side effects of 
radiotherapy include leukopenia, neutropenia, and fatigue, and there is concern that radiotherapy 
treatment for bone metastases in breast cancer patients concurrently receiving palbociclib and 
hormone therapy may exacerbate pre-existing neutropenia and fatigue stemming from palbociclib 
alone.  Additionally, murine models have shown that palbociclib may be a radiosensitizing agent (9), 
potentially increasing the risk of injury to the bone, and other critical structures incidentally treated 
with palliative radiotherapy (e.g. spinal cord), even with standard radiotherapy doses (30 Gy in 10 
fractions or 20 Gy in 5 fractions) known to palliate patient symptoms safely when given in isolation.  
However, other studies have shown that cdk4/6 inhibition may prevent radiation-induced injury (10) 
and potentially limit the efficacy of radiotherapy in palliating pain and/or decreasing the high rate of 
radiographic response (~60%) in treated bone metastases.  Alternatively, some physicians are 
concerned that holding the palbociclib during a five to ten day course of standard palliative 
radiotherapy is a time during which other metastatic disease may arise or previously responsive, non-
osseous disease may recur and progress.  Indeed, in vitro data suggests that palbociclib causes cell 
senescence, and malignant cells will start to repopulate after removing palbociclib and/or hormone 
therapy after receiving treatment with both medications for a prolonged period. (Lee et al. Abstract 
no.LB-136. presented at 2014 AACR Annual Meeting, San Diego, CA).  To date, only one 
retrospective study of five metastatic breast cancer patients treated with concurrent conventionally 
fractionated radiotherapy and palbociclib has been published.(11)  These results do not indicate any 
increase in toxicity or decrease in treatment efficacy compared with radiotherapy and/or palbociclib 
treatment alone.  Furthermore, three of the participating sites on this trial, have continued palbociclib 
and hormone therapy during palliative radiation in metastatic breast cancer patients since FDA 
approval of palbociclib.  Collectively, they have treated hundreds of metastatic breast cancer patients 
with this combination of treatments over the last 3 years and have not noticed an increase in toxicity 
(see attached letters of support).  However, these findings need to be confirmed in a prospective 
setting.  The purpose of this study is to evaluate the safety and efficacy of concurrent radiotherapy, 
palbociclib, and hormone therapy in a Phase II multi-institutional study. 
2.1 Rationale for Duration of Palbociclib Treatment prior to Enrollment
Metastatic breast cancer patients who develop grade 3 or 4 neutropenia due to palbociclib and 
hormone therapy are highly likely to develop this side effect within the first 28 days of treatment.  For 
this proposed study, patients will be required to be on palbociclib for at least 1 cycle (3 weeks of 
palbociclib and 1 week off) with concomitant hormone therapy followed by a complete blood cell 
count with differential prior to receiving radiotherapy in order to best distinguish the additional impact 
radiotherapy may have on leukopenia and neutropenia above and beyond that due to palbociclib and 
hormone therapy.  Given that the majority of metastatic breast cancer patients are initially treated with 
systemic therapy, this required duration of palbociclib treatment prior to radiotherapy should not 
preclude a significant number of patients from enrollment.      
2.2 Rationale for radiation dose selection:
Two of the most widely used fractionation schemes for palliative radiotherapy in the treatment of bone 
metastases are 30 Gy in 10 fractions or 20 Gy in 5 fractions.  A survey of the radiation oncologists 


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
Bone Metastasis in Breast Cancer Patients
Protocol version date 08/23/2022
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who staff the seven participating institutions of the proposed study have confirmed the common use 
of these fractionation schemes in their own practices.  Both regimens are considered standard of care 
with adequate efficacy and low rates of toxicity and have been evaluated in previous randomized 
trials of palliative radiotherapy. These radiation treatment doses also allow for real time monitoring of 
radiotherapy side effects over a several day period while a patient is being actively treated. 
Stereotactic body radiotherapy, high dose radiotherapy (20-35 Gy) given over one to five fractions, is 
used in a small percentage of metastatic breast cancer patients with oligometastases and typically on 
trial (i.e. NRG BR002).  As the safety of SBRT in breast cancer patients has not been completely 
evaluated, SBRT will not be allowed in the current study to allow for full evaluation of the efficacy and 
safety of the most commonly used palliative radiotherapy (30 Gy in 10 fractions or 20 Gy in 5 
fractions) in the setting of breast cancer patients with metastatic disease.   
2.3 Rationale for Study Endpoints: 
2.3.1 Response Rate
Response rate at 3 months post radiotherapy will be the primary endpoint of this study.  The majority 
of enrolled patients will be prescribed radiotherapy for pain symptoms arising from bone metastases, 
and in these patients, we will use the validated Brief Pain Inventory to assess response.  A 2 point 
score difference in the maximum pain score item on the BPI is considered a clinically meaningful 
difference, and has been used in other studies of palliative radiotherapy for bone metastases.(7, 12, 
13)  Among patients who are treated for painful bone metastases, the BPI will serve as the primary 
measure of response irrespective of imaging findings.  In other patients, radiotherapy will be 
prescribed to stabilize bone, neurological symptoms, or prevent fracture, and in these patients, 
response will be assessed by imaging.  Previous studies of PET/CT, MRI, and bone scan have been 
used to evaluate breast cancer bone metastases and response to radiotherapy within the bone with 
some finding an imaging correlate of pain relief.(14-17)  In one study, 96% of patients had at least a 
partial response to radiotherapy on PET/CT with a median time to first post-therapy PET of 1.2 
months (range; 0.5-4.1).(16)  Although PET/CT is not standard imaging in metastatic breast cancer, 
similar findings have been seen in CT and bone scan studies, as well as MRI.  Using the Brief Pain 
Inventory or imaging to assess response will allow us to fully explore if the same number of patients 
who typically respond to radiotherapy alone (~60%) also respond to palbociclib, hormone therapy, 
and radiotherapy administered concurrently.(7, 17, 18) Admittedly, RECIST criteria (version 1.1) 
cannot be strictly used to assess bone metastases response without soft tissue component, and there 
are some studies which have found a high false positive rate of disease progression at three months 
post radiotherapy.(19)  Therefore, among patients who present with pain, responders will be 
considered those patients who have a 2 point decrease in the maximum pain item on the BPI, and 
among those who do not present with pain (radiotherapy due to risk of unstable fracture or risk of 
cord compression), responders will be considered those without development of a pathologic fracture 
or worsening neurologic compromise (cord compression) due to cancer on imaging. 
Response will be defined, therefore, by the following criteria:

At least a 2 point decrease in the Brief pain Inventory item maximum pain score at 3 
months post radiotherapy compared with baseline measures among patients with a 
painful bone metastases to be treated on protocol at the time of enrollment
-or-


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
No development of outcome for which radiotherapy was administered  (e.g. 
prevention of new pathologic fracture or new cord compression as appropriate) or 
obvious tumor growth within the radiotherapy treated area on imaging 3 months 
post radiotherapy among patients who do not have pain in the bone metastases to be 
treated on protocol at the time of enrollment 
 
Nonresponders will be considered if the following occur:

Less than a 2 point decrease in the Brief Pain Inventory maximum pain item score at 
3 months post radiotherapy compared with baseline measures in patients who present 
with painful bone metastases
-or-

Progression – Either a new pathologic fracture due to cancer progression or new cord 
compression symptoms/neurologic compromise among patients who are treated for 
non-painful bone metastases. 
 
Images will be submitted for central review for possible secondary analysis at the conclusion of the 
study period.
Secondary assessments of response:
An Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical 
Trials in Bone Metastases and personal communication with Dr. Edward Chow, lead author of these 
guidelines and palliative radiotherapy expert, have recommended using the BPI item rating the worst 
pain in the index site over the last 3 days and analgesic intake for pain in the index site in the last 24 
hours to assess response in clinical trials of palliative radiotherapy.(20) A 2 point score difference in 
the BPI item rating the worst pain at the treated site is considered a clinically meaningful difference 
and is indicative of at least partial response if there is no increase in pain medication intake; this 
criteria has been used in other studies of palliative radiotherapy for bone metastases.(7, 12, 13, 20, 
21) A complete response to radiotherapy is a BPI maximum pain score of 0 at the index site without 
increase in analgesic usage.(20)  Among patients who are treated for painful bone metastases, the 
BPI item rating the worst pain in the last 3 days and analgesic intake in the last 24 hours, will serve as 
a secondary measure of response  consistent with the international consensus on palliative 
radiotherapy endpoints.
In other patients, radiotherapy will be prescribed to stabilize bone, neurological symptoms, or prevent 
fracture, and patients who do not present with pain at the index site will be considered responders if 
they do not develop the outcome for which radiotherapy was administered (e.g. prevention of new 
bone fracture or cord compression) or do not develop obvious tumor growth on imaging, as in the 
primary measure of response above.  Therefore, among patients who present with pain, responders 
will be considered those patients who fulfill the International Bone Consensus response criteria (see 
below) using the BPI item rating maximum pain over the last 3 days at the index site and analgesic 
usage for the treated site within the last 24 hours prior to assessment.(20)   Among patients  who do 
not present with pain (radiotherapy due to risk of unstable fracture or cord compression), responders 


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
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Protocol version date 08/23/2022
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will be considered those without development of a new pathologic fracture or worsening neurologic 
compromise (cord compression) due to cancer on imaging. 
Secondary measures of response defined, therefore, by the following criteria:

Among patients who present with a painful bone metastases [index site(s)] to be 
treated on protocol, response 3 months post radiation treatment will be defined by one 
of the following criteria per International Bone Consensus response categories(20) :

BPI item maximum pain Score of 0 at the index site over the last 3 days with no 
concurrent increase in analgesic intake (daily oral morphine equivalents, OMED) 
for pain in the index lesion within the last 24 hours compared with baseline 
measures
 –or-

At least a 2 point decrease in BPI item maximum pain score over the last 3 
days at the treated site without analgesic increase in daily oral morphine 
equivalent (OMED) within the last 24 hours for pain in the index lesion compared 
with baseline measures 
-or-

A 25% or more reduction in analgesics (OMED) within the last 24 hours for 
pain in the index lesion without increase in the BPI item maximum pain 
score over the last 3 days compared with baseline measures.
-or-

Among patients without pain in the index site to be treated, response will be 
categorized by the following criteria:

No development of outcome for which radiotherapy was administered  (e.g. 
prevention of new pathologic fracture or cord compression, as appropriate) 3 
months post radiotherapy
 –or-

No obvious tumor growth within the radiotherapy treated area on imaging 3 
months post radiotherapy 
 
Nonresponders will be considered if the following occur:

Increase in BPI item maximum pain score of 2 points or more 3 months post 
radiation above baseline at the treated site with stable OMED, or an increase in 
25% or more in OMED compared with baseline with the BPI item maximum pain 
score stable or 1 point above baseline.   
-or-


Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone Therapy for Treatment of 
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Protocol version date 08/23/2022
13

Progression – Either a new pathologic fracture due to cancer progression or new cord 
compression symptoms/worsening neurologic compromise among patients who present 
with a non-painful bone metastases.
Indeterminate Response

 Less than a 2 point decrease in the Brief Pain Inventory score at 3 months post 
radiotherapy at the treated site with less than a 25% reduction in daily OMED for pain at the 
treated site or more than a 2 point decrease in Brief Pain Inventory Score at the treated site 
with increase in OMED for the treated site 3 months post radiotherapy compared with 
baseline measures in patients who present with painful bone metastases
2.3.2 Rationale for Patient Reported Outcome Assessments 
Completion of Patient Reported Outcomes instruments is critical for understanding the impact of 
palbociclib, hormone therapy, and radiotherapy concurrently for bone metastases in breast cancer 
patients.  The primary endpoint of response to treatment will rely completely on the Brief Pain 
Inventory (BPI, see below) among patients who present with pain stemming from bone metastases to 
be treated on protocol.  However, quality of life (SF-36, EORTC QLQ-BM22, and EORTC QLQ-C15-
PAL,), fatigue (MFI-20), and depression (HADS) will also be evaluated as secondary endpoints.  The 
bodily domain of the SF-36 will allow for assessment of patients who present without pain and for side 
effects from hormone therapy, namely discomfort arising from night sweats, insomnia, vaginal 
dryness, and arthralgias.(22)
Pain Assessment:
Brief Pain Inventory Short Form (BPI) will be used to assess the severity and location of pain, its 
impact on daily functions, and pain medications before, during, and up to 3 months post radiotherapy 
(see Figure 1).(13)  A clinically meaningful improvement in pain severity is > a 2 point decrease in the 
BPI in metastatic breast cancer patients.(12)  The BPI has been used in previous randomized trials of 
palliative radiotherapy for bone metastases conducted by the RTOG and is endorsed by the National 
Cancer Institute as an important, valid, reliable, and responsive tool best applied in the research 
setting to evaluate pain.(7)   Since metastatic breast cancer patients can have pain in other areas 
besides the intended area to be treated on protocol (e.g. diffuse arthralgias, neuropathy, post-
mastectomy pain), the question will be modified by adding “pain in and around the bone to be treated 
on this study with radiotherapy” to make the items more specific as previously done in prior trials.(23) 
Participants will be specifically asked to attribute their pain to one or more of several factors including 
the cancer, radiotherapy treatment, aging, hormone therapy, other medical conditions or medications.  
Psychosocial Assessments:
Medical Outcomes Study 36-Item Short Form Version 2 (SF-36) will also be used to evaluate 
quality of life.  The SF-36 has been validated in a population of healthy women, and it is one of the 
most commonly used instruments to assess QOL. Our group and others have used the SF-36 in 
previous studies of breast cancer patients treated with radiation therapy and chemotherapy in 
patients with and without pain.(24) 


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European Organization for Research and Treatment of Cancer Metastases Module  (EORTC 
QLQ-BM22) will also be used to evaluate quality of life and pain outcome.  The EORTC-QLQ-BM22 
is a bone metastases module which supplements the quality of life instrument, EORTC QLQ-C15-
PAL (see below).  This instrument has been designed and validated specifically in cancer patients 
with bone metastases and is reliable, applicable across cultures and a sensitive tool to assess pain, 
functional interference, and psychosocial aspects of quality of life in patients with bone 
metastases.(25)  The EORTC QLQ-BM22 has been used in previous studies of radiotherapy 
treatment for bone metastases in breast cancer patients.(26, 27)   The update of the International 
Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone Metastases has 
made a formal recommendation for the use of the EORTC QLQ-BM22 in all trials of palliative 
radiotherapy along with the EORTC QLQ-C15-PAL.(20)  
EORTC Quality of Life Questionnaire Core 15 for Palliative Care (EORTC QLQ-C15-PAL)  is a 
shortened version of the EORTC QLQ-C30, one of the most widely used health-related quality of life 
questionnaires in oncology for palliative care research.  This 15-item questionnaire retains 
items/scales pertaining to pain, physical function, emotional function, fatigue, global health 
status/quality of life, nausea/vomiting, appetite, dyspnea, constipation and sleep without reducing 
measurement precision found with the larger EORTC QLQ-C30 instrument. (28)  The instrument has 
been validated in multiple cancer patient populations with metastatic disease and has been used in 
breast cancer patients receiving palliative radiotherapy for bone metastases.(29-31)  The update of 
the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone 
Metastases has made a formal recommendation for the use of the EORTC QLQ-BM22 in all trials of 
palliative radiotherapy along with the EORTC QLQ-C15-PAL, as the two questionnaires are 
complementary to one another.(20) 
Multidimensional Fatigue Inventory (MFI-20) will be used to evaluate the presence and severity of 
fatigue among subjects by self-report.(32)  The MFI-20 assesses 5 dimensions of fatigue, including 
general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation.(33, 34)  
The MFI has been used to quantify fatigue in cancer patients, and a minimal clinically important 
difference of 10 points has been established.(35) 
Hospital Anxiety and Depression Scale (HADS) will be used to evaluate depression and 
anxiety.(36)  HADS has been used in previous studies of metastatic breast cancer patients and is 
cited by the National Cancer Institute as a commonly used screening tool for depression in oncology 
patients.(37, 38)
These assessments are a minimal burden to patients and take approximately 30 minutes to complete.  
At Emory University, ongoing longitudinal studies of patients receiving radiotherapy and using these 
instruments has established feasibility and over 95% compliance with completing these forms.  
 
2.3.3 Translational Research Endpoints
Rationale for Collection of Blood Samples
Collection of longitudinal blood samples before and up to 3 months post radiotherapy will allow us to 
determine biomarkers of local response to radiotherapy, disease progression both locally and 
systemically, as well as side effects of treatment including hematologic toxicities and fatigue.  


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Blood Collection - Blood samples will be drawn at the same time of day between 8-11 am (to reduce 
potential circadian effects) under sterile conditions at visits corresponding to the pre-treatment and 3 
months post radiation visit noted in the SCHEMA above. Whole blood will be collected into EDTA 
vacutainer and Tempus Blood RNA tubes for plasma separation as well as mRNA, and ctDNA 
isolation.  
A CBC with differentialwill also be performed to assess hemoglobin, platelet count, and the proportion 
of immune cell types in each sample prior to treatment, last day of treatment, 1 month and 3 months 
post radiotherapy.  A complete metabolic panel will also be performed prior to radiotherapy, 1 month 
and 3 months post radiotherapy.
Circulating tumor DNA (ctDNA) – Plasma levels of ctDNA will be measured using targeted assays 
to detect point mutations including mutations in PIK3CA and ESR1, genes associated with hormone 
therapy resistance.(39, 40)  ctDNA has been shown to be a real time biomarker of response to 
palbociclib and fulvestrant which can be collected from blood, an advantage in this study, as tissue 
sampling from bone can be technically difficult, risky, and uncomfortable for patients.(41) Plasma can 
be frozen for future ctDNA extraction, another advantage for this study given the number of proposed 
enrollment centers. Dr. Aditya Bardia, Assistant Professor Medicine at Harvard Medical School and 
Attending Physician in Medical Oncology at Massachusetts General Hospital will provide his expertise 
in ctDNA analyses.  Specimens will be shipped to the Circulating Tumor Cell Center at 
Massachusetts General Hospital where Dr. Bardia will oversee ctDNA processing.    
Plasma Analysis of Inflammatory Markers - Plasma concentrations of sTNFR2 and IL-6 will be 
determined as previously described using sandwich ELISA according to manufacturer’s protocol (R & 
D Systems, Minneapolis, MN).  High sensitivity CRP will be measured using a standard turbidimetric 
assay.  These inflammatory markers have been associated with of depression and fatigue in our 
previous studies of breast cancer patients (42-44), as well as other studies of pain in breast cancer 
patients.(45, 46)  These samples will be shipped to Dr. Andrew Miller’s laboratory at Emory University 
where concentrations of sTNFR2, IL-1ra, and IL-6 will be determined using sandwich ELISA 
according to manufacturer’s protocol (R & D Systems, Minneapolis, MN).  Each determination 
(excluding the soluble cytokine receptors which require less sample) requires 100-150 ul of sample; 
all samples will be assayed in duplicate. Quality control plasma of both low and high cytokine 
concentrations will be included with every assay.  The mean inter- and intra-assay coefficients of 
variation for control samples are reliably 10% or less.  Dr. Miller is a Professor in the Emory 
Department of Psychiatry and Behavioral Sciences and has extensive experience conducting these 
assays and performing studies on the impact of inflammation on the brain and behavior in cancer 
patients.  CRP will be measured in the CLIA certified laboratory of the Emory University Hospital 
using a standard turbidimetric assay.
Gene Expression - mRNA will be extracted from bloodcollected directly into Tempus™ Blood RNA 
Tubes.  The A260/A280 ratio will be used to assess purity, and the RNA will be reverse transcribed 
using the cDNA Archive kit (Applied Biosystems).  RNA concentrations will be determined by 
Nanodrop fluorometry and sample integrity will be assessed on the Bioanalyzer, which provides an 
‘RNA Integrity Number’ considered a reliable and industry standard for RNA quality and integrity. 
RNA samples will be shipped to Dr. Felger’s laboratory and mRNA expression will be determined 
using the Roche KAPA Stranded RNA Seq Kits with RiboErase (HMR) (Pleasonton, CA, USA) in the 
Emory Integrated Genomics Core. This platform interrogates all known exons of >20,000 well-


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annotated human genes and can be run on as little as 100 pg of total RNA, or as few as 10 cells. The 
format allows for transcript variant (splicing) analysis as well as full length transcript data. Synthetic 
ERCC spike-in controls will be used and hybridized to the array as an internal normalization control 
for total input RNA. Arrays will be processed using the Expression Console (Affymetrix) software, and 
gene expression returned as a log signal intensity after normalization.  Our previous studies indicate 
that the top 2 biologic processes represented in gene ontology analysis among depressed and 
fatigued breast cancer patients are the immune and defense responses, while transcription factor 
analysis indicates a relationship between the nuclear factor kappa B pathway and fatigue and 
depression in these patients.(43) Dr. Jennifer Felger, Assistant Professor, Department of Psychiatry 
and Behavioral Sciences at Emory University, has expertise in gene expression analyses and will 
provide bioinformatics analyses of these data.   
2.4 Benefit-Risk Assessment
Findings from this trial will answer a highly clinically relevant question.  Among the seven participating 
institutions, three continue palbociclib and hormone therapy during radiotherapy for bone metastases 
while five withhold palbociclib during the 5 to 10 days of radiation treatment.  Anecdotally, there have 
been reports where patients progress elsewhere in the body when palbociclib is withheld during 
radiation.  Given the large number of metastatic breast cancer patients who are currently taking and 
will receive palbociclib in the future, the results of the proposed study could have a large and far 
reaching impact on the clinical management of these patients both with bone metastases and other 
sites of non-osseous disease. For example, if the concurrent treatment of palbociclib, hormone 
therapy, and radiotherapy is found to be safe and efficacious, an argument could be made to continue 
this drug regimen when treating liver or lung metastases and potentially disease within the brain with 
radiotherapy.
Neutropenia is the most frequent and severe side effect of palbociclib, but it is almost always 
reversible and not associated with infectious complications.  Additionally, growth stimulating factors 
are not typically needed. 
The study visits, additional blood tests, and completion of questionnaires are of minimal additional 
burden.  The majority of the study visits occur during standard of care visits (e.g. baseline visit, last 
day of radiation, 1 month post radiation).  The additional visit 3 months post radiation may occur at 
the same time as a routine visit and assessment with their medical oncologist who would typically see 
metastatic breast cancer patients at least every 3 months.    
2.5 Rationale for Multi-institutional Participation: 
To meet accrual goals within a 12 month period the following seven institutions have agreed to 
participate in this study.  All breast cancer physicians within these centers strongly believe this study 
will answer a highly clinically relevant question and are committed to its success (see attached letters 
of support).  Emory Glenn Family Breast Center at Winship Cancer Institute, Maine Medical Center, 
Piedmont Cancer, John B. Amos Cancer Center, Northside Hospital Cancer Institute, Georgia Cancer 
Center at Augusta University, and the Nancy N. and J.C. Lewis Cancer & Research Pavilion have 
agreed to enroll patients on the proposed study.  Emory and Maine Medical are academic centers with 
physicians who serve approximately 50 and 25 annual, eligible patients at each institution, respectively.  
At Emory, there have been 272 patients given prescriptions for palbociclib since 2015.  Many of these 
patients will likely progress within the bone during the study time period, and therefore, our pool of 


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patients to recruit from is likely going to be larger than 50 per year.  The remaining cancer centers are 
community hospitals within the state of Georgia: Piedmont Cancer, John B. Amos Cancer Center, 
Northside Hospital Cancer Institute, Georgia Cancer Center at Augusta University, and Nancy N. and 
J.C. Lewis Cancer & Research Pavilion are community hospitals with strong research experience, 
particularly with radiation therapy oncology group and now NRG Oncology studies, and infrastructure 
to support such studies (i.e. IROC certification).  Each of these community hospitals treat approximately 
10-50 eligible patients annually.  
Among major metropolitan cities in the United States, Atlanta was recently noted to have one of the 
largest disparities in breast cancer outcomes among African American and Caucasian women with 
black women 40% more likely to die of their disease.(47)  Emory, Piedmont, and Northside combined 
account for 70% of the breast cancer care in the city of Atlanta, and more than 40% of patients served 
by these hospital systems as well as John B. Amos Cancer, Peyton Anderson Cancer Center, and 
Nancy N. and J.C. Lew Cancer & Research Pavilion, are African American.  This study, therefore, has 
the potential to address disparities in clinical trial participation due to the number of African American 
patients we serve in Georgia and Emory’s track record of successful recruitment of African American 
breast cancer patients to clinical trials (~45% of all patients on radiotherapy trials, in particular).(24)   
Although triple negative breast cancer is more prevalent in African American than Caucasian patients, 
hormone receptor positive breast cancer is still the most prevalent subtype  among all women including 
African American patients and significant disparities are seen in our state regardless of tumor subtype.  
There are several advantages to including all of these sites:
1) Accrual goals will be met in a short period of time
2) The study results will be generalizable to more patients, as we will accrue patients served at 
both academic and community practices, and at least 40% of the patients served by all of the 
institutions in Georgia are African American, while 95% of the patients at Maine Medical 
Center are Caucasian.  Therefore, there will be the opportunity to evaluate how race may 
impact our results.  
2.6 Hypothesis:
We hypothesize that palliative radiotherapy in combination with palbociclib for treatment of bone 
metastases in hormone receptor positive, Her2 neu negative breast cancer patients will be equally 
effective to radiotherapy alone in alleviating pain and controlling disease locally (based on historical 
data) without significant increase in toxicity typically associated with radiotherapy or palbociclib 
independently.  
3.0 PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA
Note: Per NCI guidelines, waivers for inclusion and exclusion criteria are not permitted.  
For questions concerning eligibility, please contact the study PI, Dr. Mylin Torres.  
3.1 Patient Selection Guidelines
a) Patients must have the psychological ability and general health that permits completion of the 
study requirements and required follow up.


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b) Women of childbearing potential who are sexually active should be willing and able to use 
medically acceptable forms of contraception during protocol treatment. 
3.2 Inclusion Criteria:
A patient cannot be considered eligible for this study unless ALL of the following conditions 
are met.
3.2.1 Pathologically confirmed metastatic breast cancer
3.2.2 Known estrogen, progesterone, and Her2 status of either primary tumor or metastasis
3.2.3 Metastatic ER+ or PR+, Her2/neu negative breast cancer patients with imaging confirming 
bone metastasis within 60 days of radiation simulation 
3.2.4 Must be actively receiving palbociclib (125 or 100 or 75 mg PO daily for 3 weeks followed by a 
week off during 28-day cycles) plus one of the following hormone therapies for at least 28 
days: 
a) Fulvestrant (500mg IM injection on days 1 and 15 cycle one and then on day one of 
each subsequent cycle (28 days) -or-
b) Letrozole (2.5 mg PO daily) -or-
c) Anastrozole (1mg PO daily) -or-
d) Exemestane (25mg PO daily) -or-
e) Tamoxifen (20mg PO daily)
3.2.5  Patients must be willing and able to provide written informed consent/assent for the trial
3.2.6  Age > 18 years
3.2.7  ECOG Performance Status < 2, KPS > 60% within 60 days prior to registration
3.2.8  Must have bone disease that is either symptomatic (i.e. pain) or has a lytic or mixed lytic 
disease that can be assessed by CT, MRI, bone scan or PET/CT within 60 days prior to radiotherapy 
on this study 
3.2.9  Female or male patients allowed
3.2.10  One previous line of chemotherapy in advanced disease is allowed
3.2.11  Appropriate stage for study entry based on the following diagnostic workup:

History and Physical Examination within 60 days prior to registration

Clinical grade CT scans of the chest, abdomen, and pelvis with radionuclide bone scan 
OR whole body PET/CT documenting metastatic disease prior to radiotherapy on this 
protocol or MRI documenting site of metastatic disease to be treated on protocol
3.2.12  Patient must be eligible for palliative radiotherapy (conventional radiation either 30Gy in 10 
fractions or 20 Gy in 5 fractions) for up to 4 separate anatomic regions containing bone metastases 
defined by 4 separate  and not overlapping radiation plans.
3.2.13  CBC with differential obtained within 14 days prior to registration on study, with adequate 
bone marrow function defined as follow:

Absolute neutrophil count > 1000/mcl

Platelets > 75,000 mm3

Hemoglobin  > 8.0 g/dl (Note: The use of transfusion or other intervention to achieve 
Hgb > 8.0g/dl is acceptable)
3.2.14  For females of child-bearing potential, negative serum or urine pregnancy test within 14 days 
prior to radiation simulation.
3.2.15. The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry.
3.2.16. Prior Treatment:
a) Patients may or may not have received radiotherapy or neoadjuvant or adjuvant 
chemotherapy in the treatment of their initial, non-metastatic breast cancer, but must be 


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entered on study after their last dose of radiotherapy, last cycle of chemotherapy and 
biologic therapy (if applicable) and have sufficient resolution of side effects per physician 
assessment at time of radiotherapy
b) Patients must have not active wound healing issues from surgery and sufficient 
resolution of surgical side effects, per physician assessment, at time of radiotherapy
c) If patients have one line of chemotherapy for advanced disease, patients must be 
entered on study after their last dose of chemotherapy and have sufficient resolution of side 
effects per physician assessment at time of radiotherapy.
d) Patients must have already initiated palbociclib (3 weeks on, 1 week off) and hormone 
therapy for at least 28 days prior to radiotherapy.
e) During radiotherapy, no other investigation or commercial agents or therapy for cancer 
other than palbociclib, bisphosphonates, rank ligand inhibitors, and hormone therapy 
should be administered.
f)
Patients may have received bisphosphonates or rank ligand inhibitors prior to 
enrollment on study.       
3.3 Ineligibility (Exclusion) Criteria:
Patients with any of the following conditions are NOT eligible for this study.  
3.3.1 Co-existing or prior invasive non-breast malignancy (except non-melanomatous skin cancer), 
unless disease free for a minimum of 3 years
3.3.2 Previous radiation dose, date, fraction size, must be reported for prior invasive malignancy.. 
3.3.3  Previous palliative radiation to the disease to be treated on protocol (including 
radiopharmaceuticals)
3.3.4  Patients prescribed SBRT for bone metastasis to be treated on this protocol will be excluded
3.3.5  Metastases to be treated on protocol located within 2 cm from a previously irradiated structure:
a) Spinal cord previously irradiated to > 40 Gy (delivered in < 3Gy/fraction)
b) Brachial plexus previously irradiated to >50Gy (delivered in < 3Gy/fraction)
c) Small intestine, large intestine, or stomach previously irradiated to > 45Gy (delivered in 
< 3Gy/fraction)
d) Brainstem previously irradiated to >50Gy (delivered in < 3Gy/fraction)
e) Whole lung previously irradiated with prior V20Gy >35% (delivered in < 3Gy/fraction)
3.3.6  Untreated brain metastases or unstable/progressive brain metastases (imaging of treated brain 
metastases must be performed within 28 days of registration for this protocol to confirm brain 
metastases stability)
3.3.7  Severe, active co-morbidity such as CHF or unstable angina within last 6 months, transmural 
myocardial infarction within the last 6 months. Acute bacterial or fungal infection requiring IV 
antibiotics at time of registration, COPD or other respiratory illness requiring hospitalization at time of 
registration
3.3.8  Lactating females must cease expression of milk prior to registration. 
3.3.9  Temperature above 100.4 degrees Fahrenheit 
3.3.10  HIV positive with CD4 count <200 cells/ microliter.  HIV positive patients are eligible, provided 
they are receiving treatment with highly active antiretroviral therapy (HAART) and have a CD4 count 
> 200 cells/microliter within 28 days prior to registration.  HIV testing is not required for eligibility for 
this protocol. This exclusion criteria is necessary because the treatments involved in this protocol may 
be significantly immunosuppressive.  
3.3.11 Previous chemotherapy or radiotherapy within 2 weeks prior to registration or patients who 
have not recovered from adverse events due to previous chemotherapy and radiotherapy


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3.3.12  Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has 
undergone potentially curative therapy. Indolent cancers (such as low risk prostate or In-Situ cancers) 
that are not being treated are acceptable
3.3.13  Has active autoimmune disease that has required continued systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
3.3.14  Has an active infection requiring systemic therapy 
3.3.15  Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full duration of 
the trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator. 
3.3.16  Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
3.3.17  Cannot receive concurrent cytotoxic chemotherapy (e.g. taxanes, Cytoxan, anthracyclines, 
platinum based aged, capecitabine) at time of registration or during radiation treatment on this study
3.3.18  Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 90 days after the last 
dose of trial treatment. 
3.3.19  Absolute neutrophil count <1000/mcL
3.3.20  Platelets < 75,000 mm
3.3.21  Hemoglobin < 8.0 g/dl
3.3.22  Concurrent therapy with other Investigational Products is not allowed
3.3.23  Receiving medications or substances that are potent inhibitors or inducers of CYP3A 
isoenzymes, as palbociclib is primarily metabolized by CYP3A4 enzymes, within 7 days of 
registration:  

Inhibitors – boceprevir, clarithromycin, indinavir, delavirdine, conivaptan, itraconazole, 
ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, suboxone, telaprevir, telithromycin, voriconazole, amprenavir, 
atazanavir, diltiazem, erythromycin, fosamprenavir, verapamil, and grapefruit, grapefruit 
juice or any product containing grapefruit

Inducers – carbamazepine, phenytoin, primidone, rifampin, rifapentine, St. John’s wort, 
felbamate, nevirapine, phenobarbital, rifabutin
3.3.24  Receiving hormone replacement therapy (e.g. topical estrogens, but not intra-vaginal 
preparations, raloxifene, megestrol acetate)
3.3.25  Patients with clinical signs of cord compression.  Patients with radiographic evidence of cord 
compression are eligible for enrollment but cannot have clinical signs of cord compression. 
4.0 RESPONSE/FAILURE DEFINITIONS
A responder will be defined as a patient who has one of the following:
a. At least a 2 point decrease in the Brief Pain Inventory item maximum pain score  at 3 
months post radiotherapy compared with baseline measures in patients who present with 
pain from bone metastasis to be treated on protocol at the time of enrollment
-or-


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b. No development of outcome for which radiotherapy was administered  (e.g. prevention of 
new pathologic fracture or new cord compression, as appropriate) or obvious tumor growth 
within the radiotherapy treated area on imaging 3 months post radiotherapy among patients 
who do not have pain in the bone metastases to be treated on protocol at the time of 
enrollment
Patients who do not fulfill one of the above criteria will be considered a non-responder.  
Imaging – Bone metastases must be seen on standard imaging (CT, MRI, Bone Scan, PET/CT) 
within 60 days prior to radiotherapy simulation.  3 months post radiotherapy (See Figure 1), providers 
must make every effort to use the same imaging method that was used to originally detect the 
metastases being treated on protocol.  Using the Brief Pain Inventory or imaging to assess response 
will allow us to fully explore if the same approximate number of patients who typically respond to 
radiotherapy alone (~60%) also respond to palbociclib, hormone therapy, and radiotherapy 
administered concurrently.(7, 17, 18)  RECIST criteria (version 1.1) cannot be strictly used to assess 
bone metastases response without soft tissue component, and there are some studies which have 
found a high false positive rate of disease progression at three months post radiotherapy.(19)  
Therefore, among patients who present with pain, responders will be considered those patients who 
have a 2 point decrease in the BPI, and among those who do not present with pain, responders will 
be considered those who do not have obvious growth of cancer or development of pathologic fracture 
due to cancer on imaging compared with baseline studies.  Response will be defined, therefore, by 
any of the following criteria:

At least a 2 point decrease in the Brief Pain Inventory item maximum pain score  at 3 
months post radiotherapy compared with baseline measures in patients who present 
with pain from bone metastasis to be treated on protocol at the time of enrollment
-or-

No development of outcome for which radiotherapy was administered  (e.g. prevention 
of new pathologic fracture or new cord compression, as appropriate) or obvious tumor 
growth within the radiotherapy treated area on imaging 3 months post radiotherapy 
among patients who do not have pain in the bone metastases to be treated on protocol 
at the time of enrollment
 
Nonresponders will be considered if the following occur:

Less than a 2 point decrease in the Brief Pain Inventory item maximum pain score at 
3 months post radiotherapy compared with baseline measures in patients who present 
with painful bone metastases
-or-

Progression – Either a new pathologic fracture due to cancer progression or cord 
compression symptoms/neurologic compromise patients who are treated for non-painful 
bone metastases. 
 


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Images will be submitted for central review for possible secondary analysis at the conclusion of the 
study period.
Secondary assessment of response:
An Update of the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical 
Trials in Bone Metastases and personal communication with Dr. Edward Chow, lead author of these 
guidelines and palliative radiotherapy expert, have recommended using the BPI item rating the worst 
pain in the index site over the last 3 days and analgesic intake for pain in the index site in the last 24 
hours to assess response in clinical trials of palliative radiotherapy.(20) A planned secondary 
assessment of response will therefore take these measures into account in accordance with 
International Consensus Guidelines using the following criteria:
Among patients who present with a painful bone metastases [index site(s)] to be treated on 
protocol, response 3 months post radiation treatment will be defined by one of the following criteria 
per International Bone Consensus response categories(20) :

BPI item maximum pain Score of 0 at the index site over the last 3 days with no 
concurrent increase in analgesic intake (daily oral morphine equivalents, OMED) 
for pain in the index lesion within the last 24 hours compared with baseline 
measures
 –or-

At least a 2 point decrease in BPI item maximum pain score over the last 3 days 
at the treated site without analgesic increase in OMED within the last 24 hours 
for pain in the index lesion compared with baseline measures 
-or-

A 25% or more reduction in analgesics (OMED) within the last 24 hours for pain 
in the index lesion without increase in the BPI item maximum pain score over the 
last 3 days compared with baseline measures.
-or-
Among patients without pain in the index site to be treated, response will be categorized by 
the following criteria:

No development of outcome for which radiotherapy was administered  (e.g. 
prevention of new pathologic fracture or cord compression, as appropriate) 3 
months post radiotherapy
 –or-

No obvious tumor growth within the radiotherapy treated area on imaging 3 
months post radiotherapy 
 


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Nonresponders will be considered if the following occur:

Increase in BPI item maximum pain score of 2 points or more 3 months post 
radiation above baseline at the treated site with stable OMED, or an increase in 
25% or more in OMED compared with baseline with the BPI item maximum pain 
score stable or 1 point above baseline.   
-or-

Progression – Either a new pathologic fracture due to cancer progression or new cord 
compression symptoms/worsening neurologic compromise among patients who present 
with a non-painful bone metastases.
Indeterminate Response

 Less than a 2 point decrease in the Brief Pain Inventory score at 3 months post 
radiotherapy at the treated site with less than a 25% reduction in daily OMED for pain at the 
treated site or more than a 2 point decrease in Brief Pain Inventory Score at the treated site 
with increase in OMED for the treated site 3 months post radiotherapy compared with 
baseline measures in patients who present with painful bone metastases
4.1 Disease Progression and Subsequent Treatment 
The following definitions are used for confirmation of oncologic events:
Local recurrence (i.e. non-responder) – defined as pathologic fracture due to disease recurrence or 
cord compression/neurological compromise or obvious radiological evidence of disease recurrence 
within the bone site treated with radiotherapy on this protocol or within the bone treated on this 
protocol.  Radiologists will take care to differentiate treated, sclerotic bone reaction from true 
progression of disease.  
Distant disease progression – defined as radiological evidence of disease progression or 
recurrence in location (s) other than those treated on this protocol
Progression Free Survival - length of time from start of radiotherapy for the breast cancer bone 
metastases that a patient lives with the disease but it does not get worse
Overall Survival -  length of time from the start of radiotherapy for the breast cancer bone 
metastases that patients diagnosed with the disease are still alive
Patients who develop disease progression should receive best medical therapy as judged per their 
treating physician.  This may include, but not limited to chemotherapy, hormonal therapy, biologic 
therapy, radiosurgery, cryotherapy, and radio-frequency ablation (RFA). 


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5.0 TREATMENT PLAN/REGIMEN DESCRIPTION
5.1 Trial Design 
This Phase II study is designed to determine the efficacy and safety of administering concurrent 
palliative conventionally fractionated radiotherapy to bone metastases in hormone receptor positive, 
Her2/neu negative breast cancer patients who are actively receiving palbociclib and hormone 
therapy.  
5.2 Participant Selection
42 hormone receptor positive, Her2/neu negative biopsy proven metastatic breast cancer patients 
with bone disease and receiving treatment with palbociclib and hormone therapy will be recruited for 
this study.  Assuming a 20% dropout rate, a minimum of 33 patients will be available for analyses.
Patients must have bone lesions that cause symptoms which require palliation or if asymptomatic, are 
at risk for impending clinical event such as cord compression or pathologic fracture.   
NOTE: SBRT is not allowed for the lesion to be treated on this protocol.  
5.3 Assessments
Screening Phase is the time between the date a patient provides written informed consent and the 
patient begins radiotherapy.  Data collection and procedures during this time period include patient 
demographics, eligibility requirements, type of endocrine therapy, concomitant medications, medical 
history, physical examination/vital signs, imaging results, ECOG performance status assessment, 
adverse events, serious adverse events, laboratory measurements, pregnancy testing (if applicable), 
biospecimens (blood samples), and PRO assessments.  All narcotic analgesics, including regular and 
breakthrough medications and doses, route of administration (e.g. PO, IV, transdermal), for pain in 
the index site(s) should be tracked for the 24 hour period prior to assessment and converted to daily 
oral morphine equivalent for analgesic scoring.  For patients presenting with a painful bone 
metastasis to be treated on protocol and whose analgesic use is sub-optimal and who require titration 
or changes in pain medications, a ‘run-in’ period of 1 week between analgesic dosing adjustment and 
initiation of radiation is recommended to minimize the risk that analgesic effects will confound the 
measurement of radiation effects.(20)  
Only AEs deemed to be serious and related to protocol mandated and not routinely performed 
procedures have to be reported during this phase.
TABLE 1. PRE-RADIOTHERAPY TREATMENT ASSESSMENTS
Assessments
Prior to Registration 
(calendar days)
Prior to Radiation Treatment
(calendar days)
History/physical examination, 
Performance Status
< 14 days
MRI or CT Scans of the chest, 
abdomen, pelvis with 
radionuclide bone scan OR 
whole body PET/CT
< 60 days


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CBC with differential & ANC, 
platelets, complete metabolic 
panel
< 14 days
Serum/urine pregnancy test (if 
applicable)
< 14 days
Plasma ctDNA,  inflammatory 
cytokine, and RNA blood 
collection
< 14 days
Patient Reported Outcome 
Assessments*:

Brief Pain Inventory 
Short Form (BPI)**

Multidimensional Fatigue 
Inventory (MFI-20)

European Organization 
for Research and 
Treatment of Cancer 
Metastases Module 
(EORTC QLQ-BM22)

EORTC Quality of Life 
Questionnaire Core 15 
for Palliative Care (QLQ-
C15-PAL)  

Medical Outcomes Study 
36-Item Short Form 
Version 2 (SF-36

Hospital Anxiety and 
Depression Scale 
(HADS)
< 14 days
*The baseline pre-treatment assessments are essential and should be undertaken as close as 
possible to the time of first radiation treatment delivery.  
**If more than one anatomic region containing bone metastases is treated, a BPI short form 
must be completed for each anatomic region treated at each assessment.   


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TABLE 2. DURING RADIOTHERAPY TREATMENT ASSESSMENTS
Assessment
Weekly Radiation Treatment 
Visit per Standard of Care
Last Day of Radiation
Patient Reported Outcome 
Assessments:

Brief Pain Inventory 
Short Form (BPI)**

Multidimensional Fatigue 
Inventory (MFI-20)

European Organization 
for Research and 
Treatment of Cancer 
Metastases Module 
(EORTC QLQ-BM22)

EORTC Quality of Life 
Questionnaire Core 15 
for Palliative Care (QLQ-
C15-PAL)  

Medical Outcomes Study 
36-Item Short Form 
Version 2 (SF-36)

Hospital Anxiety and 
Depression Scale 
(HADS)
X
Adverse event evaluation
X
X
Physical Examination
X
X
Performance Status
X
X
CBC with differential & ANC
X
**If more than one anatomic region containing bone metastases is treated, a BPI short form 
must be completed for each anatomic region treated at each assessment. The acceptable 
assessment window for “Last Day of Radiation” assessments is +/- 48 hrs for physical examination, 
performance status, and CBC w/ differential & ANC.
TABLE 3. POST-RADIOTHERAPY TREATMENT FOLLOW-UP ASSESSMENTS
Assessment
Post-Radiation Treatment (months)
Patient Reported Outcome Assessments:

Brief Pain Inventory Short Form (BPI)**

Multidimensional Fatigue Inventory (MFI-
20)

European Organization for Research and 
Treatment of Cancer Metastases Module 
(EORTC QLQ-BM22)

1 month

3 months


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
EORTC Quality of Life Questionnaire 
Core 15 for Palliative Care (QLQ-C15-
PAL)  

Medical Outcomes Study 36-Item Short 
Form Version 2 (SF-36)

Hospital Anxiety and Depression Scale 
(HADS)  
CBC with differential & ANC, platelets, complete 
metabolic panel

1 month

3 months
Plasma ctDNA,  inflammatory cytokine, and RNA 
blood collection

3 months
MRI or CT Scans of the chest, abdomen, pelvis 
with radionuclide bone scan or whole body 
PET/CT*

3 months
Adverse event evaluation

1 month

3 months
Physical Examination

1 month

3 months
Performance Status

1 month

3 months
*Note: We strongly encourage the use of the same imaging performed at baseline.  The acceptable 
assessment window for “1 month” post radiotherapy assessments is within 3 to 7 weeks post last day 
of radiotherapy treatment.  The acceptable window for “3 months” post radiotherapy assessments is  
within 11 to 16 weeks post last day of radiotherapy treatment. 
**If more than one anatomic region containing bone metastases is treated, a BPI short form 
must be completed for each anatomic region treated at each assessment.  
5.4 Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy
Patients receiving more than 1 line of chemotherapy for advanced disease prior to registration are 
NOT eligible.  Standard of care systemic therapy should be administered at the discretion of the 
treating medical oncologist in the event of disease progression.  It is recommended that the systemic 
therapy follow standard guidelines for use of chemotherapy, hormonal therapy, bone protective 
therapy, and biologic therapy as appropriate for the patient’s metastatic breast cancer.  While 
receiving radiotherapy to bone metastases on this protocol, concurrent cytotoxic chemotherapy is not 
allowed.  However, concurrent bisphosphonate and rank ligand inhibitors are allowed.  
Palbociclib and Hormone Therapy  
 
Eligible patients are those who have had 1 or more cycles of palbociclib (3 weeks of palbociclib at 75 
or 100 or 125mg QD, 1 week off for a total of 28 days) and hormone therapy, immediately prior to 
initiation of radiotherapy.  It is required that radiotherapy will be given concurrently with hormone 
therapy and at least the second cycle (or higher) of palbociclib.  No dose reduction for endocrine 
therapy is permitted, but dosing interruptions are allowed although treating physicians should make 
every effort to encourage compliance with prescribed hormone therapy by changing medications or 


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providing drug holidays if necessary.  Endocrine therapy treatment interruptions for up to 2 
consecutive weeks within 14 days of initiation radiation and during radiation treatment for endocrine 
therapy-related toxicities or personal reasons are allowed as per investigator’s best medical 
judgment.  However, no more than 2 cumulative weeks off endocrine therapy is recommended while 
patient is on study.  Subjects missing more than 2 cumulative weeks of endocrine therapy during the 
period mentioned above (within 14 days of initiating radiotherapy and during radiotherapy treatment) 
will be noted and reasons for discontinuation will be recorded.  These patients will be continued to be 
followed according to post treatment follow up.
While receiving radiotherapy to bone metastases on this protocol, patients must be actively receiving 
palbociclib (125 or 100 or 75 mg PO daily for 3 weeks followed by a week off during 28-day cycles) 
plus one of the following hormone therapies: 
a) Fulvestrant (500mg IM injection on days 1 and 15 cycle one and then on day one of 
each subsequent cycle (28 days) -or-
b) Letrozole (2.5 mg PO daily) -or-
c) Anastrozole (1mg PO daily) -or-
d) Exemestane (25mg PO daily) -or-
e) Tamoxifen (20mg PO daily)
Palbociclib and hormone therapy will be prescribed to hormone receptor positive, Her2 negative 
breast cancer patients participating on this study as standard of care.  Patients will be reminded to 
store palbociclib capsules at room temperature (59-86 degrees Fahrenheit) in their original container.  
Palbociclib (75mg or 100mg or 125 mg) is taken orally once per day with food for 21 days and then 7 
days off to complete a 28 day cycle.  Patients self-administer the medication.  Missed doses of 
palbociclib should not be made up even if a dose is vomited.  Dose should be skipped and NOT 
retaken the next day.  Patient who inadvertently take 1 extra dose during a day must skip the next 
day’s dose.  If patients take more than 2 doses of palbociclib in a day, the treating physician should 
be notified.
Patients should be instructed to record daily administration of both palbociclib and hormone therapy 
in a drug diary.  
During radiotherapy, no other investigation or commercial agents or therapy for cancer other than 
palbociclib, bisphosphonates, rank ligand inhibitors, and hormone therapy should be administered.  
Endocrine therapy will be given at standard treatment doses (see above).  Adjuvant endocrine 
therapy will have started for at least 28 days prior to radiation initiation and will be given concurrently 
with radiation treatment.  
For premenopausal women, tamoxifen or LHRH agonist (monthly injections rather than 3 month 
depot injections are preferred) in combination with tamoxifen or AI is recommended.
For postmenopausal women, non-steroidal aromatase-inhibitors (anastrozole, letrozole) or steroidal 
aromatase inhibitors (exemestane) are recommended.  
In patients who have received radiologic ablation of the ovaries, an LHRH agonist is still needed if the 
patient is given an aromatase inhibitor.   


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Hormone therapy is self-administered.  Recommended dosing regimens are stated above. Storage 
conditions are detailed in the package insert and should be followed.
Missed doses of endocrine therapy should not be made up.  If a patient had difficulty tolerating 
endocrine therapy, the treating provider must make every effort to continue the patient on endocrine 
therapy, including changing the endocrine agent or using short drug holiday, while continuing 
treatment with palbociclib.  For endocrine therapy on this protocol, one treatment cycle is 28 days for 
data collection purposes.     
5.5 Radiotherapy Treatment
 
The Radiotherapy Treatment Phase is the time period between and including Day 1 and the last day 
of radiotherapy.  Enrolled patients will take palbociclib and hormone therapy during radiotherapy 
treatment.  
Patients will undergo CT simulation in preparation for radiation planning. Patients can be treated with 
2-D, 3-D, intensity modulated radiation therapy (IMRT), and Volumetric Arc Therapy (VMAT). 4-20 
MV photon beams or 5-20MeV electron beam may be used.  Cobalt-60 and proton radiotherapy are 
not allowed.  
More than 1 osseous site may be included in one radiation treatment field.  Up to 4 radiation 
treatment fields separated by at least 2cm may be treated on protocol.
Dose Fractionation
30 Gy at 3 Gy per fraction or 20 Gy at 4 Gy per fraction given over sequential business days 
excluding weekends and holidays are allowed on this protocol. 
95% of the prescribed dose must cover 95% of the PTV (90% of the prescribed dose to 90% of the 
PTV is permitted and is considered Variation Acceptable).  Dmax should not exceed > 115% and is 
not permitted on this study.  Other radiation fractionation schemes and SBRT are not allowed.     
All institutions must use heterogeneity correction dose calculation algorithms.  
Isocenter Placement – It is best to place isocenter near the center of the target lesion.  If there are 
multiple lesions that cannot be treated in a single field, multiple isocenters should be placed with each 
centered in a separate target lesion.
Patient Immobilization, Simulation, and Localization 
Participating subjects will be positioned in a reproducible, comfortable, and stable pose to allow for 
both reliable and accurate target position during treatment.  The immobilization and pose must be 
reliable enough to ensure that the GTV does not deviate beyond the confines of the PTV.  Ideally, 
multiple bone metastases treated on this study would be treated in one treatment position.  However, 
more treatment positions can be used at the discretion of the treating radiation oncologist.   
CT-based treatment planning is required for all patients.  


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The CT scan must encompass the target metastases, as well as the following necessary organs at 
risk (OAR) when included in the radiation field:

Heart

Organ

Lungs

Kidneys

Spinal Cord

Brain

Brainstem

Lens

Brachial plexus
CT scans should have uniform slice thickness of <5mm.  The use of IV contrast is left to the discretion 
of the treating radiation oncologist but is not required.  
On board imaging (OBI) using KV, MV x-rays, cone beam CT or CT on rails at least once every 5 
fractions, per standard of care, is required.
Target Volumes
The treating radiation oncologist will contour the gross tumor volume (GTV), clinical target volume 
(CTV) and planning target volume (PTV), as well as relevant normal structures within the radiation 
field (e.g. spinal cord, kidneys, lung, and heart).
Metastasis Location Definition:
When defining the GTV, the simulation CT window should be leveled to bone/soft tissue and the 
radiation oncologist should use additional diagnostic studies as needed to define the GTV which is 
the entirety of the metastasis.   
The bone where each metastasis to be treated on protocol needs to be identified and annotated in 
the case reports:

Spinal metastases will be demarcated spinal if the GTV arises within the vertebral 
bodies or the vertebral body and pedicle or posterior elements.  The CTV will include 
the entire vertebral body (ies) containing the GTV metastases and PTV will be at least a 
5mm expansion on the CTV and could include up to one vertebral body above and 
below the vertebral body (ies) containing the GTV.  

Non-spinal osseous metastases will be demarcated by the bone from which the target 
lesion primarily arises.  CTV will be at least a 7mm expansion on the GTV, contoured at 
the discretion of the treating radiation oncologist to expand more generously when 
clinically indicated (e.g. in the case of a femoral neck metastasis, a radiation oncologist 
may choose to contour the entire femoral head, neck and inferiorly to below the lesser 
trochanter as CTV). PTV will be an additional 5mm expansion on the CTV.  


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Treatment Planning
The radiation field should include all of the GTV, CTV, and PTV with at least 90% of the prescription 
isodose line covering 90% of the PTV, where the maximum hotspot is 115%.  Heterogeneity 
corrections must be used.  Every effort should be made to place hotspots in the target lesion. 
  
Planning priorities
Every attempt should be made to achieve planning goals and OAR criteria without receiving a plan 
score of Deviation Unacceptable.  The following are a list of suggested priorities of planning goals:
a) Do not exceed spinal cord, brachial plexus, sacral plexus or cauda equina dose 
constraints
b) Meet critical structure constraints (see below)
c) PTV coverage with 95% of PTV covered by the 95% isodose line  
90% of the prescribed dose to 90% of the PTV is permitted and is considered Variation Acceptable. 
Dmax should not exceed > 115% and is not permitted on this study.  Other radiation fractionation 
schemes and SBRT are not allowed.     
Overlap with prior radiation volumes is not allowed.  Radiation fields to be administered on this 
protocol must be more than 2cm from prior radiation treatment, as the toxicity of palbociclib with 
radiation is unknown and could be enhanced in areas where radiation has been previously 
administered.   
Critical Structures:
Note: If any of the structures below are within 3cm of any metastases or included in any of the 
radiation fields to be treated on this protocol, it is required that the included structures are 
contoured and labeled as listed below for radiation data submission in DICOM format. 
 
Table 4. STRUCTURE CONTOURING GUIDELINES
Standard Name
Description
GTV
GTV 

When defining the GTV, the simulation 
CT window should be leveled to bone/soft 
tissue and the radiation oncologist should 
use additional diagnostic studies as 
needed to define the GTV which is the 
entirety of the metastasis
CTV
GTV with at least a 7mm expansion, contoured 
at the discretion of the treating radiation 
oncologist to expand more generously when 
clinically indicated, or if spinal metastasis, entire 
vertebral body (s) containing the GTV should be 
considered the CTV
PTV
CTV with at least a 5mm expansion, excluding 
expansion outside of the external contour + 


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0.5cm internal to the external contour, and could 
include up to one vertebral body above and 
below the vertebral body (ies) containing the 
GTV when treating vertebral metastasis(es)
External
Body Surface
SpinalCord
Spinal cord

Should be contoured starting at least 
10cm above superior extent of PTV and 
continuing on every consecutive CT slice 
at least 10cm below inferior extent of PTV 
but does not extend inferiorly below L2
Heart
Heart

Start contouring at the bifurcation of the 
pulmonary arteries and continue on every 
CT slice containing heart and extend 
inferiorly to the apex of the heart

Include the pericardial sac in the contour 
BowelBag
Bowel Bag

The small bowel, cecum, and ascending, 
transverse and/or sigmoid colon should 
be contoured in one bowel bag starting 
1cm above the superior extent of PTV 
and continuing on every consecutive CT 
slice to 1cm below PTV excluding muscle 
and bones and subtract any overlapping 
non-gastrointestinal normal structures.
R_Kidney
Right Kidney

Right kidney, excluding renal 
pelvis/collecting system, should be 
contoured
L_Kidney
Left Kidney

Left kidney, excluding renal 
pelvis/collecting system, should be 
contoured
Kidneys
Total Kidneys

Both right and left kidney, excluding renal 
pelvis/collecting system, should be 
contoured in their entirety
R_Lung
Right Lung

Right lung should be contoured on lung 
windowing on CT
L_Lung
Left Lung

Left lung should be contoured on lung 
windowing on CT
Lungs
Combined Left and Right Lungs

Both lungs should be contoured as one 
structure on lung windowing on CT


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Esophagus
Esophagus

Use mediastinal windowing on CT to 
delineate the esophagus to include all 
layers, lumen, and fatty adventitia 

Begin contouring at least 10cm above the 
superior extent of the PTV and continuing 
every CT slice to at least 10cm below the 
inferior extent of the PTV
R_BrachialPlexus
Right Brachial Plexus

Contour the major trunks of the Right 
brachial plexus using subclavian and 
axillary vessels as a surrogate for the 
location of the brachial plexus. 

Start contouring proximally at the 
bifurcation of the brachiocephalic trunk 
into the Right jugular/subclavian veins (or 
carotid/subclavian arteries) and contour 
along the subclavian to the axillary vein 
ending after the neurovascular structures 
cross the second rib.  
L_BrachialPlexus
Left Brachial Plexus

Contour the major trunks of the Left 
brachial plexus using subclavian and 
axillary vessels as a surrogate for the 
location of the brachial plexus. 

Start contouring proximally at the 
bifurcation of the brachiocephalic trunk 
into the Left jugular/subclavian veins (or 
carotid/subclavian arteries) and contour 
along the subclavian to the axillary vein 
ending after the neurovascular structures 
cross the second rib.  
BrachalPlexus
Total Brachial Plexus

Contour the major trunks of the brachial 
plexus using subclavian and axillary 
vessels as a surrogate for the location of 
the brachial plexus. 

Start contouring proximally at the 
bifurcation of the brachiocephalic trunk 
into the jugular/subclavian veins (or 
carotid/subclavian arteries) and contour 
along the subclavian to the axillary vein 
ending after the neurovascular structures 
cross the second rib.  
CaudaEquina
Cauda Equina


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
Includes the entire spinal canal starting at 
L1/L2 where the conus begins and 
extending into the sacrum and filum
Sacralplexus
Sacral plexus

Extends from L5 to S3 and includes the 
bilateral nerve roots from the 
neuroforamina to the coalescing of the 
nerves at the obturator internus muscle
Critical Organ Dose-Volume Limits
Planning priorities for Organs at Risk:
An unacceptable deviation will be assigned to radiation plans which exceed the absolute limits of the 
spinal cord, cauda equina, sacral plexus, or brachial plexus (i.e. 115% of the prescribed dose to 
>0.03cc of any of these OARs).  
Every effort will be made to cover 100% of the GTV with 100% of the prescribed dose.  Ultimately, at 
least 90% of the PTV must be covered by at least 90% of the prescribed dose or the plan will be 
considered deviation unacceptable.  Radiation plans will be considered unacceptable if any of the 
criteria below in the table “CRITICAL ORGAN DOSES” are not fulfilled. 
TABLE 5. CRITICAL ORGAN DOSES
Structure
Volume
Dose/Volume
Spinal Cord
<0.03cc
>115% prescribed total dose
Brachial plexus
<0.03cc
>115% prescribed total dose
Cauda equina
<0.03cc
>115% prescribed total dose
Sacral plexus
<0.03cc
>115% prescribed total dose
BowelBag
<0.03cc
>115% prescribed total dose
Total Lungs
V20
<35% 
Esophagus
Mean
<30 Gy
Kidney, bilateral 
Mean
<15 Gy
Kidney, bilateral 
V12
<55%
Heart
Mean
<20 Gy
Brain, brainstem
<0.03cc
>115% prescribed total dose
Composite Dose Calculations
When more than one radiation field is used to treat multiple metastases, composite plans which 
include total dose summation from the multiple treatment sites on a single CT scan that encompasses 
relevant anatomy, must be generated to incorporate dose to surrounding normal tissues. These 
composite plans must include a planning CT dataset that incorporates all targets and relevant critical 
structures.  When more than one field is used to treat multiple bone metastases, it is advisable to 
treat all lesions with the patient in the same position.  Contact the study PI, Dr. Mylin Torres, if there 
are technical challenges in summing dose and generating composite plans.


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Composite dose plans including all treated metastases and OARs must be submitted.  To facilitate 
composite planning, dose to all metastases should be calculated on a single CT scan.  If this is not 
possible, dose from each separate metastasis treatment plan should be generated and incorporated 
on the composite plan.  
5. Documentation Requirements
Treatment interruptions, including reasons for treatment breaks, must be clearly documented in the 
treatment record.  However, treatment interruptions should be avoided generally.
Sites will record dose-volume values for all required structures on a datasheet which will be submitted 
with the digital radiation data to Emory University for review.
If re-irradiation of the index lesion is deemed necessary after protocol treatment, it is preferred that re-
irradiation be performed 3 months or later after initial radiation and after the last protocol assessment 
and should only be considered at least 4 weeks after initial treatment on protocol.  If re-irradiation of 
the index lesion occurs, it must be documented.
6.0 BIOSPECIMEN COLLECTION AND SUBMISSION
Tables 1 and 3 summarize the biospecimens that are to be collected from participants at specific 
study time points.  For all participants, biospecimen collection is mandatory, unless otherwise 
specified and/or specifically prohibited by local regulations or patient refusal.  Instructions for 
collection, on-site processing, storage, and shipping are listed below.
Collection
Blood samples (35 mL total) will be drawn at the same time of day between 8-11 am (to reduce 
potential circadian effects) on a fasting stomach under sterile conditions at study visits corresponding 
to the pre-treatment and 3 months post radiation visit noted in Figure 1. STUDY SCHEMA above.
TABLE 6. BLOOD COLLECTION TIMEPOINTS
Sample Type
< 14 Days Prior to Radiation
3 Months Post Radiation 
Completion
Plasma for circulating 
tumor DNA (ctDNA)
X
X
Plasma for cytokines
X
X
RNA Tempus Tube
X
X
6.1 Circulating Tumor DNA
Step #1 - Blood Draw
a) 20ml (or two 10 ml Cell-Free DNA BCT Streck tubes) is collected by any standard phlebotomy 
technique from a peripheral access point or from a central line by trained personnel.
b) Tubes are inverted about 10 times immediately after collection.
c) Samples are the prepared for transportation to the laboratory for processing (within 24 hours).


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Step #2 - Plasma Processing (in Laboratory)
a) Perform this step once for each patient (does not need to be repeated for subsequent blood 
draws): transfer 1 mL whole blood with a pipette to a pre-labeled 2 mL cryogenic vial, round 
bottom, self-standing
b) Streck tubes are centrifuged at room temperature for 10 min at 1600 (±150) g.
c) After centrifugation, remove tubes from centrifuge and transfer supernatant of the Streck tubes 
to one fresh 10 ml polypropylene centrifuge tube without disturbing the cellular layer using a 
disposable serological pipette or disposable bulb pipette. 
d) Centrifuge the plasma in the 10 ml centrifuge tube at room temperature for 10 min at 3000 
(±150) g.  
e) After centrifugation, remove tubes from centrifuge and transfer supernatant to a fresh 10 ml 
centrifuge tube without disturbing the cellular layer using a disposable serological pipette or 
disposable bulb pipette. After transferring the plasma to a new 10 ml centrifuge tube as 
described, gently mix plasma and record total plasma volume (~8-10 ml plasma per 20 ml 
blood).
f)
Transfer 1 ml plasma aliquots with a pipette to 2 ml pre-labeled cryogenic vials.
g) Place plasma tubes into storage box and freeze plasma in freezer upright in storage box at -
80°C or colder. Short time storage at -20°C is possible.
Step #3 - Specimen Storage
a) Sample are maintained continuously at -80°C or colder.
b) When outside the freezer, such as when transferring to a different freezer in another location 
or preparing for shipment, boxes containing tubes should be covered with dry ice.
c) Freezer or dry ice specimen storage container temperature must be checked and monitored 
Document any deviation from protocol.
d) The freezer or dry ice storage box containing the specimens should either be locked or in a 
secure area accessible only to authorized study staff.
e) A backup storage plan should be in place in the event of freezer failure.
6.2 Inflammatory Markers and RNA  
15 mL is collected for cytokines and RNA analysis from patients under conditions noted above and at 
the same time as blood collection for ctDNA.  
Cytokines/Inflammatory Markers:
1. Collect blood using two purple-top 4mL EDTA vacutainers. 
2. Carefully and slowly invert the lavender top tube 3 times
3. Within 1 hour of collection, centrifuge sample under the following settings:

3000rcf, 10 minutes, 4°C, brake on.
4. Gather six (6) 1.5ml microcentrifuge tubes and place on wet ice to cool.
5. Once centrifuged, pipette 500µl of plasma into 6 microcentrifuge tubes. 
Buffy Coat Extraction:
6. Using a blunt-tip pipette, collect thin white layer between plasma and red blood cells from each 
vacutainer, and transfer to two 1.5mL microcentrifuge tubes.
7. Immediately store all plasma and buffy coat tubes at -80°C.


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Tempus Tube for RNA:
1. Collect blood using 3mL Tempus Tube
2. After collection, shake thoroughly and vigorously for 10-15 seconds and place on wet ice.
3. Store immediately at 4°C to temporarily cool.
4. Following plasma/buffy coat extraction, store tempus tubes at -20°C in designated freezer box. 
Vortex or shake well before transferring to freezer.
Label each tube collected above before freezing.  Labels should have the following information:
1. Study Name
2. Patient ID
3. Visit (Pre radiotherapy or Post radiotherapy)
4. Sample Type (plasma, RNA)
5. Date
6. Corresponding Barcode (if applicable)
6.3 SHIPPING OF BIOSPECIMENS 
Only an authorized shipper can send out biological samples. 
6.3.1 Shippers will schedule a pickup beforehand, via FedEx (phone or web):
1.1.1.
1-800-GO-FEDEX [1-800-463-3339]
1.1.2.
FedEx.com
6.3.2 The study sponsor and PI will be responsible for setting up a FedEX account for all 
participating institutions to use to ship samples.
6.3.3 Arrange shipment on the same day that samples are to be packaged, as to avoid thawing 
of dry ice. Whenever possible, please store samples locally and then ship in batch, after 
last specimen collection from last enrolled subject, to Emory University (plasma for 
inflammatory markers, buffy coat, tempus tubes) or Massachusetts General Hospital 
(plastma for ctDNA from Streck tubes).  
6.3.4 Packaging samples:
Items needed:
6.3.5 Dry Ice
6.3.6 Styrofoam cooler
6.3.7 Cardboard box regulated and designated for shipping
*cooler must fit tightly in cardboard box as to not allow room for movement.
6.3.5 Before preparing shipment, make sure that all packaging is not damaged.
6.3.6 Place cooler in cardboard box and fill cooler about ¼ full with dry ice.
6.3.7 Place sample box (or boxes) in biohazard bag.
6.3.8 Place box in cooler, then proceed to fill cooler with dry ice around the sides and top, if 
possible. 
*DO NOT TIGHTEN COOLER LID, AS THIS CAN CAUSE THE PACKAGING TO 
EXPLODE.
Label package with appropriate stickers and information:
6.3.9  FedEx Shipping Form
6.3.10 Class 9 Hazard label, for dry ice.
6.3.11 Shipper/Receiver contact information
6.3.12 Dry Ice weight (kg). 
6.3.13 UN3373 label – for Biological Substance, category B


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6.3.14 Include an itemized list of contents between the secondary container and outer packaging.
6.3.15 Record shipping departures in appropriate log. 
7.0 COMPLIANCE CRITERIA
Radiation
Each bone metastases may be treated to a dose of 30 Gy at 3 Gy per fraction or 20 Gy at 4 Gy per 
fraction on protocol.  Treatments should be given on sequential business days, excluding weekends 
and holidays.  

If a patient receives 30 Gy at 3 Gy per fraction, acceptable variation is treatment completing in 
>2 but <3 weeks.  Unacceptable Deviation is >3 weeks.

If a patient receives 20 Gy at 4 Gy per fraction, acceptable deviation is treatment completing in 
>1 but <2 weeks.  Unacceptable Deviation is >2 weeks.  
PTV goal coverage is at least 95% of the PTV covered by at least 95% of the prescribed dose with 
dose not exceeding 115% of the prescribed dose.

Variation acceptable is at least 90% of the PTV covered by at least 90% of the prescribed 
dose

Deviation unacceptable is <90% of the PTV covered by at least 90% of the prescribed dose or 
<90% of the dose covering 90% of the PTV.  
Palbociclib and Hormone Therapy
To capture adherence to both standard dose regimens of oral palbociclib and hormone therapy, drug 
diaries will be maintained for all patients.  Diaries will be completed by the patient and reviewed for 
accuracy with the patient at each study visit.  Patients who are non-adherent with their medications 
may receive phone calls and/or extra study visits to encourage adherence.  Non-adherence will be 
documented within the chart and reported to the study PI.
Data from the drug diaries of all enrolled patients will be entered into the electronic data submission 
forms.  For each 28 day cycle, data regarding the number of days palbociclib and/or endocrine 
therapy were taken as well as number of days palbociclib and/or endocrine therapy should have been 
taken will be entered.  Adherence will be determined by number of days taken divided by number of 
days drug should have been taken over the time period of the study. 
8.0 DISEASE MONITORING
All patients, including those who discontinue protocol therapy early, will be followed for oncological 
events and death per ASCO guidelines until last study visit.
The following definitions are used for confirmation of oncologic events:
Local recurrence (i.e. non-responder) – defined as radiological evidence of disease recurrence 
within the bone site treated with radiotherapy on this protocol or pathologic fracture, cord 
compression/neurological compromise due to disease recurrence within the bone treated on this 
protocol.  Radiologists will take care to differentiate treated, sclerotic bone reaction from true 
progression of disease.


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Distant disease progression – defined as radiological evidence of disease progression or 
recurrence in location other than those treated on this protocol
Progression Free Survival - length of from start of radiotherapy for the breast cancer bone 
metastases that a patient lives with the disease but it does not get worse
Overall Survival -  length of time from the start of radiotherapy for the breast cancer bone 
metastases that patients diagnosed with the disease are still alive
9.0 SUPPORTIVE CARE GUIDELINES AND GENERAL CONCOMITANT MEDICATION USE
The following concurrent medications are permitted and should be recorded in the source documents 
and transferred to the electronic data submission forms:

Antiemetics

Antidiarrheal therapy

Antiallergic measures, such as antihistamines, and corticosteroids

Bisphosphonates – patients may be on it already or may initiated treatment while on 
protocol therapy

Agents used to assist in management of endocrine therapy-induced side effects (NSAIDS, 
gabapentin, duloxetine, venlafaxine)

Diabetes management medication including metformin

Rank Ligand inhibitors

Pain medications
All supportive therapy will be given during the study period at the discretion of the attending 
physician(s) to optimize medical care as long as they are within the parameters of the protocol 
and documented on each site’s source documents as concomitant medication: 

Anticonvulsants if indicated

Anti-emetics may be given prior to each fraction to prevent nausea

Antidiarrheal as indicated by symptomatic diarrhea 

Analgesic premedication or to avoid general discomfort during simulation and treatment is 
recommended when appropriate.

Analgesic medications to decrease pain from the bone metastases

Medications for neuropathy (e.g. gabapentin)

Corticosteroids if indicated

Hematopoietic growth factors should not be used during radiation protocol therapy. G-CSF or 
pegylated G-CSF may have been given as part of prior chemotherapy as indicated by standard 
parameters, but ANC must be recovered to entrance values for the protocol without ongoing 
support.   

Herbal products are at the treating physicians’ discretion and should be captured on the 
concomitant medication forms. 

Nutritional supplementation may be administered per standard indications and should be 
captured on the concomitant medication forms. 


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
Highly active antiretroviral therapy (HAART) is permitted for HIV affected individuals

Medications for gastritis and esophagitis including proton pump inhibitors and magic 
mouthwash 
Systemic Therapy
All hormonal therapy is expected to be continued during radiation.  Bone supportive therapy may be 
continued during radiotherapy.  Cytotoxic chemotherapy and everolimus are not permitted during the 
administration of protocol specific radiation.  Cytotoxic chemotherapy must be held for at least 28 
days prior to radiation treatment on the protocol.   Only one prior line of chemotherapy in the 
advanced stage setting is permitted prior to radiation treatment on this protocol.  In the event of 
disease progression, everolimus or cytotoxic chemotherapy may be initiated or resumed 28 days post 
radiation in the absence of infection or non-healing wound and will be clearly documented.  Surgery is 
not allowed for 30 days prior to or during radiotherapy but may be permitted after radiotherapy is 
completed.  
Changes in systemic treatment including bisphosphonates and hormonal therapy within 4 weeks prior 
to delivery of radiotherapy and up to 3 months post radiotherapy treatment on protocol should be 
recorded.  Surgery or cytotoxic chemotherapy treatment after completion of radiotherapy on protocol 
should also be recorded.   
Prohibited Concomitant Medications include:

CYP3A Inhibitors/Inducers (see exclusion criteria)

Anticancer therapies such as chemotherapy, immunotherapy, targeted therapy, etc. other 
than allowed on protocol during active treatment.  

Hormone replacement therapy (see exclusion criteria)
Medications not recommended:

Herbal medicine is not recommended during the treatment phase

Chronic immunosuppressive therapies should be avoided
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s), as described in Section 11 below

Patient decides to withdraw consent for participation in the study, or

General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
  


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10.0 TREATMENT MODIFICATIONS/MANAGEMENT
Expected toxicities and potential risks of both palbociclib and hormone therapy can be found in the 
package inserts (see Appendix).
10.1 Palbociclib Dose Modification and Toxicity Management
Dose or treatment modification for palbociclib are allowable and may occur as dose interruptions 
(within a cycle), dose delays (between cycles) or dose reductions.  In general, cycles should be 28 
days long unless the start of a new cycle is delayed.  If doses are missed within a cycle and 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 
cycles should be delayed according to guidelines below if the AE requiring a dose hold has not 
resolved by Day of the next planned cycle.  

Palbociclib dose may need to be reduced from 125mg to 100mg or to 75mg, following a cycle 
delay or dose interruption

Investigators should manage their patients according to medical judgement and no specific 
dose adjustments are recommended for Grade 1 or short lasting Grade 2 (<4 weeks) 
treatment-related toxicity.

Palbociclib dose reduction from 125mg to 100mg  or to 75mg is recommended for all 
subsequent cycles when the patient develops Grade 2 toxicity lasting >4 weeks (excluding 
alopecia) or for palbociclib related Grade 3 toxicities despite maximum supportive care.  
Taking palbociclib with food should be confirmed and reinforced.  Once a dose has been 
reduced for a given patient, all subsequent cycles should be administered at that dose level, 
unless further dose reduction is required.  If a patient is taking 75 mg daily of palbociclib, the 
subjects will still be eligible for enrollment.  Dose re-escalation of palbociclib from 75 to 100 mg 
or 100 to 125 mg is not allowed.  If the dose reduction occurs after radiation, this will be noted 
in the chart and the patient will be assessed at all post radiation study time points per study 
guidelines.    
Palbociclib treatment may be interrupted/delayed until criteria for retreatment are met:

Uncomplicated Grade 3 or 4 neutropenia resolves so that the ANC >1000/mcL

Grade 3 or 4 neutropenia with documented infection or fever > 100.4 degrees Fahrenheit 
resolves

Grade >3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and hypertension 
only if persisting despite optimal medical treatment) resolves

All the following parameters are met – platelet count >75,000/mcl, ANC>1000/mcl and no fever 
and any persistent grade >2 treatment-related non-hematologic AEs considered related to 
palbociclib have recovered to Grade <1 or baseline.
CBC with differential including absolute neutrophil count must be done by Day 3 of each cycle of 
palbociclib.  Whenever retreatment after dose delay occurs, the first palbociclib dose day would count 
as Day 1 of the cycle.  If the treatment delay is due to hematologic parameters, the frequency of 
blood count assessment should be adjusted as clinically indicated.  If retreatment parameters are met 
within 4 weeks of treatment interruption or cycle delay, palbociclib may be resumed.  


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Palbociclib treatment may be interrupted/delayed if Grade 2 non-hematologic toxicity persists despite 
optimal medical treatment, lasting more than 3 weeks, and unacceptable to patient and/or provider.  
Palbociclib treatment will be permanently discontinued if >3x upper limit of normal ALT and 2x upper 
limit of normal Total Bilirubin, at any time during the trial.  
Patients should not hold or discontinue palbociclib for side effect potentially or likely related to 
endocrine therapy, as per the physician’s judgement.  
10.2 Endocrine Therapy Dose Modification and Toxicity Management
No dose reduction for endocrine therapy is permitted, but dosing interruptions are allowed.  However, 
endocrine therapy treatment interruptions for up to 2 consecutive weeks within 14 days of initiation 
radiation and during radiation treatment for endocrine therapy-related toxicities or personal reasons 
are allowed as per investigator’s best medical judgement.  However, no more than 2 cumulative 
weeks off endocrine therapy is recommended while patient is on study.  Subjects missing more than 
2 cumulative weeks of endocrine therapy during the period mentioned above (within 14 days of 
initiating radiotherapy and during radiotherapy treatment) will be noted and reasons for 
discontinuation will be recorded.  These patients will be continued to be followed according to post 
treatment follow up.
Providers are allowed to change the approved endocrine therapy agents to improve patient 
adherence (e.g. tamoxifen to AI or vice versa).  If a patient has difficulty tolerating a specific 
endocrine therapy, the provider should make every effort to continue the patient on endocrine therapy 
by using short drug holidays or changing the prescribed endocrine agent while continuing palbociclib.  
Patients who discontinue palbociclib, endocrine therapy, or radiotherapy will continue to be followed 
according to post treatment follow up.  
10.3 Radiation Therapy Dose Modification and Toxicity Management
Each bone metastases may be treated to a dose of 30 Gy at 3 Gy per fraction or 20 Gy at 4 Gy per 
fraction on protocol.  Treatments should be given on sequential business days, excluding weekends 
and holidays.  No dose reduction in radiation is permitted, but dose interruptions are allowed.  
Radiation treatment breaks for up to 2 consecutive business days for radiotherapy-related toxicities or 
personal reasons are allowed as per the investigator’s best medical judgement.  However, no more 
than 2 missed consecutive doses of radiotherapy (weekends and holidays excluded) is recommended 
per radiotherapy treatment course. 
The Supportive Care Guidelines and General Concomitant Medication section 9.0 above lists 
permissible medications for management of toxicities from radiotherapy, endocrine therapy, and 
palbociclib.  
11.0 ADVERSE EVENTS
All treatment related AEs will be scored according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)  
Adverse events related to treatment on this protocol are dependent on the location of the metastases 
treated as well as OARs included in the radiation field.  Fatigue may occur but should be transient 


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from the radiation.  Neutropenia is likely to occur from the palbociclib treatment but this will be 
monitored for exacerbation during and after radiation treatment with complete blood cell counts and 
differentials, including the absolute neutrophil count.   
11.1 REPORTING ADVERSE EVENTS (AEs)/ SERIOUS ADVERSE EVENTS (SAEs)
All treatment-emergent AEs (events occurring during and up to 3 months post radiotherapy) will 
be recorded.  For participating subsites, adverse events collected at weekly radiation treatment 
visits are to be entered into OnCore no later than 14 calendar days after data collection. 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) or 
Research Ethics Board (REB) responsible for oversight of the patient according institutional 
policy.  Site investigators must report all serious adverse events (SAEs) and unanticipated 
problems to the sponsor-investigator within 24 hours of the participating site becoming aware of 
the event. The participating site will submit the Serious Adverse Event Report Form  to the 
Winship regulatory staff and will also enter the data into OnCore within the specified timelines 
above. The Emory sponsor must review and sign off on the event and return to the Winship 
regulatory staff.  Regulatory will review the assessment to determine IRB reporting 
requirements. Subsites are not permitted to report directly to the coordinating center IRB.  All 
external site SAEs are to be reported to the coordinating center multi-site regulatory specialist.  
The coordinating center multi-site coordinator will facilitate submission of external site SAEs to 
the coordinating center IRB. All SAEs and other adverse events must be recorded on Serious 
Adverse Event Report Forms. In addition, all SAEs must be reported to the coordinating center 
principal investigator and coordinating center multi-site regulatory specialist within 24 hours of 
knowledge of the event using the Serious Adverse Event Report Form.Copies of de-identified 
source documentation pertaining to the SAE must be submitted to the coordinating center. 
If a patient is permanently withdrawn from the study because of an SAE, this information must 
be included in the initial or follow-up form. All SAEs must be submitted to the local IRB per local 
IRB and institutional policy. Upon request of additional data or information that is deemed 
necessary must be reported to the coordinating center as soon as possible but no later than 5 
calendar days.
11.2 Definition of an adverse event (AE)
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug or radiation related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the use of 
a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probably, or definite).  
(International Conference on Harmonisation (ICH), E2A, E6).
For multi-modality trials, adverse event reporting encompasses all aspects of protocol treatment 
including radiation therapy, surgery, device, and drug. 
For example, radiation-related acute toxicities should be recorded in addition to surgical intervention 
at the treated site, pathological fracture, spinal cord compression, and re-irradiation of the treated site 
after completion of radiation treatment on protocol.   


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Pregnancy of a study participant must be reported to the sponsor-investigator in an expedited 
manner, due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents.   
11.3 Assessment of causality of adverse events
Investigators should use their knowledge of the patient, the circumstances surrounding the adverse 
event, and an evaluation of potential alternative causes to determine whether or not an adverse event 
is considered to be related to radiation, palbociclib, and endocrine therapy.  The following guidelines 
should be used:

Temporal relationship of event and treatment with radiotherapy

Course of the event, considering dose reduction, discontinuation, or re-introduction of 
palbociclib, hormone therapy, or radiotherapy

Known side effects of palbociclib, hormone therapy, and radiotherapy

Natural history of hormone receptor positive, Her2-neu/negative metastatic breast cancer

Presence of concomitant medications or concomitant illnesses

Presence of non-treatment-related factors known to be associated with occurrence of the 
event
11.4 Radiation Adverse Events
Lung Injury
Pneumonitis due to radiation may occur weeks to months after treatment and is caused by 
inflammation of the end bronchioles and alveoli.  Radiation oncologists will be expected to participate 
in the care and monitoring of enrolled patients for this symptom per standard of care.  Patients 
reporting fever, shortness of breath, dry cough, and/or chest pain should be immediately evaluated 
and treated.  Mild radiation pneumonitis may be treated with nonsteroidal anti-inflammatory agents or 
steroid inhalers.  For severe cases, systemic steroids, bronchodilators, and pulmonary hygiene may 
be prescribed.  Concurrent infections should be treated with antibiotics.  Radiation fibrosis is a late 
manifestation of radiation lung injury.
Gastrointestinal/Esophageal Injury
Radiation may cause esophagitis or dysphagia which typically resolves within a few weeks of 
radiation.  It may also cause permanent injury, although infrequent at the proposed radiation 
treatment doses, which manifests as dysphagia with stenosis or esophageal ulceration with 
perforation in the extreme cases.  Any of these toxicities must be clearly documented.    
Cardiac and pericardial Injury
Although uncommon at the proposed radiation doses on this protocol, radiation treatment to the heart 
has been associated with pericarditis, endocarditis, coronary artery disease, hypertension, myocardial 
infarction, and heart failure.
Kidney Injury
Radiation may cause kidney injury but not typically at the doses prescribed on this protocol. 
Spinal injury 


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Radiation can cause myelitis which manifests as paresthesia, sensory changes, and motor weakness 
including paralysis.  Because there is no effective treatment for myelitis, it is critical to prevent and 
avoid injury to the spinal cord.  Corticosteroids may help with symptoms.  
Osseous injury
Pathologic fractures and vertebral body compression fractures are extremely uncommon (<8%) at the 
proposed radiation doses of this protocol.  Fractures of bones treated on this protocol will be reported 
immediately to the study monitor and study PI, Dr. Mylin Torres.
Alopecia, erythema, desquamation are common side effects from radiation for osseous metastasis.  
Edema, pain, and neuralgia may be additional side effects of the treatment.  
11.5 Palbociclib and Hormone Therapy Adverse Events
Palbociclib and hormone therapy are both approved for metastatic disease in the United States.  
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 and/or 
hormone therapy may need to be adjusted.  Neutropenia, leukopenia, fatigue, anemia, nausea, hot 
flashes, alopecia, and diarrhea are common side effects of palbociclib.  Arthralgias, vaginal dryness, 
hot flashes, and mood swings, are common side effects of aromatase inhibitors.  Hot flashes, mood 
swings, vaginal changes, and blood clot are possible side effects of tamoxifen.
11.6 Adverse Event Reporting Exceptions
Recurrence or progression of the underlying malignancy is reportable only if the patient dies due to 
recurrence or progression within the study period.  Hospitalization solely due to recurrence or 
progression of malignancy should not be reported as an SAE.  Clinical symptoms of recurrence or 
progression may be reported as AEs if the symptoms 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.  
12.0 REGISTRATION, STUDY ENTRY, DATA COLLECTION AND WITHDRAWAL PROCEDURES
12.1 IRB Approval
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol 
and submit IRB approval and supporting documentation to the Winship Regulatory Office before they 
can be approved to enroll patients.  Assignment of site registration status assures that there is a valid 
IRB approval, and compliance with all protocol specific requirements. 
A.
Registration and Eligibility
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’.  Patients must have signed 
and dated all applicable consents and authorization forms within 30 days of starting 
radiotherapy on this protocol.
After each subject signs consent, the Central Subject Registration form is to be completed 
and sent to Winship within 24 hours of consent. This form, along with the valid, signed 
informed consent form/HIPAA authorization form, is to be faxed or emailed to Winship’s 


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Central Subject Registrar per instructions on the form. Once a subject is registered, each 
participating site will be notified via e-mail.
The Eligibility checklist is to be printed from OnCore and verified by 2 people, of which one 
must be a clinical investigator or co-investigator. The completed and signed eligibility 
checklist along with all redacted supporting source documentation must be submitted to 
the Winship Multi-site Coordinator (MSC) or designee (fax 404-778-0417) within 14 days 
after pre-registration but no later than 2 business days prior to scheduled treatment 
visit.  Eligibility will be confirmed by the site investigator or co-investigator and the MSC or 
designee within 1 business day of receipt of all eligibility documentation and confirmation 
will be sent to the participating site along with a unique patient number or identifier which 
will remain the same throughout the entire study, if subject meets criteria.
Please contact sponsor principal investigator if there are any questions.
B.
Data Collection/Management/Electronic Data Capture
The trained investigator site staff will enter the data required by the protocol into the 
electronic forms from source documents (e.g. medical records and study specific data 
capture forms as needed).  All information on these electronic forms must be traceable to 
these source documents.  Electronic data forms will be completed for all subjects.  For 
subjects who do not initiate radiotherapy or do not complete radiotherapy, electronic forms 
will be completed with all data collected up to and at the time of subject study 
discontinuation. 
Automatic validation programs or manual checks for data discrepancies in the electronic 
data submission form may result in queries for resolution by the investigational site.  
Designated investigator site staff is required to respond to these queries and make any 
necessary changes to the data.  Winship Cancer Institute and the Study PI will perform 
audits quarterly for quality assurance of the database.  
The clinical management system being used for this study is The Online Collaborative 
Research Environment (OnCore). OnCore will be used to record all study related 
information for all registered subjects, including their assigned patient ID and radiation 
treatment dose. All data must be entered no later than 30 days following registration and 
each visit completion. All queries are to be resolved within 4 weeks of issue. The MSC will 
provide OnCore training to each and request access to the appropriate staff at the 
participating site.
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 are considered postmenopausal if any of the following are true:


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
Age > 60 years -or-

Age < 60 years with intact uterus and amenorrhoeic for > 12 consecutive 
months prior to chemotherapy and/or endocrine therapy exposure -or-

Prior bilateral oophorectomy -or-

Age <60 years with prior hysterectomy and FSH and plasma estradiol levels 
in the postmenopausal range according to local policies prior to 
chemotherapy and/or hormone therapy
All other patients who do not fulfill any of the above criteria are considered premenopausal.  
If there is any question regarding a patient’s menopausal status, the physician’s judgement 
needs to be documented in the patient’s note and electronic data submitted for the study.   
Previous type of neoadjuvant and/or adjuvant therapy (i.e. chemotherapy, radiation, 
surgery, hormone therapy, targeted therapy, etc.) including start date and end date must 
be recording in the electronic data submission form by the investigator or delegate at the 
participating site.
Demographic data will include age, sex, and self-reported race/ethnicity.
Concomitant Medications
Any concomitant medications and treatment will be recorded from 30 days prior to 
radiotherapy treatment and up to the last study assessment (3 months post radiotherapy 
completion) whether they are breast or non-breast cancer related therapies.
Physical Examination and Vital Signs
Prior to radiotherapy treatment, a physical examination including assessment of 
tenderness to palpation over the bone metastases and neurological examination (if 
applicable), height, weight, blood pressure, and pulse rate is required.
Symptom-directed and treatment directed physical examinations, blood pressure, weight, 
and pulse rate will be performed at subsequent visits.
All physical exams and vital signs assessments should be performed by a physician or 
registered nurse or other qualified health care provider according to local regulations. 
 
Laboratory Assessments
It is highly recommended that laboratory assessments be performed at the research center, 
but if this is not feasible, laboratory tests for individual patients should be performed at the 
same lab.  The frequency of blood draws is detailed in the assessment schedule above.  
All initial laboratory assessments must be performed within 14 days of radiotherapy 
treatment.

Hgb, white blood cell count (WBC), absolute neutrophil and platelet count

Serum/urine pregnancy test if required
Additional hematology/chemistry panels (e.g. liver function tests) may be performed as 
clinically indicated.  


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Serum or urine pregnancy test must be negative in women judge premenopausal within 14 
days of radiotherapy or in women with amenorrhea of less than 12 consecutive months at 
time of registration.  Pregnancy testing does not need to be done in patients who are 
postmenopausal.  
Radiation Dose
The prescribed radiation dose, number of fractions, anatomic site(s) to be treated with 
radiation, reason for treatment (e.g. pain) will be recorded and collected. 
Treatment Compliance
Adherence to both the prescribed radiotherapy treatment regimen as well as palbociclib 
and hormone therapy will be recorded and collected (please see Compliance above).  
Protocol deviations from the approved protocol will be documented and explained.  The 
investigator will promptly report any deviations that might impact patient safety and data 
integrity to the Sponsor and if locally applicable, to the local IRB in accordance with local 
policies.  
Patient Reported Outcome Measures  
To fully evaluate the impact of radiotherapy on metastatic breast cancer patients receiving 
palbociclib and hormone therapy, a comprehensive benefit and risk assessment that 
includes the patient perspective, in addition to efficacy and safety, will be performed.  The 
BPI, MFI, SF-36, EORT QLQ-BM22, EORTC QLQ-C15-PAL, and HADS will be used to 
assess pain, fatigue, quality of life and depression, respectively (see Background and 
Rationale).  The questionnaires take approximately 30 minutes to complete and will be 
collected at baseline (prior to radiation), last day of radiation, and 1 and 3 months post 
radiation time points.
Digital Imaging and Radiotherapy Data Submission
Both patient imaging and radiotherapy data from participating institutions will be exported 
from the institution's diagnostic imaging department and radiation treatment planning 
system in DICOM format, and subsequently anonymized using the Velocity Anonymize 
software from Varian Medical Systems, a software that anonymize images, contours, plan 
and dose data without compromising the essential links between these radiotherapy 
objects and thus preserving their ability to be imported in a different treatment planning 
system at another institution. This vendor-neutral data on patients analyzed in this 
proposal will be collected on a dedicated research server already available at Emory. 
Research coordinators or assistants are able to submit standard of care imaging through 
the same method.  (See appendix for detailed instructions)
For patient images stored on a PACS system at the participating institution or site, these 
images can be sent to Velocity in DICOM format where a research database will be used 
that does not contain any PHI, only the subject identifier number.  Images from the clinical 
database will be saved to a directory, anonymized using a commercial anonymizer 
available in the Emory Department of Radiation Oncology (Velocity Anonymize, Varian 
Medical Solutions), and then uploaded in the research system. The anonymization 
procedure takes about 10 minutes to complete. 


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The research server is ideally suited for such projects as it replicates the clinical software 
environment but has its own database holding project-specific datasets. In addition, the 
research station has installed the Eclipse Advanced Scripting Programming Language 
(ESAPI) where researchers can write code in C# to create customized software scripts to 
extract and analyze patient data according to a project's design. For analysis, we will re-
use a script created in the frame of previous research to automatically output plan quality 
measures to an Excel file for statistical processing. Extracted measures are plan indices 
such as the conformity, homogeneity and gradient indexes, dose statistics inside targets 
and critical structures, complete dose-volume histogram graphs, standard constraints 
values as well as any user-defined DVH points in any either absolute or relative formats for 
the dose or volume. With an extended version of the script, we can extract radiomics 
measures such as image features, statistics, and textures. These radiomics features can 
be extracted from either the patient's CT dataset or the plan's dose distribution. Extracted 
features also include segmentation characteristics such as the volume, area and tortuosity 
of each structure in the plan. Once imported in the research database, data received from 
the participating institutions will be processed with scripts to generate measures for 
statistical analysis.  
If there are any questions regarding this process, please contact Edi Schreibmann, 
eschre2@emory.edu, 404-778-5667.
C.
Monitoring Plan
At the time of study initiation at a non-Emory site, the Emory Sponsor, Winship regulatory 
specialist, and Winship research coordinators will perform a site initiation teleconference. 
During this teleconference, the Emory team will review the study, enrollment, reporting, and 
regulatory compliance. The participating site will have internal monitoring meetings. These 
meetings, which will include the participating site investigator, the clinical research 
coordinator and the regulatory affairs coordinator, will meet at least on a monthly basis to 
review and discuss study data to ensure subject safety. The research coordinators will 
maintain a spreadsheet which will be de-identified and will summarize all the patient data for 
subjects actively being treated on the trial as well as a roadmap detailing pending 
tests/treatments for each individual subject. The spreadsheet will be shared with the Emory 
PI via e-mail. 
Winship’s multi-site coordinator will perform an on-site or remote monitoring visit within the 
first three months of enrollment of the first subject. Quarterly monitoring visits will occur 
(once annually onsite and three times remotely) until subject follow-up is terminated. 
Monthly reviews of data in OnCore will be conducted to ensure compliance or identify 
discrepancies. 
At least monthly teleconferences between Emory PI and participating site.
Teleconferences will be conducted at least once monthly between the PI at Emory and the 
research team at the participating site(s). The purpose of the meetings is to discuss the 
enrollment, regulatory updates, monitor toxicities, and evaluate the progress of the 
trial.  Scheduled teleconferences may stop after all patients have completed assigned 
protocol therapy. The PI at Emory will communicate with participating sites via monthly 
email. The minutes from the teleconference will be maintained in the regulatory binder for 


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the study. In addition, electronic copies will be sent via email to the principal investigators at 
each site. 
NOTE:  Per NCI policy all institutions that participate on protocols with a radiation therapy component 
must participate in the Image and Radiation Oncology Core (IROC) monitoring program.  If this form 
has been previously submitted to CTSU it does not need to be resubmitted unless updates have 
occurred at the RT facility.  All participating sites on this protocol are IROC certified.
12.2 Multi-Site Monitoring Guidelines 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute at Emory 
University will provide oversight for the conduct of this study.  The DSMC functions 
independently within Winship Cancer Institute to conduct internal monitoring functions to ensure 
that research being conducted by Winship Cancer Institute Investigators produces high-quality 
scientific data in a manner consistent with good clinical practice (GCP) and appropriate 
regulations that govern clinical research.   Depending on the risk level of the protocol, the DSMC 
review may occur every 6 months or annually.  For studies deemed High Risk, initial study 
monitoring will occur within 6 months from the date of the first subject accrued, with 2 of the first 
5 subjects being reviewed.  For studies deemed Moderate Risk, initial study monitoring will occur 
within 1 year from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.Subsequent monitoring will occur in routine intervals per the Winship Data and Safety 
Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a preliminary report of monitoring findings 
to the PI and other pertinent individuals involved in the conduct of the study.  The PI is required 
to address and respond to all the deficiencies noted in the preliminary report.  Prior to the 
completion of the final summary report, monitors will discuss the preliminary report responses 
with the PI and other team members (when appropriate).  A final monitoring summary report will 
then be prepared by the monitor.  Final DSMC review will include the final monitoring summary 
report with corresponding PI response, submitted CAPA (when applicable), PI Summary 
statement, and available aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI 
is responsible for ensuring that instances of egregious data insufficiencies are reported to the 
IRB.  Continuing Review submissions will include the DSMC recommendation letter.  Should 
any revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the 
PI will be responsible for notifying the DSMC of such changes.  The Committee reserves the 
right to conduct additional audits if necessary. 
13. DRUG INFORMATION
Please see Background and Rationale, Treatment Planning/Regimen Description, Treatment 
Modifications/Management, and Adverse Events Sections above for information regarding palbociclib 
and hormone therapy.  The United States Package inserts of both palbociclib and hormone therapy, 
including letrozole, anastrozole, tamoxifen, fulvestrant, and exemestane provide publicly available 


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and complete information which serve as the Single Reference Safety Documents for these 
compounds (See Appendix).    
14. SPECIAL STUDIES: None
15. MODALITY REVIEWS
The Study PI will perform a radiotherapy Quality Assurance Review after complete data for the first 
10 cases enrolled has been received at Emory. These reviews will be on going.
 
16.0 STATISTICAL CONSIDERATIONS
16.1 Study Endpoints
Primary Endpoint -  Response rate at 3 months post radiotherapy, relative to baseline, defined 
according to criteria stated above (BPI or imaging). 
Secondary Endpoints:
a.  Response rate at 3 months post radiotherapy relative to baseline incorporating BPI and 
analgesic measures according to International Consensus Guideline Criteria(20)
b. PFS
c. OS
d. Adverse Events scored according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5
e. Fatigue, as measured by MFI before and after radiotherapy, actual scores and change from 
baseline
f.
Quality of Life, as measured by SF-36, EORTC QLQ-BM22, and EORTC QLQ-C15-PAL, 
actual scores and change from baseline
g. Depression, as measured by HADS, actual scores and change from baseline
h. Adherence, measured by drug diary, and radiation treatment compliance with prescribed 
radiation dose and days of treatment
16.2 Statistical Methods
Sample size considerations:
Sample size is determined using a non-inferiority study design.  We achieve 80% power with a 
sample size of 33 to detect a non-inferiority proportion of 60% using a one-sided binomial test for 
non-inferiority and assuming a Type I error of 0.05.  This assumes that the current response rate, 
using the BPI, is 80%.  These assumptions are consistent with previous randomized trials of palliative 
radiotherapy for bone metastases.(7)  Assuming an attrition rate of 20%, we will enroll 42 patients.  
Accrual will take place at 7 different institutions (see appendix with letters of support).  Each hospital 
system sees between 10 and 50 eligible patients annually, and accrual is expected to reach a rate of 
4 patients per month with our last patient enrolled during the last quarter of Year 1.  Primary endpoint 
completion should take place during the first quarter of Year 2.  


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Primary Endpoint
Response will be estimated as the number of responders divided by the number of patients evaluated 
for response.  A 95% confidence interval for the response rate will be reported using the Clopper-
Pearson method.(48)  Response rates and confidence intervals will also be reported for subgroups, 
stratified by bisphosphonate or rank ligand inhibitor use, prior chemotherapy for advanced disease, 
and number of treated radiation fields.
Secondary Endpoints
Based on an Update of the International Consensus on Palliative Radiotherapy Endpoints for Future 
Clinical Trials in Bone Metastases, a planned secondary analysis of response incorporating both the 
BPI and analgesic measures will also be performed.  Adverse events, such as bone fracture following 
radiotherapy, any Grade 3 toxicity (except neutropenia or leukopenia) including gastrointestinal 
toxicities, Grade 4 neutropenia, Grade 4 leukopenia, Grade 3 febrile neutropenia, or Grade 3 brachial 
plexopathy or spinal cord injury, will be summarized descriptively, using frequencies and 
percentages.  Fatigue as measured by MFI will be summarized descriptively both before and after 
radiotherapy.  Pre- and post-radiation MFI scores will be compared using paired t-tests or Wilcoxon 
signed-rank tests, where appropriate.  Quality of Life as measured by SF-36, EORTC QLQ-BM22, 
and EORTC QLQ-C15-PAL, will be summarized descriptively.  Progression-free survival is defined as 
time from registration to death or progression and will be estimated using the Kaplan-Meier method.  
Overall survival is defined as time from registration to death and will be estimated using the Kaplan-
Meier method.  Stratification factors such as bisphosphonate or rank ligand inhibitor use, prior 
chemotherapy for advanced disease, and number of treated radiation fields will be evaluated across 
presence of adverse events using chi-squared tests or Fisher’s exacts tests for categorical variables, 
and t-tests or Mann Whitney U tests for continuous variables where appropriate.  Univariate and 
multivariable logistic regression models will be considered for these factors, modeling the presence of 
adverse events.  Stratification factors also will be evaluated across survival endpoints using log-rank 
tests.  Univariate and multivariable Cox proportional hazards models will be considered, and model 
assumptions will be checked and verified.
Correlative research:
Biomarkers such as cytokines and circulating tumor DNA (ctDNA) will be collected at baseline and 3 
months post radiotherapy and will be summarized descriptively at each time point.  Mixed models 
with random intercepts will also be considered, in order to evaluate the biomarkers longitudinally.   
Biomarker value at baseline and 3 months post radiotherapy, as well as change in biomarker value 
will be analyzed across response using t-tests or Mann Whitney U tests, where appropriate.  
Stratification factors such as bisphosphonate or rank ligand inhibitor use, prior chemotherapy for 
advanced disease, and number of treated radiation fields will be included as fixed effects in the 
longitudinal biomarker models.
Analysis Datasets:
All eligible patients who receive at least one dose of protocol therapy will be included in the primary 
efficacy analysis. Safety analysis will be conducted using the Safety Population, defined as any 
participant receiving at least one dose of study treatment. 
 
16.3 Interim analyses
Stopping rules for toxicity: After 10 patients have been enrolled, we will stop the study if any of the 
following rates of toxicities are exceeded:


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1) >85% of patients develop grade 3 neutropenia 
2) >25% of patients develop grade 4 neutropenia
3) >10% of patient develop grade 4 leukopenia
4) >10% of patients develop grade 3 febrile neutropenia  
5) >10% of patients develop bone fracture following radiotherapy
6) >5% of patients develop Grade 3 brachial plexopathy (assessed by LENT/SOMA or RTOG 
criteria) or Grade 3 spinal cord injury assessed by CTCAE version 5
7) >15% of patients develop other Grade 3 toxicities (excluding neutropenia and leukopenia) not 
mentioned above
17.0 GENDER/RACE/ETHNICITY DISTRIBUTION
Women and men of all race and ethnic groups are eligible for this study.  In conformance with the 
national Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and 
minorities in clinical research, possible interactions between race/ethnicity and treatment have been 
considered.  Based on the racial make-up of breast cancer patients in Georgia (at least 40% African 
American), and Emory’s previous success in enrolling African American patients to breast cancer 
trials (~45% of subjects are African American), treatment, efficacy, and safety comparisons may be 
explored among Caucasian and African American metastatic breast cancer patients. 
 
TABLE 7. PROJECTED GENDER/RACE/ETHNICITY DISTRIBUTION OF ENROLLED PATIENTS
Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
1
0
1
Not Hispanic or Latino
40
1
41
Total
41
1
42
Gender
Racial Category
Females
Males
Total
American Indian or 
Alaska Native
0
0
0
Asian
1
0
1
Black or African 
American
17
0
17
Native Hawaiian or 
other Pacific Islander
0
0
0
White
23
1
24
Total
41
1
42
 


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18. STUDY TIMELINE 
TABLE 8. STUDY TIMELINE
GOALS
Year 1
Year 2
Year 3
Milestone
Site
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Emory Glenn 
Family Breast 
Center
Atlanta, GA
2
3
1
2
1
2
1
2
4
4
4
2
Piedmont Cancer 
Institute 
Atlanta, GA 
0
0
0
0
0
0
0
0
1
0
0
0
Georgia Cancer 
Center at Augusta 
University
0
0
0
0
0
0
0
0
0
1
0
0
John B. Amos 
Cancer Center
Columbus, GA
0
0
0
1
0
0
0
0
0
0
0
0
The Nancy N. and 
J.C. Lewis Cancer 
& Research 
Pavilion
St. 
Joseph’s/Candler
Savannah, GA
0
0
0
0
0
0
0
0
1
0
0
0
Cancer Institute, 
Maine Medical 
Center
Portland, ME
0
0
0
0
0
0
0
0
1
0
0
0
Participant 
Accrual*
Northside Cancer 
Institute, 
Atlanta, GA
0
1
1
1
1
1
1
1
1
1
0
0
Interim Analysis 
after 10th
Patient is 
accrued and 
has finished 3 
months post 
radiotherapy 
visit
All study sites
x
Final 
Assessments 
Complete
(3 months post 
radiotherapy 
visit)
All study sites
x


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Inflammatory 
Markers
Andrew Miller 
Laboratory
x
x
Gene 
Expression
Emory Integrated 
Genomics Core, 
Office of Jennifer 
Felger
x
x
ctDNA Assay 
and Analysis
Circulating Tumor 
Cell Center
Massachusetts 
General Hospital
Harvard University
Office of Aditya 
Bardia
x
x
x
Final Data 
Analysis, 
reporting, and 
manuscript 
submission
Offices of Jeff 
Switchenko 
and Mylin Torres
x
x
*Numbers reflect estimated total number of patients accrued to the protocol at each site by the end of 
the indicated quarter but could exceed these numbers for any individual site as long as 42 total 
subjects are enrolled on the study from all sites.  Therefore,  numbers of patients enrolled at each 
specific location could vary accordingly.  Peripheral blood draws, Behavioral assessments, clinical 
and demographic information will be collected at the timepoints indicated in the Schema. IRB 
approval for all sites will occur during the fourth quarter of 2018 and first and second quarter of 2019.  
Georgia Cancer Center in Augusta, GA is still working on local IRB approval.   
During the second year of this study, abstracts of our findings will be submitted to the annual ASTRO 
and ASCO conference for presentation.  The publication plan is to submit manuscripts of our finding 
to the Journal of Clinical Oncology and International Journal of Radiation Oncology, Biology, and 
Physics at the end of year 3.  
 
Enrollment period: 24 months starting third quarter of 2019.  IRB approval for all sites will occur 
during the fourth quarter of 2018 and first and second quarter of 2019.  See above study timelines.  


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nuclear medicine. 2005; 35:84-99.
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Bone Metastases Consensus Working P. Update of the international consensus on palliative radiotherapy endpoints for 
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Cancer. 2016; 16:909. PMCID: PMCPMC5117527.
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KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with 
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Mao JJ, Xie SX, Farrar JT, Stricker CT, Bowman MA, Bruner D, DeMichele A. A randomised trial of electro-
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Xiao C, Miller AH, Felger J, Mister D, Liu T, Torres MA. A prospective study of quality of life in breast cancer 
patients undergoing radiation therapy. Advances in radiation oncology. 2016; 1:10-16. PMCID: PMCPMC4950982.
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Chow E, Nguyen J, Zhang L, Tseng LM, Hou MF, Fairchild A, Vassiliou V, Jesus-Garcia R, Alm El-Din MA, Kumar A, 
Forges F, Chie WC, Bottomley A. International field testing of the reliability and validity of the EORTC QLQ-BM22 module 
to assess health-related quality of life in patients with bone metastases. Cancer. 2012; 118:1457-1465.
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Mendez LC, Raman S, Wan BA, da Silva JLP, Moraes FY, Lima K, Silva MF, Diz M, Chow E, Marta GN. Quality of life 
in responders after palliative radiation therapy for painful bone metastases using EORTC QLQ-C30 and EORTC QLQ-
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After Radiation Therapy for Bone Metastases as a Function of Age: A Secondary Analysis of the NCIC CTG SC-Twenty-
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1013.

ICF_000.pdf: 
 
 
 
 
 
Informed Consent Form 
 
 
A Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and 
Hormone Therapy for Treatment of Bone Metastasis in Breast Cancer Patients 
 
 
NCT Number: NCT03691493 
 
 
Document IRB Approval Date: 7/20/2022 


PI: Mylin Torres, MD                                                Page 1 of 14                                               Version Date: 02/05/2021
Protocol #: Winship4472-18
           IRB Form 12152017
 
You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge. This knowledge may be 
used to help others. Research studies are not intended to benefit you directly, though 
some might.  
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, 
you can change your mind later on and withdraw from the research study. 
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.  
What Is This Document?
This form is an informed consent document. It will describe the study risks, procedures, 
and any costs to you.
This form is also a HIPAA Authorization document. It will describe how your health 
information will be used and by whom.
Signing this form indicates you are willing to take part in the study and allow your 
health information to be used.
What Should I Do Next?
1. Read this form, or have it read to you.
2. Make sure the study doctor or study staff explains the study to you.
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, 
etc.) 
4. If there will be medical treatment, know which parts are research and which are 
standard care.
5. Take time to consider this, and talk about it with your family and friends.
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Emory University, Grady Health System, and Saint Joseph’s Hospital
Consent to be a Research Subject / HIPAA Authorization 
Title: A Phase II Multi-institutional Study of Concurrent Radiotherapy, Palbociclib, and Hormone 
Therapy for Treatment of Bone Metastasis in Breast Cancer Patients
Principal Investigator: Mylin A. Torres, MD
Study-Supporter: Pfizer Oncology
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything 
you need to think about before you decide if you want to be a part of the study.  It is entirely your 
choice.  If you decide to take part, you can change your mind later on and withdraw from the 
research study. The decision to join or not join the research study will not cause you to lose any 
medical benefits.  If you decide not to take part in this study, your doctor will continue to treat you.
Before making your decision:

Please carefully read this form or have it read to you

Please listen to the study doctor or study staff explain the study to you 

Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether 
you would like to participate. You may wish to discuss your decision with family or friends. Do not sign 
this consent form unless you have had a chance to ask questions and get answers that make sense to 
you.  By signing this form you will not give up any legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most the Web site will include a 
summary of the results. You can search this Web site at any time.
Why am I being asked to participate in this research?
You are being asked to participate in a research study because you have hormone receptor positive 
(HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer that has 
spread to your bones and you are currently taking palbociclib (i.e. ibrance) and hormone therapy (e.g. 
exemestane, arimidex, tamoxifen, fulvestrant, or letrozole) to treat it.  A member of the research team will 
explain what is involved in this study and how it will affect you. This consent form describes the study 
procedures, the risks and benefits of participation, as well as how your confidentiality will be maintained. 
Please take your time to ask questions and feel comfortable making a decision whether to participate or 
not. This process is called informed consent. If you decide to participate in this study, you will be asked to 
sign this form.
What is the purpose of this study?
The purpose of this study is to is to evaluate how safe and effective radiation treatment is in treating 
breast cancer that has spread to the bones while a patient is receiving palbociclib (i.e. ibrance) and 
hormone therapy (e.g. exemestane, arimidex, tamoxifen, fulvestrant, or letrozole) at the same time.   This 
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research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational 
combination of radiation, palbociclib, and hormone therapy for metastatic breast cancer that has spread to 
the bone.  
Radiation is a routine, medical treatment which improves pain, weakness, feelings of numbness, and/or 
prevents bones from breaking in patients who have breast cancer that has spread to the bones.
Palbociclib has been approved by the FDA to be used in combination with an aromatase inhibitor, a form 
of anti-hormone therapy, to treat metastatic, HR+/HER2- breast cancer, which is cancer that has spread 
from the primary site (breast) to other parts of the body (distant sites). Palbociclib is a drug that may stop 
cancer cells from growing. Palbociclib blocks activity of two closely related enzymes (proteins that help 
chemical reactions occur in the body), called Cyclin D Kinases 4 and 6 (CDK 4/6). These proteins are part 
of a pathway, or a sequence of steps, which is known to regulate cell growth. Laboratory testing has 
suggested Palbociclib may stop the growth of HR+ breast cancer. 
Anti-hormone therapy prevents breast cancer cell growth by blocking estrogen receptor stimulation. 
During this study, anti-hormone therapy will consist of either tamoxifen, faslodex, or aromatase inhibitor 
(anastrozole, letrozole, exemestane). Premenopausal women may also receive an injection drug called an 
LHRH (luteinizing hormone-releasing hormone) agonist to shut down ovary function. Standard care for 
people with HR+ breast cancer is anti-hormone therapy. Your study doctor will determine which standard 
anti-hormone therapy you will receive during this research study, and you will continue taking palbociclib 
and anti-hormone therapy during radiation treatment for your bone metastasis.
The purpose of this study is to determine any good and bad effects of 5 to 10 days of standard radiation 
treatment to the bone in metastatic breast cancer patients who are also taking standard palbociclib and 
hormone therapy.  
We anticipate enrolling 42 subjects onto the study at Emory and elsewhere.  
What will I be asked to do? 
Radiation is often routinely prescribed to improve pain, weakness, feelings of numbness, and/or prevent 
bones from breaking in patients who have breast cancer that has spread to the bones.   Palbociclib (i.e. 
ibrance) and hormone therapy (e.g. exemestane, arimidex, tamoxifen, fulvestrant, or letrozole) given 
together is the standard treatment for metastatic breast cancer patients that have cancer which is 
hormone receptor positive (e.g. estrogen and/or progesterone receptor positive) and Her2 negative.  If you 
have hormone receptor positive breast cancer that has spread to the bone and you have been taking 
palbociclib and hormone therapy for at least 28 days, you will be asked to continue taking palbociclib (i.e. 
ibrance) and hormone therapy (e.g. exemestane, arimidex, tamoxifen, fulvestrant, or letrozole) during the 
5 or 10 days of radiation treatment prescribed to the boney areas where the breast cancer is causing you 
symptoms or is weakening the bone.  
Your doctor will prescribe 5 or 10 days of radiation treatment to site of boney disease.  If you receive 5 
days of radiation, you will be seen within 2 weeks prior to radiation (baseline visit) and the last day of 
radiation (day 5). If you receive 10 days of radiation, you will be seen within 2 weeks prior to radiation 
(baseline visit) the last day of radiation (day 10).  All enrolled patients will then be seen at two additional 
follow up assessments: 3-7 weeks post last day of radiation and 11 to 16 weeks after the last day of 
radiation treatment.  There are a total of 4 study visits corresponding to your usual visits with physicians 
who would see you at these time points whether you do or do not participate on this study.
At each time point, you will be asked to fill out questionnaires about your symptoms, including pain, fatigue, 
quality of life, and mood.  These will include: a demographic datasheet, a pain survey (Brief Pain Inventory), an 
anxiety and depression survey (HADS), a health and quality of life survey (SF-36), and a fatigue survey (MFI).  
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These questionnaires take about 20 to 30 minutes in total to complete.  Additionally, medical records will be 
accessed and a pregnancy test may occur if patients are of child bearing potential.
So that side effects can be assessed, blood tests to monitor your red, white, and platelet blood counts along 
with blood chemistries such as potassium, liver function tests will be done before and after radiation treatment 
at 3-7 weeks after the last day of radiation, and again, at 11 to 16 weeks after your last day of radiation 
treatment.  A blood test to monitor your red, white, and platelet blood counts will also be done on your last day 
of radiation.  These tests will be charged to you and your insurance as normal care. This will allow your 
physician to monitor your blood counts and provide you with additional support if needed. 
Before the first radiation treatment and 11 to 16 weeks after the last radiation treatment, you will also be asked 
to give a small sample of blood (up to 35 mL, or about 2 tablespoons), collected from a vein in your arm or port 
by a healthcare professional.  We will use this blood to determine if there are substances within your blood 
which help us to better understand metastatic breast cancer or side effects from treatment.  To prepare for 
these blood draws which will occur first thing in the morning, you will be asked not to eat or drink anything but 
water and your medications after midnight.  After the blood draw, you will be able to eat and drink as normal.  
The entire procedure should take approximately 5 minutes or less.   
How long will I be in this study? 
Participants of this trial will be monitored up to 16 weeks after radiation treatment completion. 
What tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for the care of your 
cancer. However, there are some extra exams that you will need to have if you take part in this study. 
Screening Procedures 
You will need to have the following exams to find out if you can continue in the study: 
• Demographic information about you will be collected (age, sex, race/ethnicity) 
• Your medical history will be examined. 
• Full Physical Exam with vital signs (height, weight, blood pressure and pulse). 
• You will be asked about medications you are taking. 
• The study doctor will evaluate your performance status (how well you can carry out daily activities) 
• Blood or urine pregnancy test (if you are premenopausal, able to have children). The study doctor or study 
staff will tell you if the pregnancy test results are positive. The results of the pregnancy testing must be 
negative in order for you to be in the study. 
• Blood tests to evaluate your red, white, and platelet blood counts along with blood chemistries such as 
potassium, liver function tests, etc. 
• Blood draw for study specific research lab assessment, described in further detail above. 
During the main part of the study: 
If you continue in the study after screening, you will have to come to the study site prior to starting radiation, 
during radiation, and after you stop taking radiation treatment (but still taking your anti-hormone therapy and 
palbociclib). During your participation on the study, there will be four total visits to the study site.
 
The following procedures will be performed. To find out which procedures occur at which visit, please ask the 
study doctor or study staff: 
• Medical history – your study doctor will ask you questions about your health, general condition, complaints, 
and medications that you are taking or have taken prior to randomization (the day you are assigned to a study 
arm). It is important that you tell your study doctor about all the medications that you have been taking, 
including any medications or herbal remedies that you may have bought for yourself. 
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• Tumor Assessments (e.g. Chest X-ray, Computerized Tomography (CT) Scan, PET/CT, MRI or Bone Scan): 
The study doctor or study staff will collect the results from scans you have as part of your regular care to help 
assess your tumor. 
• Physical examination – your study doctor will periodically examine your body, including measuring your 
height and weight, your blood pressure, and pulse rate. 
• A check of your performance status (your ability to carry out daily activities) will also be performed. 
• Blood tests – to allow monitoring of the body’s function and its response and reaction to study drug and 
breast cancer, up to 35 ml blood will be taken at screening and at each of your study visits until end of dosing. 
This will help determine how you are tolerating treatment.  Your blood may also be tested to see if you are 
pregnant and if your ovaries are still actively producing sex hormones. There is also a test for tumor DNA 
circulating in your blood. 
• Questionnaires – You will be asked to fill out 4 forms assessing pain, quality of life, fatigue, anxiety, and 
depression, described above.  Each form will take about 5-10 minutes to complete. The forms will ask about 
things like fatigue and sexual function. You may feel uncomfortable answering some of the questions, and you 
can skip any you do not want to answer. Completing all of the forms will take about 20-30 minutes. 
While you are in the study, you must: 
• Follow instructions you are given. 
• Come to the study center for all visits with the study doctor or study staff. 
• Tell the study doctor or study staff about any changes in your health or the way you feel. 
• Tell the study doctor or study staff if you want to stop being in the study at any time. 
Will I need time to recover after my participation in the study? 
Ask the study doctor or study staff for the estimated recovery time of your participation in this study.
How will my medicine be provided? 
The palbociclib and hormone therapy you take are part of the usual approach for the care of your cancer.  
These medications will be prescribed to you by your treating physician and dispensed by the pharmacy directly 
to you.  Because these treatments are the usual care for your breast cancer, your insurance will pay for these 
medications. You will be asked to complete forms which allow us to determine whether you are taking your 
medications as prescribed.
Who owns my study information and samples?
If you join this study, you will be donating your samples and study information.  You will not receive any 
compensation if your samples or information are used to make a new product. If you withdraw from the study, 
data and samples that were already collected may be still be used for this study.  
What are the possible risks and discomforts?
The exact side effects of radiation treatment given with palbociclib and hormone therapy is not known at this 
time.
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or study doctor’s office than usual 
• You may be asked sensitive or private questions which you normally do not discuss, although you may 
choose not to answer 
The study doctor will be testing your blood and will let you know if changes occur that may affect your health. 
  
The most common risks and discomforts expected in this study are: fatigue, low white blood cell count, 
anemia, and sunburn type reaction from radiation which may occur in 30% or more of patients.
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The less common risks and discomforts expected in this study are: nausea, diarrhea, hair loss which may 
occur in 10% to 30% of patients.
Rare but possible risks include: weakness, shortness of breath, cough, difficulty urinating, chest pain, 
abdominal pain, indigestion, dry mouth, fever, asthenia (general weakness), swelling of hands and feet, 
irritation or sores in the lining of hollow organs like mouth, throat, stomach, bowels; influenza (flu) like illness, 
pain in the muscles and bone including around the chest, muscle cramps, increases in blood liver markers that 
may indicate liver damage, dry skin, itching, mouth/throat pain, nosebleed, impaired sense of taste, high blood 
pressure, depression, bone fracture, and fall which may occur in up to 5 to 10% of patients .
The following side effects have been reported in <5% of patients on palbociclib, radiation, and hormone 
therapy, but are still deemed important: fever associated with dangerously low levels of a type of white blood 
cell (neutrophils), decreases in lymphocyte blood cells (infection fighting cells), blurred vision, increased 
tearing, nerve injury, paralysis, heart attack, death, and dry eye.
Here are important points about side effects: 
The study doctors do not know who will or will not have side effects. 
• There might be other side effects that researchers do not yet know about. 
• Some side effects may go away soon, some may last a long time, or some may never go away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drug dosages to try to reduce side effects. 
For information on risks of anti-hormone therapy, please talk to your study doctor. 
Ask the study doctor if you have questions about the signs or symptoms of any side effects that you read about 
in this consent form. 
You should get medical help and contact the study doctor or study staff if you have any of these or any other 
side effects during the study. 
It is possible that taking Palbociclib or anti-hormone therapy may change how your regular medications, 
vaccines, or supplements work. It is very important that you tell the study doctor about any medications, 
supplements, or vaccines before you take them during the study. 
Please tell the study doctor or study staff right away if you have any side effects. Please tell them if you have 
any other problems with your health or the way you feel during the study, whether or not you think these 
problems are related to the study drug. 
It is possible that you could have problems and side effects of Palbociclib or anti-hormone therapy that nobody 
knows about yet, which include your cancer getting worse or even death.
If you are a woman: to protect against possible side effects of the study drug, women who are pregnant or 
nursing a child may not take part in this study. If you become pregnant, there may be risks to you, the embryo, 
or fetus. These risks are not yet known. If you are a woman of childbearing ability, you and the study doctor 
must agree on a method of birth control or abstinence for the duration of the study.  If you think that you have 
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gotten pregnant during the study, you must tell the study doctor immediately.  Pregnant women will be taken 
out of the study.
If you are a man: the effect of the study drug on sperm is not known.  To protect against possible side effects, 
if you are a man you should not get a sexual partner pregnant while taking the palbociclib, hormeone therapy 
and for 3 months after the last dose.  You and the study doctor should agree on a method of birth control to or 
abstinence use throughout the study.
Radiation Risks
In addition to radiation therapy you may receive additional radiation from diagnostic procedures to evaluate 
your condition. The principal risk associated with a radiation dose is the possibility of developing a radiation-
induced cancer later in life. However, the additional risk of radiation-induced cancer from these diagnostic 
procedures is low compared to the risks from the radiation therapy.
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not.  You 
may be asked to sign a new consent form that includes the new information if you decide to stay in the study.
Will I benefit directly from the study? 
It is not possible to know at this time if radiation given with palbociclib and hormone therapy is better than 
radiation alone. This study will help researchers learn things that may help people in the future. 
Will I be compensated for my time and effort?
You will not be offered compensation for being in this study.  
What are my other options?
If you decide not to enter this study, there is care available to you outside of this research study.  For example, 
you could:

Receive standard radiation treatment without taking palbociclib and hormone therapy at the 
same time

Receive chemotherapy, surgical treatment, or radioactive pharmaceuticals for your bone 
metastasis, if possible

Take part in a different study, if one is available

Choose not to be treated for cancer
The study doctor will discuss these with you.  You do not have to be in this study to be treated for metastatic 
breast cancer.
Taking part in this study, however, may make you unable to participate in some other research studies, if they 
exclude people who have taken certain treatments.  You should discuss this with the researchers if you have 
concerns. You may wish to research other study options at websites like clinicaltrials.gov and 
ResearchMatch.org.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and 
other identifying information will not appear when we present or publish the study results.
Study records can be opened by court order.  They also may be provided in response to a subpoena or a 
request for the production of documents. 
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Storing and Sharing your Information
De-identified data from this study, including your de-identified genetic information, may be shared with the 
research community at large to advance science and health. Data from this study may be placed into public 
databases where, in addition to having no direct identifiers, researchers will need to sign data use agreements 
before accessing the data. We will remove or code any personal information that could identify you before your 
information is shared. This will ensure that, by current scientific standards and known methods, it is extremely 
unlikely that anyone would be able to identify you from the information we share. Despite these measures, we 
cannot guarantee anonymity of your personal data.
What research samples are collected and how will they be used?
Your blood and tissue samples contain DNA, which makes up the genes that serve as the "instruction book" for 
the cells in our bodies. Researchers are interested in the way genes affect how the body responds to drugs. 
Using DNA from your blood, researchers will study your entire genetic sequence, known as your genome. The 
genome sequence will be read and this information will be stored. Your genomic data will be used to find 
differences and similarities among people with regard to response to or side effects of palbociclib, anti-
hormone therapy, and radiation. Your genomic data and health information will be studied along with 
information from other participants in this study, and it will be stored for future studies by this research team. 
The results of genetic tests are for research only. Neither you nor your study doctor will be notified when 
research will be conducted or given reports or other information about any research that is done using your 
samples. Because the research tests on your blood samples collected for this study are not used for regular 
medical care, the test results will not be put in your medical record. These samples will be sent to and stored at 
Emory University. If you do not want these samples to be taken for the research, you should not join the study. 
Blood Samples: Blood samples specifically for research will be taken during the pre-radiation visit, and at 1 
other time point during your participation (11-16 weeks after radiation completion).  These samples are 
required in order for you to take part in this study because the research on the samples is an important part of 
the study. They will help us determine if there are markers in your blood that are linked to how you respond to 
palbociclib, anti-hormone therapy, and radiation.
How will the information about me be kept private in the biobank? 
Your identity will be protected as required by law and according to the policies of the biobank. Your privacy is 
very important to the researchers and they will make every effort to protect it. Here are just a few examples of 
the steps they will take: 
1) When your sample(s) is sent to the researchers, no information identifying you (such as your name) will be 
sent. Samples will be identified by a unique code only. 
2) The list that links the unique code to your name will be kept separate from your sample and health 
information and will not be available to the biobank. 
Information that identifies you will not be given to anyone, unless required by law. Some of your genetic and 
health information may be placed in central databases that may be public, along with information from many 
other people. Information that could directly identify you will not be included. If research results are published, 
your name and other personal information will not be used. Note that the FDA or the European Medicines 
Agency (EMA) or other regulatory agencies may have access to biobank records. 
What are the possible risks associated with the biobank? 
1) There is a risk that someone could get access to the personal information in your medical records or other 
information researchers have stored about you. 
2) The information shared may include your DNA results. Because your DNA information is unique to you, 
there is a chance that someone could trace it back to you. The risk of this happening is small, but may be 
greater in the future. 
3) There is a risk that someone could trace the information in a central database back to you. Even without 
your name or other identifiers, your genetic information is unique to you. The researchers believe the chance 
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that someone will identify you is small, but the risk may change in the future as people come up with new ways 
of tracing information. 
4) In some cases, this information could be used to make it harder for you to get or keep a job or insurance. 
There are laws against the misuse of genetic information, but they may not give full protection. There can also 
be a risk in knowing genetic information. New health information about inherited traits that might affect you or 
your blood relatives could be found during a study. The researchers believe the chance these things will 
happen is small, but cannot promise that they will not occur. 
What if I change my mind about the banked samples? 
If you decide you no longer want your samples to be used, you can call the study doctor, at the number on the 
first page of this form. The study doctor will let the researchers know. Then, any sample that remains in the 
biobank will no longer be used and related health information will no longer be collected. Samples or related 
information that have already been given to or used by researchers will not be returned.
How is my Genetic Information Protected? What are the Risks? 
The Genetic Information Nondiscrimination Act (GINA) is a federal law that generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against you based on your 
genetic information. This law generally will protect you in the following ways: 
• Health insurance companies and group health plans may not request your genetic information that we get 
from this research. 
• Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information that we get from this research 
when making a decision to hire, promote, or fire you or when setting the terms of your employment. 
Be aware that GINA does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance, and does not apply to employers with less than 15 
employees. 
In addition to GINA, the State of Georgia has laws that prohibit insurers from using genetic testing information 
for any non-treatment purpose. However, like GINA, this state law protection has exclusions: life insurance 
policies, disability income policies, accidental death or dismemberment policies, medicare supplement policies, 
long-term care insurance policies, credit insurance policies, specified disease policies, hospital indemnity 
policies, blanket accident and sickness policies, franchise policies issued on an insurance policy written as a 
part of workers’ compensation equivalent coverage, or other similar limited accident and sickness policies. 
Privilege 
In the State of Georgia, your genetic information has special legal protections called “privilege,” which means 
that the information cannot be used as evidence in a court. By signing this form and allowing us to use and 
disclose your genetic information for the purposes described in this consent, you waive any privilege with 
regard to that genetic information, meaning that the information loses this legal protection.
Medical Record:
If you have been an Emory, Grady Health System, and/or Saint Joseph’s Hospital patient before, then you 
already have an Emory, Grady Health System, and/or Saint Joseph’s Hospital medical record.  If you have 
never been an Emory, Grady Health System, and/or Saint Joseph’s Hospital patient, you do not have one.   An 
Emory, Grady Health System, and/or Saint Joseph’s Hospital medical record will be made for you if an Emory, 
Grady Health System, and/or provider or facility gives you any services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory, Grady Health System, 
and/or Saint Joseph’s Hospital medical record you have now or any time during the study.  
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Emory, Grady Health System, and/or Saint Joseph’s Hospital may create study information about you that can 
help with your care.  For example, the results of study tests or procedures.  These study results will be put in 
your Emory and Grady Health System medical record. Anyone who has access to your medical records will be 
able to have access to all the study information placed there.  The confidentiality of the study information in 
your medical record will be protected by laws like the HIPAA privacy rule.  State and federal laws may not 
protect the research information from disclosure. 
The results of some study tests and procedures will be used only for research purposes and will not be placed 
in your medical record.  
Tests and procedures done at non-Emory, Grady Health System, and/or Saint Joseph’s Hospital places may 
not become part of your Emory, Grady Health System, and/or Saint Joseph’s Hospital medical record. Also, if 
you decide to be in this study, it is up to you to let your other health providers know. 
In Case of Injury  
If you get ill or injured from being in the study, Emory, Grady Health System, or Saint Joseph’s Hospital will 
help you get medical treatment.   Emory, Grady Health System, Saint Joseph’s Hospital and the study 
supporter have not, however, set aside any money to pay you or to pay for this medical treatment. The only 
exception is if it is proven that your injury or illness is directly caused by the negligence of an Emory, Grady 
Health System, Saint Joseph’s Hospital, or study supporter employee.  “Negligence” is the failure to follow a 
standard duty of care. 
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you 
do not have insurance, or if your insurer does not pay, then you will have to pay these costs.  
If you believe you have become ill or injured from this research, you should contact Dr. Torres at 
. You should also let any health care provider who treats you know that you are in a research study. 
If you have Medicare or Medicaid: the sponsor may need information about your identity and your study 
treatment to give to the government agencies that run these programs. 
Costs
The study supporter will pay for certain items and services that you may receive if you take part in this study.  
For example, although often part of routine medical care, it is possible that blood draws including complete 
blood cell count with differential may not be paid for by insurance, and in these instances, the study sponsor 
will be pay for this procedure.  Although imaging studies like MRI, PET/CT, Bone Scans, and CT scans are 
also done as part of routine medical care in patients with metastatic breast cancer, the study sponsor may pay 
for these tests if not paid for by insurance.  
Palbociclib, hormone therapy, and radiation are part of regular medical care and will be paid for by insurance.  
If you have insurance, Emory will submit claims to your insurance for items and services that the sponsor does 
not cover.    
You will have to pay for the items or services for which the study supporter does not pay. The study supporter  
will not pay for your regular medical care. If you have insurance, Emory, Grady Health System, and/or Saint 
Joseph’s Hospital will submit claims to your insurance for items and services that the sponsor does not cover.  
Emory, Grady Health System, and/or Saint Joseph’s Hospital will send in only those claims for items and 
services that it reasonably believes your insurance will pay and that the study supporter has not paid. 
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The actual amount that you have to pay depends on whether or not you have health insurance and whether or 
not that insurance will pay for any research study costs. Generally, insurance companies will not pay for items 
and services that are required just for a research study. Some insurance companies will not pay for regular 
medical treatment or treatment for complications if you are in a study.  How much you will have to pay for any 
co-payments, deductibles or co-insurance depends on your plan.  Emory, Grady Health System, Saint 
Joseph’s Hospital, and the study supporter will not pay for these costs. 
It is a good idea to contact your insurance provider and tell them you want to be in this research study.  Ask 
them what they will pay for and what they will not pay for.  You can also ask the study team for help in figuring 
out what you will have to pay. 
If you do not have insurance, Emory, Grady Health System, and/or Saint Joseph’s Hospital will review your 
case as part of its program for low-income patient care.  The standard policies of that program will apply.  The 
program will figure out if you have to pay any costs for taking part in the study and what those costs will be.
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to have 
some of the final steps done.  
The researchers also have the right to stop your participation in this study without your consent for any reason, 
especially if they believe it is in your best interest or if you were to object to any future changes that may be made 
in the study plan.
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that identifies you, 
your “protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, 
including the Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of 
these laws as the “Privacy Rules.”  Here we let you know how we will use and disclose your PHI for the study.
Main Study
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:

Medical information about you including your medical history and present/past medications.

Results of exams, procedures and tests you have before and during the study.

Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will use and 
share your PHI to provide you with study related treatment and for payment for such treatment.  We will 
also use and share your PHI to conduct normal business operations.  We may share your PHI with 
other people and places that help us conduct or carry out the study, such as laboratories, data 
management centers, data monitors, contract research organizations, Institutional Review Boards 
(IRBs) and other study sites. If you leave the study, we may use your PHI to determine your health, vital 
status or contact information. 
Use and Disclosure of Your Information That is Required by Law:  
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We will use and disclose your PHI when we are required to do so by law. This includes laws that 
require us to report child abuse or abuse of elderly or disabled adults. We will also comply with legal 
requests or orders that require us to disclose your PHI. These include subpoenas or court orders.  
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in this document. 
You do not have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign 
this form, then you may not participate in the research study or receive research-related treatment.  
You may still receive non-research related treatment.  
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the research study:

The Principal Investigator and the research staff will use and disclose your PHI to conduct the 
study and give you study related treatment.

Emory, Grady Health System, and/or Saint Joseph’s Hospital may use and disclose your PHI to 
get payment for study related treatment and to run normal business operations. 

The Principal Investigator and research staff will share your PHI with other people and groups, 
including co-investigators, to help conduct the study or to provide oversight for the study.

 Pfizer Oncology is the supporter of the study.  The supporter may use and disclose your PHI to 
make sure the research is done correctly and to collect and analyze the results of the research.  
The Sponsor may disclose your PHI to other people and groups like study monitors to help 
conduct the study or to provide oversight for the study.  

The following people and groups will use your PHI to make sure the research is done correctly 
and safely:
o
Emory, Grady Health System, and/or Saint Joseph’s Hospital offices that are part of the 
Human Research Participant Protection Program and those that are involved in study 
administration and billing. These include the Emory IRB, Grady Research Oversight 
Committee, the Emory Research and Healthcare Compliance Offices, and the Emory 
Office for Clinical Research, and the IRB, research and healthcare compliance offices, 
and offices of clinical research at Maine Medical Center, Piedmont Healthcare, John B. 
Amos Cancer Center, Peyton Anderson cancer Center at Navicent Health, Nancy N. and 
J.C. Lewis Cancer & Research Pavilion at St. Joseph’s/ Candler Hospital System, and 
Massachusetts General Hospital, Harvard University. 
o
Other researchers and centers that are a part of this study (see above). 
o
Government agencies that regulate the research including:  Food and Drug 
Administration.
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.

Sometimes a Principal Investigator or other researcher moves to a different institution. If this 
happens, your PHI may be shared with that new institution and their oversight offices. PHI will 
be shared securely and under a legal agreement to ensure it continues to be used under the 
terms of this consent and HIPAA authorization.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If 
you want to do this, you must contact the study team at:
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Mylin A. Torres, MD (PI)
Director, Glenn Family Breast Center
Louise and Rand Glenn Family Chair in Breast Cancer Research
Winship Cancer Institute
Associate Professor
Rm. 1307-A
Department of Radiation Oncology
Emory University School of Medicine
1365 Clifton Road NE
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the 
information you already gave them so they can follow the law, protect your safety, or make sure that the study 
was done properly and the data is correct.  If you revoke your authorization you will not be able to stay in the 
study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, 
health care payers, and health care clearinghouses.  If we disclose your information to people who are not 
covered by the Privacy Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  
People who do not have to follow the Privacy rules can use or disclose your information with others without 
your permission if they are allowed to do so by the laws that cover them. 
To maintain the integrity of this research study, you generally will not have access to your PHI related to this 
research until the study is complete.  When the study ends, and at your request, you generally will have access 
to your PHI that we maintain in a designated record set.  A designated record set is data that includes medical 
information or billing records that your health care providers use to make decisions about you. If it is necessary 
for your health care, your health information will be provided to your doctor. 
We may remove identifying information from your PHI.  Once we do this, the remaining information will not be 
subject to the Privacy Rules.  Information without identifiers may be used or disclosed with other people or 
organizations for purposes besides this study.  
Contact Information
Contact Dr. Mylin Torres at 
3:

if you have any questions about this study or your part in it,  

if you feel you have had a research-related injury or a bad reaction to the study drug, or

if you have questions, concerns or complaints about the research
Contact the Emory Institutional Review Board at 
:

if you have questions about your rights as a research participant.

if you have questions, concerns or complaints about the research.

You may also let the IRB know about your experience as a research participant through our Research 
Participant Survey at http://www.surveymonkey.com/s/6ZDMW75.
If you are a patient receiving care from the Grady Health System and have a question about your rights, you may 
contact the Office of Research Administration at research@gmh.edu.
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Consent and Authorization
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in this research study.. By signing this 
consent and authorization form, you will not give up any of your legal rights. We will give you a copy of the signed 
form to keep.
Name of Subject 
____:____ am / pm
Signature of Subject (18 or older and able to consent)
Date
Time (please circle)
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
____:____ am / pm
Signature of Person Conducting Informed
Date
Time (please circle)
Consent Discussion
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