Conditions: Breast Cancer
Keywords: Breast cancer Hormone-positive bone-dominant metastatic breast cancer Ra-223 dichloride Xofigo Radium-223 chloride Radium-223 dichloride Alpharadin Denosumab AMG 162 Prolia Hormone therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 45
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if Xofigo® (also called Ra-223 dichloride) combined with hormone therapy and denosumab can help to control breast cancer that has spread to the bones and/or bone marrow. The safety of this study drug combination will also be studied.

This is an investigational study. Denosumab and the hormone therapies used in this study are FDA-approved and commercially available for the treatment of metastatic breast cancer. Ra-223 dichloride is FDA-approved and commercially available for the treatment of bone metastases. It is considered investigational to use the combination of Ra-223 dichloride, hormone therapy and denosumab to treat patients with bone cancer that has spread to the bones.

The study doctor can explain how the study drugs are designed to work.

Up to 36 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive Ra-223 dichloride by vein over no more than 1 minute on Day 1 of each 28-day study cycle.

You will also receive denosumab as an injection under the skin on Day 1 of Cycles 1- 6.

You will also receive hormone therapy while on study. Your doctor will discuss with you what type of hormone therapy you will have, how it will be given, and its risks.

Study Visits:

On Day 1 of Cycle 1, blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2-5:

* You will have a physical exam.
* Blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycle 6:

* Blood (about 2 teaspoons) and urine will be collected for routine tests.
* Blood (about 3 tablespoons) will be drawn for biomarker testing, including genetic biomarkers.
* Blood (about 5 teaspoons) will be drawn to test for CTCs, tumor markers, and genetic testing.
* You will have a PET-CT scan and a bone scan to check the status of the disease. If the doctor thinks it is needed, you will also have an MRI.

Length of Study Participation:

You may continue taking the study drugs for up to 6 cycles. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation will be over after the end-of-study visit.

End-of-Study Visit:

After your last dose of study drug:

* You will have a physical exam.
* Blood (about 2 teaspoons) and urine will be collected for routine tests.
* Blood (about 3 tablespoons) will be drawn for biomarker testing, including genetic biomarkers.
* Blood (about 5 teaspoons) will be drawn to test for CTCs, tumor markers, and genetic testing.
* You will have a PET-CT scan and either a bone scan or a CT scan to check the status of the disease. If the doctor thinks it is needed, you will also have an MRI.
* If the doctor thinks it is needed, you will have a bone marrow aspiration/biopsy to check the status of the disease.

Arms:
arm 1: Ra-223 dichloride 55 kBq/kg administered as a bolus intravenous (IV) injection (over 1 minute) through a secure in-dwelling catheter on day 1 of the study and then every four weeks thereafter for 6 cycles.

Denosumab 120 mg by subcutaneous (SC) injections on Day 1 of Cycles 2-5.

A single hormonal agent (ie, Tamoxifen or Aromatase Inhibitor or Fulvestrant) administered daily while on study. Physician to decide what type of hormone therapy participant will receive.

Interventions: intervention 1: Ra-223 dichloride intervention 2: Denosumab intervention 3: Hormone Therapy
Intervention descriptions: intervention 1: 55 kBq/kg by vein on Day 1 of each 28 day cycle, and then every four weeks thereafter for 6 cycles. intervention 2: 120 mg by subcutaneous (SC) injections on Day 1 of Cycles 2-5. intervention 3: A single hormonal agent administered daily while on study. Physician to decide what type of hormone therapy participant will receive.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
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Title page 
 
Phase II Trial of Ra-223 dichoride in combination with Hormonal Therapy and 
Denosumab in the Treatment of Patients with Hormone-Positive Breast Cancer with 
Bone-Dominant Metastasis 
Test drug(s): 
Ra-223 dichloride  (BAY 88-8223)  
[Study purpose:] 
Defining efficacy 
Clinical study phase: 
Phase II 
 
 
Date: 
  23 January 2018  
Amendment no.: 
10  
 
    
Bayer Study no.: 
XXXXX 
Institution Study no.: 
2014-0508 
Principal Investigator: 
 
  Naoto T. Ueno, MD, Ph.D 
Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 1354, Houston, TX 77030 
Phone: 713-792-8754 
 
Co-Principal Investigator:  Beth Chasen, MD 
 
Statistician:  Yu Shen Ph.D.,  Diane Liu, Ph.D. 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the guidance of 
the clinical investigation.  Reproduction or disclosure of this document - whether in part or in full - to parties 
not associated with the clinical investigation, or its use for any other purpose, without the prior written consent 
of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, the appearance of 
product names without these symbols does not imply that these names are not protected. 


 
 
 
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Synopsis 
 
Title 
Phase II Trial of Ra-223 dichoride in combination with Hormonal 
Therapy and Denosumab in the Treatment of Patients with 
Hormone-PositiveBreast Cancer with Bone-Dominant Metastasis 
Clinical study phase 
Phase II 
Study objective(s) 
Primary objective:  
• To determine the disease control rate at 9 months in 
subjects with bone dominant metastatic breast cancer 
treated with Ra-223 dichloride + Hormonal agent + 
Denosumab  
Secondary objectives 
• To determine the tumor response rate at 6 months using 
PERCIST criteria.  
• To determine the safety of Ra-223 dichloride + 
Hormonal agent + Denosumab. 
 
Exploratory objectives 
• To determine the proportion of CTCs detected by 
CellSearch.  
• To determine the proportion of  EMT-CTCs and 
investigate the correlation to CTCs by CellSearch. 


 
 
 
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Name of active ingredient 
Dose(s)  
Route of administration 
Ra-223 dichloride 
55 kBq/kg body weight after implementation of NIST 
Intravenous 
Indication 
 
Diagnosis and main criteria 
for inclusion 
• Pathologically or radiographically diagnosed Stage IV breast 
cancer with metastases to the bone and/or bone marrow. 
• No limit in number of prior hormonal agents in metastatic 
breast cancer. 
• Breast tumors with hormone receptor positive disease 
(ER+/PR+, ER+/PR- regardless of HER2 status).  
• ECOG performance score of 0, 1. 
• Age ≥ 18 years. 
• All acute toxic effects of any prior treatment have resolved to 
NCI-CTCAE v4.03 Grade 1 or less at the time of signing the 
Informed Consent Form (ICF). 
Study design 
Study Treatment 
• After signing informed consent, confirmation of eligibility, 
participants will receive Ra-223 dichloride + hormonal agent 
+ denosumab. 
Dosing Regimen 
• Ra-223 dichloride, 55 kBq/kg will be administered as a bolus 
intravenous (IV) injection (up to 1 minute) through a secure 
in-dwelling catheter on day 1 of the study and then every four 
weeks thereafter for 6 cycles.  
• A single hormonal agent (e.g., Tamoxifen or Aromatase 
Inhibitor or Fulvestrant) will be administered per standard 
FDA approved dosage.  
• Patients will receive subcutaneous (SC) injections of 
denosumab 120 mg every four weeks.   
Type of control 
This is a single arm study. 
Number of subjects 
36 
Study Endpoints 
The primary endpoint is disease control rate at 9 months. 


 
 
 
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Plan for statistical analysis The primary endpoint is disease control rate at 9 months. With 36 
patients, we will have an 85% power to detect the disease control 
rate of 90% against 70% with a two-sided exact binomial test at a 
significance level of 5%. 
 


 
 
 
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Amendment Rationale 
The quantification of radium-223 radioactivity in Xofigo® is based on the primary 
standardization performed by the US National Institute of Standards and Technology (NIST).  
The NIST Standard Reference Material is used to calibrate the instruments in production and 
quality control of both the drug substance and drug product.  Additionally, the calibrated 
instruments in production at the Institute for Energy Technology (IFE, Norway) are used to 
prepare the NIST traceable radium-223 reference material, which are then sent to the 
treatment sites (e.g., nuclear medicine laboratory physicians or technicians) for dial setting of 
their dose calibrators, to allow verification of the patient dose.  A reassessment of the primary 
standardization was initiated by the NIST.  A discrepancy of approximately 10% between the 
published NIST primary standardization (Cessna, 2010, NIST 2010) and current 
measurements was confirmed and a revised NIST primary reference standard has been issued 
(Zimmerman, 2015, NIST update).  As a result of the revised NIST primary standardization, 
an adaption of the numerical description of patient dose and the description of radioactive 
concentration of the drug product solution becomes necessary.  This concerns Xofigo® for 
commercial use and product used in clinical trials.   
After the implementation of the new standard (NIST update) the numerical description of the 
patient dose will be adjusted from 50 kBq/kg to 55 kBq/kg, and the numerical description of 
the radioactivity in the vial will be changed from 1,000 kBq/mL to 1,100 kBq/mL 
The values in this protocol have been revised as per the United States National Institute of 
Standards and Technology (NIST) standardization update. 
Bayer has submitted a variation application to the FDA.   The current standard (NIST 2010), 
dial setting and dose will remain in effect until  Bayer has confirmed  the unique 
implementation date in the 2nd quarter of  2016 as agreed with FDA and notified  the 
principal investigator Naoto T. Ueno, MD at The University of Texas MD Anderson Cancer 
Center. 
 
 
 
 
 


 
 
 
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Table of Contents 
Title page  
1 
Synopsis 
2 
1 
Introduction 
7 
 
1.1 
Background 
7 
 
1.2 
Rationale of the study 
10 
 
1.3 
Ra-223 dichloride 
12 
 
 
1.3.1 
Mechanism of Action 
12 
 
 
1.3.2 
NIST Standardization 
12 
 
 
1.3.3 
Preclinical 
13 
 
 
1.3.4 
Clinical Experience Summary 
 
13 
2. 
Study Objectives 
16 
3. 
Investigators and other study participants 
17 
4. 
Study design 
17 
5. 
Study population 
17 
 
5.1 
Elegibility 
17 
 
 
5.1.1 
Inclusion criteria 
17 
 
 
5.1.2 
Exclusion criteria 
18 
 
 
5.1.3 
Excluded therapies and medications, previous and concomitant 
19 
 
5.2 
Withdrawal of subjects from study 
20 
 
 
5.2.1 
Withdrawal 
20 
 
 
5.2.2 
Screen Failures/Dropouts 
21 
 
 
5.2.3 
Replacement 
 
21 
6. 
Treatments 
21 
 
6.1 
Treatment assignment 
21 
 
6.2 
Ra-223 dichloride 
21 
 
 
6.2.1 
Treatments to be administered 
21 
 
 
6.2.2 
Identity of study treatment 
21 
 
 
6.2.3 
Instructions for use / handling 
22 
 
 
 
6.2.3.1 General warning 
22 
 
 
 
6.2.3.2 Radiation protection 
22 
 
 
6.2.4 
Dose calibration 
25 
 
 
6.2.5 
Dosimetry 
22 
 
 
6.2.6 
Dose handling 
23 
 
 
6.2.7 
Dose calculation 
24 
 
 
6.2.8 
Dose preparation 
24 
 
 
6.2.9 
Dose administration 
25 
 
 
6.2.10 Dose Modification 
25 
 
6.3 
Drug logistics and accountability 
26 
 
 
6.3.1 
Accountability 
26 
 
 
6.3.2 
Destruction and Return 
 
26 
 
6.4 
Treatment compliance 
26 
 
6.5 
Prior and concomitant therapy 
26 


 
 
 
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7. 
Procedures and variable 
27 
 
7.1 
Schedule of procedures 
27 
 
 
7.1.1 
Tabulated overview 
27 
 
 
7.1.2 
Timing of assessments 
28 
 
 
7.1.3 
Medical history 
29 
 
 
7.1.4 
Efficacy 
30 
 
 
7.1.5 
Radiographical Methodology 
30 
 
7.2 
Safety 
31 
 
 
7.2.1 
Adverse events 
31 
 
 
 
7.2.1.1 
Definitions 
32 
 
 
 
7.2.1.2 
Classifications for adverse event assessment 
34 
 
 
 
 
7.2.1.2.1 Intensity 
34 
 
 
 
 
7.2.1.2.2 Casual relationship 
34 
 
 
 
 
7.2.1.2.3 Action taken with study treatment 
35 
 
 
 
 
7.2.1.2.4 Other specific treatments of adverse events 
36 
 
 
 
 
7.2.1.2.5 Outcome 
36 
 
 
 
7.2.1.3 
Reporting of serious adverse events 
36 
 
 
 
7.2.1.4 
Expected adverse events 
38 
 
 
7.2.2 
Pregnancies 
38 
 
 
7.2.3 
Further safety 
38 
 
7.3 
Appropriateness of procedures / measurements 
 
38 
8. 
Statistical methods and determination of sample size 
38 
9. 
Data handling and quality assurance 
40 
 
9.1 
Data recording 
40 
 
9.2 
Audit and inspection 
40 
 
9.3 
Archiving 
 
40 
10. 
Premature termination of the study 
41 
11. 
Ethical and legal aspects 
41 
 
11.1 
Ethical and legal conduct of the study 
41 
 
11.2 
Subject information and consent 
42 
 
11.3 
Confidentiality 
 
42 
12. 
Reference 
43 
 
 
 
 
 
 
 
 
 


 
 
 
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List of abbreviations 
AE   
 
Adverse Event 
ALP  
 
Alkaline Phosphatase 
ALSYMPCA  
Alpharadin in Symptomatic Prostate Cancer 
ALT  
 
Alanine Aminotransferase 
ANC  
 
Absolute Neutrophil Count 
AST  
 
Aspartate Aminotransferase 
BPI-SF  
 
Brief Pain Index (Short Form) 
BSoC  
 
Best Standard of Care 
CBC  
 
Complete Blood Count 
CRO  
 
Clinical Research Organization 
CRPC  
 
Castration Resistant Prostate Cancer 
CT   
 
Computed tomography 
CTCAE  
 
Common Terminology Criteria for Adverse Events; version 4.03 
DK  
 
Decay Correction Factor 
EBRT  
 
External Beam Radiation Therapy 
ECOG  
 
Eastern Co-operative Oncology Group 
eCRF  
 
Electronic Case Report Form 
EU   
 
European Union 
GCP  
 
Good Clinical Practice 
GCL  
 
Global Clinical Leader 
GMP  
 
Good Manufacturing Practice 
HRPC  
 
Hormone Resistant Prostate Cancer 
IB   
 
Investigator Brochure 
ICF  
 
Informed Consent Form 
ICH  
 
International Conference on Harmonization 
IDMC  
 
Independent data monitoring committee 
IEC  
 
Independent Ethics Committee 
IRB 
 
 Institutional Review Board 
IV   
 
Intravenous 
IxRS 
 
 Interactive Voice/Web Response System (IVR/IVRS) 
kBq  
 
Kilobecquerel; SI Unit of Radioactivity 
kg   
 
Kilogram 
LHRH  
 
Luteinizing-Hormone-Releasing Hormone; also known as Gonadotropin- 
Releasing Hormone (GnRH) 
mCi  
 
Millicuries 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
mL  
 
Milliliter 
MRI  
 
Magnetic Resonance Imaging 
NCI  
 
National Cancer Institute 
NIST 
 
National Institutes of Standards and Technology 
NYHA  
 
New York Heart Association 
OS   
 
Overall Survival 
PS   
 
Performance Status 
PSA  
 
Prostate Specific Antigen 
QoL  
 
Quality of life 
SAE  
 
Serious Adverse event 
SAP  
 
Statistical Analysis Plan 
SAS  
 
Statistical Analysis Software 
SRE  
 
Skeletal-related Events 
SUSAR  
 
Suspected Unexpected Serious Adverse Reaction 
TEAE  
 
Treatment-emergent Adverse Event 
ULN  
 
Upper Limit of Normal 
WHO-DD   
World Health Organization – Drug Dictionary 
 
 
 


 
 
 
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Definitions of terms 
 
Ra-223 dichloride      
The investigational product, a targeted alpha-pharmaceutical (a 
radiopharmaceutical emitting alpha particles), is a ready-to-use solution 
for intravenous injection containing the drug substance radium chloride. 
The active moiety is the alpha particle emitting nuclide Ra-223, present 
as a divalent cation (223Ra2+). 
Dose                                  
Doses are given as kilobecquerel (kBq) per kilogram body weight, with 
the corresponding dose given in millicurie (mCi) per kilogram in 
parenthesis. The term “dose” is used to describe the quantity of 
radioactivity from Ra-223 dichloride administered. 
 
1. Introduction 
 
1.1 Background 
Breast Cancer Bone metastasis:  
Bone is the most common metastatic site for breast cancer, and bone metastases develop 
in 65-75% of patients with metastatic breast cancer.1, 2 These metastases can result in 
substantial morbidity in the form of skeletal-related events (SREs) that are defined as 
pathological fractures, spinal cord compression, hypercalcemia, or pain that requires 
radiation or surgery of the bone. Once bone metastases become established, they are 
usually incurable and the goal of treatment becomes focused on palliation and 
prevention of SREs. 
 
Treatment for Breast Cancer Bone Metastasis 
Modalities used to treat breast cancer that has metastasized to the bone include 
chemotherapy, hormonal therapy, analgesics, radiotherapy, and orthopedic surgery. 
Because breast cancer patients who have bone metastasis may face severe reduced 
quality of life due to bone-related complications, there is a need for development of 
bone targeting therapy for patients with hormone positive breast cancer. There is 
currently no bone metastasis targeted specific treatment in breast cancer. Strontium-89 
and samarium-153 are FDA-approved radiopharmaceutical agents indicated for severe 
bone pain due to bone metastasis. But they are not indicated for a treatment of breast 
cancer bone metastasis. 
 
Role of Circulating Tumor Cells in Metastatic Breast Cancer:  
The FDA-approved CellSearch System (Veridex, Raritan, NJ) is the first diagnostic test 
to identify and enumerate circulating tumor cells (CTCs) in the bloodstream of patients 
with metastatic breast cancer. The analysis is based on the enumeration of epithelial 
cells, which are isolated from the blood by anti-EpCAM coated ferrous nanoparticles 


 
 
 
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and stained with antibodies to cytokeratin (CK) and common leukocyte antigen (CD45) 
and DAPI.  CTCs are characterized as cells with a nucleus (DAPI+) that express surface 
EpCAM, cytoplasmic CK, and lack expression of CD45. CTC are an independent 
prognostic factor for progression-free and overall survival in metastatic breast cancer 
(MBC). Circulating tumor cells (CTCs) are cancer cells of epithelial origin that are 
found in the peripheral blood (PB) and are believed to be shed from primary lesions.  In 
patients with MBC, the number of CTCs in the PB before and during treatment is an 
independent predictor of PFS and OS.3, 4 Superior PFS and OS were observed among 
patients with fewer than 5 CTCs per 7.5 mL of peripheral blood regardless of primary 
tumor histology, hormone receptor and HER2/neu status, sites of first metastases, or 
whether the patient had recurrent or de novo metastatic disease. Between 10% and 30% 
of patients with stage I to III breast cancer and 50% to 70% of women with metastatic 
breast cancer have detectable CTCs.3-5 In both cases, presence and elevation of CTCs 
are associated with worse prognosis. In the metastatic setting, persistent CTC after 3 to 
5 weeks of a new therapy seem to indicate lack of activity of that regimen, and an 
ongoing prospective randomized clinical trial is addressing the relative worth of 
changing to an alternative treatment rather than waiting for classic clinical and 
radiologic evidence of progression. Early studies already suggest a role of CTCs in 
selected patients with metastatic disease. Coupled with an increasing understanding of 
the need for well-designed and well-conducted trials, better understanding of the 
biology of CTC will result in their becoming a routine part of the clinical evaluation of 
at least patients with metastatic breast and other cancers, and perhaps even in early stage 
disease. 
 
Epithelial Mesenchymal Transition of CTC 
In order to metastasize to distant organs, breast cancer cells must detach from the 
primary tumor, traverse the peripheral circulation, extravasate into the parenchyma, and 
establish a new tumor.  A number of studies have shown that carcinoma cells often 
activate a transdifferentiation program, termed epithelial-mesenchymal transition 
(EMT), to acquire the traits needed to execute the multiple steps of metastasis.  Through 
this EMT process, epithelial cells lose cell-cell contacts and cell polarity, downregulate 
epithelial-associated genes, acquire mesenchymal gene expression, and undergo major 
changes in their cytoskeleton.  This cellular process culminates in a mesenchymal 
appearance and increased motility and invasiveness. Cancer cells can be induced to 
undergo EMT by several signaling pathways, most notably those involving the 
cooperation between TGF-β1 signaling and oncogenic Ras or other receptor tyrosine 
kinases, as well as Wnt, Notch, and the signaling activated by Hedgehog.  In addition, 
certain transcription factors, including TWIST1, SNAIL1, SLUG, ZEB1, and FOXC2 
can induce EMT in mammary epithelial cells and/or breast cancer cells.  In addition, 
blocking the expression of Twist in the highly metastatic 4T1 murine mammary cell 
line reduced both metastatic burden and the number of CTCs in mice bearing xenograft 


 
 
 
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mammary tumors thus linking EMT, metastasis, and the presence of CTCs.  These 
findings suggest that the expression of epithelial-cell surface markers, such as EpCAM, 
may not be optimal for detecting heterogeneous CTC population due to a 
subpopulation(s) with mesenchymal phenotype.  We recently demonstrated that 
CellSearch is incapable of detecting CTC undergoing EMT (EMT-CTC) and have 
developed a PCR-based assay to detect EMT-inducing transcription factors (EMT-TFs) 
in breast cancer patients.6  
 
Imaging of Bone Metastasis Ability of PET/CT to detect the tumor response 
2-[Fluorine-18]fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography 
(PET) is more sensitive than conventional imaging in the detection of breast cancer 
metastases at any site. PET has the potential to revolutionize the definition of 
measurable tumors because it introduces imaging criteria based on function. The 
regular, well-defined tumor margins that are necessary for reproducible anatomic 
measurements are of lesser importance in functional imaging. FDG is a radiolabeled 
form of glucose that cannot be metabolized and therefore accumulates in cells, which 
take up the molecules as if they were normal glucose. Through this accumulation, FDG 
activity acts as a surrogate for glucose metabolism.  
 
Since many malignancies are highly metabolic and accumulate FDG, it is the most 
commonly used PET agent for oncologic indications. FDG–PET/computed tomography 
(CT) allows for fusion of functional and anatomic datasets, resulting in more accurate 
evaluation of disease, which has resulted in a better detection and reflection of the tumor 
activity in MBC, in particular of bone metastases.  Recent prospective study, a possible 
correlation between>5 CTCs at baseline and the presence of bone metastases as 
detected by whole-body bone scan was noted. The superiority of FEG-PET/CT over 
bone scan in specificity and sensitivity for detection of bone metastases is well 
documented. So there is a possibility to detect the response of radium-223 accompanied 
with the reduction of CTCs in FDG-PET/CT. 
 
The most widely used criteria are based on the anatomic measurement of solid tumors. 
Because bone metastases are typically located in irregularly shaped bones and are 
difficult to measure with rulers, they have been previously considered unmeasurable 
disease.  New developments in cancer response criteria have increased awareness of the 
importance of the response of bone metastases to therapy. The recently updated 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) now consider bone 
metastases with soft tissue masses > 10 mm to be measurable disease.  Response criteria 
specific to bone metastases have been developed at The University of Texas MD 
Anderson Cancer Center (MDA criteria) and can be used to assess therapeutic response 
in numerous types of bone metastases. Functional imaging criteria, such as the recently 
developed Positron Emission Tomography Response Criteria in Solid Tumors 


 
 
 
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(PERCIST) allow response to be measured in the absence of anatomic change through 
assessment of metabolic activity.7-10  
 
As monitoring tumor response of bone metastases becomes more important in the 
management of cancer, so does the demand on radiologists and nuclear medicine 
physicians for accurate interpretation of the behavior of these lesions. The WHO criteria 
include radiograph-based guidelines for the interpretation of bone metastases; however, 
RECIST or RECIST 1.1 did not adopt these guidelines. The resultant void regarding 
the evaluation of bone metastases led to the development of bone-specific response 
criteria at MD Anderson Cancer Center in 2004.  
 
The MDA criteria updated the UICC and WHO bone response criteria by expanding 
radiographic assessment and incorporating both CT and MRI. In a study comparing the 
MDA, UICC, and WHO criteria in 41 breast cancer patients with bone-only metastases, 
the MDA criteria were shown to better differentiate responders to chemotherapy from 
nonresponders and were the only set of criteria to correspond to progression-free 
survival. According to the MDA criteria, time to disease progression was 5.5 months 
for nonresponders and 23.3 months for responders (P = 0.025), compared with 10.4 
months and 12.4 months, respectively, according to the WHO criteria (P = 0.55). The 
MDA criteria identified nonresponders earlier and better correlated with clinical 
response in the first 2-6 months of therapy than did the WHO criteria. Early signs of 
disease progression are valuable, allowing the halting of ineffective therapy in a timely 
fashion and the possible substitution of effective therapy. In addition to their utility for 
guiding treatment decisions, the MDA bone response criteria closely reflect the 
behavior of bone metastases on radiography and CT and can be used as guidelines for 
the interpretation of these studies whether or not a patient is enrolled in a therapeutic 
trial10 
1.2 
Rationale of the study 
The objective of this protocol is to determine the progression events at 9 months by Ra-
223 dichloride + hormonal agent + denosumab. Currently Ra-223 dichloride is 
approved by FDA only for castration resistant prostate cancer and for breast cancer the 
drug has been still under clinical experiments. The clinical safety of Ra-223 dichloride 
was evaluated in advanced breast cancer patients. 11Its efficacy has been evaluated in 
castration-resistant prostate cancer patients with bone metastases in phase III 
multicenter study (ALSYMPCA), which demonstrated a significant survival benefit 
from Ra-223 dichloride. 12  
After determining its efficacy, we will plan for a definitive randomized study in SWOG. 
Denosumab is a FDA-approved bone modification agent. Use of denosumab and 
hormonal therapy for bone metastasis dominant breast cancer is considered a standard 
of care. 
 


 
 
 
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We will use progression events (the total number of events of progression among the 
participating patients within 9 months) instead of determining progression-free survival 
as the primary endpoint so that we can complete the study in a timely manner. The 9-
month timeframe was chosen because our group reported that the median progression-
free survival duration for patients diagnosed with hormone-positive bone-only 
metastatic breast cancer is 12 to 18 months and that for patients with HER-2 positive is 
10 to 24 months.1 This data suggest that there will be no progressive of disease about 
70% at 9 months when bone only metastatic disease is treated with endocrine therapy 
alone. 
 
We will also use FDG PET-CT scans at 6 months and 9 months to evaluate the tumor 
response using PERCIST criteria.8 The assessment of the tumor response is a secondary 
objective. 
 
1.3    Ra-223 dichloride 
          1.3.1  Mechanism of Action  
 
Radium-223 dichloride is a therapeutic alpha particle-emitting pharmaceutical with 
targeted anti-tumor effect on bone metastases. Ra-223 dichloride mimics calcium and 
selectively targets bone, specifically areas of bone metastases, by forming complexes 
with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters 
(80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in 
adjacent cells, resulting in a potent and localized anti-tumor effect. The alpha particle 
range from radium-223 is less than 100 micrometers (less than 10 cell diameters), which 
minimizes damage to the surrounding normal tissue.  
 
1.3.2   NIST Standardization 
 
The quantification of radium-223 radioactivity in Xofigo (radium-223 dichloride;BAY 
88-8223) is based on the primary standardization performed by the US NIST.  National 
Institue of Standards and Technology prepares the standard reference material (SRM) 
using an official dial setting (primary standardization) as published. The NIST SRM is 
used to calibrate the instrucments in production and quality control for both the drug 
substance and drug product. Additionally, the NIST SRM is used to prepare the NIST 
traceable Ra-223 reference materials which are then sent to the end-users (e.g., nuclear 
medicine laboratory physicians or technicians) for dial-setting of their dose calibrators, 
to allow verification of the patient dose. In 2014, NIST performed a re-assessment of 
the primary standardization based on preliminary information suggesting a potential 
discrepancy of approximately 8-10% between the published NIST primary 
standardization and results obtained by other national metrology institutes (United 
Kingdom, Germany and Japan).  After completion of the re-assessment, NIST reported 
their findings and had to issued a revised NIST SRM in 2015. The discrepancy in the 


 
 
 
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NIST standardization was determined to be -9.5 % between activity values obtained 
using the old reference standard relative to the new primary standardization.  
 
Consequently, the current numerical values need to be corrected by approximately + 
10. 5 %. The current NIST standard for radium-223 dichloride will remain in effect until 
the FDA has fully approved theregulatory variation submitted for Xofigo and is 
anticipated in the 2nd quarter of 2016. 
The change in the numerical description of the patient’s dose, product strength and 
labeled vial activity does not impact the safety or efficacy of Xofigo, The change in the 
NIST radium-223 standard has no impact on subjects; dose subjects are receiving, and 
will continue to receive.  
 
Subjects will receive the same actual dose and volume that was studied in Study 15245 
(BC1-06 dosimetry study) and is associated with the proven safety and efficacy of 
radium-223 dichloride, though the stated nominal radiation dose received is being 
updated to reflect the new standard. 
1.3.3 Preclinical13-16 
In single and repeated dose toxicity studies in rats, the main findings were reduced body 
weight gain, hematological changes, reduced serum alkaline phosphatase and 
microscopic findings in the bone marrow (depletion of hematopoietic cells, fibrosis), 
spleen (secondary extra-medullary hematopoiesis) and bone (depletion of osteocytes, 
osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the 
physis/growth line). These findings were related to radiation-induced impairment of 
hematopoiesis and a reduction of osteogenesis and and started at the lowest dose of  of 
20 (0.00056 mCi) – 80 kBq (0.0022 mCi) per kg body weight, (22 (0.00061 mCi)- 
88kBq (0.0024m Ci after implementation of the NIST) with the exception of body 
weight decreases.  
Dose-limiting myelotoxicity was seen in dogs after single administration of 450 kBq 
(0.012 mCi) (497 kBq/kg after implementation of NIST update) Ra-223 dichloride per 
kg body weight (9 times the clinically recommended dose).   
Osteosarcomas, a known effect of bone-seeking radionuclides, were observed at 
clinically relevant doses in rats 7 – 12 months after start of treatment. Osteosarcomas 
were not observed in dog studies. The presence of neoplastic changes, other than 
osteosarcomas, was also reported in the longer term (12 to 15 months) rat toxicity 
studies. Due to its mode of action, and as seen with conventional radiotherapy and other 
radiotherapeutics, radium-223 dichloride may have the potential to induce secondary 
malignancies. No case of osteosarcoma has been reported in clinical studies with Ra-
223 dichloride. The risk for patients to develop osteosarcomas with exposure to Ra-223 
dichloride is unknown at present  
 
Studies on reproductive and developmental toxicity have not been performed. Since Ra-
223 dichloride binds to bone, the potential risk for toxic effects in the male gonads in 
cancer patients with castration-resistant prostate cancer is very low, but cannot be 
excluded. Studies on the mutagenic and carcinogenic potential of Ra-223 dichloride 
have not been performed. 


 
 
 
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No histological changes were observed in organs involved in the excretion of Ra-223 
dichloride. No significant effects were seen on vital organ systems, i.e. cardiovascular 
(dog), respiratory or central nervous systems (rat), after single dose administration of 
450 to 1,000 kBq (0.012  to 0.027 mCi) corresponding to 497-1100kBq ( 0.014 to 0.03 
mCi)  per kg body weight after implementation of the NIST (9 (dog) to 20 (rat) times 
the clinically recommended dose. 
 
            1.3.4  Clinical Experience Summary12, 17-20 
 
The clinical development of Ra-223 dichloride includes phase I and phase II studies in 
prostate cancer patients with bone metastases. The results of these completed studies 
indicated that safety and tolerability of Ra-223 dichloride in CRPC/HRPC patients with 
bone metastases was well tolerated, and that there was evidence of dose related efficacy 
against bone markers and other markers of disease. In addition there was an effect on 
median overall survival in a Phase II (BC1-02) placebo-controlled study. These studies 
enabled the initiation of the Phase III ALSYMPCA (ALpharadin in SYMptomatic 
Prostate CAncer) study. 
 
The clinical safety and efficacy of Ra-223 dichloride have been evaluated in a double-
blind, randomized, multiple dose, phase III multicenter study (ALSYMPCA) in 
castration-resistant prostate cancer patients with bone metastases. The primary efficacy 
endpoint was Overall Survival (OS).  
At the cut-off date of the pre-planned interim analysis, a total of 809 patients were 
randomized 2:1 to receive Ra-223 dichloride 50kBq (0.0012mCi) (55 kBq (0.0014 
mCi)/kg after implementation of the NIST intravenously every 4 weeks for 6 cycles 
(N=541) plus best standard of care or matching placebo plus best standard of care 
(N=268). Best standard of care included e.g. local external beam radiotherapy, 
corticosteroids, antiandrogens, estrogens, estramustine or ketoconazole.  
 
An updated descriptive analysis of safety and of OS was performed in 921 randomized 
patients prior to implementing crossover (i.e. offering patients in the placebo group to 
receive Ra-223 dichloride treatment). 
The results of both, interim and updated analysis, revealed that OS was significantly 
longer in patients treated with Ra-223 dichloride plus best standard of care compared to 
patients treated with placebo plus best standard of care. For the updated analysis, an 
increase in median overall survival of 3.6 months was seen with Ra-223 dichloride plus 
best standard of care compared to placebo plus best standard of care (HR =0.695 (95% 
CI 0.581/0.832), median OS 14.9 months versus 11.3 months, respectively). 
In the ALSYMPCA study, the results of the interim analysis and the updated analysis 
showed also a significant improvement in all main secondary endpoints in the Ra-223 
dichloride arm compared to the placebo arm: 
 


 
 
 
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Time to first SRE (defined as time to EBRT, time to first pathological bone fracture, 
time to spinal cord compression and time to surgical intervention) was statistically 
significantly longer in the radium-223 chloride group compared to placebo (median 
number of months=15.6 for radium-223 chloride versus 9.8 months for placebo 
(HR=0.658, 95 CI 0.522–0.830, p= 0.00037). 
Time to total ALP progression (defined as ≥ 25% increase compared to baseline/nadir) 
was statistically significantly longer in the radium-223 chloride group 7.4 months 
compared to placebo 3.8 months  (HR = 0.167, 95% CI 0.129 – 0.217; p= <0.00001). 
Time to PSA progression (defined as a ≥ 25% increase and an increase in absolute value 
of ≥ 2 ng/mL compared to baseline/nadir ) was also significantly prolonged in patients 
receiving Ra-223 dichloride compared to patients receiving placebo (HR = 0.643, 95% 
CI 0.539,0.768; p = <0.00001) 
A total ALP  response (defined as a confirmed ≥ 30% or ≥ 50% reduction compared to 
baseline) at week 12 was observed in higher proportions of subjects who were treated 
with radium-223 chloride group (47%  and 3% respectively) compared to those in the 
placebo (3% and <1% respectively) group.  
 
Subgroup survival analysis showed a consistent survival benefit for treatment with Ra-
223 dichloride, independent of total alkaline phosphatase (ALP), current use of 
bisphosphonates, prior use of docetaxel and baseline ECOG status. The results from the 
phase III ALSYMCA study regarding time to external beam radiation therapy (EBRT) 
for pain relief and fewer patients reporting bone pain as an adverse event in the Ra-223 
dichloride group indicate a positive effect on bone pain.  
 
Most common hematologic adverse events all grades were anemia (31.2%), neutropenia 
(5%) and thrombocytopenia (11.5%). Most common non-hematologic all grades 
adverse events occurring in more than 15% of patients were: bone pain, diarrhea, 
nausea, vomiting and constipation. 
Table 1 shows adverse reactions occurring in ≥ 1% of patients and for which the rate 
for Ra-223 dichloride exceeds the rate for placebo.  
 
Table 1 Adverse Reactions in the Phase III Randomized Trial12 
System/Organ 
Class 
Preferred Term 
Ra-223 dichloride (n=600) 
Placebo (n=301) 
All 
Grades  
% 
Grades 3-
4 
% 
All 
Grades  
% 
Grades 3-
4 
% 
Blood and lymphatic system disorders  
Thrombocytopenia 
11.5 
6.3 
5.6 
2 


 
 
 
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Neutropenia 
5 
2.2 
1 
0.7 
Leukopenia 
4.2 
1.3 
0.3 
0.3 
Pancytopenia 
2 
1.2 
0 
0 
Gastrointestinal disorders 
Diarrhea 
25 
1.5 (grade 
3 only) 
15 
1.7 (grade 
3 only) 
Vomiting 
18.5 
1.7 (grade 
3 only) 
13.6 
2.3 (grade 
3 only) 
Nausea 
35.5 
1.7 (grade 
3 only)  
34.6 
1.7 (grade 
3 only) 
General disorders and administration site conditions 
Injection site 
reactions 
(including 
erythema, pain 
and swelling) 
1.2  
0 
0 
0 
Adverse reactions are identified using MedDRA version 14.1 and graded according to 
CTCAE version 3.0. 
An additional clinically important adverse reaction observed in less than 1% of Ra-223 
dichloride -treated patients and at a higher incidence than in placebo-treated patients was 
lymphopenia (0.8% vs. 0.3%). 
 
Secondary malignant neoplasms 
No cases of radiation-induced cancer have been reported in reported in clinical trials with 
radium-223 dichloride in follow-up of up to three years. However, the radiation dose 
resulting from therapeutic exposure may result in higher incidence of cancer (e.g. sarcomas 
of the bone, or leukemia), mutations and a potential for development of hereditary defects. 
First clinical experience with alpha-emitting Ra-223 in the treatment of skeletal metastases 
of bone was well tolerated. Ten breast cancer patients was enrolled in a phase I trial received 
a single i.v. injection of Ra-223. Pain relief was reported by 52%, 60%, and 56% of the 
patients after 7 days, 4, and 8 weeks, respectively. 223Ra cleared rapidly from blood and 
was below 1% of initial level at 24 hours.21 
2. Study objectives 
 


 
 
 
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Primary objective:  
• To determine the disease control rate at 9 months in subjects with bone 
dominant metastatic breast cancer treated with Ra-223 dichloride + Hormonal 
agent + Denosumab  
Secondary objectives 
• To determine the tumor response rate at 6 months using PERICST criteria.  
• To determine the safety of Ra-223 dichloride + Hormonal agent + 
Denosumab. 
 
 Exploratory objectives 
• 
To determine the proportion of CTCs detected by CellSearch. 
• 
To determine the proportion of EMT-CTCs and investigate the correlation to CTCs 
by CellSearch. 
 
 
3. Investigators and other study participants 
 
 
Principal Investigator  
 
Naoto T. Ueno, MD, PhD, FACP 
Department of Breast Medical Oncology 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 1354, Houston, TX 77030 
e-mail: nueno@mdanderson.org 
Phone: 713-792-8754 
Fax: 888-375-2139   
4. Study design 
Study Treatment 
• After signing informed consent, confirmation of eligibility, participants 
will receive Ra-223 dichloride + hormonal agent + denosumab. 
 
Dosing Regimen 
• Ra-223 dichloride, 50 kBq/kg ( 55kBQ/kg after implementation of the 
NIST) will be administered  as a bolus intravenous (IV) injection (up to 1 
minute) through a secure in-dwelling catheter on day 1 of the study and 
then every four weeks thereafter for 6 cycles.  
• A single hormonal agent (eg, Tamoxifen or Inhibitor or Fulvestrant) will be 
administered per standard FDA approved dosage.  
• Patients will receive subcutaneous (SC) injections of denosumab 120 mg 
every four weeks.   


 
 
 
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5. Study population 
5.1 Eligibility 
5.1.1 Inclusion criteria 
• Stage IV breast cancer with metastases to the bone and/or bone marrow. 
• Pathological or radiographical confirmation of metastases to the bone and/or 
bone marrow. The definition of radiologic diagnosis of bone metastasis is 
based on typical and highly reliable imaging findings in studies such as bone 
scan (new or multiple TC99m positive lesions), PET/CT  (new or multiple 
FRG positive lesions), and MRI (typical T1w replacement, T2w positive and 
T1 plus contrast media positive) for bone metastasis with 2 or more lesions. 
If the bone metastasis is highly suspected or not well defined by imaging, 
bone biopsy is necessary for confirmation.  
• Visible uptake in at least one lesion on bone scanning prior to radium 
therapy. 
• No limit in number of prior hormonal agents in metastatic breast cancer; 
only one prior  chemotherapy is allowed in metastatic setting.  Anti-HER2 
targeting therapy, CDK4/6 inhibitor, other targeted therapy (e.g., mTOR or 
PI3K inhibitor)  in combination with hormonal treatment will be counted as 
one hormonal agent. Any anti-HER2 targeting therapy in combination with 
chemotherapy will not be counted as one additional treatment.Breast tumors 
with hormone receptor positive disease (ER+/PR+, ER+/PR).  
• ECOG performance score of 0, 1. 
• Age ≥ 18 years. 
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE 
v 4.03 Grade 1 or less at the time of signing the Informed Consent Form 
(ICF). 
• Subjects (men and women) of childbearing potential must agree to use 
adequate contraception beginning at the signing of the ICF until at least 6 
months after the last dose of study drug.  The definition of adequate 
contraception will be based on the judgment of the principal investigator or 
a designated associate. 
• Acceptable hematology and serum biochemistry screening values: 
o White Blood Cell Count (WBC) ≥ 3,000/mm3 
o Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 
o Platelet (PLT) count ≥ 100,000/mm3 
o Hemoglobin (HGB) ≥ 10 g/dl 
o Total bilirubin level ≤ 2.0 x institutional upper limit of normal 
(ULN) 


 
 
 
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o Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 3.0 x ULN  
o Creatinine ≤ 1.5 x ULN 
• Subjects must be able to understand and be willing to sign the written 
informed consent form.  A signed informed consent form must be 
appropriately obtained prior to the conduct of any trial-specific procedure. 
5.1.2 Exclusion criteria 
• Following breast cancer disease conditions are not eligible. 
o Single Bone Lesion 
o Two or more visceral metastasis 
*Single visceral lesion < 2 cm without any laboratory changes or 
clinical symptoms due to the metastatic lesion is permitted. 
o Presence of brain metastases 
o Imminent spinal cord compression based on clinical findings and/or 
magnetic resonance imaging (MRI). * 
o Impending fracture, spinal cord compression, and/or potentially 
unstable compression fracture of vertebral body with possibility of 
cord compression.* 
o Life expectancy severely limited by concomitant illness (less than 12 
months). 
*Concurrent external beam radiation therapy to non target lesion is 
permitted.  Following prior treatments are not eligible. 
o Use of any investigational agent within 30 days preceding 
enrollment. 
o Treatment with cytotoxic chemotherapy within previous 4 weeks 
o Failure to achieve </= Grade 2 AE resolution from cytotoxic 
chemotherapy administered more than 4 weeks previous (however, 
ongoing neuropathy is permitted). 
o Received systemic therapy with radionuclides (e.g., strontium-89, 
samarium-153, rhenium-186, or rhenium-188, or Ra-223 dichloride) 
for the treatment of bony metastases.   
• Following medical conditions are not eligible. 
o Other malignancy treated within the last 3 years (except non 
melanoma skin cancer or low-grade superficial bladder cancer or 
cervical dysplasia)  
o Any other serious illness or medical condition, such as but not 
limited to:  
o Any infection ≥ National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03 Grade 2  
o Cardiac failure New York Heart Association (NYHA) III or IV 


 
 
 
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o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia or Myelodysplastic syndrome.  
o Women who are pregnant or breast-feeding. Women of childbearing 
potential must have a negative serum pregnancy test performed 
within 7 days prior to the start of study drug. Post-menopausal 
women (defined as no menses for at least 1 year) and surgically 
sterilized women are not required to undergo a pregnancy test. 
o Any condition which, in the investigator’s opinion, makes the subject 
unsuitable for trial participation. 
o Major surgery within 30 days prior to start of study drug. 
 
5.1.3 Excluded therapies and medications, previous and concomitant 
• Concurrent anti-cancer therapy (chemotherapy, surgery, immunotherapy, 
biologic therapy, anti-HER 2 targeting therapies, or tumor embolization) other 
than Ra 223 dichloride. Concurrent external beam radiation therapy to non 
target lesion is permitted. Prior use of Ra-223 dichloride. 
• Concurrent use of another investigational drug or device therapy (i.e., outside 
of study treatment) during, or within 4 weeks of trial entry (signing of the 
informed consent form). 
5.2 Withdrawal of subjects from study 
5.2.1 Withdrawal 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
• Subject withdraws consent from study treatment and study procedures.  A subject 
must be removed from the trial at his/her own request or at the request of his/her 
legally acceptable representative.  At any time during the trial and without giving 
reasons, a subject may decline to participate further.  The subject will not suffer 
any disadvantage as a result. 
• Subject is lost to follow-up. 
• Death. 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug and  trial procedures, or both; 
including the use of anti-cancer therapy not prescribed by the study protocol. 
• Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who have been 
withdrawn from treatment with study drug because of pregnancy should not 
undergo CT scans [with contrast]/MRI or bone scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to the 
subject's well-being. 


 
 
 
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• The development of a second cancer except for carcinoma in situ in cervics and 
curatively excisable skin cancer such as basal cell carcinoma.  
• Development of an intercurrent illness or situation which would, in the judgment 
of the investigator, significantly affect assessments of clinical status and trial 
endpoints. 
• Deterioration of ECOG performance status to 4. 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial 
result. 
Any subject removed from the trial will remain under medical supervision until 
discharge or transfer is medically acceptable. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
 
5.2.2 Screen Failures/Dropouts 
A subject who discontinues study participation prematurely for any reason is defined as 
a “dropout” if the subject has already been randomized; assigned to treatment/run-
in/wash-out and administered at least one dose of study drug. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates 
the study before the time point used for the definition of “dropout” (see above) is 
regarded a “screening failure”. 
5.2.3 Replacement 
If patients are withdrawn before the actual start of treatment, patients will be replaced. 
 
6. Treatments   
6.1 Treatment assignment 
Upon providing informed consent, the completion of all screening tests, and 
determination of eligibility, the participants will be assigned a treatment.  
6.2 Ra-223 dichloride 
6.2.1 Treatments to be administered 
Ra-223 dichloride, 50kBq/Kg (55 kBq/kg after implementation of the NIST) body 
weight will be administered as a bolus intravenous (IV) injection (up to 1 minute) at 
intervals of every 4 weeks for up to 6 cycles. In addition, subject will also receive 
denosumab and endocrine therapy as a standard of care during the first 6 cycles of Ra-
223 dichloride treatment. 


 
 
 
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6.2.2 Identity of study treatment 
The alpha-pharmaceutical Ra-223 dichloride is a ready-to-use, sterile, non-pyrogenic, 
clear and colorless aqueous solution of Ra-223 dichloride (223RaCl2) for IV 
administration. Ra-223 dichloride is an alpha particle emitter with a physical half-life 
of 11.4 days. The product is isotonic and has a pH of 6.0-8.0. The radioactive 
concentration at the reference date is 1000kBq/ml( 1,100 kBq/mL after implementation 
of NIST). The product has a pre-calibration of 14 days. When administered on a day 
other than the reference day, the volume should be corrected according to the physical 
decay table. 
 
Radium Ra 223 dichloride, is manufactured by Bayer Healthcare LLC will provide Ra-
223 dichloride, which will be manufactured by Algeta’s contract manufacturer: Institute 
for Energy Technology, Isotope laboratories, Kjeller, Norway. The product is produced 
according to Good Manufacturing Practice (GMP). The product will be delivered in a 
glass vial, ready-to-use with a certified activity. Ra-223 dichloride is shipped in a lead 
container and Type A radioactive package according to international transportation 
guidelines for radioactive materials.  
 
 
The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after implementation 
of NIST update) at the reference day. Radium Ra-223 dichloride has a shelf life of 28 
days from production day, when stored at ambient temperature. The shelf life has been 
demonstrated for temperatures from cold storage (2-8°C) up to 40°C. In addition, it has 
been shown that the product quality is not jeopardized upon freezing. 
 
All study drugs will be labeled according to the requirements of local law and 
legislation. For all study drugs, a system of numbering in accordance with all 
requirements of GMP will be used, ensuring that each dose of study drug can be traced 
back to the respective bulkware of the ingredients.  
6.2.3 Instructions for use / handling  
6.2.3.1 General warning 
Radium 223 dichloride should be received, used and administered only by authorized 
persons in designated clinical settings. The receipt, storage, use, transfer and disposal 
Radium 223 dichloride are subject to the regulations and/or appropriate licenses of the 
competent official organization. Radium 223dichloride should be handled by the user 
in a manner which satisfies both radiation safety and pharmaceutical quality 
requirements. Appropriate aseptic precautions should be taken. 
6.2.3.2 Radiation protection  
The administration of Ra-223 dichloride is associated with potential risks for other 
persons (e.g. medical staff, caregivers and members of the patient’s family) from 
radiation or contamination from spills of body fluids such as urine, feces, or vomit. 
Therefore, radiation protection precautions must be taken in accordance with national 


 
 
 
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and local regulations. Radium-223 is primarily an alpha emitter, with a 95.3% fraction 
of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and 
the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure 
associated with handling of patient doses is considerably lower in comparison to other 
radiopharmaceuticals for therapeutic purposes as the administered radioactivity will 
usually be below usually be below  8 MBq (0.216 mCi) corresponding to 
8.8MBq(0.238mCi)  after implementation of the  NIST update. 8.8 MBq (0.216 238 
mCi).  In keeping with the As Low As Reasonably Achievable (ALARA) principle, for 
minimization of radiation exposure, it is recommended to minimize the time spent in 
radiation areas, to maximize the distance to radiation sources, and to use adequate 
shielding. Any unused product or materials used in connection with the preparation or 
administration are to be treated as radioactive waste and should be disposed of in 
accordance with local regulations. 
The gamma radiation associated with the decay of radium-223 and its daughters allows 
for the radioactivity measurement of Ra-223 dichloride and the detection of 
contamination with standard instruments. 
 
6.2.4 Dose calibration 
Ra-223 dichloride can be measured in a normal dose calibrator instrument. When 
written approvals for the use of Ra-223 dichloride from the Radiation Protection 
Agency for the specific center have been received by the sponsor, a vial of Ra-223 
dichloride for technical use will be sent to the study center. A new reference vial will 
be sent to each center corresponding to the updated NIST reference material. 
 
Different clinical study centers possess dose calibrators from various suppliers thus, the 
isotope calibration factor may differ from center to center. Consequently, each center 
must perform the Ra-223 dichloride dial setting on their relevant dose calibrator(s) 
(upon notification by Bayer each center is required to update dial settings to correspond 
to the new NIST standard). The current dial settings are to remain in effect until Bayer 
obtains FULL approval from the FDA for implementation. In preparation for 
implementation of the NEW dial setting, the clinical study center will receive a sealed 
vial labeled NIST standard containing a Radium Ra-223 dichloride solution for 
calibration only. The vial is identical to the vials used for study treatment. The amount 
of Radium Ra-223 dichloride in the vial will be stated on the label. Instructions for the 
dial setting, including the calibration log form will be enclosed with the dispatch of the 
calibration sample. All sites will be notified by Bayer when FINAL regulatory approval 
from the FDA is in place and the updated NIST standardization is to be implemented. 
 
6.2.5 Dosimetry 
 The absorbed radiation dose calculation was performed based on clinical 
biodistribution data. Calculations of absorbed doses were performed using 
OLINDA/EXM (Organ Level INternal Dose Assessment/EXponential Modeling), a 
software based on the Medical Internal Radiation Dose (MIRD) algorithm which is 
widely used for established beta and gamma emitting radionuclides. For radium-223, 
which is primarily an alpha emitter, additional assumptions were made for the intestine, 


 
 
 
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red marrow and bone/osteogenic cells to provide the best possible absorbed dose 
calculations for Ra-223 dichloride considering its observed biodistribution and specific 
characteristics. 
For an administered activity of 3.65 MBq (0.0987 Ci) 55 kBq (.0015 mCi) per kg body 
weight to a 73-kg adult) after implementation of the NIST, the calculated absorbed 
doses to the bone (osteogenic cells) is 4.2050 Gy (420.5 rad) and to the red marrow is 
0.5066 Gy (50.66 rad). The calculated absorbed doses to the main excretory organs are 
0.0265 Gy (2.65 rad) for the small intestine wall, 0.1180 Gy (11.8 rad) for the upper 
large intestine wall and 0.1696 Gy (16.96 rad) for the lower large intestine wall.  
The calculated absorbed doses to other organs are low, e.g. heart wall (0.0063 Gy, 0.63 
rad), lung (0.0003 Gy, 0.03 rad), liver (0.0109 Gy, 1.09 rad), kidneys (0.0117 Gy, 1.17 
rad), urinary bladder wall (0.0147 Gy, 1.47 rad), testes (0.0003 Gy, 0.03 rad), and spleen 
(0.0003 Gy, 0.03 rad).  
The hematological adverse drug reactions observed in the clinical studies with Ra-223  
are much lower in frequency and severity than what could be expected from the 
calculated absorbed doses to the red marrow. This may be related to spatial distribution 
of alpha particle radiation resulting in non-uniform radiation dose to the red marrow. 
6.2.6 Dose handling 
The Ra-223 dichloride vials must be stored inside their lead container in a secure 
facility. The study drug should be used within 28 days of production. Ra-223 dichloride 
is an alpha-pharmaceutical and should be handled by individuals who are qualified by 
training and experience in the safe handling of radionuclides. One dedicated person and 
a back-up designee will have responsibility as assigned from the Primary Investigator 
for handling and storage of Ra-223 dichloride. All administrations of Ra-223 dichloride 
are based on the certified activity of Ra-223 dichloride at the calibration date. 
 
6.2.7 Dose calculation 
After implementation of the NIST, the dosage of Radium Ra-223 dichloride is 55 
kBq/kg body weight. The patient dose is calculated based on date of injection, a decay 
correction factor (DK) specific to number of days from reference date applied to correct 
for physical decay of  radium 223, and patient weight. A table with DK values according 
to physical decay of the study medication will be provided with every shipment of 
Radium Ra-223 dichloride.  Radium-223 is an alpha particle emitter with a physical t 
½  of 11.4 days. The radioactive concentration at the reference date adjusted to 
correspond to the new NIST standard is 1,100 kBq/mL. The volume to be administered 
for the current dose is calculated as follows: Body weight (kg) X dose (55kBq/kg body 
weight)/DK factor X 1100kBq(0.0297 mCi)/mL. 
Data regarding activity should be recorded on the appropriate electronic case report 
form (eCRF) page. 
 
6.2.8 Dose preparation 
Personnel should use the appropriate protective clothing (i.e. medical gloves/protective 
glasses) and equipment during syringe filling and application to prevent contamination 


 
 
 
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with the radioactive solution. The individual responsible for study drug preparation will 
draw the correct volume of study drug into a syringe. The size of the syringe should be 
chosen according to the applied volume to reach the required dosing accuracy. Ra-223 
dichloride should not be diluted or mixed with any solutions. Do not store above 40°C 
(104°F). If the vials have been stored in a refrigerator, they should be left at room 
temperature for 1 hour prior to use, since cold material should not be injected in a 
patient. Store Ra-223 dichloride in the original container or equivalent radiation 
shielding. This preparation is approved for use by persons under license by the Nuclear 
Regulatory Commission or the relevant regulatory authority of an Agreement State. 
 
 
6.2.9 Dose administration 
Before administration of study drug, the patient must be well hydrated; the patient 
should be instructed to drink ad libitum. Aseptic technique should be used in the 
administration of Ra-223 dichloride by the individual who will perform the injection. 
The study medication will be administered as a bolus intravenous (IV) injection (up to 
1 minute). After administration, the equipment that was used in preparation and 
administration of the study drug, should  be treated as radioactive waste and disposed 
in accordance with local procedure for the handling of radioactive material.  
           6.2.10 Dose Modification  
Every effort should be made to administer the full dosing regimen of Ra-223 dichloride.  
Adjustment of dose level is not permitted.   
Study visits during the treatment period should occur at 4 weeks intervals (within a 
window of +/- 7 days).  Dosing delays may be instituted under the following 
circumstances: 
 
Myelosuppression:   
Treatment-related changes in hematology parameters may occur. 
• If a patient experiences CTCAE v4.03 Grade 3 or 4 neutropenia, thrombocytopenia, 
or anemia, the administration of study drug should be delayed until recovery to Grade 
2 or better.  
• If a patient experiences CTCAE v4.03 Grade 3 or 4 neutropenia, thrombocytopenia, 
or anemia lasting > 14 days, further study drug administrations must be discontinued.  
•  Blood transfusion is acceptable between study drug administrations but not prior to 
the start of the study.  Use of biologic response modifiers, such as G-CSF or GM-CSF, 
is allowed in the management of acute toxicity. 
Gastrointestinal events: 
Diarrhea should be treated as per local practice.  A further dose of study medication 
should not be given before diarrhea is recovered to CTCAE v4.03 Grade 2 or baseline 
levels.  


 
 
 
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Nausea or vomiting should be treated as per local practice.  A further dose of study 
medication should not be given before nausea or vomiting is recovered to CTCAE 
v.4.03 Grade 2 or baseline levels. 
Spinal Cord Compression: 
If the patient experiences spinal cord compression during the treatment period, the 
patient should be treated for the event, and may receive further study drug 
administration if adequately recovered.  
Surgical Intervention: 
If surgery is required, the patient should continue with study treatment if this is 
considered safe in the treating Investigator’s opinion.  The surgeon should be notified 
that the patient has been given radioactive drug, and should  follow the guidelines for 
radioactive protection.   
Non-pathological fractures: 
For traumatic fractures in weight-bearing bones during treatment phase, the study drug 
administration should be delayed for 2-4 weeks from the time of fracture.  
Pathological fractures: 
Pathological fractures may occur as the result of either progressive disease or increased 
physical activity associated with significant pain palliation.  Pathologic fractures are to 
be treated in a manner that attempts to maintain the best functional status and quality of 
life. Study treatment may continue as planned. 
Any Other Toxicity:   
Local practice will apply. 
 
6.3 Drug logistics and accountability 
All study drugs will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements. 
The instructions will be inaccessible to unauthorized personnel. 
6.3.1 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent in accordance with 
institutional requirements. 
6.3.2 Destruction and Return 
At the end of the study, unused supplies of Ra 223 dichloride should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. The certificate of destruction should be sent to Bayer. 


 
 
 
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6.4 Treatment compliance 
An adequate record of receipt, distribution, and destruction of all study drugs must be 
kept in the form of a Drug Accountability Form.  
Subject compliance with the treatment and protocol includes willingness to comply with 
all aspects of the protocol, and to have blood collected for all safety evaluations.  At the 
discretion of the principal investigator, a subject may be discontinued from the trial for 
non-compliance with follow-up visits or study drug. 
6.5 Prior and concomitant therapy- 
All medication that is considered necessary for the subject’s welfare, and not expected 
to interfere with the evaluation of the study treatment may be given at the discretion of 
the investigator.  All medications (including contrast media) taken within 2 weeks prior 
to the start of the study and during the study must be recorded in the subject’s source 
documentation and in the CRF (including start/stop dates, dose frequency, route of 
administration, and indication). 
 
 
Permitted  
• Treatment with non-conventional therapies (e.g., herbs [with the exception of St. 
John’s Wart], acupuncture) and vitamin/mineral supplements is acceptable 
provided that, in the opinion of the investigator, such treatment will not interfere 
with the trial endpoints. 
• Subjects may receive standard of care for any underlying illness. 
• In the event of neutropenia, anemia, or thrombocytopenia, subjects may receive 
appropriate supportive care (e.g., transfusion, biologic response modifiers such as 
G-CSF or GM-CSF, prophylactic antibiotics, antifungals and/or antivirals, 
hematopoietic growth factors).  This supportive care should not substitute a 
recommended dose modification. 
• Blood transfusions and erythropoietin are allowed during the study period but not 
within 4 weeks prior to first dose of study drug.  
• If surgery is required during study drug treatment, the surgeon needs to be notified 
that the patient has been treated with a radioactive product and adequate precautions 
for radioactive protection should be applied during the surgical procedure.  The 
patient should continue with study treatment if considered safe in the treating 
Investigator's opinion. 
 
7. Procedures and variables 
7.1 
Schedule of procedures 
7.1.1 Tabulated overview 


 
 
 
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Evaluation and Treatment 
Screening 
Cycle 1 
Day 1 
Cycles 2-5 
Day 1 
Cycle 6 
End of study 
(9 month)  
Time 
Baseline 
Prior to  
Ra-223 
dichloride 
injection 
Receiving  
 Ra-223    
dichloride 
injection 
 
 
Ra-223 dichloride IV 
 
X 
X 
X 
 
Denosumab SC every 4 weeks 
X 
Hormonal agent 
*per treating physician 
Eligibility, Screening, Consent, 
Registration 
X 
 
 
 
 
Medical History (prior therapies 
and procedures for breast 
cancer) 
X 
 
 
 
 
Pain Assessment 
 
X 
 
X 
X 
Physical Examinations, Vital 
Signs 
X 
 
X 
 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
Hematology assessment (7.1.2) 
X 
X 
X 
X 
X 
Biochemical Profiles, tumor 
markers* (7.1.2) 
X 
 
 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
PET-CT  
X 
 
 
X 
X 
Bone scan 
X 
 
 
X 
X 
MRI (if clinically indicated) 
X 
 
 
X 
X 
Bone Marrow Aspiration and 
biopsy (if clinically indicated) 
X 
 
 
 
X 
CTC 
X 
 
 
X 
X 
Translational Research Studies 
X 
 
 
X 
X 
Urine NTx 
X 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
After 9 months, medical history, physical examination, basic laboratory test, PET-CT and 
bone scan will be done every 3-6 months as part of the standard of care. 
Patients will be clinically screened for adequate calcium and vitamin D supplementation. 
If no contraindication, calcium and vitamin D will be provided using standard of care 
guideline. 
 
Adverse reactions are identified using MedDRA version 14.1 and graded according to      
CTCAE version 4.03. 
7.1.2 Timing of assessments 
Hematology assessments 


 
 
 
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Hematology assessment will include a complete blood count with differential, and 
chemistry (bilirubin, creatinine, ALT, AST, BUN, serum creatinine, sodium, 
magnesium, potassium, albumin, total bilirubin,  and alkaline phosphatase, chloride, 
bicarbonate, total protein, glucose, calcium, and phosphrus.  
 
Biochemical profiles and tumor markers 
CEA and CA15.3 are to be performed at the time points indicated in sections 7.1.1. 
 
Urine N-telopeptide (NTX) 
Urine NTx is to be performed at the time points indicated in sections 7.1.1. 
 
 
MRI 
If spinal cord compression is clinically suspected or PET-CT cannot determine the 
existence of the bone metastases, patients will require an MRI of the spine. If MRI could 
only detect the bone metastases, MRI will be used to monitor the response at 6 and 9 
months.  
 
Bone marrow aspiration and biopsy 
If bone marrow involvement by breast cancer is suspected or radiographical diagnosis 
of bone metastases is not reliable, bone marrow aspiration and biopsy should be 
performed.  (See the details in section 5.1.1 Inclusion criteria) If the bone marrow 
involvement by breast cancer is detected then, the patient will require to be tested for 
the bone marrow aspiration and biopsy at 6 and 9 months. 
 
CTC  
7.5ml Peripheral blood at baseline, cycle 6 and end of study will be collected in 
CellSave collection tubes for enumeration of CTC by CellSearch.   
 
Translational research studies: 
5.0 ml of peripheral blood at baseline, cycle 6 and end of study will be collected in 
AdnaCollect tubes for the detection of CTCs using AdnaTest, a PCR-based assay that 
measures the expression of CTC-related gene transcripts, EpCAM, MUC1, and Her2 in 
EpCAM-enriched cells.   
 
EMT-CTC  
10.0 ml of peripheral blood at baseline, cycle 6 and end of study will be collected in 
EDTA for the detection of EMT-CTC in peripheral blood mononuclear cells 


 
 
 
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sequentially depleted of CD326+ epithelial cells and leukocytes (CD45+) and then 
assessed for the presence of EMT-TFs by qRT-PCR.   
 
7.1.3 Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all 
criteria listed below will be collected: 
• Not pertaining to the study indication 
• Start before signing of the informed consent  
• Considered relevant to the study. 
Detailed instructions on the differentiation between (i) medical history and (ii) adverse 
events can be found in Section 0.1. 
 
 
 7.1.4 Efficacy 
 
All subjects who receive at least one dose of study treatment will be valid for the 
efficacy analysis. Efficacy evaluation will be done by bone scan and PET-CT. This trial 
will use the PERCIST criteria for assessment of efficacy in both primary and secondary 
endpoints.8 The disease control rate at 9 months will be recorded as primary endpoint 
and the duration until progression and tumor response rate at 6 months as secondary 
efficacy endpoint. 
 
7.1.5   Radiographical Methodology 
 
PET-CT will be used to assess the treatment efficacy. PERCIST criteria will be used 
 
for efficacy evaluation for the patients with bone-metastasis only. If new lesions are 
 
detected, the disease will be defined as progression according to RECIST 1.1. Patients 
 
who require radiotherapy for a bone metastasis should be scored as a disease 
 
progression.  
 
The PERCIST  measurements will be performed by Dr. Beth Chasen. 
 
 
Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST)8 
 
Response Category 
Criteria 
Complete metabolic 
response 
Normalization of all lesions (target and nontarget) to SUL less than 
mean liver SUL and equal to normal surrounding tissue SUL 
Verification with follow-up study in 1 month if anatomic criteria 
indicate progression 


 
 
 
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Partial 
metabolic 
response 
>30% decrease in SUL peak; minimum 0.8 unit decrease* 
Verification with follow-up study if anatomic criteria indicate disease 
progression 
Progressive 
metabolic response 
>30% increase in SUL peak; minimum 0.8 unit increase in SUL peak* 
>75% increase in TLG of most active lesion or lesions (up to 5 lesions 
maximum) 
Visible increase in extent of FDG uptake 
New lesions 
Verification with follow-up study if anatomic criteria indicate 
complete of partial response 
Stable 
metabolic 
response 
Does not meet other criteria 
*Primary outcome determine is measured on the single most active lesion on each scan (not 
necessarily the same lesion). Secondary outcome determination is the summed activity of up 
to 5 most lesions (no less than 2 lesions ) 
Table modified from Wahl et al. 22 
 
 
7.2  Safety 
The sponsor is responsible to comply with the local regulation and legislation for 
adverse events reporting. 
All subjects who receive at least one dose of study treatment will be valid for the safety 
analysis.  
All observations pertinent to the safety of the study treatment will be recorded and 
included in the final report. 
All AEs whether considered drug-related or not, will be reported with a diagnosis, 
start/stop dates, action taken, whether treatment was discontinued, any corrective 
measures taken, outcome, and other possible causes.  For all events, the relationship to 
treatment and the intensity of the event will be determined by the investigator. 
This trial will use the NCI-CTCAE v4.03 criteria for assessment of toxicity and SAE 
reporting with regard to toxicity grade.  
Safety variables may include but not limited to the following: laboratory changes 
(complete blood counts, electrolytes, chemistry, and coagulation), changes in vital signs 
(blood pressure, heart rate, respiratory rate, and temperature) and ECG and, in some 
instances, changes in chest x-ray images, as produced at the investigator’s discretion 
(e.g., for evaluation for pneumonia). 
           7.2.1 Adverse events 
Investigators should refer to the Safety Information section of the current IB for Ra 223 
dichloride, including the DCSI (development core safety information), for the expected 
side effects of Ra 223 dichloride.  As with any agent, there is always the potential for 
unexpected AEs, including hypersensitivity reactions.  The IB will be updated if any 
new relevant safety data are obtained. 


 
 
 
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Therapeutic monitoring should be performed following dose selection of Ra 223 
dichloride in a manner consistent with the local clinical standard of care.  In general, 
subjects should be closely monitored for side effects of all concomitant medications 
regardless of the path of drug elimination. 
All concomitant medications must be recorded in the subject’s source documentation. 
Subjects must be carefully monitored for AEs.  This monitoring also includes clinical 
laboratory tests.  Adverse events should be assessed in terms of their seriousness, 
intensity, and relationship to the study drug, or other chemotherapy/treatment. 
7.2.1.1 Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  IF CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, correspondent to grades 1-4.  The PI 
or physician designee is responsible for verifying and providing source documentation for all 
adverse events and assigning attribution for each event for all subjects enrolled on the study.  
PDMS/CORe will be used as the electronic case report form for this protocol.  
 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE if the condition worsens compared to baseline). 
 
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g. seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis). 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. 
Definition of serious adverse event (SAE) 
It is the responsibility of the PI and the research teams to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 


 
 
 
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An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death. 
b. Is life-threatening. 
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization. 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours. 
- The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
- The admission is not associated with an AE. 
(e.g. social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
d. Results in persistent or significant disability / incapacity. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect. 
f. Is another medically important serious event as judged by the investigator. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
a. Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the INDIND Sponsor, IND Office. 
b. All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Unanticipated Adverse Events for 


 
 
 
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Drugs and Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
c. All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge 
of the event to the Safety Project Manager in the IND Office.   
d. Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
e. Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
f. Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
    7.2.1.2  Classifications for adverse event assessment 
7.2.1.2.1  Intensity 
The intensity of the AE is classified according to the CTCAEv4.03.  Grade refers to 
the severity (intensity) of the AE: 
CTCAEv4.03 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4.03 Grade 2: moderate; minimal, local, or noninvasive intervention is 
indicated; limiting to age-appropriate instrumental activities of daily living (ADL; 
instrumental ADL refers to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc.). 
CTCAEv4.03 Grade 3: Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization is indicated; disabling; 
limiting to self care ADL (self care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden). 
CTCAEv4.03 Grade 4: life-threatening consequences; urgent intervention is indicated. 
CTCAEv4.03 Grade 5: death due to an AE. 
7.2.1.2.2  Causal relationship  
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information. 
The causality assessment should be done separately for each study treatment. 
The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. 


 
 
 
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Possible answers are “yes” or “no”. 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical 
site. 
or 
     2.  Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is      
associated with the use of the study treatment. 
Factors to be considered in assessing the relationship of the AE to study treatment   
include: 
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge): 
- Subject’s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in 
question. 
- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered. 
[Causal relationship to protocol-required procedure(s)] 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” 
to protocol-required procedure(s). 
Possible answers are “yes” or “no”. 
 7.2.1.2.3  Action taken with study treatment  
    Any action on study treatment to resolve the AE is to be documented using the categories 
    listed below.      


 
 
 
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   The study treatment action should be recorded separately for each study treatment. 
 ־Drug withdrawn 
 ־Drug interrupted 
 ־Dose not changed 
 ־Dose increased 
 ־Not applicable 
 ־Unknown 
7.2.1.2.4  Other specific treatment(s) of adverse events 
 ־None 
 ־Remedial drug therapy 
 ־Other 
 7.2.1.2.5  Outcome 
The outcome of the AE is to be documented as follows:  
 ־Recovered/resolved 
 ־Recovering/resolving 
 ־Recovered/resolved with sequelae 
 ־Not recovered/not resolved 
 ־Fatal 
 ־Unknown 
  
7.2.1.3  Reporting of serious adverse events 
The definition of serious adverse events (SAEs) is given in Section 0.1. 
Each serious adverse event must be followed up until resolution or stabilization, by submission 
of updated reports to the designated person. An isolated laboratory abnormality that is assigned 
grade 4, according to CTC definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE.  CTC grade 4 baseline 
laboratory abnormalities that are part of the disease profile should not be reported as an SAE, 
specifically when they are allowed or not excluded by the protocol inclusion/exclusion criteria.   
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. When required, and according to local law and 
regulations, serious adverse events must be reported to the Ethics Committee and Regulatory 
Authorities.  
 


 
 
 
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All serious adverse events should be reported to Bayer within 24 hours.  In the event of such 
an event, the investigator should refer to the Pharmacovigilance section of the contract for 
reporting procedures and report SAE to Bayer. 
 
Requirements for Reporting of Serious Adverse Events:  
All SAEs must be reported to Bayer within 24 hours of the Principal Investigator’s 
awareness and must include the following minimum information:  
1. The name and contact information of the reporter  
2. The name of the study drug(s)  
3. A description of the reported SAE  
4. A patient identified by one or more of the following:  
a. Patient initials  
b. Patient number  
c. Knowledge that a patient who experienced the adverse event exists  
d. Age  
e. Sex  
5. An investigator assessment of study drug causality. For studies with combination 
therapy, a separate causality assessment should be provided for each study drug.  
Additional data which would aid the review and causality assessment of the case include but 
are not limited to:  
The date of onset  
The severity  
The time from administration of study drug(s) to start of the event  
The duration and outcome of the event  
Any possible etiology for the event  
The final diagnosis or syndrome, if known  
 
 
The Investigator may report serious adverse drug reactions (SADRs) using either: 
 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
 
OR 
  
 A MedWatch form available at http://www.fda.gov/medwatch/  
 
    
All reports shall be sent electronically to:  
 
Electronic Mailbox:  
DrugSafety.GPV.US@bayer.com  
 
Facsimile:    
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare  
P.O. Box 915  


 
 
 
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Whippany, NJ 07981-0915 
 
Address:   
 
 
100 Bayer Blvd. Whippany, NJ 07981 
FDX or UPS only                 67 Whippany Rd. Whippany, NJ 07981 for UPS 
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept:  
 
Phone:  
 
 
1-888-842-2937 
 
7.2.1.4  Expected adverse events 
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) / summary of product characteristics. 
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites. 
The expectedness of AEs will be determined by Bayer according to the applicable reference 
document and according to all local regulations. 
7.2.2  Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject, or in his 
partner, during the subject’s participation in this study.  The report should be submitted within 
the same timelines as an SAE.   
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
7.2.3  Further safety 
Death 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the 
investigator will inform Bayer and record the cause of death in detail (using the SAE Form) 
within 24 hours. 
 
7.3  Appropriateness of procedures/measurements 
The assessments described in the previous sections are widely used and generally recognized 
as reliable, accurate, and relevant for determining the safety and efficacy of therapies in this 
disease. 


 
 
 
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8. Statistical methods and determination of sample size 
This is a single-arm, open label, phase II trial to assess the ability of Ra-223 dichloride + 
Hormonal agent + Denosumab responsiveness in patients with Hormone-Positive Bone-
Dominant Metastatic Breast Carcinoma. 
 
 
The primary endpoint is disease control rate at 9 months. With 36 patients, we will have an 85% 
power to detect the disease control rate of 90% against 70% based on our previous report with 
a two-sided exact binomial test at a significance level of 5% (See section 1.2 for details).1 
 . 
 
The severe toxicity events defined as irreversible grade 3 and any grade 4 or greater adverse 
events according to CTC definition will be monitored at cohorts of 5. Toxicity rate of 20% or 
higher will be considered unacceptable. Bayesian beta-binomial posterior probability will be 
evaluated in determining the toxicity stopping boundaries. The prior distribution of toxicity 
rate is assumed to follow a Beta (0.2, 0.8) distribution with one patient worth of information. 
At any time after 5 patients have completed toxicity evaluations, the trial will be stopped if the 
following statement is true 
 
Pr[toxicity rate > 20% | data]  > 0.90, 
 
which means that the trial will be stopped for toxicity if the posterior probability of the toxicity 
rate being greater than 20% is greater than 90%. The early stopping boundaries for toxicity, 
shown in the format of 
 
(The number of patients with severe toxicities) / (The number of patients treated), 
 
are ≥ 3/5, 4/10,  6/15, 7/20,  8/25, 10/30,  and 11/35. 
 
 
Table 1. Operating characteristics for the stopping rules for excessive toxicity monitoring 
 
True 
DLT Rate 
Probability 
Stop Early 
Mean sample 
size 
0.05 
0.0020 
34.95 
0.10 
0.0202 
34.48 
0.15 
0.0828 
33.01 
0.20 
0.2024 
30.47 
0.25 
0.3984 
26.22 
0.30 
0.6242 
21.38 
0.35 
0.7868 
17.55 
 


 
 
 
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The toxicity monitoring boundaries and the operating characteristics are provided using Multc 
Lean V2.1 developed by the Department of Biostatistics at UT MD Anderson Cancer Center. 
 
By the end of study, patients’ demographic and clinical characteristics at baseline will be 
summarized using descriptive statistics such as frequency distribution, mean (± s.d.) and 
median (range). Due to the small scale of the study, exploratory results will be summarized 
based on descriptive analysis. 
 
Disease control rate will be estimated with 95% confidence interval.   
 
 
Time-to-event outcomes, including progression free survival and overall survival, will be 
estimated using the Kaplan-Meier method.   
 
Toxicity data will be summarized by frequency tables, which will include any patient who 
received the treatment regardless of the eligibility nor the duration or dose of the treatment 
received. 
Exploratory Research Analysis 
The obtained data in all patient groups will be summarized with use of descriptive statistics 
such as mean, standard deviation, median, and range. Any discrete measurements of markers 
will be analyzed by using the Chi-square test or Fisher exact test, depending on distributions. 
9. Data handling and quality assurance 
9.1  Data recording 
 
It is the expectation that all data has source documentation available at the site.  The site must 
implement processes to ensure this happens.  Data collected from the study will be entered in 
PDMS/CORe. The Principal Investigator is responsible for assuring that the data entered into 
the database is complete, accurate, and that entry is performed in a timely manner. 
 
9.2 Audit and Inspection 
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) are 
possible.  The investigator should notify Bayer immediately of any such inspection. 
9.3 Archiving 
 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 


 
 
 
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Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. 
 
10. Premature termination of the study 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
- Safety findings from this study (e.g. SAEs) 
- Results of any interim analysis 
- Results of parallel clinical studies 
- Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law. 
• In case of a partial study closure, ongoing subjects, including those in post study follow-
up, must be taken care of in an ethical manner. 
Details for individual subject's withdrawal can be found in Section 5.2.1. 
11. Ethical and legal aspects 
11.1 Ethical and legal conduct of the study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the investigator abide by Good Clinical 
Practice (GCP) guidelines and under the guiding principles detailed in the Declaration of 
Helsinki.  The study will also be carried out in keeping with applicable local law(s) and 
regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers before start of the study, according to GCP, local laws, regulations and organizations.  
When necessary, an extension, amendment or renewal of the EC/IRB approval must be 
obtained and also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   


 
 
 
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Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Bayer.  However, the investigator may implement a deviation 
from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects 
without prior IEC/IRB/Bayer approval/favorable opinion.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution.  Any deviations 
from the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented. 
Publications and NIST 
 
Bayer recommends inclusion of the new NIST standard in abstracts/ publications submitted 
OR pending  publication January 2016 onwards    from IIRs and other non- Bayer supported 
abstracts/publications for consistency. Investigators may choose to add a footnote to the 
publication or within the body of the publication include the new NIST standard. 
 
11.2 Subject Information and consent 
 
This adhere to the following regulations: 
• Section 4.8 of the ICH E6 Guideline for Good Clinical Practice. 
• Health Insurance Portability and Accountability Act (HIPAA) 
• See informed consent for details. 
11.3 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual. 
All laboratory and clinical data gathered in this protocol will be stored in a password-protected 
database. All patient information will be handled using anonymous identifiers. Linkage to 
patient identity is only possible after accessing a password-protected database. Access to the 
database is only available to individuals directly involved in the study. 
 


 
 
 
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Information gathered for this study will not be reused or disclosed to any other person or entity, 
or for other research. Once the research has been completed, identifiers will be retained for as 
long as is required by law and by institutional regulations, and at that point will be destroyed. 
12. Reference 
 
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patients with bone-only metastases of breast cancer: a single-institution retrospective analysis. 
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2. 
Niikura N, Liu J, Hayashi N, et al. Retrospective analysis of antitumor effects of 
zoledronic acid in breast cancer patients with bone-only metastases. Cancer 2012; 118(8): 
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3. 
Budd GT, Cristofanilli M, Ellis MJ, et al. Circulating tumor cells versus imaging--
predicting overall survival in metastatic breast cancer. Clinical cancer research : an official 
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Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, 
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6. 
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Costelloe CM, Rohren EM, Madewell JE, et al. Imaging bone metastases in breast 
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Costelloe CM, Chuang HH, Madewell JE, Ueno NT. Cancer Response Criteria and 
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Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in 
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Hamaoka T, Costelloe CM, Madewell JE, et al. Tumour response interpretation with 
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11. 
Coleman R, Aksnes AK, Naume B, et al. A phase IIa, nonrandomized study of radium-
223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast cancer 
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12. 
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in 
metastatic prostate cancer. The New England journal of medicine 2013; 369(3): 213-23. 


 
 
 
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13. 
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Henriksen G, Fisher DR, Roeske JC, Bruland OS, Larsen RH. Targeting of osseous sites 
with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. Journal of nuclear 
medicine : official publication, Society of Nuclear Medicine 2003; 44(2): 252-9. 
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Lloyd RD, Miller SC, Taylor GN, Bruenger FW, Angus W, Jee WS. Comparison of 
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Miller CE, Finkel AJ. Radium retention in mice after single intravenous injection. 
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Nilsson S, Strang P, Aksnes AK, et al. A randomized, dose-response, multicenter phase 
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Suominen MI, Rissanen JP, Kakonen R, et al. Survival benefit with radium-223 
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Vapiwala N, Glatstein E. Fighting prostate cancer with radium-223--not your Madame's 
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Wissing MD, van Leeuwen FW, van der Pluijm G, Gelderblom H. Radium-223 
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Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting 
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Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving 
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