Conditions: Breast Neoplasms
Keywords: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 283
Healthy volunteers: no

Brief summary:
The objective of this study is to assess efficacy and safety of radium 223 dichloride in subjects with human epidermal growth factor receptor 2 (HER2) negative hormone receptor positive breast cancer with bone metastases treated with exemestane and everolimus

After implementation of CSP Amendment 10, only a limited number of subjects will remain in this study, in order to reduce the burden to study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, and OS. Once subjects are rolled over, the long-term safety will be collected and assessed entirely in the separate extended safety follow-up study.

Detailed description:

Arms:
arm 1: Up to 6 cycles of radium-223 dichloride 50kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice. arm 2: Up to 6 cycles of saline injection (placebo) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.

Interventions: intervention 1: Radium-223 dichloride (Xofigo, BAY88-8223) intervention 2: Placebo (saline) intervention 3: Exemestane intervention 4: Everolimus
Intervention descriptions: intervention 1: Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update) intervention 2: Up to 6 cycles of saline injection intervention 3: One 25 mg tablet once daily after a meal. intervention 4: The recommended dose of everolimus administered in the study is 10 mg once daily with or without food.

Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

Protocol document:
Prot_000.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
A phase II randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with exemestane and 
everolimus versus placebo in combination with exemestane and 
everolimus when administered to metastatic HER2 negative 
hormone receptor positive breast cancer subjects with bone 
metastases 
NCT Number: 
NCT02258451 
Document Date: 
04 Dec 2019 
 


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Cover page of the integrated clinical study protocol 
A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride 
in combination with exemestane and everolimus versus placebo in combination with 
exemestane and everolimus when administered to metastatic HER2 negative hormone 
receptor positive breast cancer subjects with bone metastases 
For this study, the protocol and subsequent protocol amendment were released as follows: 
•
Original protocol, Version 1.0, dated 06 MAY 2014
•
Amendment 1 (global amendment described in Section 15.1) forming integrated
protocol Version 2.0, dated 16 MAR 2015
•
Amendment 2 (local amendment, France only) dated 29 APR 2015
•
Amendment 3 (global amendment described in Section 15.2) forming integrated
protocol Version 3.0, dated 29 JUL 2015
•
Amendment 4 (local amendment Italy only) 25 JUL 2015
•
Amendment 5 (global amendment described in Section 15.3) forming integrated
protocol Version 4.0, dated 09 MAR 2016
•
Amendment 6 (local amendment Japan only) dated 13 SEP 2016
•
Amendment 7 (local amendment France only) dated 31 OCT 2016
•
Amendment 8 (global amendment described in Section 15.4) forming integrated
protocol Version 5.0, dated 23 MAY 2017
•
Amendment 9 (global amendment described in Section 15.5) forming integrated
protocol Version 6.0, dated 03 APR 2018
•
Amendment 10 (global amendment described in Section 15.6) forming integrated
protocol Version 7.0, dated 04 DEC 2019
This document integrates the original protocol and all global amendments. 


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1. 
Title page 
A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride 
in combination with exemestane and everolimus versus placebo in combination with 
exemestane and everolimus when administered to metastatic HER2 negative hormone 
receptor positive breast cancer subjects with bone metastases 
Study of radium-223 dichloride in combination with exemestane and everolimus versus 
placebo in combination with exemestane and everolimus in subjects with bone predominant 
HER2 negative hormone receptor positive metastatic breast cancer 
Test drug: 
BAY 88-8223 / Radium-223 dichloride / Xofigo® 
Study purpose: 
Efficacy and Safety 
Clinical study phase: 
2 
Date: 
04 DEC 2019 
Registration: 
EudraCT: 2014-002114-23 
Version no.: 
7.0 
Sponsor’s study no.: 
17096 
 
 
Sponsor: 
Bayer AG, D-51368 Leverkusen, Germany 
US territory: Bayer Healthcare Pharmaceuticals Inc.,  
100 Bayer Boulevard, P.O. Box 915 
Whippany NJ 07981-0915 USA 
Sponsor’s medical expert: 
 
 
  
100 Bayer Boulevard │ 
 
Whippany, NJ 07981-0915, US 
Phone:  
 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonisation-Good Clinical Practice 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 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
PPD
PPD
PPD


04 DEC 2019 
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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
Date: 
A \ i)e_.,(: 2P AC\ 
Role: 
Signature: 
PPD
PPD


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Signature of principal investigator 
 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Name: 
 
Affiliation:  
Date: 
 
 
Signature:  
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s Investigator site file. 


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2. 
Synopsis 
Title 
A phase II randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with exemestane and 
everolimus versus placebo in combination with exemestane and 
everolimus when administered to metastatic HER2 negative 
hormone receptor positive breast cancer subjects with bone 
metastases  
Short title 
Study of radium-223 dichloride in combination with exemestane 
and everolimus versus placebo in combination with exemestane and 
everolimus in subjects with bone predominant HER2 negative 
hormone receptor positive metastatic breast cancer 
Clinical study phase 
Phase 2 
Study objectives 
The objective of this study is to assess efficacy and safety of 
radium-223 dichloride in combination with exemestane and 
everolimus in subjects with human epidermal growth factor 
receptor 2 (HER2) negative, hormone receptor positive breast 
cancer with bone metastases. 
The primary endpoint is: 
1. Symptomatic skeletal event-free survival (SSE-FS) 
The secondary endpoints are: 
2. Overall survival 
3. Time to opiate use for cancer pain 
4. Time to pain progression (only in subjects with baseline 
worst pain score (WPS) ≤8) 
5. Time to cytotoxic chemotherapy 
6. Radiological progression-free survival (rPFS) 
7. Pain improvement rate 
8. Safety, acute and long term, including new primary 
malignancies and hematopoietic reserve for tolerability of 
subsequent chemotherapy*  
The study will also include the following exploratory endpoints: 
9. Time to first on-study symptomatic skeletal event (SSE) 
10. Time to bone alkaline phosphatase (ALP) progression 
11. Bone ALP response at Week 12 and 4 weeks (± 7 days) after 
last radium-223 dichloride/placebo dose 
12. Bone-specific rPFS 
13. Resource utilization 


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14. Biomarker assessments 
15. Time to visceral metastases onset (in subjects with no 
visceral disease at baseline) 
*Safety endpoints were reported/measured as AEs. Acute safety 
was documented as the incidence of TEAEs. Long-term safety was 
documented as the incidence of post-treatment AEs. Hematopoietic 
reserve for tolerability of subsequent chemotherapy was assessed 
via the incidence of treatment emergent hematological toxicity and 
the incidence of post-treatment chemotherapy-related AEs.  
 
Note: After implementation of CSP Amendment 9, subjects who 
completed the EOT visit could be transferred to a separate extended 
safety follow-up study for their remaining follow-up. After 
implementation of CSP Amendment 10, all such subjects will be 
transferred; only subjects on oral treatment will remain on study, 
and no post-treatment data will be collected beyond the 30-day 
safety follow-up (EOT visit).   
 
As the key efficacy objectives will have been accomplished, long-
term safety transferred, and only a limited number of subjects will 
remain in this study, in order to reduce the burden to study subjects, 
collection of data will be reduced and will focus mainly on acute 
safety, SSE, and OS. Once subjects are rolled over, the long-term 
safety will be collected and assessed entirely in the separate 
extended safety follow-up study  
Test drug 
BAY 88-8223 
Name of active 
ingredient 
Radium-223 dichloride  
Dose 
50 KiloBecquerel (kBq)/kg (55 kBq/kg after implementation of 
National Institute of Standards and Technology [NIST] update) 
body weight every 4 weeks for 6 cycles 
Route of 
administration 
Intravenous (IV) injection (slow bolus)  
Duration of treatment 
6 cycles at 4-week intervals (24 weeks) 
Reference drug 
Matching placebo (normal saline) 
Name of active 
ingredient 
Not applicable 
Study treatment 
All study subjects will receive study treatment with exemestane and 
everolimus, and best supportive care 


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Indication 
Subjects with HER2 negative, hormone receptor positive breast 
cancer with bone metastases treated with radium-223 dichloride in 
combination with exemestane and everolimus  
Diagnosis and main 
criteria for inclusion 
and exclusion 
Subjects must meet the following criteria for inclusion in the study: 
1. Have provided written informed consent.  Subjects must be 
able to understand and be willing to sign the written 
informed consent.  A signed informed consent form (ICF) 
must be appropriately obtained prior to the conduct of any 
trial-specific procedure. 
2. Documentation of histological or cytological confirmation 
of estrogen receptor positive (ER+) and HER2 negative 
adenocarcinoma of the breast must be available.  Human 
epidermal growth factor receptor 2 status should be 
determined by an accredited/Ministry of Health approved 
laboratory by immunohistochemistry, fluorescence in situ 
hybridization (FISH), chromogenic in situ hybridization 
(CISH) or other validated in situ hybridization (ISH) assay 
for detection of HER2 gene expression. 
3. Tumors (from either primary or metastatic sites) must be 
ER+ defined as ≥10% positive tumor nuclei in the analyzed 
sample.  Estrogen receptor positive/progesterone receptor 
positive (PR+) and ER+/ progesterone receptor negative 
(PR-) subjects are eligible whereas estrogen receptor 
negative (ER-)/PR+ and ER-/PR- disease will not be 
eligible. 
4. Women (≥18 years of age) with metastatic breast cancer not 
amenable to curative treatment by surgery or radiotherapy.  
Women of reproductive potential and their male partners 
must agree to use adequate contraception during treatment 
and for 6 months following the completion of treatment with 
radium-223 dichloride/placebo. 
5. Documentation of menopausal status: postmenopausal 
subjects or premenopausal subjects with ovarian radiation or 
concomitant therapy with a luteinizing hormone-releasing 
hormone (LH-RH) agonist/antagonist are eligible. 
o Premenopausal subjects with ovarian radiation or 
concomitant treatment with an LH-RH 
agonist/antagonist must have a plasma/serum 
estradiol assay within local laboratory 
postmenopausal range at screening, performed 
within 7 days prior to randomization.  These subjects 
must also have a negative pregnancy test at 
screening and agree to use an adequate method of 
contraception as recommended by their treating 


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physicians. 
o Postmenopausal status is defined either by:  
 age ≥55 years and one year or more of 
amenorrhea,  
 age <55 years and one year or more of amenorrhea 
with a plasma/serum estradiol assay within local 
laboratory postmenopausal range, performed within 
7 days of randomization, 
 bilateral ovariectomy. 
6. Subjects with bone-dominant disease with at least 2 skeletal 
metastases identified at baseline by bone scintigraphy and 
confirmed by computed tomography (CT)/magnetic 
resonance imaging (MRI). Presence of metastases in soft 
tissue (skin, subcutaneous, muscle fat, lymph nodes) and/or 
visceral metastases is allowed. 
7. Measurable or non-measurable disease (but radiologically 
evaluable) according to Response Evaluation Criteria in 
Solid Tumors v1.1 criteria.  All disease burdens must be 
assessed within 3 weeks prior to randomization by CT or 
MRI of chest, pelvis, and abdomen and any additional fields 
as needed.  A technetium-99m bone scan should also be 
done within 3 weeks prior to randomization for all subjects. 
CT/MRI done as part of the standard of practice within 
3 weeks prior to randomization and standard-of-care 
technetium-99m bone scans done within 3 weeks prior to 
randomization are acceptable. 
F-18 fluorodeoxyglucose (FDG) positron emission 
tomography (PET) scan, if performed as part of standard of 
care imaging, can be used as an adjunct to CT/MRI in line 
with Response Evaluation Criteria in Solid Tumors 1.1 
guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a 
diagnostic CT (See also Appendix 16.2). 
FDG PET/CT or NaF PET/CT scan is acceptable as an 
alternative to technetium-99m bone scintigraphy if it is the 
standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
8. Subjects must have experienced recurrent/progressive 
disease following treatment with a non-steroidal aromatase 
inhibitor (letrozole or anastrozole) in an adjuvant or 
metastatic setting. 
9. Subjects must have received at least one line of hormonal 
therapy in the metastatic setting. 
Note: A change of the hormone agent due to progression (as 


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per the Investigator assessment) is counted as a new line of 
therapy.  A switch of hormone therapy from one agent to 
another due to toxicity or other reasons (e.g., subject’s 
preference), in absence of progressive disease at time of 
switch, will be counted as one line although 2 different 
agents have been administered. 
10. Subjects who are eligible, as per the Investigator’s 
assessment and according to the local label, for treatment 
with exemestane and everolimus as a second line or greater 
of therapy in a metastatic setting.  Subjects enrolled in the 
current study will start treatment with exemestane and 
everolimus, after randomization, either before or 
simultaneously to the first injection of radium-223 
dichloride/placebo. 
11. Subjects must have experienced no more than 
2 skeletal-related events (SREs) prior to study entry defined 
as: Need for external beam radiotherapy (EBRT) to bone, 
pathological bone fracture (excluding major trauma), spinal 
cord compression and/or orthopedic surgical procedure.  
Subjects with no prior SREs are not permitted.  
Note: All prior SRE-related procedures (i.e., orthopedic 
surgery, EBRT) must be administered prior to 
randomization. Separate SRE events are the ones that occur 
at least 21 days apart from each other to ensure that linked 
events (eg, surgery to repair a fracture or multiple doses of 
radiation during a course of treatment) are not counted as 
separate events. In case of bone pain that occurs in several 
anatomical locations and requires separate EBRT sessions 
for the different anatomical locations, it should be counted 
as one event if the EBRT sessions are administered within a 
period of 21 days. 
12. Subjects must be on therapy with bisphosphonates or 
denosumab for at least 1 month before start of study 
treatment. 
13. Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) 0 or 1. 
14. Life expectancy ≥6 months. 
15. Laboratory requirements:  
o Absolute neutrophil count ≥1.5 x 109/L  
o Platelet count ≥100 x109/L without platelet transfusion 
within 4 weeks prior to randomization 
o Hemoglobin (Hb) ≥9.0 g/dL (90 g/L; 5.6 mmol/L) 
without transfusion or erythropoietin within 4 weeks 
prior to randomization 
o Total bilirubin ≤1.5 x institutional upper limit of 


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normal (ULN) (except for subjects with documented 
Gilbert’s disease) 
o Aspartate aminotransferase and alanine 
aminotransferase ≤2.5 x institutional ULN 
o Pulse oximetry O2 saturation >92% if lung metastases 
are present 
o Creatinine ≤1.5 x ULN 
o Estimated glomerular filtration rate 
≥30 mL/min/1.73 m2 according to the Modification 
of Diet in Renal Disease abbreviated formula. (Note: 
please refer to local labeling for administration of 
full dose of bisphosphonates) 
o International normalized ratio of prothrombin time 
(INR) and partial thromboplastin time (PTT) or 
activated PTT ≤1.5 x ULN at study entry.  Subjects 
treated with warfarin, heparin, enoxaparin, 
rivaroxaban, dabigatran, apixaban or aspirin (e.g. 
≤100 mg daily) will be allowed to participate in the 
study if no underlying abnormality in coagulation 
parameters exists per prior history; weekly 
evaluation of INR/PTT will be required until 
stability is achieved for anticoagulants that require 
their monitoring as per local label. 
o Serum albumin >30 g/L 
16. Able to swallow oral medication. 
Exclusion criteria 
Eligible subjects must not meet any of the exclusion criteria 
listed below: 
1. 
HER2-positive breast cancer (immunohistochemistry [IHC] 
=3+, positive FISH, or positive CISH); equivocal or 
unknown HER2 status 
Note: Subjects with 3+ by IHC cannot be chosen regardless 
of their FISH/CISH/other ISH validated assay status and 
those with positive FISH/CISH /other ISH validated assay 
cannot be chosen either, regardless of the IHC findings.  
Subjects with 2+ by IHC will not be eligible if no negative 
FISH/CISH/other ISH validated assay for detection of 
HER2 gene expression is available. 
2. Patients with immediately life-threatening visceral disease, 
for whom chemotherapy is the preferred treatment option 
3. Lymphangitic carcinomatosis 
4. Patients with ascites requiring paracentesis within 2 weeks 
prior to study entry (signature of informed consent) and 


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during the screening period 
5. Subjects with inflammatory breast cancer 
6. Subjects who have either received chemotherapy for 
metastatic disease or are considered by the treating 
Investigator to be appropriate candidates for chemotherapy 
as current treatment for metastatic breast cancer are 
excluded.  Chemotherapy administered for adjuvant/neo-
adjuvant disease is acceptable. 
7. Subjects with any previous untreated or concurrent cancer 
that is distinct in primary site or histology from the cancer 
under study except treated basal cell carcinoma, or superficial 
bladder tumor (Ta and Tis, American Joint Committee on 
Cancer, 7th edition).  Subjects surviving a cancer that was 
curatively treated and without evidence of disease for more 
than 3 years before enrollment, are allowed.  All cancer 
treatments must be completed at least 3 years prior to study 
entry (i.e., signature date of ICF). 
8. Subjects with known or history of brain metastases or 
leptomeningeal disease: subjects with neurological 
symptoms must undergo a contrast CT scan or MRI of the 
brain within 28 days prior to randomization to exclude active 
brain metastasis.  Imaging of the central nervous system is 
otherwise not required. 
9. Imminent or established untreated spinal cord compression 
based on clinical findings and/or MRI.  Following treatment 
of spinal cord compression, the subject may be eligible if all 
other eligibility criteria are fulfilled. 
10. Prior treatment with radium-223 dichloride. 
11. Prior hemibody external radiotherapy.  Subjects who 
received other types of prior external radiotherapy are 
allowed provided that bone marrow function is assessed and 
meets the protocol requirements for Hb, absolute neutrophil 
count, and platelets. 
12. Prior systemic radiotherapy with strontium-89, samarium-
153, rhenium-186, or rhenium-188. 
13. ECOG PS ≥2. 
14. Blood transfusions, platelet transfusions or use of 
erythropoietin within 4 weeks prior to randomization.   
15. Use of biologic response modifiers, such as granulocyte 
macrophage colony-stimulating factor or granulocyte 
colony-stimulating factor, within 4 weeks prior to 
randomization. 
16. Treatment with an investigational drug or with any anti-


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cancer treatments not permitted by the protocol, within 4 
weeks prior to randomization 
17. Chronic conditions associated with non-malignant abnormal 
bone growth (e.g., confirmed Paget’s disease of bone) 
18. Any other serious illness or medical condition such as, but 
not limited to: 
o Any uncontrolled infection 
o Cardiac failure New York Heart Association Class III 
or IV 
o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia 
19. Previous assignment to treatment in this study 
20. Breast-feeding women 
21. Known hypersensitivity to the active substance or to any of 
the excipients of radium-223 dichloride, exemestane, and 
everolimus or to other rapamycin derivatives 
22. Subjects who received prior treatment or are already 
receiving everolimus treatment prior to study entry are not 
eligible 
23. Known presence of osteonecrosis of jaw 
 
All local label specific criteria for exemestane and everolimus as 
well as standard-of-care denosumab and bisphosphonates will 
apply.  Subjects must be treated according to the local standard-of-
care requirements. 
Study design 
International, phase II, double-blind, randomized, placebo-
controlled, parallel group study.  Randomization will be stratified 
by: 
• Geographical regions (Europe/North America [including 
Israel] versus Asia) 
• Previous lines of hormone therapy in metastatic setting 
(1 versus 2 or more): for the purpose of counting the number 
of prior lines of hormone therapy, only a change of the 
hormone agent due to progression is counted as a new line 
of therapy.  A switch of hormone therapy from one agent to 
another due to toxicity or other reasons (e.g., subject’s 
preference) in absence of progressive disease at time of 
switch will be counted as one line although 2 different 
agents have been administered. 
• Visceral disease yes versus no 


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Methodology 
Prior to the primary analysis, the study comprised 4 periods: 
screening, randomization, treatment, and the follow-up period 
(active follow-up with clinic visits and active follow-up without 
clinic visits). 
Screening period:  
All trial related procedures and evaluations will only be performed 
after the subject has agreed to participate and has signed the ICF.  
The screening period will consist of multiple evaluations that will 
take place within 3 weeks prior to randomization to ensure that all 
eligibility criteria are met. 
Randomization:  
After all screening assessments have been completed and the 
subject’s eligibility has been confirmed and documented, eligible 
subjects will be randomized in a ratio of 1:1 to treatment with 
radium-223 dichloride (Arm A - investigational arm) or placebo 
(Arm B - control arm).  All subjects receive open-label study 
treatment exemestane and everolimus and supportive care according 
to the local standard of practice.  
Treatment period:  
The total treatment period is defined from the day of randomization 
until 4 weeks after the last administration of study treatment 
(radium-223 dichloride/placebo and exemestane and everolimus 
whichever occurs last). 
The study treatment consists of up to 6 cycles of 
radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation 
of NIST update) body weight (Arm A) or placebo (Arm B) each 
separated by an interval of 4 weeks ±7 days, in combination with 
exemestane and everolimus followed by ongoing treatment for all 
subjects with exemestane and everolimus as applicable.  
Subjects enrolled in the current study, will start treatment with 
exemestane and everolimus, after randomization, either before or 
simultaneously to the first injection of radium-223 
dichloride/placebo.  Subjects already receiving exemestane and 
everolimus prior to study entry are not eligible. 
After Primary Analysis (after implementation of Amendment 10): 
Following the administrative data review (per Amendment 8) 
conducted on DEC 2017 by a small group of unblinded Sponsor 
employees, independent of the study team, subject enrollment in 
this trial was discontinued on APR 2018. Following primary 
analysis cutoff, treatment with exemestane and everolimus will 
continue until disease progression, initiation of new anti-cancer 
therapy, unacceptable toxicity occurs, discontinuation of study 
treatment for other reasons, or study is terminated, whichever 
occurs first.  All subjects will receive supportive care, as per local 


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standard of practice.  
Assessments following primary analysis will mainly focus on acute 
safety, SSE and OS, as described below. At the time Amendment 
10 is implemented, all subjects completed or discontinued radium-
223 dichloride/placebo treatment.  
During the treatment period, subjects will be assessed for safety at 
each treatment visit, every 8 weeks. Subjects will be assessed for 
radiologic progression according to local standard practice. 
• All bone fractures and bone associated events (e.g., 
osteoporosis) need to be reported as either AE(s) or SAEs, if 
the criteria of SAE were met, regardless of the Investigator’s 
causality assessment.  
• All occurrences of any additional malignancies, including 
AML, and hematological conditions such as MDS, aplastic 
anemia, or myelofibrosis must be reported as SAEs, 
regardless of the Investigator’s causality assessment.   
• Subjects who experience disease progression during the 
protocol defined treatment period, initiate new anti-cancer 
therapy, experience unacceptable toxicity or discontinue the 
study treatment for other reasons, at the end of the treatment 
period, will be transferred to the separate extended safety 
follow-up study (BAY 88-8223 study 16996 / 
NCT02312960). 
All ongoing subjects at the time of study termination will finish all 
study treatments as part of the study.  
Follow-up period: 
Following primary analysis, active follow-up in this study will be 
discontinued. Follow-up will be conducted in the separate extended 
safety follow-up study (please refer to the applicable section 
below). 
Long-term follow-up in the separate extended safety follow-up 
study: 
All subjects who have completed at a minimum the EOT visit or 
30 days from last study treatment dose, whichever is latest, will be 
transitioned into a separate extended safety follow-up study 
(BAY 88-8223 study 16996 / NCT02312960). The separate 
extended safety follow-up study has been set up to follow subjects 
who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials. The primary objective of this study 
is to define the long-term safety profile of radium-223 dichloride. 
All subjects who transition into this separate extended safety 
follow-up study will require a separate signed informed consent. All 
efforts will be made to transition all subjects to the extended safety 
follow-up study.  


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This study will end at the time the last subject on treatment 
discontinues oral exemestane and/or everolimus treatment and 
completes end of treatment visit or discontinues from this study for 
another reason (e.g., death, consent withdrawn and active objection 
for further data collection). Until the transition to the extended 
safety follow-up study, subjects will continue to follow all the 
protocols required procedures and visits in the current protocol.  
Type of control 
Placebo-control arm 
Number of subjects 
311 subjects in total (with 1:1 randomization) 
Primary variable 
Symptomatic skeletal event-free survival 
Time point/frame of 
measurement for 
primary variable(s) 
The primary variable/endpoint, SSE-FS, is defined as the time from 
randomization to the occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone 
fractures (vertebral or non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause  
Note: All prior SRE-related procedures (i.e., orthopedic surgery, 
EBRT) must be administered prior to randomization.  
Plan for statistical 
analysis 
The analysis of efficacy will be performed using the intent-to-treat 
population, defined as all subjects who are randomized.  
The primary efficacy analysis of SSE-FS will be performed using a 
log-rank test, stratified by the same factors as the randomization 
factors (i.e., geographic region, prior lines of hormone therapy in 
metastatic setting, and visceral disease).  A one-sided alpha of 0.1 
will be used for the analysis of SSE-FS.  
Assuming a one-sided alpha of 0.1, power of 90%, the median 
SSE-FS for the control group is 8.3 months and a randomization 
ratio of 1:1 between treatments, approximately 160 events will be 
required to detect a 50% increase in SSE-FS for a total of 
311 subjects in the 2 treatment groups combined.  
The secondary time-to-event efficacy endpoints will be analyzed 
using a log-rank test, stratified by the same factors as the 
randomization factors.  
The exploratory time-to-event efficacy endpoints will be analyzed 
using a log-rank test, stratified by the same factors as the 
randomization factors.  


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The analysis of safety will be descriptive only (no statistical test 
will be applied). 
Following primary analysis, at the closure of the study, after the last 
subject has discontinued treatment and study assessments, an 
updated analysis will be performed. The updated analysis will be 
descriptive only and may consist of listings. 
 
 


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Table of contents 
 
Cover page of the integrated clinical study protocol ............................................................. 1 
1. 
Title page ............................................................................................................................ 2 
Signature of the sponsor’s medically responsible person ..................................................... 3 
Signature of principal investigator ......................................................................................... 4 
2. 
Synopsis .............................................................................................................................. 5 
Table of contents ..................................................................................................................... 17 
Table of tables ......................................................................................................................... 21 
List of abbreviations ............................................................................................................... 22 
Definitions of terms ................................................................................................................ 24 
3. 
Introduction ..................................................................................................................... 25 
3.1 
Metastatic breast cancer ................................................................................................. 25 
3.2 
HER2 negative and hormone receptor-positive metastatic breast cancer ...................... 25 
3.2.1 
Bone metastasis in HER2-negative and hormone receptor-positive metastatic breast 
cancer .......................................................................................................................... 27 
3.3 
Study medications .......................................................................................................... 29 
3.3.1 
Radium-223 dichloride ............................................................................................... 29 
3.3.1.1 
Drug development ................................................................................................... 29 
3.3.1.2 
Benefits and risks .................................................................................................... 30 
3.3.1.3 
Dosing rationale ...................................................................................................... 31 
3.3.2 
Study treatments exemestane and everolimus ............................................................ 31 
3.4 
Study rationale ............................................................................................................... 32 
4. 
Study objectives ............................................................................................................... 34 
5. 
Study design ..................................................................................................................... 35 
5.1 
Design overview ............................................................................................................ 35 
5.1.1 
Study periods and duration ......................................................................................... 35 
5.1.2 
Study endpoints .......................................................................................................... 37 
5.2 
Primary variables ........................................................................................................... 38 
5.3 
End of study ................................................................................................................... 38 
6. 
Study population ............................................................................................................. 39 
6.1 
Inclusion criteria ............................................................................................................ 39 
6.2 
Exclusion criteria ........................................................................................................... 42 
6.3 
Withdrawal of subjects from study ................................................................................ 44 
6.3.1 
Withdrawal ................................................................................................................. 44 
6.3.1.1 
Withdrawal from treatment period (collection of follow-up data) .......................... 44 
6.3.1.2 
Withdrawal from treatment period and/or all follow-up (no further data collection)46 
6.3.2 
Replacement ............................................................................................................... 46 
6.4 
Subject identification ..................................................................................................... 46 
7. 
Treatments ....................................................................................................................... 46 
7.1 
Treatments to be administered ....................................................................................... 46 
7.2 
Identity of study treatment ............................................................................................. 47 


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7.2.1 
Investigational medicinal product............................................................................... 47 
7.2.1.1 
Radium-223 dichloride ............................................................................................ 47 
7.2.1.2 
Saline ....................................................................................................................... 48 
7.2.1.3 
Study treatment with exemestane and everolimus .................................................. 48 
7.2.2 
Non-investigational medicinal products ..................................................................... 49 
7.2.2.1 
Bone-targeted agents, bisphosphonates and denosumab ......................................... 49 
7.3 
Treatment assignment .................................................................................................... 49 
7.4 
Dosage and administration ............................................................................................. 50 
7.4.1 
Dose calibration .......................................................................................................... 50 
7.4.2 
Radium-223 dichloride dose handling ........................................................................ 51 
7.4.3 
Radium-223 dose calculation ..................................................................................... 51 
7.4.4 
Study drug dose preparation ....................................................................................... 52 
7.4.5 
Dose administration .................................................................................................... 53 
7.4.6 
Dose adjustments, delays, and treatment discontinuations ......................................... 53 
7.4.6.1 
Radium-223 dichloride dose delays and treatment discontinuations guidance ....... 53 
7.4.7 
Supportive care guidelines .......................................................................................... 56 
7.5 
Blinding .......................................................................................................................... 57 
7.6 
Drug logistics and accountability ................................................................................... 58 
7.7 
Treatment compliance .................................................................................................... 59 
8. 
Non-study therapy ........................................................................................................... 59 
8.1 
Prior and concomitant therapy ....................................................................................... 59 
8.1.1 
Prohibited concomitant therapy .................................................................................. 59 
8.1.2 
Permitted concomitant therapy ................................................................................... 60 
8.2 
Post-study treatment therapy .......................................................................................... 61 
9. 
Procedures and variables ................................................................................................ 61 
9.1 
Tabular schedule of evaluations ..................................................................................... 61 
9.2 
Visit description ............................................................................................................. 66 
9.2.1 
Screening period (Visit 0 to 1).................................................................................... 66 
9.2.2 
Randomization ............................................................................................................ 68 
9.2.3 
Treatment period ......................................................................................................... 68 
9.2.3.1 
Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) ............ 69 
9.2.3.2 
Visits 3, 5 and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) .................... 71 
9.2.3.3 
Ongoing treatment with exemestane and everolimus (Visits 11, 12 and onwards, 
and unscheduled visits) ........................................................................................... 72 
9.2.3.4 
End of treatment visit .............................................................................................. 73 
9.2.4 
Active follow-up ......................................................................................................... 74 
9.2.5 
End of study ................................................................................................................ 74 
9.2.6 
Radiological assessment: tumor and response evaluation .......................................... 75 
9.3 
Population characteristics .............................................................................................. 76 
9.3.1 
Demographic............................................................................................................... 76 
9.3.2 
Medical history ........................................................................................................... 76 
9.3.3 
Other baseline characteristics ..................................................................................... 76 
9.4 
Efficacy .......................................................................................................................... 76 
9.4.1 
Efficacy variables ....................................................................................................... 76 
9.4.2 
Definition of efficacy variables .................................................................................. 77 
9.4.2.1 
Primary endpoint ..................................................................................................... 77 
9.4.2.2 
Secondary efficacy endpoints .................................................................................. 78 
9.4.2.3 
Exploratory efficacy endpoints: .............................................................................. 79 


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9.5 
Pharmacokinetics ........................................................................................................... 80 
9.6 
Safety ............................................................................................................................. 80 
9.6.1 
Adverse events ............................................................................................................ 80 
9.6.1.1 
Definitions ............................................................................................................... 80 
9.6.1.2 
Classifications for adverse event assessment .......................................................... 82 
9.6.1.3 
Assessments and documentation of adverse events ................................................ 84 
9.6.1.4 
Reporting of serious adverse events ........................................................................ 85 
9.6.1.5 
Expected adverse events .......................................................................................... 86 
9.6.2 
Pregnancies ................................................................................................................. 86 
9.6.3 
Reporting of medical device failures .......................................................................... 86 
9.7 
Other procedures and variables ...................................................................................... 86 
9.7.1 
Resource utilization .................................................................................................... 86 
9.7.2 
Biomarker assessments ............................................................................................... 86 
9.7.2.1 
Urine and blood based biomarker analysis .............................................................. 87 
9.7.2.2 
Collection of circulating tumor cells for biomarker analyses ................................. 87 
9.7.3 
Analysis of the impact of body weight on SSE-FS and AEs ...................................... 87 
9.8 
Appropriateness of procedures / measurements............................................................. 87 
10. Statistical methods and determination of sample size ................................................. 88 
10.1 General considerations ................................................................................................... 88 
10.2 Analysis sets ................................................................................................................... 88 
10.3 Variables and planned statistical analyses ..................................................................... 88 
10.3.1 Primary efficacy analysis ............................................................................................ 89 
10.3.2 Secondary efficacy analysis ........................................................................................ 89 
10.3.3 Exploratory efficacy analysis ..................................................................................... 89 
10.3.4 Safety analysis ............................................................................................................ 89 
10.4 Determination of sample size ......................................................................................... 89 
10.5 Planned interim data review ........................................................................................... 90 
11. Data handling and quality assurance ............................................................................ 90 
11.1 Data recording ................................................................................................................ 90 
11.2 Monitoring ..................................................................................................................... 91 
11.3 Data processing .............................................................................................................. 91 
11.4 Missing data ................................................................................................................... 91 
11.5 Audit and inspection ...................................................................................................... 91 
11.6 Archiving ....................................................................................................................... 92 
12. Premature termination of the study .............................................................................. 92 
13. Ethical and legal aspects ................................................................................................. 93 
13.1 Investigators and other study personnel ......................................................................... 93 
13.1.1 Independent data monitoring committee .................................................................... 93 
13.1.2 Independent radiological review................................................................................. 93 
13.1.3 Independent Data Review Committee (IDRC) ........................................................... 93 
13.2 Funding and financial disclosure ................................................................................... 94 
13.3 Ethical and legal conduct of the study ........................................................................... 94 
13.4 Subject information and consent .................................................................................... 94 
13.5 Publication policy and use of data ................................................................................. 95 
13.6 Compensation for health damage of subjects / insurance .............................................. 96 
13.7 Confidentiality ............................................................................................................... 96 


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14. Reference list .................................................................................................................... 97 
15. Protocol amendments .................................................................................................... 102 
15.1 Amendment 1 ............................................................................................................... 102 
15.1.1 Overview of changes to the study ............................................................................. 104 
15.1.2 Changes to the protocol text ..................................................................................... 116 
15.2 Amendment 3 ............................................................................................................... 116 
15.2.1 Overview of changes to the study ............................................................................. 117 
15.2.2 Changes to the protocol text ..................................................................................... 123 
15.3 Amendment 5 ............................................................................................................... 123 
15.3.1 Overview of changes to the study ............................................................................. 124 
15.3.2 Changes to the protocol text ..................................................................................... 130 
15.4 Amendment 8 ............................................................................................................... 130 
15.4.1 Overview of changes to the study ............................................................................. 130 
15.4.2 Changes to the protocol text ..................................................................................... 132 
15.5 Amendment 9 ............................................................................................................... 133 
15.5.1 Overview of changes ................................................................................................ 133 
15.5.1.1 Modification 1 ....................................................................................................... 133 
15.5.1.2 Modification 2 ....................................................................................................... 134 
15.5.1.3 Modification 3 ....................................................................................................... 134 
15.5.1.4 Modification 4 ....................................................................................................... 134 
15.5.1.5 Minor clarifications ............................................................................................... 134 
15.5.2 Changes to the protocol text ..................................................................................... 134 
15.6 Amendment 10 ............................................................................................................. 134 
15.6.1 Overview of changes ................................................................................................ 134 
15.6.2 Changes to the protocol text ..................................................................................... 137 
16. Appendices ..................................................................................................................... 138 
16.1 National Cancer Institute-Common Terminology Criteria, version 4.03 .................... 138 
16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) .................................... 138 
16.3 Calculation for glomular filtration rate ........................................................................ 144 
16.4 New York Heart Association Functional Classification .............................................. 144 
16.5 ECOG performance status ........................................................................................... 145 
16.6 Interaction of everolimus with other medicinal products ............................................ 145 
16.7 BPI-SF .......................................................................................................................... 147 
16.8 Resource utilization questionnaire ............................................................................... 151 
16.9 Patient Reported Questionnaire Information Sheet ..................................................... 153 
  
 


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Table of tables 
 
Table 7–1:  Everolimus dose adjustment recommendations .................................................... 55 
Table 9–1:  Schedule of assessments ....................................................................................... 62 
Table 16–1:  Target lesion response ....................................................................................... 141 
Table 16–2:  Non-target lesion response ................................................................................ 141 
Table 16–3:  Visit Response:  Patients with target lesions (with or without non-target lesions)
 ............................................................................................................................. 143 
Table 16–4:  Time Point Response:  Patients with non-target lesions only ........................... 144 
Table 16–5:  Effects of other active substances on everolimus ............................................. 145 
 


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List of abbreviations  
AE 
Adverse event 
AI 
Aromatase inhibitor 
ALP 
Alkaline phosphatase 
ALSYMPCA 
Alpharadin in Symptomatic Prostate Cancer 
ALT 
Alanine aminotransferase 
AML 
Acute myelocytic leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BCE 
Bone collagen equivalents 
BPI-SF 
Brief Pain Index-Short Form  
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CI 
Confidence interval 
CISH 
Chromogenic in situ hybridization 
Cl 
Chloride 
CR 
Complete response 
CRO 
Contract Research Organization 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE  
Common Terminology Criteria for Adverse Events; version 4.03 
DK 
Decay correction factor 
EBRT 
External beam radiotherapy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of study 
EOT 
End of treatment 
ER 
Estrogen receptor 
ER- 
Estrogen receptor negative 
ER+ 
Estrogen receptor positive 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FDG 
F-18 fluorodeoxyglucose 
FISH 
Fluorescence in situ hybridization 
G-CSF 
Granulocyte colony stimulating factor 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HER2 
Human epidermal growth factor receptor 2 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IBW 
Ideal body weight 
ICF 
Informed consent form 
ICSR 
Individual case safety reports 


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ICTP 
I collagen telopeptide 
IDRC 
Independent Data Review Committee 
IEC 
Independent Ethics Committee  
IHC 
ImmunoHistoChemistry 
IMP 
Investigational medicinal product 
INR 
International normalized ratio of prothrombin time 
IPM 
Increase in pain management 
IRB 
Institutional Review Board 
ISH 
In situ hybridization 
ITT 
Intent-to-treat 
IUD 
Intra-uterine device 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
K 
Potassium 
kBq 
KiloBecquerel; SI unit of radioactivity 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LH-RH 
Luteinizing hormone-releasing hormone 
MDRD 
Modification of Diet in Renal Disease 
MDS 
Myelodysplastic syndromes 
mL 
Milliliter 
mRECIST 1.1 
Modified Response Evaluation Criteria in Solid Tumors version 1.1 
MRI 
Magnetic resonance imaging 
Na 
Sodium 
NCI 
National Cancer Institute 
NIST 
National Institute of Standards and Technology 
NSAI 
Non-steroidal aromatase inhibitor 
NTX 
N-terminal telopeptide (a bone biomarker for collagen crosslinking) 
OS 
Overall survival 
PD 
Progressive disease/pharmacodynamic(s) 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PRD 
Patient ready dose 
PR 
Progesterone receptor 
PR- 
Progesterone receptor negative 
PR+ 
Progesterone receptor positive 
PS 
Performance status 
PSA 
Prostate specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RANKL 
Receptor activator of NF–κB ligand 
RAVE 
Medidata Rave; electronic data capture tool 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiological progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SERM 
Selective estrogen receptors modulator 


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SPECT 
Single photon emission tomography 
SRE 
Skeletal-related event 
SSE 
Symptomatic skeletal event 
SSE-FS 
Symptomatic skeletal event – free survival 
SUSAR 
Suspected unexpected serious adverse reaction 
TBW 
Total body weight 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WPS 
Worst pain score 
 
Definitions of terms 
Radium-223 
dichloride  
The investigational product, a targeted alpha particle emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous injection 
containing the drug substance radium-223 dichloride.  The active moiety is 
the alpha particle emitting nuclide radium-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 
radium-223 administered.  
 
 
 


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3. 
Introduction 
3.1 
Metastatic breast cancer 
Breast cancer is by far, the most common cancer among women worldwide with an estimated 
1.67 million new cancer cases diagnosed in 2012 (25% of all cancers).  It is the most frequent 
cause of cancer death in women in less developed regions (324,000 deaths, 14.3% of total) 
and the second cause of cancer death in more developed regions (198,000 deaths, 15.4%) after 
lung cancer.(1) 
Despite recent progress in diagnostic and therapeutic approaches of early breast cancer, a 
significant proportion of patients relapse following adjuvant treatment and approximately 5% 
to 6% of women present with metastatic disease at the time of their initial diagnosis.  
The clinical presentation in the metastatic setting may range from an aggressive clinical 
course in patients with multiple and/or extensive organ involvement, to a rather indolent 
clinical course in those with a solitary or only few metastatic lesions (oligometastatic disease).  
Depending on the extent of metastatic involvement, the prognosis is variable ranging from a 
median overall survival (OS) time of 26 months in patients with bone metastases only, to 
21 months in patients with bone and visceral metastases, and 18 months in patients with 
visceral metastases only.(2) 
Patients with metastatic disease are unlikely to be cured with actual available therapies.  As 
cure is unlikely in the metastatic setting, prolongation of survival, disease control, 
improvement/maintenance of quality of life and palliation of cancer-related symptoms are 
reasonable goals of therapy.  
Various therapeutic approaches are available; however, there are few widely accepted 
standards.  Most patients will receive systemic therapies such as chemotherapy, endocrine 
therapy, biologic/targeted molecular therapies, bone-targeted agents as well as supportive 
care.  The selection of a certain type of therapy over the other depends upon factors such as, 
tumor/disease characteristics (hormone receptor status, human epidermal growth factor 
receptor 2 [HER2] status, extent of metastatic involvement, disease clinical behavior, etc.), 
prior therapies and disease response to prior therapies, patient characteristics (i.e., 
comorbidities and estimated treatment tolerability, menopausal status), availability and costs 
of therapeutic agents and, last but not least, patient preference.  
Participation in well-designed clinical trials should always be considered in patients with 
metastatic breast cancer.  
Patients with rapidly progressing or symptomatic or visceral disease as well as those patients 
with hormone receptor–negative tumors or with disease that is resistant to hormonal therapy 
are candidates for chemotherapy. 
Patients with HER2/neu positive disease are candidates for anti-HER2-targeted agents (i.e., 
herceptin, lapatinib). 
3.2 
HER2 negative and hormone receptor-positive metastatic breast cancer 
Presence of estrogen receptor (ER) and/or progesterone receptor (PR) is one of the most 
important prognostic/predictive factors in breast cancers.  Approximately 70% to 75% of 
patients with invasive breast cancer have hormone receptor (ER and/or PR) positive disease at 
the time of diagnosis.(3) 


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Patients with hormone receptor positive disease and HER2-negative disease are candidates for 
endocrine therapy unless one of the factors described above would prompt the selection of 
another type of therapy (i.e., chemotherapy in a patient with an aggressive clinical course and 
rapid pace of progression).  Endocrine therapy will very likely have a beneficial effect in these 
patients and fewer side effects in comparison with chemotherapy.(4,5) 
Selection of the first-line endocrine agent is generally based on the menopausal status, type of 
endocrine agent in the adjuvant setting, timing of relapse following treatment in the adjuvant 
setting and tolerability.  First-line endocrine therapy is usually continued until the patient 
experiences disease progression or unacceptable toxicity.  
Additional lines of therapy may include another endocrine agent (not previously administered) 
or another type of therapy such as cytotoxic therapy.  There are no widely accepted 
standards/definitive recommendations for a specific treatment sequence, number of lines of 
endocrine therapy, and the therapeutic decision should be again based on the factors described 
above. 
Endocrine therapy exerts its action either by reducing estrogen production or by interacting 
with ERs.  
Various endocrine agents are currently in use:  
• Selective estrogen receptor modulators (SERM):  Tamoxifen and toremifene.  SERMs 
act by antagonizing the action of estrogen in breast tissue.  At the same time they also 
mimic the action of estrogen in other tissues, such as bone and endometrium.(6)   
• Third generation aromatase inhibitors (AIs) block peripheral estrogen synthesis by 
inhibiting aromatase, the enzyme responsible for the peripheral conversion of 
androgens to estrogen.(7)  Currently available third generation aromatic inhibitors 
(AIs) are the non-steroidal AIs (NSAI) anastrazole and letrozole and the steroidal AI, 
exemestane.  In the first-line setting, large phase III trials have shown that all 3, 
anastrozole, letrozole and exemestane are equivalent or superior to tamoxifen in 
women with metastatic disease.(8,9,10,11) 
• Estrogen receptor down regulators:  Fulvestrant is a competitive ER antagonist.  It 
blocks the actions of estrogens at the level of the receptor without any known partial 
agonist (estrogen-like) activity.  Fulvestrant has been approved by the United States 
(US) Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
for the treatment of hormone receptor positive metastatic breast cancer in 
postmenopausal women with disease progression following prior anti-estrogen therapy 
based on results of published clinical studies.(12,13,14) 
• Luteinizing hormone-releasing hormone analogues: Goserelin, leuprorelin, triptorelin.  
• Other: estrogens, progestins, anabolic steroids 
Recently published data from a phase II study shows that addition of everolimus to tamoxifen 
in hormone receptor positive HER2 negative patients who progressed on prior AI treatment 
significantly improved the clinical benefit rate, time to progression (TTP).(15) 
In addition to this, data from the phase III BOLERO-2 study showed that the addition of 
everolimus to exemestane significantly improved progression-free survival (PFS) compared 
with single-agent exemestane in estrogen receptor positive (ER+), HER2-negative patients 
whose metastatic disease was refractory to prior treatment with letrozole or anastrozole.(16)  
This led to the recent marketing approval of everolimus by the FDA and EMA for the 


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treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in 
combination with exemestane, in postmenopausal women without symptomatic visceral 
disease after recurrence or progression following a NSAI. 
At the time of final analysis with a median follow-up of 18 months, the median PFS (as per 
Investigator review) was 7.8 months for everolimus and exemestane versus 3.2 months for 
placebo and exemestane (hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.38 to 
0.54; log-rank p<0.0001).(17)  
Subgroup analyses also indicate that the effect of everolimus in addition to exemestane was 
consistent across patient subgroups and substantially prolonged median PFS regardless of 
prior therapies or baseline disease characteristics such as presence of visceral disease or 
skeletal involvement.  In patients with bone-only metastases at the time of study entry (21% 
of total study population), the median PFS was 12.88 months in the everolimus plus 
exemestane group versus 5.29 months in patients on exemestane only (HR = 0.33).  Patients 
with visceral metastases had a worse outcome, however, the improvement in median PFS was 
significant with median PFS of 6.83 months for everolimus plus exemestane group versus 
2.76 months for placebo plus exemestane group (HR = 0.47). 
3.2.1 
Bone metastasis in HER2-negative and hormone receptor-positive 
metastatic breast cancer 
Bone is a frequent site of metastatic spread with approximately 65% to 75% of patients with 
metastatic breast cancer having skeletal involvement.(18)  The skeleton is the first site of 
distant spread in 46% to 47% of patients with breast cancer.  The presence of skeletal 
metastases correlates significantly with estrogen and progesterone receptor positivity.(19,20)  
Bone-only metastases have been reported to occur in 17% to 37% of women with metastatic 
breast cancer.(21,22,23) 
Results of a recent meta-analysis from 41 randomized trials that compared bisphosphonates to 
no bisphosphonates and including data from 17,751 breast cancer patients, suggests that 
adjuvant bisphosphonates reduce bone recurrences and improve breast cancer survival in 
postmenopausal women.  Reductions in bone recurrence for postmenopausal women were 
similar independent of ER status, nodal involvement, bisphosphonate type, treatment 
schedule, or use of concomitant chemotherapy.(24) 
Prognosis of patients with metastases confined to bone-only seems to be better compared to 
patients with visceral involvement with median survival times from the diagnosis of 
metastatic disease to death between 24 to 36 months as reported per different 
publications.(2,22,23,25,26)  Occurrence of osseous metastases interferes with normal bone 
homeostasis and impacts the normal remodeling process by disrupting the fine balance 
between new bone formation and bone resorption processes.  This finally results in loss of 
bone integrity and loss of function.  
The most common sites of bone involvement are axial bones, however, other locations may 
also be encountered although with a lower frequency.  Bone lesions may be of osteolytic, 
osteoblastic or mixed phenotype as per the radiographic appearance of the lesions.  It is well 
known that bone metastases from breast cancer usually show osteolytic changes.  However, 
interestingly, as per a retrospective study, when comparing the morphology of breast cancer 
bone metastases by computed tomography (CT) in the time period 1996 to 2000 versus 2001 
to 2005, a higher prevalence of osteoblastic metastases was observed in the later period (1996 
to 2000: osteolytic 53.7%, osteosclerotic 32.1%, mixed type 14.3%; 2001 to 2005: osteolytic 


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9.4%, osteosclerotic 71.9%, mixed type 18.7%).  This might be due to the application of 
systematic bisphosphonate treatment.(28)   
Due to the disrupted bone remodeling process, patients with metastatic bone lesions are at risk 
of increased morbidity including skeletal-related events (SREs) such as bone pain requiring 
intervention (i.e., radiotherapy or surgery), pathologic fractures, spinal cord compression, as 
well as symptomatic hypercalcemia and bone marrow infiltration.  These events will 
ultimately impair patient’s quality of life and functional independence. 
A multidisciplinary therapeutic approach is generally recommended in patients presenting 
with bone metastases.  Current therapeutic options include systemic therapies such as 
endocrine therapies, chemotherapy, and bone-targeted agents (i.e., bisphosphonates, 
denosumab).  Local therapies such as external beam radiotherapy (EBRT) as well as other 
supportive interventions (i.e., orthopedic interventions for prevention/correction of 
pathological fractures) are also an important part of the therapeutic management for symptom 
palliation. 
Use of systemic bone-targeted agents such bisphosphonates as well as the newer anti-receptor 
activator of nuclear factor Kappa-B ligand (RANKL) antibody, denosumab demonstrated a 
beneficial effect in patients with metastatic bone disease.  While bisphosphonates inhibit 
osteoclast-mediated bone resorption, denosumab, a monoclonal antibody, inhibits key 
pathways in the vicious cycle of bone metastases by binding to RANKL, a mediator that 
stimulates increased osteoclast activity.  
Several clinical trials have demonstrated the efficacy of bisphosphonates in women with bone 
metastases from breast cancer.(29,30,31,32) 
More recently, denosumab has been found to be more effective than zoledronic acid as 
measured by the time to first and subsequent on-study SREs in patients with bone 
metastases.(33,34)  The median time to the first on-study SRE was 26.4 months for zoledronic 
acid and was not yet reached for denosumab at time of reporting.  Denosumab was approved 
for the treatment of patients with bone metastases from solid tumors, including breast cancer.  
A recent review of 34 trials performed in this patient population provided further confirmation 
that the use of bisphosphonates or denosumab (in addition to their other cancer treatments) 
reduces the risk of developing SRE and delay the time to SREs.  However, questions on the 
optimal timing and duration of treatment with these agents in patients with bone metastases 
from breast cancer remain unanswered.(35)  Bone-targeted agent therapy (i.e., 
bisphosphonates and denosumab) is actually recommended for patients with breast cancer 
with evidence of bone metastases.(36)  
Patients with multiple, mainly osteoblastic lesions and pain syndrome may also benefit from 
treatment with radionuclide therapy.  Bone-seeking radionuclides have been developed for 
palliation of bone pain from metastases.(37) 
Metastron (strontium-89) and Quadramet (samarium-153 ethylene diamine tetramethylene 
phosphonate) have been approved in several countries for symptom palliation in patients with 
bone metastases.(38)  The bone-seeking nature of these agents results in direct delivery of 
beta radiation to the sites of disease.  Due to the long range of the beta particles from these 
radioisotopes, the major dose-limiting factor with this treatment modality is toxicity to the 
bone marrow cells, limiting the use of these agents to pain palliation only as they have not 
demonstrated an OS benefit.  This toxicity has seriously limited their clinical use. 


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The limited hematological toxicity resulting from the short particle range of new alpha emitter 
radiopharmaceutical radium-223 dichloride may allow an easier integration with other anti-
cancer therapies.  Beside pain palliation effect, the high absorbed dose delivered by alpha-
emitting radionuclides might have a direct antitumor effect in bone. 
Multimodality therapy such as bisphosphonate/denosumab and radiopharmaceutical agents in 
addition to the anti-cancer treatment might offer superior symptom control and even 
prolonged progression-free and OS. 
3.3 
Study medications 
3.3.1 
Radium-223 dichloride 
3.3.1.1 
Drug development 
Radium-223 dichloride solution for injection is a novel alpha particle emitting 
radiopharmaceutical.  The bone targeting property of radium-223 is similar to that of other 
earth alkaline elements, like calcium or strontium-89.  However, the radiation characteristics 
of an alpha particle emitting radionuclide appear to be more advantageous than of a 
beta-emitting radionuclide.  Radium-223, with a physical half-life of 11.4 days, emits high 
linear energy transfer alpha radiation, with a range limited to less than 100 micrometers.  The 
high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of 
double-strand deoxyribonucleic acid breaks in adjacent cells, resulting in an antitumor effect 
on bone metastases.  The alpha particle range from radium-223 dichloride is less than 
100 micrometers (less than 10 cell diameters) which limits damage to the surrounding normal 
tissue. 
Biodistribution studies have shown that radium-223 is selectively concentrated in bone 
compared to soft tissues, and that radium-223 is retained in the bone matrix.(39,40)  Due to 
increased bone metabolism in skeletal metastases, preferential uptake in these lesions 
compared to normal bone is observed.  A significant radium-223 antitumor effect has been 
demonstrated in an experimental skeletal metastases model in nude rats.(40) 
The clinical development of radium-223 dichloride was initiated in August 2001.  A phase I 
clinical study in subjects with skeletal metastases from breast and prostate cancer was 
performed to evaluate whether the product could be administered safely at therapeutically 
relevant doses.  A total of 31 subjects were enrolled.  Twenty-five subjects received a single 
intravenous (IV) injection in the dose escalating part of the study, with 5 subjects at each dose 
level of 46, 93, 163, 213 and 250 KiloBecquerel (kBq)/kg body weight radium-223 dichloride.  
The results of this phase I study were encouraging (low toxicity, significant pain relief, and 
decreased serum alkaline phosphatase [ALP]); thus, a phase II trial (BC1-02 study) for 
castration-resistant prostate cancer (CRPC) was conducted,(39) where subjects received 
multiple doses of either 50 kBq/kg body weight radium-223 dichloride or saline 4 times at 
4-week intervals.  In both studies, the results showed modest dose-dependent reversible 
hematological toxicity.  No significant deleterious changes in chemistry parameters were seen, 
and the most frequent adverse event (AE) was transient diarrhea, which responded well to 
medication.  In terms of efficacy, the BC1-02 phase II results showed a significant 
improvement in serum bone markers, i.e., bone ALP (a primary efficacy endpoint), and 
perhaps more importantly, a delayed time to prostate specific antigen (PSA) progression.  
Median OS at 2 years was 65.3 weeks for radium-223 dichloride and 46.3 weeks for placebo 
(HR = 2.1; p value=0.017 based on an intent-to-treat [ITT] population and adjusting for 
baseline covariates).  


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Following the positive results of the phase II trial, the phase III, double-blind, randomized, 
BC1-06, ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial was started in 
2008.  A total of 922 subjects with CRPC and symptomatic bone metastases were randomized 
to receive 6 injections of radium-223 dichloride (50 kBq/kg IV) or matching placebo every 4 
weeks.  Based on data of an interim analysis (n=809), the study was unblinded in June 2011, 
since radium-223 dichloride significantly improved OS compared to placebo (the median OS 
was 14.0 versus 11.2 months, respectively; HR=0.695; p=0.00185).  Symptomatic skeletal 
events (SSEs) were lower in the radium-223 dichloride arm, and time to first SSE was 
significantly delayed (the median time to SSE was 13.6 months, versus 8.4 months, 
respectively; HR= 0.610; p=0.00046).  A low incidence of myelosuppression was observed, 
with Grade 3/4 events of neutropenia (1.8%) and thrombocytopenia (6.2%).  Adverse events 
of any grade were described in 88% of the subjects who received radium-223 dichloride, 
versus 94% in the placebo arm (Grade 3/4 AEs were described for 51% and 59%, 
respectively).  The updated analysis (performed in June 2012) also showed that radium-223 
dichloride significantly improved OS compared to placebo (median OS 14.9 versus 
11.3 months, respectively; p=0.00007; HR=0.695).(41)  
In an open-label, multicenter, single-arm, phase IIa study (BC1-09), 23 subjects with 
metastatic breast cancer with bone-dominant disease were administered 4 injections of 
radium-223 dichloride (50 kBq/kg IV) every 4 weeks.  Bone markers were assessed at 
baseline, prior to every treatment, and thereafter at each follow-up visit.  The primary efficacy 
endpoints were changed in urine levels of N-terminal telopeptide (NTX) and bone ALP from 
baseline at Week 16.  Median urine NTX levels were reduced by 20% (from 36 to 
29 nmo1 bone collagen equivalents (BCE)/mmo1 creatinine; p=0.03) and 33%(from 36 to 
23 nmo1 BCE/mmo1 creatinine; p=0.0124) at Week 8 and Week 16, respectively; 17/23 and 
9/13 subjects (for whom data were available) had a decrease in urine NTX at Week 8 and 
Week 16, respectively.  Median bone ALP levels were reduced by 33% (from 22.1 to 
12.1 ng/mL; p=0.0001) at Week 8 and 42% (from 22.1 to 10.94 ng/mL; p=0.04) at Week 16.  
Bone ALP levels were reduced in 20/22 subjects at Week 8 and in 10/12 subjects (for whom 
data were available) at Week 16.  Radium-223 dichloride was found to be safe and well-
tolerated.  Three subjects had serious AEs (SAEs), none related to study drug; 1 of them died 
due to disease progression.(42) 
Further details can be found in the Investigator's Brochure, which contains comprehensive 
information on the study drug. 
3.3.1.2 
Benefits and risks 
Anticipated benefits of treatment with radium-223 dichloride include prolongation of 
symptomatic skeletal event-free survival (SSE-FS), OS and radiological progression-free 
survival (rPFS), delay of SSEs, palliation of bone pain, and improvement in quality of life. 
The risk profile attributed to radium-223 dichloride is favorable compared with available 
products for the treatment of metastatic breast cancer.  The anticipated risks attributed to 
radium-223 dichloride include the following AEs: gastrointestinal (constipation, transient but 
treatable diarrhea, nausea, and vomiting); hematological (transient reduction in neutrophil 
count, mild to moderate myelosuppression, low grade thrombocytopenia).  Due to its 
radioactive nature, radium-223 dichloride has the potential of inducting long-term toxicities 
such as other primary cancers.  Current ongoing studies have an increased follow-up of 
7 years to assess this potential. 


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3.3.1.3 
Dosing rationale 
The proposed dosing regimen in this phase II trial is 50 kBq/kg body weight (55 kBq/kg after 
implementation of National Institute of Standards and Technology [NIST] update) every 
4 weeks for a 6-month treatment period (6 injections).  In the completed phase I safety, 
tolerability, and pharmacokinetic (PK) clinical study (ATI-BC-1), subjects diagnosed with 
prostate or breast carcinoma and skeletal metastases were administered radium-223 dichloride 
in single doses of 46, 93, 163, 213, or 250 kBq/kg body weight (25 subjects) or multiple doses 
of 5 administrations of 50 kBq/kg body weight at 3-week intervals (3 subjects) or 
2 administrations of 125 kBq/kg body weight at 6-week intervals (3 subjects).  In the 
completed phase II study, 64 subjects with CRPC and painful skeletal metastases, received 
4 injections of 50 kBq/kg body weight radium-223 dichloride (33 subjects) or placebo 
(31 subjects) at 4-week intervals, to examine the effects of radium-223 dichloride on 
biomarkers of disease progression, SSEs, pain palliation, survival, and safety parameters.  The 
completed phase III trial, ALSYMPCA, enrolled 922 subjects diagnosed with CRPC and 
symptomatic bone metastases who received 6 injections of radium-223 dichloride (50 kBq/kg 
IV) in 4-week intervals.  Endpoints included OS, time to disease-related events, TTP as
measured by serum PSA and total ALP concentrations, pain palliation, acute and long-term
safety profile, and health-related quality of life (HRQoL).  The efficacy and safety data from
the ALSYMPCA trial support the selection of a dosing regimen of 6 doses of 50 kBq/kg body
weight (55 kBq/kg after implementation of NIST update) of radium-223 dichloride at 4-week
intervals.  This dose and schedule was determined to be efficacious, with only minor side
effects and no indication of cumulative effect on bone marrow suppression following multiple
administrations of radium-223 dichloride.
Currently, no data are available to assess if similar effects could be achieved with a dose 
lower than 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update). 
The same dose was used in a phase II breast cancer study BC-109 which provided preliminary 
evidence of the effects of radium-223 on bone markers, Brief Pain Index – Short Form (BPI-
SF) score, and tumor metabolism assessed by serial F-18 fluorodeoxyglucose (FDG) positron 
emission tomography (PET) imaging and supports further investigations to confirm 
effectiveness of radium-223 in treating bone metastases in patients with breast cancer and 
bone-dominant disease.  Data were communicated at the San Antonio Breast Cancer 
Symposium 2011 and published in 2014.(42)  The study results are presented in detail in 
Section 3.3.1.1. 
3.3.2 
Study treatments exemestane and everolimus 
Exemestane is an irreversible steroidal AI that has demonstrated efficacy in the treatment of 
postmenopausal patients with breast cancer.  Beside its use in the adjuvant setting, exemestane 
is also indicated in the metastatic setting for postmenopausal patients with hormone receptor 
positive disease that has progressed following tamoxifen therapy (in the US) or following 
anti-estrogen therapy (in Europe).  In a study of exemestane versus megestrol acetate in 
postmenopausal women who experienced failure of tamoxifen, exemestane demonstrated 
improvement in median OS (74.6 weeks for exemestane versus 55.0 weeks for megestrol 
acetate).(43)  
In the first-line setting, a phase III study comparing exemestane versus tamoxifen showed that 
exemestane is an effective and well-tolerated first-line hormonal treatment for 
postmenopausal women with metastatic disease and resulted in a significant early 
improvement in time to tumor progression (9.9 months [95% confidence interval or CI: 8.7 to 


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11.8 months] for exemestane versus 5.8 months [95% CI: 5.3 to 8.1 months] for 
tamoxifen).(44)  The major limitation of endocrine therapy remains however the development 
of therapeutic resistance, which will ultimately result in disease progression and eventual 
death in the majority of patients. 
The activation of the mTOR pathway is thought to be a driving factor for endocrine resistance 
in breast cancer.  The evidence of this proposed mechanism of resistance is based on the 
finding that the PI3K/Akt/mTOR pathway is constitutively activated in AI-resistant and long-
term estrogen deprived breast cancer cells. 
Everolimus, a rapamycin derivative, is an mTOR inhibitor.  The strategy of dual inhibition by 
combining an endocrine agent (exemestane) with an mTOR inhibitor (everolimus) has been 
proven to be efficacious.  Data from the phase III BOLERO-2 study showed that the addition 
of everolimus to exemestane significantly improved PFS compared with single-agent 
exemestane in ER+, HER2-negative patients whose metastatic disease was refractory to prior 
treatment with letrozole or anastrozole.  (See Section 3.2 for a more detailed summary of the 
efficacy results).  
The most common Grade 3 or 4 AEs in the everolimus + exemestane group versus placebo 
plus exemestane group were as follows: stomatitis (8% versus 1%), anemia (6% versus <1%), 
dyspnea (4% versus 1%), hyperglycemia (4% versus <1%), fatigue (4% versus 1%), and 
pneumonitis (3% versus 0%).The efficacy and safety results led to the recent marketing 
approval of everolimus by the FDA and EMA for the treatment of hormone receptor-positive, 
HER2/neu negative advanced breast cancer, in combination with exemestane, in 
postmenopausal women without symptomatic visceral disease after recurrence or progression 
following an NSAI.  
3.4 
Study rationale 
The treatment options for patients with bone predominant metastasis of breast cancer are still 
limited.  
Radium-223 dichloride has shown significant antitumor activity in phase II and phase III trials 
in subjects with bone predominant metastatic CRPC and in the phase II metastatic breast 
cancer study. 
The safety profile and tolerability for radium-223 dichloride appear to be acceptable in this 
study population. 
This trial is blinded, randomized, and placebo-controlled for radium-223 dichloride, and it is 
unblinded for standard-of-care exemestane and everolimus treatment that will be received by 
all subjects (both arms).  Best supportive care will also be received by both arms. 
The mode of action of the exemestane and everolimus therapy differs from that of 
radium-223. 
The AI exemestane binds irreversibly to the active site of the enzyme aromatase, causing its 
inactivation, at the primary sites of estrogen synthesis which in postmenopausal women are 
peripheral tissues such as adipose tissue, muscle and breast tissue.  Everolimus is a selective 
mTOR inhibitor and acts by targeting the mTOR pathway which is thought to be a driving 
factor for endocrine resistance in breast cancer.  Radium-223 dichloride delivers alpha 
radiation to bone lesions of breast cancer.  Based upon these individual effects, it is expected 
that radium-223 dichloride treatment will prolong SSE-FS compared to placebo, when 


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administered to HER2 negative, hormone receptor positive metastatic breast cancer patients 
with bone metastases that receive standard-of-care treatment with exemestane and everolimus.  
Primary efficacy endpoints 
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause 
Since the definition for measuring skeletal events will not use pre-specified imaging 
assessments, the use of imaging to identify a fracture or spinal cord compression will be 
triggered by symptoms.  As such, only symptomatic events will be captured; asymptomatic 
radiographic events are not included in this composite endpoint.  A delay or a reduction of 
SSEs represents an immediate clinical benefit, as it will delay or reduce bone pain, functional 
impairment, and the need for surgical intervention.  
In ALSYMPCA, treatment with radium-223 dichloride increased the time to first SSE from 
9.8 months to 15.6 months (HR 0.658, p=0.00037, data on file).  
The median SSE-FS in ALSYMPCA was 9.0 and 6.4 months with and without radium-223 
dichloride, respectively (HR = 0.685, p=0.00004).  An ad hoc analysis (data on file) in 
subjects who did not receive docetaxel prior to radium-223 dichloride indicated that the 
median duration of SSE-FS is preserved in this subgroup of 395 subjects (SSE-FS was 
9.5 months with and 6.7 months without radium-223 dichloride). 
The occurrence of SREs in breast cancer patients with bone metastases is associated with 
worse functional, physical and emotional status and a decreased overall quality of life.(45,46)  
Prevention of SREs is, therefore, an important aim in the therapeutic management of these 
patients.  Bone-targeted agents such as bisphosphonates and denosumab have been reported to 
delay the time to SRE and reduce the risk of developing SREs.  In addition, they also reduced 
bone pain and showed an improvement in quality of life.(34,35,46,47,48,49)  As per the 
American Society of Clinical Oncology treatment guidelines, they are both recommended in 
patients with breast cancer with evidence of bone metastases.(36) 
A recent study in patients with bone metastases also reported that patients rated chronic pain 
as their main symptom and the most relevant HRQoL issue related to their disease.  This was 
followed by difficulty in carrying out their usual tasks and worries about loss of independence 
and mobility.(50) 
The high incidence of bone metastases as well as the prognostic relevance of bone 
involvement, definitely suggest that improvements in a bone-targeted therapeutic approach 
could provide further patient benefit. 
In conclusion, SSE-FS is an objective variable that is likely to predict clinical benefit in the 
proposed study populations. 


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4. 
Study objectives 
The objective of this study is to assess efficacy and safety of radium-223 dichloride in 
combination with exemestane and everolimus in subjects with human epidermal growth factor 
receptor 2 (HER2) negative, hormone receptor positive breast cancer with bone metastases. 
The primary endpoint is: 
• SSE-FS 
The secondary endpoints are: 
• OS 
• Time to opiate use for cancer pain 
• Time to pain progression (only in subjects with baseline worst pain score (WPS) ≤8) 
• Time to cytotoxic chemotherapy 
• rPFS 
• Pain improvement rate 
• Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy* 
The study will also include the following exploratory endpoints: 
• Time to first on-study SSE 
• Time to bone ALP progression 
• Bone ALP response at Week 12 and 4 weeks (± 7 days) after last radium-223 
dichloride/placebo dose 
• Bone-specific rPFS 
• Resource utilization 
• Biomarker assessments 
• Time to visceral metastases onset (in subjects with no visceral disease at baseline). 
*Safety endpoints were reported/measured as AEs. Acute safety was documented as the 
incidence of TEAEs. Long-term safety was documented as the incidence of post-treatment 
AEs. Hematopoietic reserve for tolerability of subsequent chemotherapy was assessed via the 
incidence of treatment emergent hematological toxicity and the incidence of post-treatment 
chemotherapy-related AEs.  
Note: After implementation of CSP Amendment 9, subjects who completed the EOT visit 
could be transferred to a separate extended safety follow-up study for their remaining follow-
up. After implementation of CSP Amendment 10, all such subjects will be transferred; only 
subjects on oral treatment will remain on study, and no post-treatment data will be collected 
beyond the 30-day safety follow-up (EOT visit).   
As the key efficacy objectives will have been accomplished, long-term safety transferred, and 
only a limited number of subjects will remain in this study, in order to reduce the burden to 
study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, 


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and OS. Once subjects are rolled over, the long-term safety will be collected and assessed 
entirely in the separate extended safety follow-up study. 
5. 
Study design 
5.1 
Design overview 
This study is a phase II, randomized, double-blind, placebo-controlled, parallel group trial of 
radium-223 dichloride versus placebo administered with exemestane and everolimus and 
supportive care in subjects with HER2 negative hormone receptor positive breast cancer with 
bone metastases.  Randomization will be stratified by:  
• Geographical regions (Europe/North America [including Israel] versus Asia) 
• Previous lines of hormone therapy in metastatic setting (1 versus 2 or more): for the 
purpose of counting the number of prior lines of hormone therapy, only a change of 
the hormone agent due to progression is counted as a new line of therapy.  A switch of 
hormone therapy from one agent to another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of progressive disease (PD) at time of switch will be 
counted as one line although 2 different agents have been administered. 
• Visceral disease: Yes versus No  
This study will be conducted at approximately 160 investigative study sites and approximately 
311 subjects will be enrolled. 
5.1.1 
Study periods and duration 
Prior to the primary analysis, the study period comprised of 4 periods: screening, 
randomization, treatment, and the follow-up period (active follow-up with clinic visits and 
active follow-up without clinic visits). After the primary analysis (after implementation of 
Amendment 10), the follow-up will be conducted in the separate extended safety follow-up 
study, therefore, upon discontinuation of oral treatment, subjects will be directly transitioned 
to the aforementioned study. For additional details, please refer to Section 15.6. 
After Primary Analysis (after implementation of Amendment 10) 
Following the administrative data review (per Amendment 8, see Section 10.5), conducted on 
DEC 2017 by a small group of unblinded Sponsor employees, independent of the study team, 
subject enrollment in this trial was discontinued on APR 2018. 
Screening period: 
All trial related procedures and evaluations will only be performed after the subject has agreed 
to participate and has signed the informed consent form (ICF).  The screening period will 
consist of multiple evaluations that will take place within 3 weeks prior to randomization to 
ensure that all eligibility criteria are met (Section 6). 
Randomization: 
After all screening assessments have been completed and the subject’s eligibility has been 
confirmed and documented, eligible subjects will be randomized in a ratio of 1:1 to treatment 
with radium-223 dichloride (Arm A - investigational arm) or placebo (Arm B - control arm).  
All subjects will receive open-label study treatment with exemestane and everolimus and 
supportive care as per the local/institutional standard of practice. 


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Treatment period: 
The total treatment period is defined from the day of randomization until 4 weeks after the last 
administration of study treatment (radium-223 dichloride/placebo and exemestane and 
everolimus, whichever occurs last). 
The study treatment consists of up to 6 cycles of radium-223 dichloride 50 kBq/kg body 
weight (55 kBq/kg after implementation of NIST update) (Arm A) or placebo (Arm B) each 
separated by an interval of 4 weeks ±7 days, in combination with exemestane and everolimus 
followed by ongoing treatment for all subjects with exemestane and everolimus, as applicable.  
Subjects enrolled in the current study, will start treatment with exemestane and everolimus, 
after randomization, either before or simultaneously to the first injection of radium-223 
dichloride/placebo.  Subjects already receiving exemestane and everolimus prior to study 
entry are not eligible. 
Treatment with exemestane and everolimus will continue after completion of radium-223 
dichloride until disease progression, initiation of new anti-cancer therapy, unacceptable 
toxicity occurs, discontinuation of study treatment for other reasons, or study is terminated, 
whichever occurs first. All subjects receive supportive care, as per local standard of practice. 
All ongoing subjects at the time of study termination will finish all study treatments as part of 
the study.  
At the time of implementation of protocol Amendment 10, all subjects have already 
completed the radium-223 dichloride/placebo treatment.  
During the treatment period, subjects will be assessed for safety at each treatment visit, every 
8 weeks, and will be evaluated for radiologic progression according to local standard practice. 
All SSEs should be recorded until end of treatment visit, independent of whether the subject 
starts a new anti-cancer therapy (i.e., chemotherapy, other). 
Subjects who can no longer travel to the clinical site and subjects who miss 2 consecutive 
treatment visits, will be discontinued from all study treatments and will be transitioned to the 
separate extended safety follow-up study. 
Subject management, unless otherwise defined by this protocol, will be in accordance with the 
local standard of practice.  
Study treatments (radium-223 dichloride/placebo administration and exemestane and 
everolimus in all subjects) will continue until one of the study treatment withdrawal criteria 
(see Section 6.3.1) is met. 
Follow-up period: 
Note: Following primary analysis, the follow-up will be conducted in the separate extended 
safety follow-up study (please refer to the section below); therefore, upon discontinuation of 
oral treatment, subjects will be directly transitioned to the aforementioned study. For 
additional details, please refer to Section 15.6. 
Long-term follow-up – Extended safety follow-up study 
All study subjects who have completed at a minimum the EOT visit or 30 days from last study 
treatment dose, whichever is latest, will be transitioned into a separate extended safety follow-
up study (BAY 88-8223 study 16996 / NCT02312960).  The separate extended safety follow-
up study has been set up to follow subjects who received radium-223 dichloride or placebo in 


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the course of Bayer-sponsored clinical trials. The primary objective of this study is to define 
the long-term safety profile of radium-223 dichloride.  All subjects who transition into this 
separate extended safety follow-up study will require a separate signed informed consent.  All 
efforts will be made to transition all subjects to the extended safety follow-up study.  
After primary analysis, sites/subjects not transitioning to extended safety follow-up protocol 
will be encouraged to report all occurrences of leukemia, myelodysplastic syndrome, aplastic 
anemia, new primary malignancies, bone fractures, and bone associated events via Bayer 
Pharmacovigilance as individual case safety report (ICSR), including the corresponding study 
number and subject ID. 
This study will end by the time last subject on treatment discontinues oral exemestane and/ or 
everolimus treatment and completes end of treatment visit or discontinues from this study for 
another reason (e.g., death, consent withdrawn and active objection for further data collection, 
lost to follow-up). Until the transition to the extended safety follow-up study, subjects will 
continue to follow all the protocols required procedures and visits in the current protocol. 
5.1.2 
 Study endpoints 
Primary Endpoint: The primary endpoint is SSE-FS. 
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause 
Note:  Any EBRT or orthopedic surgery related to a previous SSE but administered after 
signature of the ICF will not be counted as an on-study SSE. 
Secondary Endpoints:  
• OS 
• Time to opiate use for cancer pain 
• Time to pain progression (only in subjects with baseline WPS ≤8) 
• Time to cytotoxic chemotherapy 
• rPFS 
• Pain improvement rate 
• Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy* 
Exploratory Endpoints: 
• Time to first on-study SSE 


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• Time to bone ALP progression 
• Bone ALP response at Week 12 and 4 weeks (± 7 days) after last radium-223 
dichloride/placebo dose  
• Bone-specific rPFS 
• Resource utilization 
• Biomarker assessments 
• Time to visceral metastases onset (in subjects with no visceral disease at baseline) 
*Safety endpoints were reported/measured as AEs. Acute safety was documented as the 
incidence of TEAEs. Long-term safety was documented as the incidence of post-treatment 
AEs. Hematopoietic reserve for tolerability of subsequent chemotherapy was assessed via the 
incidence of treatment emergent hematological toxicity and the incidence of post-treatment 
chemotherapy-related AEs.  
Note: After implementation of CSP Amendment 9, subjects who completed the EOT visit 
could be transferred to a separate extended safety follow-up study for their remaining follow-
up. After implementation of CSP Amendment 10, all such subjects will be transferred; only 
subjects on oral treatment will remain on study, and no post-treatment data will be collected 
beyond the 30-day safety follow-up (EOT visit).   
As the key efficacy objectives will have been accomplished, long-term safety transferred, and 
only a limited number of subjects will remain in this study, in order to reduce the burden to 
study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, 
and OS. Once subjects are rolled over, the long-term safety will be collected and assessed 
entirely in the separate extended safety follow-up study. 
5.2 
Primary variables 
The primary variable is SSE-FS.  The definition for this variable is provided in Section 5.1.2. 
5.3 
End of study 
All study subjects who have completed at a minimum the EOT visit or 30 days from last study 
treatment dose, whichever is latest, will be transitioned into a separate extended safety follow-
up study (BAY 88-8223 study 16996 / NCT02312960). The separate extended safety follow-
up study has been set up to follow subjects who received radium-223 dichloride or placebo in 
the course of Bayer-sponsored clinical trials. The primary objective of this study is to define 
the long-term safety profile of radium-223 dichloride. All subjects who transition into this 
separate extended safety follow-up study will require a separate signed informed consent. All 
efforts will be made to transition all subjects to the extended safety follow-up study.  
After primary analysis, sites/subjects not transitioning to extended safety follow-up study will 
be encouraged to report all occurrences of leukemia, myelodysplastic syndrome, aplastic 
anemia, new primary malignancies, bone fractures, and bone associated events via Bayer 
Pharmacovigilance as individual case safety report (ICSR), including the corresponding study 
number and subject ID. 
This study will end by the time the last subject on treatment discontinues oral exemestane and 
/or everolimus treatment and completes end of treatment visit or discontinues from this study 
for another reason (e.g., death, consent withdrawn and active objection for further data 


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collection, lost to follow-up). Until the transition to the extended safety follow-up study, 
subjects will continue to follow all the protocols required procedures and visits in the current 
protocol. 
For each participating European Union (EU) country, the end of the study according to the EU 
Clinical Trial Directive will be reached when the last visit of the last subject in any site has 
occurred.  
6. 
Study population 
Approximately 311 subjects with HER2 negative hormone receptor positive breast cancer 
with bone metastases will be randomized. 
Eligibility 
Eligibility is confirmed at the end of the screening period.  At that time, the subject is 
randomized and enters the treatment period.  Laboratory values will be verified prior to first 
study drug administration as per protocol.  Hematological support will be provided as needed 
according to the protocol guidance during the treatment period. 
Rescreening 
Rescreening of screen failed subjects may only be allowed after discussion with the medical 
monitor of the sponsor and after his/her approval.  Sponsor approval of rescreening must be 
documented.  Rescreening may be considered under the following circumstances: 
• Subjects who underwent screening procedures (i.e., scans and laboratory work) that 
expired (are outside of the 21-day window) may need the screening procedures to be 
repeated to be within the window required prior to randomization.  However, 
rescreening is not permitted in cases in which the initial laboratory test results do not 
support eligibility. 
• Rescreening is also permitted where the screening procedures for subject’s eligibility 
expired due to completion of washout periods as per protocol (e.g., 4 weeks from 
treatment with an investigational drug), in case of expiry of investigational product 
that requires replacement, or for extraordinary logistical issues. 
The subjects who need to repeat the screening procedures will be asked to repeat the 
consenting process for study participation. 
6.1 
Inclusion criteria 
Subjects must meet the following criteria for inclusion in the study: 
1. Have provided written informed consent.  Subjects must be able to understand and be 
willing to sign the written informed consent.  A signed ICF must be appropriately 
obtained prior to the conduct of any trial-specific procedure. 
2. Documentation of histological or cytological confirmation of ER+ and HER2 negative 
adenocarcinoma of the breast must be available.  HER2 status should be determined 
by an accredited/Ministry of Health approved laboratory by immunohistochemistry 
(IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization 
(CISH) or other validated in situ hybridization (ISH) assay for detection of HER2 gene 
expression. 


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3. Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% 
positive tumor nuclei in the analyzed sample.  ER+/progesterone receptor positive 
(PR+) and ER+/progesterone receptor negative (PR-) subjects are eligible whereas 
estrogen receptor negative (ER-)/PR+ and ER-/PR- disease will not be eligible. 
4. Women (≥18 years of age) with metastatic breast cancer not amenable to curative 
treatment by surgery or radiotherapy.  Women of reproductive potential and their male 
partners must agree to use adequate contraception during treatment and for 6 months 
following the completion of treatment with radium-223 dichloride/placebo. 
5. Documentation of menopausal status: postmenopausal subjects or premenopausal 
subjects with ovarian radiation or concomitant therapy with a luteinizing hormone-
releasing hormone (LH-RH) agonist/antagonist are eligible. 
• Premenopausal subjects with ovarian radiation or concomitant treatment with an 
LH-RH agonist/antagonist must have a plasma/serum estradiol assay within local 
laboratory postmenopausal range at screening, performed within 7 days prior to 
randomization.  These subjects must also have a negative pregnancy test at 
screening and agree to use an adequate method of contraception as recommended 
by their treating physicians (please refer to Section 8.1.2). 
• Postmenopausal status is defined either by:  
o age ≥55 years and one year or more of amenorrhea,  
o age <55 years and one year or more of amenorrhea with a plasma/serum 
estradiol assay within local laboratory postmenopausal range, performed within 
7 days of randomization, 
o bilateral ovariectomy. 
6. Subjects with bone-dominant disease with at least 2 skeletal metastases identified at 
baseline by technetium-99m bone scintigraphy and confirmed by CT/magnetic 
resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, 
muscle, fat, lymph nodes) and/or visceral metastases is allowed. 
7. Measurable or non-measurable disease (but radiologically evaluable) according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.  All disease 
burdens must be assessed within 3 weeks prior to randomization by CT or MRI of 
chest, pelvis, and abdomen and any additional fields as needed.  A technetium-99m 
bone scan should also be done within 3 weeks prior to randomization for all subjects. 
CT/MRI done as part of the standard of practice within 3 weeks prior to randomization 
and standard-of-care technetium-99m bone scans done within 3 weeks prior to 
randomization are acceptable. 
The FDG PET scan, if performed as part of standard of care imaging, can be used as 
an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the 
CT component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2). 
FDG PET/CT or 18F-sodium fluoride PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the institution, 
provided the same bone imaging modality is used throughout the study. 


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8. Subjects must have experienced recurrent/progressive disease following treatment 
with a non-steroidal aromatase inhibitor (letrozole or anastrozole) in an adjuvant or 
metastatic setting.  
9. Subjects must have received at least one line of hormonal therapy in the metastatic 
setting.  
 
Note: A change of the hormone agent due to progression (as per the Investigator 
assessment) is counted as a new line of therapy.  A switch of hormone therapy from 
one agent to another due to toxicity or other reasons (e.g., subject’s preference), in 
absence of progressive disease at time of switch, will be counted as one line although 
2 different agents have been administered. 
10. Subjects who are eligible, as per the Investigator’s assessment and according to the 
local label, for treatment with exemestane and everolimus as a second line or greater 
of hormone therapy in a metastatic setting.  Subjects enrolled in the current study will 
start treatment with exemestane and everolimus, after randomization, either before or 
simultaneously to the first injection of radium-223 dichloride/placebo.  
11. Subjects must have experienced no more than 2 SREs prior to study entry defined as: 
Need for EBRT to bone, pathological bone fracture (excluding major trauma), spinal 
cord compression, and/or orthopedic surgical procedure.  Subjects with no prior SREs 
are not permitted. 
 
Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be 
administered prior to randomization. Separate SRE events are the ones that occur at 
least 21 days apart from each other to ensure that linked events (eg, surgery to repair 
a fracture or multiple doses of radiation during a course of treatment) are not counted 
as separate events. In case of bone pain that occurs in several anatomical locations 
and requires separate EBRT sessions for the different anatomical locations, it should 
be counted as one event if the EBRT sessions are administered within a period of 21 
days. 
12. Subjects must be on therapy with bisphosphonates or denosumab for at least 1 month 
before start of study treatment. 
13. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 
14. Life expectancy ≥6 months  
15. Laboratory requirements:  
• Absolute neutrophil count ≥1.5 x 109/L 
• Platelet count ≥100 x109/L without platelet transfusion within 4 weeks prior to 
randomization 
• Hemoglobin (Hb) ≥9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or 
erythropoietin within 4 weeks prior to randomization 
• Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) (except for 
subjects with documented Gilbert’s disease) 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x 
institutional ULN 


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• Pulse oximetry O2 saturation >92% if lung metastases are present  
• Creatinine ≤1.5 x ULN 
• Estimated glomerular filtration rate ≥30 mL/min/1.73m2 according to the 
Modification of Diet in Renal Disease (MDRD) abbreviated formula (Note: please 
refer to local labeling for administration of full dose of bisphosphonates) 
• International normalized ratio of prothrombin time (INR) and partial 
thromboplastin time (PTT) or activated PTT ≤1.5 x ULN at study entry.  Subjects 
treated with warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban, or 
aspirin (e.g. ≤100 mg daily) will be allowed to participate in the study if no 
underlying abnormality in coagulation parameters exists per prior history; weekly 
evaluation of INR/PTT will be required until stability is achieved for 
anticoagulants that require their monitoring as per local label.  
• Serum albumin >30 g/L 
16. Able to swallow oral medication  
6.2 
Exclusion criteria 
Eligible subjects must not meet any of the exclusion criteria listed below: 
1. HER2-positive breast cancer (IHC=3+, positive FISH, or positive CISH); equivocal or 
unknown HER2 status 
Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH/other 
ISH validated assay status and those with positive FISH/CISH /other ISH validated 
assay cannot be chosen either, regardless of the IHC findings.  Subjects with 2+ by 
IHC will not be eligible if no negative FISH/CISH/other ISH validated assay for 
detection of HER2 gene expression is available. 
2. Patients with immediately life-threatening visceral disease, for whom chemotherapy is 
the preferred treatment option. 
3. Lymphangitic carcinomatosis 
4. Patients with ascites requiring paracentesis within 2 weeks prior to study entry 
(signature of informed consent) and during the screening period 
5. Subjects with inflammatory breast cancer 
6. Subjects who have either received chemotherapy for metastatic disease or are 
considered by the treating Investigator to be appropriate candidates for chemotherapy 
as current treatment for metastatic breast cancer are excluded.  Chemotherapy 
administered for adjuvant/neo-adjuvant disease is acceptable. 
7. Subjects with any previous untreated or concurrent cancer that is distinct in primary 
site or histology from the cancer under study except treated basal cell carcinoma, or 
superficial bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th 
edition).  Subjects surviving a cancer that was curatively treated and without evidence 
of disease for more than 3 years before enrollment, are allowed.  All cancer treatments 
must be completed at least 3 years prior to study entry (i.e., signature date of ICF). 
8. Subjects with known or history of brain metastases or leptomeningeal disease: subjects 
with neurological symptoms must undergo a contrast CT scan or MRI of the brain 


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within 28 days prior to randomization to exclude active brain metastasis.  Imaging of 
the central nervous system is otherwise not required. 
9. Imminent or established untreated spinal cord compression based on clinical findings 
and/or MRI.  Following treatment of spinal cord compression, the subject may be 
eligible if all other eligibility criteria are fulfilled. 
10. Prior treatment with radium-223 dichloride 
11. Prior hemibody external radiotherapy.  Subjects who received other types of prior 
external radiotherapy are allowed provided that bone marrow function is assessed and 
meets the protocol requirements for Hb, absolute neutrophil count, and platelets. 
12. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or 
rhenium-188 
13. ECOG PS ≥2 
14. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior 
randomization.   
15. Use of biologic response modifiers, such as granulocyte macrophage 
colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor 
(G-CSF), within 4 weeks prior to randomization 
16. Treatment with an investigational drug or with any anti-cancer treatments not 
permitted by the protocol, within the 4 weeks prior to randomization 
17. Chronic conditions associated with non-malignant abnormal bone growth (e.g., 
confirmed Paget’s disease of bone) 
18. Any other serious illness or medical condition such as, but not limited to: 
o Any uncontrolled infection 
o Cardiac failure New York Heart Association Class III or IV 
o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia 
19. Previous assignment to treatment in this study 
20. Breast-feeding women  
21. Known hypersensitivity to the active substance or to any of the excipients of radium-
223 dichloride, exemestane, and everolimus or to other rapamycin derivatives 
22. Subjects who received prior treatment or are already receiving everolimus treatment 
prior to study entry are not eligible 
23. Known presence of osteonecrosis of the jaw  
All local label specific criteria for exemestane and everolimus as well as standard-of-care 
denosumab and bisphosphonates will apply.  Subjects must be treated according to the local 
standard-of-care requirements. 


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6.3 
Withdrawal of subjects from study 
6.3.1 
Withdrawal 
Until the primary analysis, the study comprised the following 4 periods: 
1. Screening 
2. Randomization 
3. Treatment period  
4. Active follow-up period with or without clinic visits  
Note: Study drug discontinuation (i.e., discontinuation during the treatment period) does not 
constitute withdrawal from the study.  Every effort should be made to retain subjects who 
discontinue the treatment period for any reason. 
Subjects are expected to participate in the follow-up unless they explicitly object.  Withdrawal 
of consent should be documented in the subject’s medical file.  If subjects do not wish to be 
followed up further, they should sign the “Declaration of Objection to Collection of Study 
Data after Withdrawal of Consent” form.  
A “dropout” is defined as a subject who has been randomized and discontinues study 
participation prematurely for any reason. 
A “screening failure” is defined as a subject who has signed informed consent and terminates 
the study for any reason (e.g., failure to satisfy the selection criteria) before randomization.  
Any subject removed from the study will remain under medical supervision until discharge or 
transfer is medically acceptable. 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject’s 
medical records (consent withdrawal [due to AE or for other reason], lost to follow-up, or 
death). 
When a subject is withdrawn from the study, i.e., is not attending follow-up visits, the EOS 
page in the eCRF is to be completed.  
6.3.1.1 
Withdrawal from treatment period (collection of follow-up data) 
The total treatment period is defined from the day of randomization until 4 weeks after the last 
administration of study treatment (radium-223 dichloride/placebo and exemestane and 
everolimus, whichever occurs last). 
Subjects must be withdrawn from the radium-223 dichloride/placebo treatment for the 
following reasons: 
• If, in the Investigator's opinion, continuation of the radium-223 dichloride/placebo 
treatment would be harmful to the subject's well-being. 
• If the subject experiences unacceptable toxicities to radium-223 dichloride/placebo. 
• If a subject experiences National Cancer Institute (NCI)-Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 to 4 anemia, neutropenia, or 
thrombocytopenia lasting >2 weeks despite adequate supportive care treatment. 
• If a subject experiences any non-hematological Grade CTCAE Grade 4 toxicity lasting 
>1 week despite adequate treatment.  


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• Delay in radium-223 dichloride/placebo administration of >4 weeks (maximum of 
8 weeks between 2 injections of radium-223 dichloride/placebo). 
• If the subject starts treatment with a prohibited metastatic breast cancer therapy 
(Section 8.1). 
• If exemestane and everolimus or further standard of care hormonal anti-cancer therapy 
are discontinued, radium-223 dichloride/placebo must also be discontinued. 
• After primary analysis, if the subject can no longer travel to the clinical site, she will 
be discontinued from all study treatments and will be transitioned to the separate 
extended safety follow-up study (16996).  Subjects who miss 2 consecutive treatment 
visits will be considered unable to travel to the site, will be discontinued from all study 
treatments and will be transitioned to the separate extended safety follow-up study 
(16996). 
• At her own request or at the request of her legally acceptable representative. 
• At the specific request of the sponsor and in liaison with the Investigator (e.g., obvious 
non-compliance, safety concerns). 
Subjects must be withdrawn from the exemestane and everolimus treatment for the following 
reasons: 
• If, in the Investigator's opinion, continuation of exemestane and/or everolimus 
treatment would be harmful to the subject's well-being. 
• If the subject experiences disease progression or initiates a new anti-cancer therapy. 
Disease progression being defined as radiological progression (either by RECIST or 
bone progression), or clinical progression.  
• If the subject experiences unacceptable toxicities to exemestane and/or everolimus (as 
per Section 7.4.6 Dose adjustments, delays, and treatment discontinuations). 
• Delay in exemestane and everolimus administration of >4 weeks. 
• If the subject starts treatment with a prohibited metastatic breast cancer therapy 
(Section 8.1). 
• If the subject can no longer travel to the clinical site.  After primary analysis, she will 
be discontinued from all study treatments and will be transitioned to the separate 
extended safety follow-up study (16996).  Subjects who missed 2 consecutive 
treatment visits will be considered unable to travel to the site, will be discontinued 
from all study treatments and will be transitioned to the separate extended safety 
follow-up study (16996) 
• At her own request or at the request of her legally acceptable representative. 
• At the specific request of the sponsor and in liaison with the Investigator (e.g., obvious 
non-compliance, safety concerns). 
Subjects who experience disease progression (bone or non-bone) will discontinue exemestane 
and everolimus. 
Note:  Study treatment discontinuation (i.e., withdrawal from treatment period) does not 
constitute withdrawal from the study.  Following primary analysis, the follow-up will be 
conducted in the separate extended safety follow-up study; therefore, upon discontinuation of 


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oral treatment, subjects will be directly transitioned to the aforementioned study. For 
additional details, please refer to Section 15.6. 
6.3.1.2 
Withdrawal from treatment period and/or all follow-up (no further 
data collection) 
Subjects must be withdrawn from the study treatment and/or procedures and no further data 
will be collected for the following reasons: 
• Subject withdraws consent from study treatment and/or study procedures.  A subject 
must be removed from the study at her own request or at the request of her legally 
acceptable representative.  At any time during the study and without giving reasons, a 
subject may decline to participate further the subject’s rights will be protected. 
• Subject is lost to follow-up 
• Death 
Note:  Withdrawal of consent should be documented in the subject’s medical file.  If the 
subject does not wish to be followed up further, they should sign the “Declaration of 
Objection to Collection of Study Data after Withdrawal of Consent” form.  
6.3.2 
Replacement 
Withdrawn subjects will not be replaced. 
6.4 
Subject identification 
A subject number (a unique identification number) will be assigned via an Interactive 
Voice/Web Response System (IXRS) when a subject signs the ICF and is evaluated for 
inclusion into the study.  When the subject is eligible for the trial, the study site will send an 
order (using the IXRS) to the manufacturer for drug shipment based on the planned visit date 
of the subject.  See Section 7.2. 
7. 
Treatments 
7.1 
Treatments to be administered 
Investigational medicinal product (IMP): Radium-223 dichloride, 50 kBq/kg body weight 
(55 kBq/kg after implementation of NIST update) will be administered IV as a slow bolus 
injection for a maximum of 6 cycles at intervals of 4 weeks. 
Reference therapy: A solution of isotonic saline (0.9% sodium chloride solution for 
injection) will be administered IV as a slow bolus injection 6 times, at intervals of 4 weeks. 
Treatment with exemestane and everolimus: All subjects will receive exemestane and 
everolimus.  Subjects enrolled in the current study, will start treatment with exemestane and 
everolimus, after randomization, either before or simultaneously to the first injection of 
radium-223 dichloride/placebo.  Subjects already receiving exemestane and everolimus prior 
to study entry are not eligible.  The dose of exemestane administered in the study is one 
25-mg tablet once daily after a meal, which is the dose approved in US and Europe in 
advanced breast cancer.  The recommended dose of everolimus administered in the study is 
10 mg once daily with or without food, which is the dose approved in US and Europe in 
advanced breast cancer, in combination with exemestane.  Starting dose, dose modifications, 


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and administration of exemestane and everolimus must be in compliance with the local labels 
in each of the participating countries and/or in line with local standard of practice. 
Study treatment with exemestane and everolimus will continue after completion of 
radium-223 dichloride/placebo or until disease progression, initiation of new anti-cancer 
therapy, unacceptable toxicity occurs, discontinuation of study treatment for other reasons, or 
study is terminated, whichever occurs first. 
Non-investigational medicinal products: 
• Bone-targeted agents, Bisphosphonates or Denosumab:  All subjects will receive 
therapy with bisphosphonates or denosumab at the time of study entry (for at least 
1 month prior to start of radium-223 dichloride/placebo start).  Subjects should be 
maintained on bisphosphonate or denosumab therapy throughout the study, unless, in 
the Investigator’s opinion, these treatments will need to be discontinued.  
Bisphosphonates or denosumab should be administered as per the local label 
instructions and according to local standard of care.  Changes in therapy should be 
done as per the Investigator decision. 
• Other therapies: Supportive care therapies should be administered in line with local 
standard of care.  
Please refer to Section 8.1 on prior and concomitant therapy concerning prohibited and 
allowed concomitant treatments during the radium-223 dichloride/placebo administration. 
7.2 
Identity of study treatment 
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request. 
For all study drugs provided by the sponsor, a system of numbering in accordance with all 
requirements of Good Manufacturing Practices (GMP) will be used, ensuring that each dose 
of study drug can be traced back to the respective bulk ware of the ingredients.  Lists linking 
all numbering levels will be maintained by the sponsor’s clinical supplies quality assurance 
group.  For all sponsor-supplied study drugs, lists linking all numbering levels will be 
maintained by the sponsor. 
A complete record of batch numbers and expiry dates of all sponsor-supplied study treatment 
as well as the labels will be maintained in the sponsor study file. 
7.2.1 
Investigational medicinal product 
7.2.1.1 
Radium-223 dichloride 
The alpha particle emitting radiopharmaceutical radium-223 dichloride is a ready-to-use, 
sterile, non-pyrogenic, clear and colorless aqueous solution of radium-223 dichloride for IV 
administration.  Radium-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 to 8.0.  The radioactive concentration 
at the reference date is 1000 kBq/mL (1100 kBq/ mL after implementation of NIST update).  
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 supplied 
with each shipment. 


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The sponsor will provide radium-223 dichloride which is manufactured by Bayer HealthCare.  
Radium-223 dichloride/placebo will be labeled according to the requirements of local law and 
legislation.  Label text for all sponsor-supplied study drugs will be approved according to the 
sponsor’s agreed procedures.   
The product is produced according to GMP.  The product will be delivered in a glass vial, 
ready-to-use with a certified activity.  Radium-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-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°C to 8°C) up to 40°C.  In addition, it has been shown that 
the product quality is not jeopardized upon freezing.   
For study sites in the US, it is possible to have patient ready dose (PRD) prepared by a 
radiopharmacy.  Dose will be delivered to the sites in pre-filled syringes.  Cardinal Health is 
the radio pharmacy that will dispense the PRD in the US. 
It is important to note that, in general (unless otherwise agreed), in cases where study drug has 
been ordered, the time window for administration should be within 3 days of the planned 
treatment day.  If administration must be postponed more than 3 days, replacement of the drug 
order is required.  
7.2.1.2 
Saline 
Isotonic saline (0.9% sodium chloride solution for injection) will be provided by the study 
site.  Traceability of the respective manufacturers and batches will be maintained in the 
respective preparation documentation and drug accountability logs. 
For saline solution and supportive care treatment which will be provided to the subjects from 
the study site's commercial supply it is required at minimum that the assignment, batch 
numbers, and expiry dates are recorded.  The use of saline is to be recorded and 
documentation retained at the study site with a copy provided for the sponsor study file. 
7.2.1.3 
Study treatment with exemestane and everolimus 
Exemestane and everolimus will be provided with appropriate labeling to each study center by 
the sponsor.  Subjects enrolled in the current study, will start treatment with exemestane and 
everolimus, after randomization, either before or simultaneously to the first injection of 
radium-223 dichloride/placebo.  Subjects already receiving exemestane and everolimus prior 
to study entry are not eligible.  Administration of exemestane and everolimus will be in 
accordance to the local label and/or in line with local standard of practice. 
Everolimus, a rapamycin derivative, is an mTOR inhibitor, indicated for the treatment of 
postmenopausal women with advanced hormone receptor-positive, HER2-breast cancer in 
combination with exemestane.  It is supplied as tablets (2.5 mg, 5 mg, 7.5 mg, and 10 mg) and 
as tablets for oral suspension (2 mg, 3 mg, and 5 mg).  The recommended dose of everolimus 
administered in the study is 10 mg once daily with or without food, which is the dose 
approved in US and Europe in advanced breast cancer, in combination with exemestane.  
Follow special handling and disposal procedures for anti-cancer pharmaceuticals as directed 
in the local label. 


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Exemestane is an irreversible steroidal AI that is indicated for the treatment of advanced 
breast cancer in postmenopausal women whose disease has progressed following tamoxifen 
therapy.  It is supplied as tablets 25-mg tablets.  The dose of exemestane administered in the 
study is one 25-mg tablet once daily after a meal, which is the dose approved in US and 
Europe in advanced breast cancer.  Follow special handling and disposal procedures for anti-
cancer pharmaceuticals as directed in the local label. 
Exemestane and everolimus should be stored according to the label text on medication 
shipped to your site.  Storage requirements may vary by country.  
Starting dose, dose modifications, and administration of exemestane and everolimus must be 
in compliance with the local labels in each of the participating countries and/or in line with 
local standard of practice. 
These treatments will be captured in the eCRFs. 
7.2.2 
Non-investigational medicinal products 
7.2.2.1 
Bone-targeted agents, bisphosphonates and denosumab 
Bisphosphonates (diphosphonates) are a class of drugs that prevent the loss of bone mass, 
used to treat osteoporosis and similar diseases including bone metastases.  Whichever 
bisphosphonate is selected for use as therapy should be stored and administered according to 
the local label. 
Denosumab (Xgeva®), a RANKL inhibitor, is indicated for the prevention of SREs in subjects 
with bone metastases from solid tumors.  It is supplied as a single-use vial as a suspension of 
120 mg/1.7 mL and should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) in the 
original carton.  Xgeva must not be exposed to temperatures above 25°C/77°F or direct light 
and must be used within 14 days, as directed in the label. 
Bisphosphonates or denosumab will be supplied by the study site and administered as part of 
the standard of care for the subject according to the local label. 
7.3 
Treatment assignment 
To accomplish random assignment of radium-223 dichloride/placebo treatment, a 
computer-generated randomization list will be prepared by the sponsor and provided to the 
IXRS.  The IXRS will assign each eligible subject a randomization number and the respective 
treatment in a ratio of 1:1 to radium-223 dichloride/placebo.  In addition, randomization will 
be stratified by geographical regions (Europe/North America [including Israel] versus Asia), 
previous lines of hormone therapy in metastatic setting (1 versus 2 or more), and visceral 
disease yes versus no.  
The IXRS will provide only the randomization number to the caller, i.e., blinded personnel, 
but not the assigned treatment.  A confirmation e-mail containing the randomization number 
will be sent to the unblinded personnel who will have to log into IXRS in order to know the 
treatment arm assigned to the patient.  The unblinded personnel will be responsible for 
preparing the study drug for the subject for the first administration.  For US only, if a subject 
is allocated to radium-223 dichloride, the unblinded person will fax the shipment request to 
Cardinal Health for pre-filled syringe.  The timing for the drug order should be based on the 
planned subject visit date.  If the subject is allocated to placebo, the unblinded person at the 
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This should not be made available before to avoid unblinding the subject and blinded study 
personnel.  
Subsequent orders for each study drug administration will be made by calling the IXRS from 
the study site on the date of the previous injection.  If, after ordering, the order needs to be 
cancelled or amended, the Investigator should contact their monitor immediately. 
7.4 
Dosage and administration  
Written information about radium-223 dichloride and instruction about handling and injection 
of radioactive material will be provided to study personnel. 
In general, the administration of radioactive drugs involves a potential risk for third parties, 
due to radiation from the subject and due to possible contamination by spilling urine or feces.  
When radium-223 dichloride has been injected intravenously into a subject, the risk for 
external radiation exposure to third parties is extremely low, due to the short range of the 
alpha particles (<100 μm) and the low portion of beta and gamma radiation.  For these reasons 
the product can be administered on an out-patient basis.  To minimize the risk of 
contamination, the subject and her caregivers will receive oral and written instructions 
regarding hygiene precautions to abide by after receiving the radioactive drug according to the 
investigational study site radiation protection guidelines.  These instructions will be given to 
all subjects, as neither the Principal Investigator nor subject will know the assignment to 
radium-223 dichloride/placebo injections. 
7.4.1 
Dose calibration 
Radium-223 dichloride can be measured in a normal dose calibrator instrument.  When all the 
required written approvals for the use and handling of radium-223 dichloride from the 
Radiation Protection Agency/Agencies for the specific site have been received by the sponsor, 
a vial of radium-223 dichloride for technical use will be sent to the study site.  
Different clinical study sites possess dose calibrators from various suppliers; thus, the isotope 
calibration factor may differ from site to site.  Consequently, each site must perform the 
radium-223 dial setting on their relevant dose calibrator(s) if no isotope calibration factor for 
radium-223 is being provided by the vendor of the dose calibrator.  For dial setting, the 
clinical study site will receive a sealed vial or a pre-filled syringe containing a radium-223 
solution for calibration only.  The vial or syringe is identical to the vials/syringes used for 
study treatment.  The amount of radium-223 in the vial/syringe 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. 
As of Amendment 3, NIST has established an updated standardization for radium-223 
dichloride, which indicates that an approximately 10% difference existed between activity 
values obtained using the current standard and the updated standardization.  The current NIST 
standard for radium-223 dichloride (NIST 2010 [52]) will remain in effect for this protocol 
until all Health Authorities for which Bayer holds a marketing application for radium-223 
dichloride have approved the regulatory variations for Xofigo®, anticipated Q 2 2016. All sites 
will be notified by Bayer when regulatory approvals are in place and the updated NIST 
standardization is to be implemented.  Upon notification, and prior to the implementation, all 
sites will need to add a new dial-setting to their dose calibrators for the new NIST 
standardization for radium-223 dichloride (NIST update [53]), which should be documented 
on the appropriate study forms.  This step will be performed so that all sites will have the new 
dial setting (NIST update [53]) in place at the time of implementation.  The current dial 


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setting (NIST 2010 [52]) will be used until the worldwide global implementation date 
anticipated for Q 2 2016.  
The change in the NIST radium-223 standard has no impact on subjects; subjects are 
receiving, and will continue to receive, the same actual dose and volume that was studied in 
ALSYMPCA 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.  
Subjects who are on-treatment at the time the new NIST reference standard goes into effect 
will be notified of this change and will be required to sign a Patient Information Sheet to 
acknowledge that they have received information on the updated NIST standard calibration.  
All patients randomized after the new reference standard is in effect will sign a revised ICF 
that contains the updated NIST standardization.  The formula for the calculation of the volume 
to be administered has to be changed respectively. 
7.4.2 
Radium-223 dichloride dose handling 
At least 2 unblinded personnel should be nominated at each study site (Section 7.5).  The 
primary dedicated unblinded person (“the unblinded person”), who has the responsibility 
delegated from the Principal Investigator, will be responsible for the safe handling and storage 
of radium-223 dichloride and placebo control.  The unblinded person also has the 
responsibility of correctly receiving and recording the delivery of radium-223 dichloride in 
accordance with this protocol.  At least one deputy unblinded person should also be 
nominated.  Radium-223 dichloride should be handled by individuals who are qualified by 
training and experience in the safe handling of radionuclides.  
The radium-223 dichloride vials or PRDs must be stored inside their lead container in a secure 
facility.  The study drug should be used within 28 days of production or prior to the expiry 
date specified for PRDs.  
Control measurements of both the radium-223 dichloride vial (before and after dispensing) 
and syringes (before and after administration) are performed as part of the clinical trial 
documentation.  Since PRDs will be prepared at the country depot, relevant procedures are 
recorded by the country depot staff.  All administrations of radium-223 dichloride will be 
based on the certified activity of radium-223 at the reference date.  Please note that all 
documentation that contains unblinded information should be kept by the unblinded person(s) 
and not shared with the other study site personnel during the conduct of the study. 
7.4.3 
Radium-223 dose calculation 
The dosage of radium-223 dichloride is 50 kBq/kg body weight (55 kBq/kg after 
implementation of NIST update).  The total activity to be injected will be calculated 
volumetrically using the subject’s body weight within 5 days of injection (kg), the 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) dosage level, and the decay correction 
factor (DK) to correct for physical decay of radium-223.  A table with DKs according to 
physical decay of the study medication will be provided with each vial of radium-223 
dichloride.  The total amount (volume to be drawn into the syringe) to be administered to a 
subject should be calculated according to the recommended formula below: 


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Body weight (kg) x 50 kBq/kga = volume to be injected (mL) 
 
 
 
DK x 1000 kBq/mLb 
a 55 kBq/kg after implementation of NIST update  
b 1100 kBq/mL after implementation of NIST update  
Site specific volume calculation methods are acceptable as well, provided that the subject 
dose is 50kBq/kg (55 kBq/kg after implementation of NIST update). 
Data regarding activity, calculations, and volume to be injected must be recorded in the IMP 
preparation log and in the study electronic data capture tool (Medidata Rave; [RAVE]) by the 
unblinded person.  This applies to both doses that are prepared at the study site and doses that 
are prepared by an off-site vendor.  
For subjects in Arm B (placebo injection), the volume of saline to be injected will be provided 
by the IXRS based on the subject’s weight.  Data regarding the saline batch number and the 
volume to be injected should be recorded in RAVE. 
7.4.4 
Study drug dose preparation  
To keep the treating physician blinded to the assignment of study medication, the unblinded 
person (e.g., from the hospital pharmacy or nuclear medicine department) will be responsible 
for blinding the syringe, and responsible for calculating the required dosage.  Data regarding 
activity and volume to be injected should be recorded in the IMP preparation log and in the 
appropriate eCRF, both of which will not be available to the treating physician.  Copies of the 
vial label and the syringe serial number are to be attached with each entry in the IMP 
preparation log.  Additional written instructions for study drug administration, for blinded and 
unblinded personnel, will be provided. 
Personnel should use appropriate protective clothing and equipment during syringe filling and 
application to prevent contamination with the radioactive solution (lab coats, medical gloves / 
protective glasses) and to reduce radiation exposure.  Sites should adhere to all relevant 
radiation safety regulations as prescribed by local authorities administering their site radiation 
license, including as low as reasonably achievable principles.  
Filling of the syringe should take place in a safety bench or similar cabinet in the 
Radiopharmacy/Nuclear Medicine department.  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.  In 
some countries/study sites a 3rd party vendor will be used to prepare the injections to be used 
by the study site.  
Radium-223 dichloride should not be diluted or mixed with any solutions.  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 subject. 
To maintain traceability, each subject will be assigned 1 syringe label set, with a unique serial 
number.  The serial number will link the vial/batch received with the preparation and blinded 
administration of the syringe.  
For subjects in the placebo arm, a syringe with isotonic saline will be prepared in the same 
way as for the active treatment, including the use of unique serial numbers on the syringe.  
The study medication will be administered as a slow bolus IV injection.  The actual 
radioactivity administered must be within the tolerance limits of ± 10% of the calculated 
radioactivity.  After administration, the equipment used in connection with the preparation 


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and administration of drug, are to be treated as radioactive waste and should be disposed in 
accordance with hospital procedure for the handling of radioactive material and according to 
local laws.  Written information about radium-223 dichloride and instructions for the handling 
and injection of radioactive material will be provided to study personnel. 
7.4.5 
Dose administration 
In this subject population, disease progression is expected.  Expected symptoms in this 
population are: bone pain, fatigue, nausea, anorexia, depression, constipation (also secondary 
to opioids, hematological complication as well as additional visceral metastases.  
Chemotherapy is not permitted during treatment with radium-223 dichloride/placebo.  If such 
treatment is necessary, then radium-223 dichloride/placebo treatment must be stopped.  If 
possible cytotoxic chemotherapy should not be given before a 4 week washout period after 
last administration of radium-223 dichloride/placebo, provided the subject’s bone marrow is 
not compromised. 
Every effort will be made to administer the full dosing regimen.  Single dose level adjustment 
of radium-223 dichloride/placebo is not permitted.  Treatment delays or discontinuations of 
radium-223 dichloride/placebo may be instituted for the AEs described in Section 7.4.6 and 
dose adjustments, treatment delays, or discontinuations of treatment with exemestane and 
everolimus may be instituted according to the local label and/or local standard of practice. 
7.4.6 
Dose adjustments, delays, and treatment discontinuations 
Radium-223 dichloride/placebo administration may be delayed by no more than 4 weeks 
(maximum 8 weeks between 2 injections) for recovery of AEs.  If administration is delayed 
for >4 weeks (maximum 8 weeks between 2 injections), radium-223 dichloride/placebo 
administration should be discontinued.  
Adverse events will be reported and graded according to NCI-CTCAE version 4.03. 
7.4.6.1 
Radium-223 dichloride dose delays and treatment discontinuations 
guidance 
Myelosuppression 
Changes in hematology parameters may occur after injection of study drug. 
Neutropenia:  In case of NCI-CTCAE Grade 3 to 4 neutropenia, the study drug 
administration should be delayed until recovery to Grade 2 (minimum absolute neutrophil 
count [ANC] 1.0 x 109/L) or better before next study drug administration.  
Thrombocytopenia:  In case of thrombocytopenia NCI-CTCAE Grade 2 to 4, the study drug 
administration should be delayed until recovery to CTCAE Grade 1 (minimum subjects with a 
platelet count 75 x 109/L) or better before next study drug administration.  
Anemia:  In case of anemia NCI-CTCAE Grade 3 to 4, the study drug administration should 
be delayed until recovery to CTCAE Grade 2 (minimum Hb 8.0 g/dL) or better before next 
study drug administration.  
If a subject experiences CTCAE Grade 3 to 4 anemia, neutropenia or thrombocytopenia 
lasting >2 weeks in spite of adequate treatment, the subject must be discontinued from 
treatment with radium-223 dichloride/placebo. 


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Blood transfusion is acceptable between study drug administrations.  Use of biologic response 
modifiers, such as G-CSF or GM-CSF and erythropoietin, is allowed in the management of 
acute toxicity. 
Gastrointestinal events 
Diarrhea: No prophylactic treatment for diarrhea is recommended.  Anti-diarrheals can be 
used when needed.  A further dose of study medication should not be given before diarrhea 
has recovered to CTCAE Grade ≤1.  
Nausea/Vomiting: No prophylactic treatments for nausea or vomiting are recommended, but 
anti-emetic drugs can be used when needed.  A further dose of study medication should not be 
given before nausea/vomiting has recovered to CTCAE Grade ≤1. 
Constipation: Subjects can continue laxative as concomitant medication, but start of 
prophylactic treatments before study drug injection is not recommended.  Laxative can be 
used when needed.  A further dose of study medication should not be given before 
constipation has recovered to CTCAE Grade ≤1. 
Fatigue 
In cases of NCI-CTCAE Grade 3 to 4 fatigue, study drug administration should be delayed 
until recovery to Grade ≤1 before the next study drug administration.  
Osteonecrosis of jaw 
There is no specific radium-223 dose modification guidance for patients who develop 
osteonecrosis of jaw during radium-223 treatment.  The management plan of individual 
patients who develop osteonecrosis of jaw in the course of the study should be set up in close 
collaboration between the treating physician and a dentist or oral surgeon with expertise in 
osteonecrosis of jaw, and in accordance with the local labeling of denosumab and 
bisphosphonates. 
Non-pathological fractures 
For traumatic fracture in weight bearing bones during treatment phase, the study drug 
administration should be delayed 2 to 4 weeks from the time of fracture. 
Other toxicities 
If a subject experiences any non-hematological NCI-CTCAE Grade 4 toxicity lasting >1 week 
despite adequate treatment subject will have to discontinue radium-223 dichloride/placebo 
treatment. 
Exemestane 
The most frequently reported adverse effects for exemestane are gastrointestinal disturbances, 
hot flushes, arthralgia, myalgia, sweating, fatigue, and dizziness.  Other reported effects 
include headache, insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and 
peripheral and leg edema.  Thrombocytopenia and leucopenia have been reported 
occasionally.  Reductions in bone mineral density can occur with long-term use of 
exemestane. 
Based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated 
a moderate increase in non-life-threatening AEs, dosage adjustment does not appear to be 
necessary.  All local label directions must be followed. 


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Dose adjustment for everolimus due to adverse reactions 
In the clinical experience in advanced breast cancer, the most common adverse drug reactions, 
with an incidence ≥10%, reported in association with everolimus plus exemestane therapy 
were: stomatitis, rash, fatigue, decreased appetite, diarrhea, dysgeusia, nausea, pneumonitis, 
weight decreased, epistaxis, and thrombocytopenia.  Stomatitis was reported more than 5-fold 
compared to the placebo arm (64.5% vs. 10.9%).  Hemorrhages were seen twice as often as in 
the placebo group (19.5% vs. 8.9%).  The most common Grade 3 to 4 adverse drug reactions, 
with an incidence ≥2% were: stomatitis, hyperglycemia, pneumonitis, anemia, fatigue, 
elevated ALT, thrombocytopenia, elevated AST, dyspnea, and neutropenia. 
Sites must follow all the local label recommendations in each participating country. 
The following dose modifications for everolimus, based on the US and EU label guidance, are 
provided below as a general recommendation. 
All label specific instructions for treatment with exemestane and everolimus will apply.  
Please refer to the local full prescribing information for further guidance. 
Management of severe and/or intolerable suspected adverse reactions may require dose 
reduction and/or temporary interruption of everolimus therapy.  For adverse reactions of 
Grade 1, dose adjustment is usually not required.  If dose reduction is required, the 
recommended dose is 5 mg daily and must not be lower than 5 mg daily.  
Table 7–1 summarizes dose adjustment recommendations for specific adverse reactions. 
Table 7–1:  Everolimus dose adjustment recommendations 
Adverse reaction 
Severitya 
Everolimus dose adjustment 
Non-infectious pneumonitis 
Grade 2 
Consider interruption of therapy until 
symptoms improve to Grade ≤1. 
Re-initiate everolimus at 5 mg daily.  
Discontinue treatment if failure to 
recover within 4 weeks.  
Grade 3  
Interrupt everolimus until symptoms 
resolve to Grade ≤1.  
Consider re-initiating everolimus at 
5 mg daily.  If toxicity recurs at 
Grade 3, consider discontinuation.  
Grade 4 
Discontinue everolimus.  
Stomatitis 
Grade 2 
Temporary dose interruption until 
recovery to Grade ≤1.  
Re-initiate everolimus at same dose.  
If stomatitis recurs at Grade 2, 
interrupt dose until recovery to 
Grade ≤1.  Re-initiate everolimus at 
5 mg daily. 
Grade 3  
Temporary dose interruption until 
recovery to Grade ≤1.  
Re-initiate everolimus at 5 mg daily.  
Grade 4  
Discontinue everolimus.  


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Table 7–1:  Everolimus dose adjustment recommendations 
Adverse reaction 
Severitya 
Everolimus dose adjustment 
Other non-hematological toxicities 
(excluding metabolic events) 
Grade 2 
If toxicity is tolerable, no dose 
adjustment required. 
If toxicity becomes intolerable, 
temporary dose interruption until 
recovery to Grade ≤1.  Re-initiate 
everolimus at same dose. 
If toxicity recurs at Grade 2, interrupt 
everolimus until recovery to Grade ≤1.  
Re-initiate everolimus at 5 mg daily.  
Grade 3 
Temporary dose interruption until 
recovery to Grade ≤1.  
Consider re-initiating everolimus at 
5 mg daily.  If toxicity recurs at 
Grade 3, consider discontinuation.  
Grade 4  
Discontinue everolimus.  
Metabolic events  
(e.g., hyperglycemia, dyslipidemia)  
Grade 2  
No dose adjustment required.  
Grade 3  
Temporary dose interruption. 
Re-initiate everolimus at 5 mg daily.  
Grade 4  
Discontinue everolimus.  
Thrombocytopenia  
Grade 2 (<75, 
≥50 x 109/L)  
Temporary dose interruption until 
recovery to Grade ≤1 (≥75 x 109/L).  
Re-initiate everolimus at same dose.  
Grade 3 and 4 
(<50 x109/L)  
Temporary dose interruption until 
recovery to Grade ≤1 (≥75 x 109/L).  
Re-initiate everolimus at 5 mg daily.  
For sites based in Europe the 
additional dose modifications per local 
label are required. 
Neutropenia 
Grade 2  
(≥1 x 109/L)  
No dose adjustment required.  
Grade 3  
(<1, ≥0.5 x 109/L)  
Temporary dose interruption until 
recovery to Grade ≤2 (≥1 x109/L).  
Re-initiate everolimus at same dose. 
Grade 4  
(<0.5 x 109/L)  
Temporary dose interruption until 
recovery to Grade ≤2 (≥1 x109/L).  
Re-initiate everolimus at 5 mg daily.  
Febrile neutropenia 
Grade 3  
Temporary dose interruption until 
recovery to Grade ≤2 (≥1.25 x109/L) 
and no fever.  
Re-initiate everolimus at 5 mg daily.  
Grade 4  
Discontinue everolimus.  
a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03 
7.4.7 
Supportive care guidelines 
Ancillary Treatment (guidelines) 
• Persistent neutropenia (Neutrophils/Granulocytes CTCAE Grade 4 [<0.5x109/L]) 
without fever:  These subjects may be started on G-CSF 5 µg/kg/d subcutaneously 
(SC) until the neutrophil count has reached the local hospital’s reference range.  
• Neutropenia with fever (Neutrophils/Granulocytes CTCAE Grade 3 to 4 [<1x109/L]; 
fever >38.5°C):  Blood cultures will be obtained and the subject started on empiric 
antibiotics for as long as clinically indicated.  It is highly recommended that the 


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subject receive G-CSF 5 µg/kg/day subcutaneously until the neutrophil count has 
reached the local hospital’s reference range with 2 separate measurements, at least 
12 hours apart.  
• Severe thrombocytopenia (CTCAE Grade 4 [<25.0x109/L]) or bleeding with CTCAE 
Grade 3 to 4 thrombocytopenia (<50.0x109/L):  multiple platelet transfusions may be 
required to maintain platelet count ≥75 x 109/L if clinically indicated to control 
bleeding.  Epsilon aminocaproic acid may be given to subjects with mucosal bleeding 
and platelet count CTCAE Grade 3 to 4.  
• Severe anemia (Hemoglobin CTCAE Grade 3 [<80x109 g/L; 8.0 g/dL; 4.9 mmol/L]):  
Subjects will be transfused with packed red cells to maintain Hb value >80 g/L; 
8.0 g/dL; 4.9 mmol/L if clinically indicated.  Treatment with erythropoietin is allowed 
between study drug administrations for treatment of anemia.  
• During treatment with denosumab or bisphosphonates, the subjects should be 
administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily. 
Subjects must be treated according to the local standard of practice and local label 
requirements for exemestane and everolimus.  Known and theoretical interactions of 
everolimus with selected inhibitors and inducers of CYP3A4 and P-glycoprotein are listed in 
Appendix 16.6.  Please refer to the local full prescribing information for further guidance.  
7.5 
Blinding  
Every effort will be made to keep the study blinded.  Subjects will be randomized to receive 
radium-223 dichloride/placebo in a double-blind fashion.  All subjects will also receive 
exemestane and everolimus.  This treatment will be provided by the sponsor and will be 
administered in an open-label format. 
Due to the nature of radium-223 dichloride, there must be at least 2 persons in the study site’s 
nuclear medicine department who are unblinded to the treatment arms assigned to subjects.  
One of these unblinded individuals will serve as back-up for the other.  To maintain the study 
blind for the hospital personnel who provide treatment to the subject, the unblinded person at 
the study site will be responsible for filling the syringe with the correct amount of radium-223 
dichloride/placebo (saline) and labeling it.  Both radium-223 dichloride and placebo are clear 
solutions, thus syringes with radium-223 dichloride and placebo cannot be distinguished from 
each other visually.  The person performing the administration of study drug must be blinded 
to the treatment arm.  The subject will not be told whether they have received radium-223 
dichloride/placebo.  All treating physicians, clinical staff, subjects, and sponsor personnel will 
be blinded as to the treatment to which a subject is randomized, except for named 
representatives who will perform the verification of the drug accountability at the study sites 
and drug ordering.  
Treatment with exemestane and everolimus is not blinded. 
Unblinding: 
In compliance with applicable regulations, in the event of a Suspected Unexpected Serious 
Adverse Reaction (SUSAR) (see Section 9.6.1.4), the subject’s treatment code will usually be 
unblinded before reporting to the Health Authorities, ethic committees if the SUSAR was 
related to the blinded treatment.  Investigators may only unblind subjects under emergency 
unblinding rules.  If a subject is unblinded by the Investigator, they must discontinue study 
drug(s). 


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Investigators should note that the occurrence of an SAE or PD should not routinely precipitate 
the immediate unblinding of the label.   
If emergency unblinding is necessary for the treatment of a subject for an SAE, the study 
treatment can be unblinded via the IXRS system (refer to the IXRS manual for instructions).  
The participating site has unrestricted and immediate access to break the treatment code in 
IXRS.  Should the blind code be broken for a subject, the medical monitor or designee should 
be contacted by the Principal Investigator within one working day of unblinding to discuss the 
rationale for the premature unblinding. 
Following the primary analysis, the study will be fully unblinded. 
7.6 
Drug logistics and accountability 
All study drugs will be stored at the investigational study site in accordance with Good 
Clinical Practice (GCP) and GMP requirements and the instructions given by the clinical 
supplies department of the sponsor will be inaccessible to unauthorized personnel.  
In some countries/study sites, it will be required to use a 3rd party vendor to prepare the 
injections to be used by the study site.  A log of study medication (received, administered to 
subjects, and destroyed) must be maintained and signed by the dedicated person responsible 
for drug handling at each site.  Any labels or mandatory logs provided by the sponsor are to be 
utilized according to instructions.  A copy of study drug documentation will be collected for 
the sponsor file. 
The responsible study site personnel will use the study drug only within the framework of this 
clinical trial and in accordance with this protocol.  Instructions for drug handling, logistics, 
and accountability will be reviewed with study staff prior to the initiation of the study.  
Summaries of these instructions are provided below. 
For radium-223 dichloride:  
Radium-223 dichloride will be shipped to study site upon IXRS shipment request.  Lead times 
differ per country but the shipment will arrive at the study site one day before the planned 
treatment at the latest.  The responsible unblinded study site personnel will confirm receipt of 
sponsor-supplied study drug via IXRS system. 
The unblinded person at the study site is responsible for drug accountability.  A dedicated 
unblinded person representing the sponsor will monitor the drug accountability logs.  Receipt, 
distribution, and destruction of the study drug must be properly documented according to the 
sponsor’s agreed and specified procedures.  An unblinded monitor will review overall drug 
accountability and destruction per the study site documentation only.  The remains of 
radioactivity and contaminated material (i.e., vials, syringes, containers) should be disposed of 
in accordance with the local regulations and the hospital procedure, respectively.  A log of 
radium-223 dichloride (received, administered to subjects, and destroyed) must be maintained 
and signed and the appropriate eCRF pages completed by the unblinded person responsible 
for drug handling at each site. 
For locally provided isotonic saline (placebo): 
Isotonic saline (placebo) will be provided by the study site pharmacy.  Drug accountability for 
saline will also be performed.  At a minimum, storage conditions, dispensing, batch numbers, 
and expiry dates will be retained in the study site files.  A log of isotonic saline (administered 
to subjects, and destroyed) must be maintained and signed and the appropriate eCRF pages 


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completed by the unblinded person responsible for drug handling at each site.  The used vials 
must be stored until the drug accountability has been completed by the unblinded monitor. 
For study treatment with exemestane and everolimus 
Exemestane and everolimus will be shipped to the study center upon IXRS shipment request.  
The responsible site personnel will confirm receipt of sponsor-supplied study drug in writing 
and/or via IXRS.  A log of this study medication (assigned, dispensed, administered to 
subjects, returned to site by subject, and destroyed) must be maintained and signed by the 
dedicated person responsible for drug handling at each center in addition to the completion of 
the appropriate pages of the eCRF.  All study drug packages assigned (opened, unopened, or 
empty) must be stored until the drug accountability has been completed by the monitor. 
7.7 
Treatment compliance 
Subjects will receive treatment with radium-223 dichloride under supervision of a physician 
licensed in the administration of radioisotopes.  Unblinded study personnel will check the 
administration volume and total radioactivity injected.  The dose activity and the volume 
injected will be recorded in a study drug log and the eCRF pages, neither of which will be 
available to the treating physician or site personnel.  Only the unblinded monitor will review 
overall drug accountability and destruction per the site documentation. 
8. 
Non-study therapy 
8.1 
Prior and concomitant therapy 
At baseline screening, all prior cancer-related treatments are to be recorded. 
All concomitant medications taken by the subject from signing of the ICF to 4 weeks after last 
study drug administration must be recorded in the eCRF.  Thereafter, until the end of the 
active follow-up period, only medications given to treat any grade AEs related to the study 
drug, analgesic medication and any subsequent anti-cancer treatment medication need to be 
recorded in the eCRF. 
The generic name and trade name of each prior or concomitant medication, its indication, 
dosage and, when applicable, the start and stop dates will be recorded.  
The sponsor’s representative will encode all therapy and medication according to 
well-recognized dictionaries of medical codes. 
It is not required to report the administration of contrast media or radioactive tracer in 
conjunction with the protocol-specified radiological procedure (CT or bone scan) on the 
concomitant medications eCRF page unless there is an AE related to the administration of the 
contrast agent (e.g., an allergic reaction related to the administration of a contrast agent) or the 
tracer. 
8.1.1 
Prohibited concomitant therapy 
Other cancer treatment with established efficacy in breast cancer except hormonal treatments 
should not be used during the treatment period.  If such treatments are considered to be the 
best standard of care during the treatment period, further radium-223 dichloride/placebo 
administrations must be discontinued and the subject should enter the active follow-up period. 
All supportive care for the subject may be provided at the discretion of the Investigator. 


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Note that all treatments for breast cancer, including other investigational drugs taken after 
withdrawal from treatment with radium-223 dichloride/placebo, will be recorded in the eCRFs 
until the end of the active follow-up period. 
Concomitant therapy during the treatment phase of the study with any of the following listed 
is prohibited: 
• Chemotherapy 
• Radiopharmaceuticals such as strontium-89, samarium-153, rhenium-186, or 
rhenium-188 
• Hemibody external radiotherapy  
• Other investigational drugs 
• All medications that are prohibited as per the local label instructions for exemestane 
and everolimus and the supportive treatment.   
• It is the site responsibility to ensure that the study treatment with exemestane and 
everolimus is administered in line with standard practice and local label instructions.  
Same applies for bisphosphonates and denosumab. 
8.1.2 
Permitted concomitant therapy 
The following therapies are considered permissible during the study treatment: 
• Standard-of-care anti-cancer hormonal treatment: if exemestane and everolimus is no 
longer considered a treatment option and the subject must start another standard-of-
care hormonal treatment, the subject can continue radium-223 dichloride/placebo until 
completion. 
• Conventional multivitamins, selenium, and soy supplements 
• All subjects are expected to have been on therapy with either denosumab or 
bisphosphonates for at least 1 month before the start of study treatment and to continue 
on this therapy during the course of the study, with no change to therapy expected 
during the study, except for toxicity reasons. 
• During treatment with denosumab or bisphosphonates, the subjects should be 
administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.  
• In premenopausal women with ovarian suppression, treatment with LH-RH agonists or 
antagonists must start at least 4 weeks prior to enrollment (signature of informed 
consent) and continue during the treatment period.  Non-hormonal methods of 
contraception should be employed during therapy until menses resume. 
• Subjects of reproductive potential who are sexually active must agree to utilize, during 
the treatment period and for 6 months after last dose of radium-223 dichloride/placebo, 
2 reliable and acceptable methods of contraception used simultaneously: a barrier 
method such as a) condoms (male or female) with spermicidal agent or b) diaphragm 
or cervical cap with spermicide, combined with a highly effective non-hormonal birth 
control method such as intra-uterine device (IUD). 
• Blood transfusions and treatment with erythropoietin stimulating agents are allowed 
after randomization (if required to ensure that the treatment range for Hb is met at 


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Day 1 of each cycle) but not within 4 weeks prior randomization.  Platelet transfusions 
are allowed after randomization but not within 4 weeks of randomization. 
• Use of biologic response modifiers, such as G-CSF or GM-CSF, is allowed in the 
management of acute toxicity such as febrile neutropenia when clinically indicated or 
at the discretion of the Investigator.  These drugs are not allowed within 4 weeks prior 
to randomization. 
• Analgesic use will be captured via a subject diary and the eCRF (analgesic 
consumption diary and recorded analgesics, respectively, see schedule of assessments, 
Table 9–1).  Subjects will be asked to track their analgesic use in an analgesic 
consumption diary for 24 hours prior to their clinic visit.  Any medication taken for 
pain, whether for palliation of bone pain or relief of other type of pain, and any 
changes should be recorded in the eCRF at each visit.  Note that EBRT treatment 
should be recorded in the eCRFs until end of the active follow-up period without clinic 
visits. 
• Treatment with exemestane and everolimus:  subjects enrolled in the current study, 
will start treatment with exemestane and everolimus, after randomization, either before 
or simultaneously to the first injection of radium-223 dichloride/placebo. Subjects who 
received prior treatment or are already receiving everolimus prior to study entry are 
not eligible.  Administration of exemestane and everolimus will be in accordance to 
the local standard of practice and local label. 
8.2 
Post-study treatment therapy 
Treatment with radium-223 dichloride/placebo will be halted following completion of the full 
assigned treatment or at early termination.  Treatment with exemestane and everolimus will be 
terminated for disease progression or unacceptable toxicity or other reasons (Section 6.3.1.1).  
Following discontinuation of all study treatments (radium-223 dichloride/placebo treatment, 
exemestane and everolimus), subjects will be treated and followed as per the institutional 
standard-of-care and/or according to the physician’s clinical judgment.   
If possible cytotoxic chemotherapy, other systemic radioisotope, hemibody external 
radiotherapy or other investigational drug should not be given before a 4-week washout period 
after last administration of radium-223 dichloride/placebo, provided the subject’s bone 
marrow is not compromised. 
Details of post-study anti-cancer treatment will be recorded on the appropriate eCRF page. 
9. 
Procedures and variables 
9.1 
Tabular schedule of evaluations 
All laboratory analyses will be conducted by local laboratories. 
Efficacy and safety measurements obtained during the course of the study are summarized in 
the schedule of assessments (Table 9–1).  
 


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Table 9–1:  Schedule of assessments 
Study Period 
Screeninga 
Randomizati
on 
Treatmentb,c 
 
Radium-223 dichloride or Placebo 
+ 
treatment of exemestane and everolimus 
Ongoing treatment of 
exemestane and everolimus 
EOT visit 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 onwards 
(after primary 
analysis) 
 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 1 
C1, Day 
15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk post-last 
Ra-223/ 
placebo dose 
After primary 
analysis q8 wk, 
regardless of 
SSE status 
4 wk post-
last dosee 
Window (days): 
 
 
 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
± 7 
Informed consenth 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior SRE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BPI-SFi 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Resource utilization questionnaire 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
AEs, SAEs, new 1° malignanciesj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and con medsm 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cancer-related txn 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Analgesic consumption diary i, o 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Record 24 h analgesic useo 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Record opiate use 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Vital signsp 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (according to local 
standard practice) 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Weight (kg) 
X 
 
Xq 
X 
Xq 
X 
Xq 
X 
Xq 
Xq 
Xq 
Xq 
Xq 
X 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 9–1:  Schedule of assessments 
Study Period 
Screeninga 
Randomizati
on 
Treatmentb,c 
 
Radium-223 dichloride or Placebo 
+ 
treatment of exemestane and everolimus 
Ongoing treatment of 
exemestane and everolimus 
EOT visit 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 onwards 
(after primary 
analysis) 
 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 1 
C1, Day 
15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk post-last 
Ra-223/ 
placebo dose 
After primary 
analysis q8 wk, 
regardless of 
SSE status 
4 wk post-
last dosee 
Window (days): 
 
 
 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
± 7 
Physical examinationr 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Hematologys 
Xt 
 
Xu 
X 
Xu 
X 
Xu 
 
Xu 
Xu 
Xu 
Xu 
Xu 
X 
Pregnancy test and estradiol assayv 
Xt 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Clinical chemistryw 
Xt 
 
Xx 
X 
Xx 
X 
Xx 
 
Xx 
Xx 
Xx 
Xx 
Xx 
X 
Coagulation panely 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Serum, plasma, and urine 
biomarkersz 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Whole Blood for CTCsii 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
Technetium-99m bone scanaa,bb 
X 
X 
Chest, abdominal and pelvic CT 
scanaa,dd,ee 
X 
X  
SSEs  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Drug orderff  
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Radium-223 Cl2 or placebo 
injectiongg  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
Dispense exemestane + everolimus 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Drug accountability 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 


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Abbreviations:  AE = adverse event; BPI-SF = brief pain index-short form; Cl2 = dichloride; CT = computed tomography; con med = concomitant medication; Cx, Dx = Cycle x, Day x; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOT = end of treatment; FDG = F-18 fluorodeoxyglucose; ID = identification number; 
IXRS = interactive voice/web response system; q = every; PET = positron emission tomography; SAE = serious adverse event; SSE = symptomatic skeletal event; tx = treatment; WBC = white 
blood cell. 
a. All screening evaluations must be complete and reviewed prior to randomization.  Screening evaluations must be complete within 3 weeks prior to randomization.  If all screening data are 
available and the subject is eligible for the study, randomization may occur at the end of the screening visit. 
b. All assessments at treatment visits should be performed before study drug administration. 
c. Subjects will continue in the treatment period until disease progression or initiation of a new anti-cancer therapy, unacceptable toxicity occurs or subject discontinues study treatment for other 
reasons. 
d. Any unscheduled visits are to be conducted in the same manner as visits described for Visit 12 onwards. 
e. EOT follow-up visit will be conducted 4 weeks (±7 days) after last dose of study treatment (radium-223 dichloride/placebo and exemestane and everolimus) or after discontinuation from study 
treatment. 
f. 
Footnote deleted in Amendment 10. 
g. Footnote deleted in Amendment 10 
h. Informed consent is to be collected before the initiation of any study related procedures. 
i. 
Analgesic consumption diary and BPI-SF will be dispensed to the subject just the visit before Cycle 1, Day 1, Cycle 2, Day 1, Cycle 3, Day 1, Cycle 4, Day 1, Cycle 5, Day 1, Cycle 6, Day 1, 
Visit 11, and Visit 12.  Additionally, PRO Questionnaire Information Sheet is to be completed by clinical staff based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire. After primary analysis, pain and QoL assessments will no longer be conducted. 
j. 
Adverse events will be collected through 30 days post the last administration of study medications.  Investigator should check for occurrences of leukemia, myelodysplastic syndrome, aplastic 
anemia, any new malignancy. 
k. Footnote deleted in Amendment 10. 
l. 
Footnote deleted in Amendment 10. 
m. At baseline screening, all prior concomitant medications, including analgesics, are to be recorded.  Thereafter, collect all concomitant medications up to 4 weeks post-last study drug 
administration.  Analgesic use has to be recorded via the analgesic concomitant medication case report form.  
n. Record any cancer-related treatments. 
o. At screening, an analgesic consumption diary will be dispensed to the subject.  Subjects will be asked to record analgesic use 24 hours prior to their clinic visit.  Pain medication will also be 
assessed at each visit by study site.  Analgesic use will be recorded in the appropriate eCRF page. 
p. The measurement of vital signs will include:  blood pressure, heart rate, respiratory rate, and temperature. 
q. Subject’s weight should be re-checked prior to each injection to calculate appropriate drug dosing.  At all sites, weight is to be taken only once for each dose and it should be measured within 5 
days prior to dosing.  For US sites using the central patient ready dose (PRD) depot only, the subject weight for the dose day must be reported in a timely manner to the country PRD depot to 
allow adequate time for the PRD preparation and delivery (approximately 2 days).  All efforts should be made to measure weight at the same visit with the pre-dose laboratory assessments to 
avoid 2 pre-dose clinic visits.  
r. A full physical examination must include the evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, dermatological, musculoskeletal, and neurological 
systems. 
s. Hematocrit, hemoglobin, platelet counts, red blood cells counts, white blood cell counts, white blood cell differential.  Subjects with abnormal platelet count or WBC at EOT should be followed 
until resolution. 
t. 
The screening clinical chemistry and hematology values are recommended to be measured within 1 week prior to randomization and the first injection should be done as soon as possible after 
randomization.  
u. Blood sample for hematology must be taken, analyzed, and evaluated within the 5 days prior to each study drug administration.  
v. Premenopausal women must have a negative serum pregnancy test performed within 7 days prior to randomization, prior to each study drug administration (taken and evaluated within 5 days 
prior to administration) and EOT.  Post-menopausal women (as defined in Section 6.1) are not required to undergo a pregnancy test.  A plasma/serum estradiol assay is required within 7 days 
prior to randomization in premenopausal women with radiotherapy ovarian ablation or medical ovarian suppression and postmenopausal women age <55 years and one year or more of 
amenorrhea and no ovarian suppression. 
w. Sodium, potassium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, blood urea nitrogen (BUN) bilirubin (total), total cholesterol, triglycerides, 
and glucose.   
x. Blood sample for clinical chemistry must be taken and evaluated within 5 days prior to each study drug administration.   


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y. Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in the study if no underlying abnormality in 
coagulation parameters exists per prior history; weekly evaluation of PT-INR/PTT will be required until stability is achieved for anticoagulants that require their monitoring as per local label. 
Blood sample for coagulation tests must be taken and evaluated within 5 days prior to each study drug administration. 
z. Blood and/or urine sample for exploratory evaluation of biomarkers, prior to radium-223 dichloride/placebo administration.  Serum and plasma samples will be collected within 5 days of dosing 
at Cycle 1, Day 1, Cycle 4, Day 1, and Visit 11.  Urine samples will be collected at Cycle 1, Day 1, Cycle 4, Day 1, and Visit 11. After primary analysis, biomarker samples will not be collected. 
aa. After primary analysis, imaging scans will continue until until disease progression or treatment discontinuation according to local standard practice. Scans will be read locally.  Please also refer 
to Section 9.2.6 and Appendix 16.2.  
bb. FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m bone scintigraphy if it is the standard-of-care at the institution, provided the same bone imaging modality 
is used throughout the study. 
cc. Footnote removed in Amendment 10. 
dd. Chest/abdominal/pelvic magnetic resonance imaging will be accepted instead of chest/abdominal/pelvic computed tomography.  FDG PET scan, if performed as part of standard-of-care 
imaging, can be used as an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
ee. To maintain a consistent evaluation of each subject, the same imaging technique and procedure must be used through the assessment periods.  Any unexpected abnormality must be reported 
by the site personnel to the treating physician or the subject’s general practitioner. 
ff. IXRS drug (re-)supply order should be coordinated at each study visit to coincide with delivery prior to the subject’s next scheduled study visit. 
gg. The minimum time window between 2 injections of radium-223 dichloride/placebo must be 4 weeks. 
hh. Footnote removed in Amendment 10. 
ii. Details of sampling are described in the Laboratory Manual. Blood samples for analysis of circulating tumor cells will be collected within 5 days of Day 1 of Cycles 1 through 6 prior to study 
drug dosing. After primary analysis, the collection within 5 days of the EOT visit or disease progression will no longer be conducted. 
 


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9.2 
Visit description 
9.2.1 
Screening period (Visit 0 to 1) 
The screening period lasts from date of signature of informed consent until the date of subject 
randomization in IXRS.  The screening period duration is 3 weeks. 
Pre-treatment evaluations will only be performed after the subject has agreed to participate 
and has signed and dated the ICF.  No treatment or trial-related procedures will be initiated 
before the signed consent has been obtained.   
Standard-of-care imaging such as CT/MRI etc. performed within 3 weeks prior to 
randomization as well as routine bone scans performed within 3 weeks prior to planned dates 
of randomization will be accepted as baseline imaging if they meet protocol requirements 
(anatomic coverage, image acquisition as per RECIST 1.1 guidelines for CT/MRI scans).  
Pre-treatment evaluations will be performed according to the eligibility criteria.  If the subject 
is eligible for the study, the parameters at the screening visit showing subject health status 
including blood values will be recorded in the eCRF. 
The following procedure and evaluations will be performed within 3 weeks prior to planned 
randomization unless otherwise specified: 
• Sign informed consent 
• Subject registration and subject number assignment via IXRS 
• Review of inclusion and exclusion criteria and confirm eligibility 
• Demographics 
• Record medical history  
• Record disease history: HER2 status can be determined by evaluating for HER2 over-
expression using IHC and/or HER2 gene amplification using in situ hybridization, eg, 
FISH or CISH.  For subjects with equivocal HER2 IHC (IHC 2+), it is recommended 
that HER2 status be confirmed using a validated assay for HER2 gene amplification. 
• Record prior SRE 
• Record AEs 
• Record concomitant medications/therapy, including analgesics 
• Record breast cancer-related treatment (prior and current) 
• Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  
• 12-lead electrocardiograms (ECG).  Electrocardiograms should not be obtained when 
serum potassium is <3.5 mmol/L.  Hypokalemia should be corrected prior to ECG 
collection. 
• Record height (cm) and weight (kg) 
• Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems. 
• ECOG PS 


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• Radiological tumor assessment: 
o A chest/abdominal/pelvic CT or MRI.  This is not needed if standard-of-care 
chest/abdominal/pelvic CT or MRI images taken within 3 weeks prior to 
randomization are available. 
o A bone technetium-99m scan with careful identification of all disease-related 
hotspots.  This is not needed if standard-of-care bone scan performed within 
3 weeks prior to planned randomization date is available and in line with protocol 
requirements.  Confirmatory scan using single photon emission tomography 
(SPECT)-CT/MRI or CT/MRI (with and without contrast media) should be 
obtained if not performed within 3 weeks prior to randomization.  The field of 
acquisition should include all areas where bone lesions are present. 
o CT/MRI done as part of the standard of practice within 3 weeks of randomization 
and standard-of-care bone scans done within 3 weeks of randomization are 
acceptable. 
o FDG PET scan, if performed as part of standard-of-care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the 
CT component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See 
also Appendix 16.2). 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-
99m bone scintigraphy if it is the standard-of-care at the institution, provided the 
same bone imaging modality is used throughout the study. 
The following procedures and evaluations should be performed within 1 week prior to 
randomization.  Results must be available, reviewed, and signed and dated by the Investigator 
prior to randomization.  
• Blood draw for clinical chemistry: sodium (Na), potassium (K), chloride (Cl), 
calcium (Ca), ALT, AST, lactate dehydrogenase (LDH), bone ALP (if testing is 
available and can be performed locally), serum creatinine, blood urea nitrogen (BUN), 
total bilirubin, total cholesterol, triglycerides, glucose, phosphate, and albumin. 
• Blood draw for hematology: hematocrit, Hb, platelet counts, red blood cells (RBC) 
counts, white blood cell (WBC) counts, WBC differential.   
• A coagulation panel: prothrombin time (PT), PTT, INR.  Subjects treated with 
warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban, or aspirin (e.g. 
≤100 mg daily) will be allowed to participate in the study if no underlying abnormality 
in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will 
be required until stability is achieved for anticoagulants that require their monitoring 
as per local label. 
• Pregnancy test: premenopausal women must have a negative serum pregnancy test 
performed within 7 days prior to randomization.  Postmenopausal women (as defined 
in Section 6.1) are not required to undergo a pregnancy test. 
• Estradiol assay: a plasma/serum estradiol assay is required within 7 days prior to 
randomization in premenopausal women with radiotherapy ovarian ablation or medical 
ovarian suppression and postmenopausal women age <55 years and one year or more 
of amenorrhea and no ovarian suppression. 


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One week prior to randomization, the subject should be given a subject diary to be used for 
subject questionnaires and the analgesic consumption and should receive training in its use. 
Important Note: If rescreening is indicated, it must be completed with approval from the 
medical monitor of the sponsor.  No more than one rescreening attempt will be allowed for 
each subject.  Please refer to Section 6.1 for further guidance on cases in which rescreening is 
allowed and the time window for rescreening. 
9.2.2 
Randomization 
Randomization in the IXRS may occur only after the completion of the screening evaluations 
and confirmation of subject eligibility.  Randomization may coincide with the end of a 
screening visit if all evaluations are complete; otherwise, randomization may be performed in 
a separate clinic visit.  
• IXRS must be called for drug re-supply in preparation for the next study visit.  This 
should be done on the day of randomization (where possible) to provide the maximum 
time in advance of the next scheduled subject visit date and in accordance with 
country-specific order lead-times. 
9.2.3 
Treatment period 
The treatment period is defined from the day of randomization until 4 weeks (±7 days) after 
the last administration of study treatment (radium-223 dichloride/placebo and exemestane and 
everolimus whichever occurs last). 
The time between randomization and first injection of radium-223 dichloride/placebo should 
be as brief as possible in accordance with the country-specific drug order lead time.  
During the treatment period, the subject will visit the study site at regular intervals.  
Radium-223 dichloride/placebo will be injected at 4-week intervals for 6 cycles on an out-
patient basis (Section 9.1).  The minimum time window between 2 injections of radium-223 
dichloride/placebo must be 4 weeks. 
All subjects will receive treatment with exemestane and everolimus for breast cancer.  
Subjects enrolled in the current study, will start treatment with exemestane and everolimus, 
after randomization, either before or simultaneously to the first injection of radium-223 
dichloride/placebo.  Subjects who received prior treatment or are already receiving everolimus 
prior to study entry are not eligible.  Administration of exemestane and everolimus will be in 
accordance to the local standard of practice and local label. Starting dose, dose modifications, 
and administration of exemestane and everolimus must be in compliance with the local labels 
in each of the participating countries and/or in line with local standard of practice. 
Treatment with exemestane and everolimus will continue after completion of radium-223 
dichloride/placebo until disease progression, initiation of new anti-cancer therapy, 
unacceptable toxicity occurs, discontinuation of study treatment for other reasons, or study is 
terminated, whichever occurs first.  
All ongoing subjects at the time of study termination will finish all study treatments as part of 
the study. 
It is the responsibility of the unblinded person to calculate the required volume of study drug 
(i.e., dose of radium-223 dichloride/placebo) for the subject based on the subject’s body 
weight within 5 days of administration and the reference date of the received study medication 
(Section 7.4.3).  


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For US sites using the central PRD depot ONLY, the subject weight for the dose day must be 
reported to the country PRD depot in a timely manner to allow adequate time for the PRD 
preparation and delivery.  The subject’s weight measurement, order confirmation call to the 
IXRS, and prescription for the central PRD depot are to be performed 5 days prior to 
injection.  All efforts should be made to measure weight at the same visit with the pre-dose 
laboratory assessments to avoid 2 pre-dose clinic visits. 
Before administration of radium-223 dichloride/placebo, the subject must be well hydrated; 
thus, the subject should be instructed to drink ad libitum. 
Hematology parameters requirements prior to study drug administration 
The blood samples for clinical chemistry and hematology should be taken within 5 days before 
each study drug administration, and the hematology parameters must be evaluated before each 
study drug administration. 
First radium-223 dichloride/placebo administration 
Before the first administration of radium-223 dichloride/placebo (within 3 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L and Hb ≥ 8g/dL. 
Blood transfusions and treatment with erythropoietin stimulating agents are allowed after 
randomization but not within 4weeks prior randomization.  Platelet transfusions are allowed after 
randomization but not within 4 weeks prior to randomization.  
Subsequent radium-223 dichloride/placebo between study drug administrations 
The following hematological parameters value should be met prior to each subsequent 
radium-223 dichloride/placebo administration: Hb level ≥8.0 g/dL, ANC ≥1.0 x 109/L, and the 
platelet count ≥75 x 109/L. 
If Hb levels are below 8 g/dL, the Hb needs to recover to 8.0 g/dL or higher before next study 
drug administration.   
If ANC is lower than 1.0 x 109/L or platelet count is lower than 75 x 109/L, radium-223 
dichloride/placebo injection should be delayed until recovery to ANC ≥1.0 x 109/L and platelet 
count ≥75 x 109/L.   
If there is more than a 4-week delay in the next injection (i.e., more than 8 weeks between 
injections), the study drug should be permanently discontinued and the subject should enter the 
active follow-up period without clinic visits.  Treatment of low Hb is acceptable between study 
drug administrations.  
Treatment with exemestane and everolimus  
Dose modifications for the treatment with exemestane and everolimus are summarized in 
Section 7.4.6.  Please refer to the local full prescribing information for further guidance. 
9.2.3.1 
Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
Assessments to be performed PRIOR to radium-223 dichloride/placebo (“study drug”) 
administration: 
• BPI-SF questionnaire will be completed the day of the visit, prior to any other study 
assessments/procedures and should be checked for completion at the visit. 
Additionally, PRO Questionnaire Information Sheet is to be completed by clinical 
staff based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire. 


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• Resource utilization questionnaire to be completed by site 
• Record AEs, SAEs, and all occurrences of leukemia, MDS, aplastic anemia, or any 
other new primary malignancy.  
Note: Specifically for this study, relevant symptoms related to SSEs should be reported 
as AEs independent of the timing of occurrence (prior to 30 days after last dose of 
study treatment or after this interval) or relationship with study drug 
• Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication case report form  
o Analgesic consumption diary (completion to be checked by site) to be filled in by 
the subjects for 24 hours prior to the visit.  The analgesic use for 24 hours prior to 
the visit will be recorded by the Investigator on the eCRF. 
• Record opiate use 
• Record concomitant medications/therapy 
• Record breast cancer-related treatment  
• Record vital signs: blood pressure, heart rate, respiratory rate, and temperature 
• 12-lead ECG (Visit 6 [Cycle 3, Day 1] and Visit 9 [Cycle 5, Day 1]).  
Electrocardiograms should not be obtained when serum potassium is <3.5 mmol/L.  
Hypokalemia should be corrected prior to ECG collection. 
• Record weight (kg), within 5 days prior to dosing 
• Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems (all 
abnormal findings must be reported in the AE eCRF pages). 
• ECOG PS 
• Blood draw for hematology evaluation (within 5 days before radium-223 
dichloride/placebo administration): hematocrit, Hb, platelet counts, RBC, WBC, WBC 
differential.  Results to be assessed and documented prior to study drug treatment.  
The Hb values need to be confirmed to be at least 8 g/dl prior to each dose.  If blood is 
drawn the day of the administration of radium-223 dichloride/placebo, results must be 
available prior to study drug administration. 
• Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP (if 
testing is available and can be performed locally), creatinine, BUN, bilirubin (total), 
total cholesterol, triglycerides, glucose, phosphate, and albumin (blood sample for 
clinical chemistry must be taken and evaluated within 5 days prior to each study drug 
administration).  
• A coagulation panel (blood sample to be taken and evaluated within 5 days prior to 
each study drug administration): PT, PTT, and INR. 
• Pregnancy test: premenopausal women must have a negative serum pregnancy test 
performed and evaluated within 5 days before radium-223 dichloride/placebo 
administration.  Postmenopausal women (as defined in Section 6.1) are not required to 
undergo a pregnancy test. 


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• Blood draw and urine sample for exploratory biomarker analysis: Serum, plasma, and 
urine samples will be collected within 5 days of Visit 2 (Cycle 1, Day 1) and within 
5 days of Visit 8 (Cycle 4, Day 1) prior to study drug dosing. 
• Blood draw for analysis of circulating tumor cells (CTCs) collected within 5 days of 
Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6), prior to study drug dosing. 
• Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2) 
• Record SSEs.  The Investigator will assess the subject for the following disease 
events: 
o Use of EBRT to relieve skeletal symptoms 
o New symptomatic pathological bone fractures (vertebral and non-vertebral) 
o Tumor related orthopedic surgical intervention 
o Spinal cord compression 
Note:  Symptomatic skeletal events should be recorded until end of active follow-
up, independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
• Administer radium-223 dichloride/placebo.   
• Dispense exemestane and everolimus 
• Perform drug accountability  
Assessments to be performed AFTER each injection of radium-223 dichloride/placebo: 
• IXRS must be called for drug re-supply in preparation for the next study visit.  This 
should be done on the day of the current treatment visit (where possible) to provide the 
maximum time in advance of the next scheduled subject visit date and in accordance 
with country-specific order lead-times. 
• For US sites using the central PRD depot ONLY, the subject weight for the dose day 
must be reported to the country PRD depot in a timely manner to allow adequate time 
for the PRD preparation and delivery.  The subject’s weight measurement, order 
confirmation call to the IXRS, and prescription for the central PRD depot are to be 
performed 5 days prior to injection.  All efforts should be made to measure weight at 
the same visit with the pre-dose laboratory assessments to avoid 2 pre-dose clinic 
visits.  
9.2.3.2 
Visits 3, 5 and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit)  
Radium-223 dichloride/placebo will not be administered at these visits. 
• Record AEs, SAEs, and all occurrences of leukemia, MDS, aplastic anemia, or any 
other new primary malignancy 
Note: Specifically for this study, relevant symptoms related to SSEs should be reported 
as AEs independent of the timing of occurrence (prior to 30 days after last dose of 
study treatment or after this interval) or relationship with study drug. 
• Record concomitant medications/therapy, including analgesics 
• Record breast cancer-related treatment  
• Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  


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• Record weight  
• Blood draw for hematology evaluation: hematocrit, Hb, platelet counts, RBC, WBC, 
WBC differential.  (Performed only at Visit 3 [Cycle 1, Day 15] and Visit 5 [Cycle 2, 
Day 15]) 
• Blood draw for clinical chemistry is only required at Visit 3 (Cycle 1, Day 15) and 
Visit 5 (Cycle 2, Day 15): Na, K, Cl, Ca, ALT, AST, LDH, bone ALP (if testing is 
available and can be performed locally), creatinine, BUN, bilirubin (total), total 
cholesterol, triglycerides, glucose, phosphate, and albumin 
9.2.3.3 
Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards, and unscheduled visits)  
Treatment with exemestane and everolimus will continue until disease progression, initiation 
of a new anti-cancer therapy, unacceptable toxicity occurs or subject discontinues study 
treatment for other reasons, or study is terminated, whichever occurs first.  After the primary 
analysis, if the subject can no longer travel to the clinical site, she will be discontinued from 
all study treatments and will be transitioned to the separate extended safety follow-up study 
(16996).  Subjects who miss 2 consecutive treatment visits will be considered unable to travel 
to the site, will be discontinued from all study treatments and will be transitioned to the 
separate extended safety follow-up study (16996).  All ongoing subjects at the time of study 
termination will finish all study treatments as part of the study. 
During this period, clinic visits are to occur as follows: 
• In all subjects Visit 11 will be performed after 4 weeks (±7 days) after last radium-223 
dichloride/placebo dose 
• After primary analysis, regardless of the occurrence of SSE, the visits from Visit 12 
onwards will occur every 8 weeks ±7 days. 
After primary analysis, the following procedures/evaluations should be performed at these 
visits (Visit 12 onwards and unscheduled visits): 
• Record AEs, SAEs, and all occurrences of leukemia, MDS, aplastic anemia, or any 
other new primary malignancy.  
Note: Specifically for this study, relevant symptoms related to SSEs should be reported 
as AEs independent of the timing of occurrence (prior to 30 days after last dose of 
study treatment or after this interval) or relationship with study drug. 
• Record concomitant medications/therapy 
• Record breast cancer-related treatment  
• Record vital signs: blood pressure, heart rate, respiratory rate, and temperature 
• Record weight (kg), within 5 days prior to dosing 
• Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems (all 
abnormal findings must be reported in the AE eCRF pages). 
• ECOG PS 


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• Blood draw for hematology evaluation (within 5 days prior to each visit): hematocrit, 
Hb, platelet counts, RBC, WBC, WBC differential.  Results to be assessed and 
documented prior to study drug treatment.  The Hb values need to be confirmed to be 
at least 8 g/dL prior to each dose.  If blood is drawn the day of the administration of 
study drug treatment, results must be available prior to study drug administration. 
• Blood draw for clinical chemistry: Na, K, Ca, ALT, AST, creatinine, BUN, bilirubin 
(total), total cholesterol, triglycerides, and glucose (blood sample for clinical chemistry 
must be taken and evaluated within 5 days prior to each visit).  
• Pregnancy test: premenopausal women must have a negative serum pregnancy test 
performed and evaluated within 5 days prior to each visit.  Postmenopausal women (as 
defined in Section 6.1) are not required to undergo a pregnancy test. 
• Record SSEs.  The Investigator will assess the subject for the following disease 
events: 
o Use of EBRT to relieve skeletal symptoms 
o New symptomatic pathological bone fractures (vertebral and non-vertebral) 
o Tumor related orthopedic surgical intervention 
o Spinal cord compression 
• Dispense exemestane and everolimus  
• Perform drug accountability  
• 12-lead ECG should be performed at Visit 11 and then every 8 weeks (±7 days), 
independently of the frequency of the visits.  Electrocardiograms should not be 
obtained when serum potassium is <3.5 mmol/L.  Hypokalemia should be corrected 
prior to ECG collection. After primary analysis, ECGs should be done according to 
local standard practice. 
• Radiological tumor assessment: please refer to Section 9.2.6 and Appendix 16.2.  
9.2.3.4 
End of treatment visit 
An EOT visit will be performed within 4 weeks ±7 days post-discontinuation or completion of 
all study treatments.  The following procedures/evaluations should be performed at this visit: 
• Record AEs and SAEs for 30 days after the last treatment 
Note: Specifically for this study, relevant symptoms related to SSEs should be reported 
as AEs independent of the timing of occurrence (prior to 30 days after last dose of 
study treatment or after this interval) or relationship with study drug. 
• All bone fractures and bone associated events (e.g., osteoporosis) need to be reported 
as either AEs or SAEs, if the criteria of SAE were met, regardless of the Investigator’s 
causality assessment. 
• Record all occurrences of leukemia, MDS, aplastic anemia, or any other new primary 
malignancy.  
• Record concomitant medications/therapy 
• Record breast cancer-related treatment  
• Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  


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• 12-lead ECG.  Electrocardiograms should not be obtained when serum potassium is 
<3.5 mmol/L.  Hypokalemia should be corrected prior to ECG collection. After 
primary analysis, ECGs should be done according to local standard practice. 
• Record weight 
• Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems (all 
abnormal findings must be reported in the AE eCRF pages). 
• ECOG PS 
• Blood draws for hematology (within 5 days of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, WBC differential 
• Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Ca, ALT, AST, 
creatinine, BUN, bilirubin (total), total cholesterol, triglycerides, glucose  
• Pregnancy test (within 5 days of the visit): premenopausal women must have a 
negative serum pregnancy test.  Postmenopausal women (as defined in Section 6.1) are 
not required to undergo a pregnancy test. 
• Record SSEs 
• Radiological tumor assessment: please refer to Section 9.2.6 and Appendix 16.2. 
If subjects cannot travel to the clinical site due to deterioration of disease, the EOT visit will 
be replaced by a follow-up telephone call from the clinical site.  Adverse events, information 
on all occurrences of leukemia, MDS, aplastic anemia, or any other new primary malignancy, 
as well as any anti-cancer therapies, will be discussed and captured in the eCRFs.  Since this 
information will be collected over the telephone from the subject, it is the clinical site’s 
responsibility to obtain and make available the source documentation for the information 
collected from the subject and document it in the eCRF. 
9.2.4 
Active follow-up 
Following primary analysis, the follow-up will be conducted in the separate extended safety 
follow-up study. Therefore, active follow-up is no longer applicable to this study (see 
Section 5.1.1 for further details). 
9.2.5 
End of study 
All ongoing study subjects who have completed at a minimum the EOT visit or 30 days from 
last study treatment dose, whichever is latest, will be transitioned into an extended safety 
follow-up study (BAY 88-8223 study 16996 / NCT02312960). The separate extended safety 
follow-up study has been set up to follow subjects who received radium-223 dichloride or 
placebo in the course of Bayer-sponsored clinical trials. The primary objective of this study is 
to define the long-term safety profile of radium-223 dichloride. All subjects who transition 
into this separate long-term follow-up study will require a separate signed informed consent. 
All efforts will be made to transition all subjects to the extended safety follow-up study. 
After primary analysis, sites/subjects not transitioning to extended safety follow-up study will 
be encouraged to report all occurrences of leukemia, myelodysplastic syndrome, aplastic 
anemia, new primary malignancies, bone fractures, and bone associated events via Bayer 


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Pharmacovigilance as individual case safety report (ICSR), including the corresponding study 
number and subject ID. 
This study will end at the time the last subject on treatment discontinues oral exemestane and 
/or everolimus treatment and completes end of treatment visit or discontinues from this study 
for another reason (e.g., death, consent withdrawn and active objection for further data 
collection, lost to follow-up). Until the transition to the extended safety follow-up study, 
subjects will continue to follow all the protocols required procedures and visits in the current 
protocol. 
9.2.6 
Radiological assessment: tumor and response evaluation 
Radiological scans for tumor evaluation must be performed at the following time points: 
• Within 3 weeks prior to randomization: technetium-99m bone scan and CT or MRI 
(chest/abdomen/pelvis and any additional sites of disease, as applicable) 
After primary analysis: 
• CT or MRI (chest/abdomen/pelvis and any additional sites of disease, as applicable): 
according to local standard practice. 
• Technetium-99m (bone scan): according to local standard practice. 
Disease response assessment, using the modified RECIST 1.1 (mRECIST 1.1) guidelines (See 
also Appendix 16.2), is to be performed at each time point when CT/MRI scans are done. 
This schedule is to be maintained and will not be shifted because of treatment 
interruptions/delays.  
Standard-of-care CT/MRI done within 3 weeks of randomization and standard-of-care bone 
scans done within 3 weeks of randomization are acceptable provided they are in line with 
protocol requirements criteria (anatomic coverage chest/abdomen/pelvis and in line with 
RECIST 1.1/mRECIST 1.1 guidelines for image acquisition).  All suspected sites of disease 
should be imaged. 
After primary analysis, imaging scans will continue until disease progression or treatment 
discontinuation according to local standard practice. 
Note: FDG PET scan, if performed as part of standard-of-care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can document that 
the CT is of identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
A technetium-99m bone scan with careful identification of all disease-related hotspots should 
be performed for all patients at the above mentioned time points. All visible bone lesions must 
also be imaged with conventional anatomical imaging procedures such as CT or MRI scan (at 
time points when CT/MRI scans are done).  
Note: FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard-of-care at the institution, provided the same bone 
imaging modality is used throughout the study. 
The same lesions identified at baseline must be evaluated at follow-up assessments using the 
same technique and preferably by the same Investigator/radiologist. 
For details on radiological tumor assessment please also refer to Appendix 16.2.  


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9.3 
Population characteristics 
9.3.1 
Demographic  
The following demographic characteristics will be collected: 
• Date of birth 
• Age at randomization 
• Race and ethnicity (where it is allowed by local regulation) 
9.3.2 
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) AEs can be 
found in Section 9.6.1.1. 
9.3.3 
Other baseline characteristics 
The following other baseline characteristics will be collected: 
• Date of breast cancer diagnosis 
• Date of diagnosis of metastatic breast cancer 
• Stage of breast cancer at diagnosis 
• Treatment of breast cancer before enrollment (e.g., surgery, radiation, etc.) 
• Weight (kg) 
• Vital signs: blood pressure (mmHg), heart rate (beats per minute), respiratory rate 
(respirations per minute), and temperature (°C)  
• ECOG PS 
• Cancer pain assessment 
• Laboratory assessments 
o Hematology: hematocrit, Hb, platelet counts, RBC, WBC, WBC differential 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol ALT, AST, LDH, bone ALP (if 
testing is available and can be performed locally), creatinine, BUN, total bilirubin, 
triglycerides, glucose, phosphate, and albumin 
9.4 
Efficacy 
9.4.1 
Efficacy variables 
The primary efficacy variable is: 
• SSE-FS 


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The secondary efficacy variables are: 
• OS 
• Time to opiate use for cancer pain 
• Time to pain progression (only in subjects with baseline WPS ≤8) 
• Time to cytotoxic chemotherapy 
• rPFS 
• Pain improvement rate 
The study will also include the following exploratory efficacy endpoints: 
• Time to first on-study SSE 
• Time to bone ALP progression 
• Bone ALP response at Week 12 and 4 weeks (± 7 days ) after last radium-223 
dichloride/placebo dose 
• Bone-specific rPFS 
• Time to visceral metastases onset (in subjects with no visceral disease at baseline) 
Note: After implementation of CSP Amendment 9, subjects who completed the EOT visit 
could be transferred to a separate extended safety follow-up study for their remaining follow-
up. After implementation of CSP Amendment 10, all such subjects will be transferred; only 
subjects on oral treatment will remain on study, and no post-treatment data will be collected 
beyond the 30-day safety follow-up (EOT visit).   
As the key efficacy objectives will have been accomplished, long-term safety transferred, and 
only a limited number of subjects will remain in this study, in order to reduce the burden to 
study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, 
and OS. Once subjects are rolled over, the long-term safety will be collected and assessed 
entirely in the separate extended safety follow-up study. 
9.4.2 
Definition of efficacy variables 
9.4.2.1 
Primary endpoint  
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause 
Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be 
administered prior to randomization.  


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9.4.2.2 
Secondary efficacy endpoints 
Overall survival is defined as the time (days) from the date of randomization to the date of 
death due to any cause.  For subjects who are still alive, their OS will be censored at the last 
known alive date or the database cutoff date, whichever occurs first.  
Time to opiate use for cancer pain is defined as the interval from the date of randomization 
to the date of opiate use.  Subjects who have no opiate use at the time of analysis will be 
censored at the last assessment date of no opiate use.  Subjects with no on-study assessment or 
no baseline assessment will be censored at the date of randomization. 
Time to opiate use will be determined by analgesic use captured via subject diary and/or the 
eCRF (analgesic consumption diary and recorded analgesics, respectively, see schedule of 
assessments).  
Time to pain progression will be evaluated in subjects with baseline WPS ≤ 8.   
Time to pain progression is defined as the interval from randomization to the first date 
a subject experiences pain progression based on WPS.  Pain progression is defined as an 
increase of 2 or more points “worst pain in 24 hours” score from baseline observed at 2 
consecutive evaluations ≥4 weeks apart   
OR 
an increase in pain management (IPM) with respect to baseline, whichever occurs first. 
Assessments will occur on the day of the visit.  An evaluable pain assessment interval requires 
completion of a minimum of 4 out of 7 questions.  Subjects who have not experienced pain 
progression at the time of analysis will be censored on the last post-baseline pain assessment 
date the subject was known to have not progressed.  Subjects with no on-study assessment or 
no baseline assessment will be censored at the date of randomization.   
Pain improvement is defined for subjects evaluable for pain improvement, i.e., subjects with 
baseline WPS≥2, as a 2-point decrease or more in WPS from baseline over 2 consecutive 
measurements conducted at least 4 weeks apart, without an IPM. 
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS≥2).  Pain improvement rate at week 12, EOT, and any visit will 
be considered. 
The BPI-SF (Appendix 16.7 is a short, self-administered questionnaire with 11 items, which 
was designed to evaluate the intensity of, and the impairment caused by pain.  All BPI-SF 
items are scored using rating scales.  Four items measure pain intensity (pain now, average 
pain, worst pain, and least pain) using 0 (“no pain”) to 10 (“pain as bad as you can imagine”) 
numeric rating scales, and 7 items measure the level of interference with function caused by 
pain (general activity, mood, walking ability, normal work, relations with other people, sleep 
and enjoyment of life) using 0 (does not interfere) to 10 (completely interferes) rating scales. 
The items are aggregated into 2 dimensions, (1) Pain severity index, using the mean of the 
4 items on the pain intensity, and (2) Function interference index, using the mean of the 7 pain 
interference items.  All 4 severity items must be completed for aggregating the pain severity 
index.  The function interference index is scored as the mean of the item scores multiplied by 
7, given that more than 50% or 4 of 7, of the items have been completed. 


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Time to cytotoxic chemotherapy is defined as the time (days) from the date of 
randomization to the date of the first cytotoxic chemotherapy. 
Radiological progression-free survival (rPFS) is defined as the time (days) from the date of 
randomization to the date of confirmed radiological progression in either soft tissue, viscera or 
bone, or death (if death occurs before progression).  Subjects without confirmed radiological 
progression or death at the time of analysis will be censored at their last date of radiological 
tumor assessment (See Statistical Analysis Plan [SAP] for detailed censoring rules).  Bone 
scans and CT/MRIs will be read locally.  All bone lesions visible on a technetium-99m bone 
scan will need to also be imaged using conventional anatomical imaging techniques such as 
SPECT CT/MRI or CT/MRI (with or without contrast).  Bone progression will be declared 
according to the modified RECIST 1.1 criteria (see Appendix 16.2).  If a new bone lesion or 
unequivocal increase in size of bone lesions is identified on bone scan, the lesion must also be 
confirmed by CT/MRI.  If a new bone lesion or unequivocal increase in size of bone lesions is 
only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression will be 
declared without further confirmation. 
9.4.2.3 
Exploratory efficacy endpoints: 
Time to first on-study SSE is defined as the time (days) from the date of randomization to 
the date of the first on-study SSE.  
Time to bone ALP progression is defined as the time (days) from the date of randomization 
to the date of first bone ALP progression.  Bone ALP progression is defined as ≥25% increase 
from the baseline value, at least 12 weeks from baseline in subjects with no bone ALP decline 
from baseline; or ≥25% increase above the nadir value, which is confirmed by a second value 
obtained 4 or more weeks later in subjects with an initial bone ALP decline from baseline. 
Bone ALP response is defined as ≥30% reduction of the blood level at Week 12 and 4 weeks 
(± 7 days) after last radium-223 dichloride/placebo dose, compared to the baseline value.  
Confirmed bone ALP response is defined as a ≥30% reduction of the blood level, compared to 
the baseline value, confirmed by a second bone ALP value 4 or more weeks later.  
Radiological progression-free survival based on bone imaging (bone-specific rPFS) is 
defined as the time (days) from the date of randomization to the date of confirmed 
radiological progression detected by bone imaging or death (if death occurs before 
progression).  Subjects without confirmed radiological progression or death at the time of 
analysis will be censored at their last date of radiological tumor assessment.  (See SAP for 
detailed censoring rules).  Bone scans will be read locally.  All bone lesions visible on a 
technetium-99m bone scan will need to also be imaged using conventional anatomical 
imaging techniques such as SPECT CT/MRI or CT/MRI (with or without contrast).  Bone 
progression will be declared according to the modified RECIST 1.1 criteria (see 
Appendix 16.2).  If a new bone lesion or unequivocal increase in size of bone lesions is 
identified on bone scan, the lesion must also be confirmed by CT/MRI.  If a new bone lesion 
or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on 
a technetium-99m bone scan, progression will be declared without further confirmation.  
Time to visceral metastases onset (in subjects with no visceral disease at baseline) is defined 
as the time (days) from the date of randomization to the date of the first scan showing visceral 
metastatic disease. 


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9.5 
Pharmacokinetics  
No PK measurements will be performed in this study.  No PK interaction is expected between 
radium-223 dichloride and the co-administered exemestane and everolimus therapy.  
Radium-223 is an isotope and is therefore not metabolized.  There are no hints that radium is 
involved in any transporter process.  The main portion of radioactivity is excreted with the 
feces.  The liver seems not to be involved in the excretion of radium-223 or its decay 
products.  They are directly excreted into the small intestine.  The co-administered products 
are typical small molecules that are metabolized in the liver.  Thus, no direct impact of 
radium-223 on the PK of the co-administered products is expected.  
9.6 
Safety 
The Investigator(s) and the sponsor’s representative will review the safety data throughout the 
course of the study.  The following safety variables will be evaluated: 
• Adverse events: AEs will be collected and recorded on an ongoing basis throughout 
the study as described in Section 9.6.1.  
• Safety variables: Safety variables will include the analysis of acute and long-term 
effects and the appearance of new primary malignancies and hematopoietic reserve for 
tolerability of subsequent chemotherapy. Please refer to Section 5.1.2 for further 
information.  The complete list of variables to be analyzed for this study will be 
provided in the Statistical Analysis Plan (SAP).  
• Laboratory assessments: The following laboratory assessments with reference ranges, 
including Investigator determinations, will be recorded in the source documentation 
and the eCRF: 
o Hematology: hematocrit, Hb, platelet counts, RBC, WBC, WBC differential. 
o Clinical chemistry: Na, K, Ca, total cholesterol, ALT, AST, serum creatinine, 
BUN, total bilirubin, total cholesterol, triglycerides, and glucose. 
o A coagulation panel: PT, PTT, and INR.  
All subjects who receive at least one dose of study drug will be valid for safety analysis.  All 
AEs will be reported and graded according to NCI-CTCAE v4.03.  Laboratory evaluations, 
vital signs, changes in physical examination findings will also be assessed. 
9.6.1 
Adverse events 
9.6.1.1 
Definitions 
Adverse event  
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 subject 
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. 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE). 


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Adverse event versus medical history 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, or 
scans.  
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are considered 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 
considered as medical history (e.g., allergic pollinosis).  
• Symptoms that were present prior to signing of informed consent but for which the 
diagnosis was confirmed after signing of informed consent should be documented as 
medical history. 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  
Serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a through g): 
a. Results in death 
b. Is life-threatening 
 
The term “life-threatening” in the definition refers to an event in which the subject 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 in-subject 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 
functions. 


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e. Is a congenital anomaly / birth defect 
f. Is another medically important serious event as judged by the Investigator 
g. Is an occurrence of any additional malignancies including AML or hematological 
conditions such as MDS, aplastic anemia, myelofibrosis (regardless of the 
Investigator’s causality assessment).  If disease progression leads to signs and 
symptoms that meet the criteria for seriousness (e.g., hospitalization), the associated 
signs and symptoms should be reported as SAEs, not the underlying cause (i.e., 
“progressive disease” should not be recorded as an SAE).  In this case disease 
progression should be mentioned on the SAE form as an “alternative explanation.” 
An isolated laboratory abnormality that meets the criteria for CTCAE Grade 4 classification is 
not reportable as an SAE, unless the Investigator assesses that the event meets standard 
International Conference on Harmonisation criteria for an SAE.  All laboratory abnormalities, 
including CTCAE Grade 4 abnormalities, will be documented on the laboratory eCRF 
(including values reported from central laboratories). 
9.6.1.2 
Classifications for adverse event assessment 
All AEs will be assessed and documented by the Investigator according to the categories 
detailed below.  
9.6.1.2.1 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1. 
9.6.1.2.2 
Intensity 
The intensity of an AE should be documented using the NCI-CTCAE v4.03, JUN 2010; see 
Section 16.1.  
9.6.1.2.3 
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 at the time of the completion of the 
eCRF.  The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question.  Causal relationship of the study treatment 
exemestane and everolimus and concomitant medication of interest, bisphosphonates or 
denosumab, will also be collected. 
Possible answers are “yes” or “no” 
An assessment of “no” would include: 
• The existence of a clear alternative explanation, e.g., mechanical bleeding at surgical 
study site, 
or 
• 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. 


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Important 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 subject’s 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 PK of the study treatment: The PK properties (absorption, 
distribution, metabolism and excretion) of the study treatment, coupled with the 
individual subject’s pharmacodynamics (PD) 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”. 
9.6.1.2.4 
Action taken with study treatment  
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below: 
• Drug withdrawn 
• Drug interrupted 
• Dose reduced 
• Dose not changed 
• Not applicable 
• Unknown 
9.6.1.2.5 
Other specific treatment(s) of adverse events 
• None 
• Remedial drug therapy 
• Other 
9.6.1.2.6 
Outcome 
The outcome of the AE is to be documented as follows:  
• Recovered/resolved 


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• Recovering/resolving 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Fatal 
• Unknown 
9.6.1.3 
Assessments and documentation of adverse events 
All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of 
study medications must be recorded on the eCRF.  Treatment-emergent AEs and all SAEs that 
occur during the treatment period and up to 30 days after the last administration of study 
treatments must be reported on the appropriate eCRF. 
All SAEs that occur during the treatment period and up to 30 days after the last administration 
of study treatments must immediately (within 24 hours of the Investigator’s awareness) be 
reported in the appropriate eCRF.  If more than one AE occurs, each event should be recorded 
separately.  All AEs and SAEs are to be followed until resolved or as clinically required.  
All AEs and SAEs occurring beyond 30 days after the end of study treatment must be 
documented and reported if considered to be related to study medications or to study related 
procedures.  
Subjects who receive cytotoxic chemotherapy during the follow-up period will be followed up 
for the development of febrile neutropenia and hemorrhage during their chemotherapy 
treatment and for up to 6 months after chemotherapy.  Occurrence of these AEs must be 
documented and reported if considered to be related to the chemotherapy treatment.  
However, all occurrences of additional malignancies including AML, and hematological 
conditions such as MDS, aplastic anemia, myelofibrosis must be reported as SAEs, regardless 
of the Investigator’s assessment. 
Note: Specifically for this study, relevant symptoms related to SSEs should be reported as AEs 
independent of the timing of occurrence (prior to 30 days after last dose of study treatment or 
after this interval) or relationship with study drug. 
All bone fractures and bone associated events (e.g., osteoporosis) should be collected as either 
AEs or SAEs if the criteria of SAE were met, regardless of the Investigator’s causality 
assessment. 
Adverse events may be reported spontaneously by the subject or elicited through open (non-
leading) questioning during each visit to the clinic and at the end of the active follow-up 
period without clinic visits.  As far as possible, all AEs must be described by their duration 
(start and stop date), severity (graded according to the CTCAE v4.03), relationship to 
treatment, and according to the need of other specific therapy.  All information will be 
recorded in the source documentation and AE eCRF. 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the trial), requiring treatment, causing apparent clinical manifestations, or 
judged as relevant by the Investigator, should be reported as an AE.  Each event should be 
described in detail along with start and stop dates (onset and resolution of event), intensity, 
temporal and causal relationship to investigational product and/or protocol related procedures, 
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therapeutic action, and ultimate outcome of the AE.  The Investigator’s assessment of AEs 
and laboratory results with grades and causality assessments must be documented and retained 
in the source documentation.  If more than one AE occurs, each event should be recorded 
separately.  All AEs and SAEs are to be followed until resolved or as clinically required. 
9.6.1.4 
Reporting of serious adverse events 
The definition of SAEs is given in Section 9.6.1.1.  Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient. 
If disease progression leads to signs and symptoms that meet the criteria for seriousness (e.g., 
hospitalization), the associated signs and symptoms should be reported as an SAE, not the 
underlying cause (i.e., “progressive disease” should not be recorded as an SAE).  In this case, 
disease progression should be mentioned on the SAE form as “alternative explanation”. 
Reporting of additional malignancies 
All occurrences of any additional malignancies including AML, and hematological conditions 
such as MDS, aplastic anemia, myelofibrosis must be reported as SAEs, regardless of the 
Investigator’s causality assessment 
Investigator’s notification of the sponsor 
All Investigators will be thoroughly instructed and trained on all relevant aspects of the 
Investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the Investigator Site file.  This information will be updated as 
needed. 
All SAEs occurring during the observation period defined in Section 9.6.1.3 must 
immediately (within 24 hours of the Investigator’s awareness [or the next working day for 
weekends and public holidays]) be reported to the contact at the contract research organization 
(CRO), as detailed in the study manual.  An SAE form must also be completed within 
24 hours of the Investigator awareness (or the next working day for weekends and public 
holidays) and forwarded to the designated recipient.  Each SAE must be followed up until 
resolution or stabilization by the submission of updated reports to the designated recipient. 
Additionally, all occurrences of MDS, aplastic anemia, or any other new primary malignancy 
such as acute myeloid leukemia must be reported as SAEs at any time, and regardless of the 
Investigator’s causality assessment (Section 9.6.1.3).  All bone fractures and bone associated 
events (e.g., osteoporosis) need to be reported as either AEs or SAEs, if the criteria of SAE 
were met, regardless of the Investigator’s causality assessment.  Grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as SAEs, specifically 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria.  If 
Investigators are in doubt about the applicable reporting obligations, they should consult with 
the medical monitor.  
For subjects who die >30 days after the administration of the last study treatment, submission 
of the AE page of the eCRF is not required.  However, the SAE Complementary Form should 
be submitted to the applicable Bayer HealthCare Pharmacovigilance department if the death is 
considered related to study treatment.  In addition, this death information will also be 
collected in the end of active follow-up page of the eCRF. 
Serious AEs occurring after the protocol defined observation period will be processed by the 
sponsor according to all applicable regulations. 


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Notification of the independent ethics committees/institutional review boards  
Notification of the independent ethics committees/institutional review boards (IECs/IRBs) 
about all relevant events (e.g., SAEs, SUSARs) will be performed by the sponsor and/or by 
the Investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational study site 
The sponsor will inform all investigational study sites about reported relevant events (e.g., 
SUSARs) according to all applicable regulations.  The sponsor will send SUSARs to a study 
site once ready to enroll and will stop sending SUSARs once the last subject EOT visit for 
that study site (30 days after last dose) occurs. 
9.6.1.5 
Expected adverse events 
For this study, the applicable reference document is the most current version of the 
Investigator’s Brochure / summary of product characteristics. 
9.6.2 
Pregnancies 
The Investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study.  The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported. 
For all reports, the forms provided are to be used.  The Investigator should submit them within 
the same timelines as an SAE. 
9.6.3 
Reporting of medical device failures 
If required by local regulations, the Investigator must report immediately all failures of 
non-approved medical devices which could cause health damage, as well as any health 
damage that may be causally associated with a failure of a non-approved medical device.  For 
this reporting, the forms provided are to be used and sent to the designated recipient. 
9.7 
Other procedures and variables 
Other exploratory variables in this study are resource utilization, assessment of biomarkers 
and impact of baseline total body weight (TBW) and ideal body weight (IBW) on SSE-FS and 
AEs.  Further details about these exploratory endpoints will be provided in the SAP. 
Note: As of Amendment 10, collection of data will be reduced and will focus mainly on acute 
safety, SSE, and OS. Please see Section 15.6 for further information. 
9.7.1 
Resource utilization 
Information on healthcare resource use that is associated with the management of AEs as well 
as subject monitoring will be collected by questionnaire (Section 16.8). 
9.7.2 
Biomarker assessments 
Biomarker analyses planned within this study may include predictive, prognostic, and PD 
biomarkers analyzed from blood or urine.  Blood, urine, and tumor biomarker analyses will be 
dependent upon the availability of appropriate biomarker assays and may be deferred or not 
performed, if during or at the end of the study, it becomes clear that the analysis will have no 


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scientific value, or there are not enough samples or not enough responders to allow for 
adequate biomarker evaluation.  In the event the study is terminated early or does not reach a 
positive primary endpoint, completion of the biomarker assessments will be based on 
justification and intended utility of the data. Exploratory biomarker data including CTC 
analysis will be reported in a separated biomarker report. 
9.7.2.1 
Urine and blood based biomarker analysis 
Blood samples will be obtained from all subjects at the following time points: (1) Cycle 1, 
Day 1 (Visit 2) and Cycle 4, Day 1 (Visit 8) within 5 days of the visit prior to radium-223 
dichloride/placebo administration, and within 5 days of Visit 11 or disease progression, 
whichever occurs first.  Urine samples will be collected at Cycle 1, Day 1, Cycle 4, Day 1, 
and at Visit 11 or disease progression, whichever occurs first. 
• Urine and serum and plasma from blood samples may be evaluated for expression 
levels of bone-related biomarkers.  Elevated levels of bone biomarkers are indicative 
for e.g., more aggressive disease and are prognostic of worse long-term clinical 
outcome.  In this study, levels of bone biomarkers (measured before, during, and after 
treatment) that are indicative of bone remodeling (e.g., ALP and bone ALP, 
procollagen type I N-terminal propeptide) and bone resorption (e.g., urine NTX and 
I collagen telopeptide [ICTP]/ serum C-terminal telopeptide of type I collagen) may be 
evaluated and correlated with clinical outcomes (including SSEs, survival, and levels 
of other biomarkers).  
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease and/or about the drug (i.e., mode of 
action related effect or safety of the drug) may be measured, based on newly emerging data 
from other ongoing studies and/or literature data. 
9.7.2.2 
Collection of circulating tumor cells for biomarker analyses 
Circulating tumor cells (CTCs) are believed to represent a surrogate for tumor cells and can be 
used as surrogate to demonstrate efficacy of the drug by enumeration of CTCs, but also as 
source of tumor molecular characterization.  
Blood samples will be obtained from all subjects at sites in France, Germany, Israel, Italy, 
Spain, and the United Kingdom at the following time points: (1) Cycle 1, Day 1 (Visit 2) and 
every subsequent cycles, Day 1 within 5 days of the visit prior to radium-223 dichloride or 
placebo administration, and within 5 days of the EOT visit or disease progression, whichever 
occurs first. 
9.7.3 
Analysis of the impact of body weight on SSE-FS and AEs 
The impact of baseline TBW and IBW on SSE-FS and AEs will be analyzed in this study.  
Baseline TBW and IBW correspond to the subject’s total and ideal body weights on 
Cycle 1, Day 1 of the study; details will be presented in the SAP.   
9.8 
Appropriateness of procedures / measurements 
The procedures chosen for the evaluation of safety in this study population are consistent with 
the appropriate and ethical standards used in phase II trials of oncology drugs. 


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10. 
Statistical methods and determination of sample size 
10.1 
General considerations 
Subjects will be randomized to radium-223 dichloride/placebo in a 1:1 ratio.  Randomization 
will be stratified by:  
• Geographical regions: Europe/North America [including Israel] versus Asia 
• Previous lines of hormone therapy in metastatic setting (1 versus 2 or more): for the 
purpose of counting the number of prior lines of hormone therapy, only a change of 
the hormone agent due to progression is counted as a new line of therapy.  A switch of 
hormone therapy from one agent to another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of PD at time of switch will be counted as one line 
although 2 different agents have been administered. 
•  Visceral disease: yes versus no  
Statistical analysis will be performed using SAS Institute Inc® (SAS); the version used will be 
specified in the SAP.   
Data from patients who are transferred to the separate extended safety follow-up study may be 
pooled and analyzed together with the data from this study. 
10.2 
Analysis sets 
The following 2 populations will be analyzed: 
ITT: All randomized subjects.  The ITT population will be used in the analysis of all efficacy 
endpoints.  Subjects will be included in all ITT analyses according to the treatment to which 
they are randomized. 
Safety: All randomized subjects who have received at least one dose of any study drug.  This 
safety population will be used in the analyses of all safety endpoints.  Subjects will be 
included in the analyses according to the treatment they received. 
10.3 
Variables and planned statistical analyses 
Definition for each variable is given in Section 9.4. 
The primary efficacy variable is SSE-FS.  
The secondary efficacy variables are specified below:  
• OS 
• Time to opiate use for cancer pain 
• Time to pain progression (only in subjects with baseline WPS ≤8) 
• Time to cytotoxic chemotherapy 
• rPFS 
• Pain improvement rate 
Exploratory efficacy variables are:  
• Time to first on-study SSE 


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• Time to bone ALP progression 
• Bone ALP response at Week 12 and 4 weeks (± 7 days) after last radium-223 
dichloride/placebo dose  
• Bone-specific rPFS 
• Time to visceral metastases onset (in subjects with no visceral disease at baseline) 
10.3.1 
Primary efficacy analysis  
The overall one-sided type I error rate for the analysis of primary efficacy endpoint SSE-FS is 
0.1. 
The null hypothesis that both treatment groups have the same SSE-FS distribution will be 
tested against the alternative hypothesis that the distribution of SSE-FS time in the 
radium-223 dichloride is different from the placebo group.  The test statistic is assumed to be 
asymptotically normal distribution.  SSE free survival will be analyzed using a stratified log-
rank test with the same stratification factors as for randomization.  The HR (radium-223 
dichloride/placebo) will be computed together with the 2-sided 80% and 95% CI using a Cox 
regression model stratified by the same factors.  Kaplan-Meier estimates and survival curves 
for SSE-FS will also be presented for each treatment groups.  
Additional details for the analyses of primary efficacy endpoint will be provided in the SAP.  
10.3.2 
Secondary efficacy analysis  
Secondary efficacy endpoints are specified in Section 9.4.  
The secondary efficacy time-to-event endpoints will be analyzed using a stratified log-rank 
test, with the factors from the randomization used for stratification.  A HR with a 2-sided 95% 
CI from a stratified Cox proportional hazards model will also be provided.  Kaplan-Meier 
estimates and survival curves will also be presented for each treatment group. 
Additional details for the analyses of secondary endpoint will be provided in the SAP. 
10.3.3 
Exploratory efficacy analysis 
The exploratory time-to-event efficacy endpoints will be analyzed using a log-rank test, 
stratified by the same factors as the randomization factors.   
Time to visceral metastases onset (in subjects with no visceral disease at baseline) will be 
analyzed using a log-rank test, stratified by geographical region and previous lines of 
hormone therapy in metastatic setting, given a sufficient number of subjects with no visceral 
disease at baseline. 
Additional details for the analyses of exploratory endpoint will be provided in the SAP. 
10.3.4 
Safety analysis  
Safety variables will be analyzed using frequency tables and descriptive statistics.  
10.4 
Determination of sample size 
Under the original sample size calculation, sample size is calculated based on the primary 
endpoint, SSE-FS.  EAST 6.3 was used to calculate event number.  Assuming a one-sided 
alpha of 0.1, power of 90%, with a median SSE-FS for the control group of 8.3 months and a 
randomization ratio of 1:1 between treatments, approximately 160 events will be required to 


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detect a 50% increase in SSE-FS for a total of 311 subjects in the 2 treatment groups 
combined.  Dropout rate is assumed to be 15%.  Dropout was taken into account when 
calculating the sample size and study duration.  The targeted improvement of 50% is not 
based on a bibliographical reference. 
Following the administrative data review (per Amendment 8) conducted on DEC 2017 by a 
small group of unblinded Sponsor employees, independent of the study team, subject 
enrollment in this trial was discontinued on APR 2018, prior to accrual of the originally 
planned sample size.  
10.5 
Planned interim data review 
An administrative interim data review will be performed when a minimum of 80 rPFS events 
is reached. The interim data review will be primarily focused on the rPFS, and the interim 
data review results will inform on future radium-223 clinical development plans in this 
indication.  An independent unblinded review committee will be formed.  
No formal statistical testing will be performed for either SSE-FS or rPFS at the time of this 
interim review. Only summary statistics will be produced. There is no plan to stop the trial 
due to superior efficacy; therefore, no alpha adjustment is applied for this interim look at the 
primary endpoint of SSE-FS. The study will remain blinded after the interim data review. 
Details of the interim data review will be provided in the SAP. 
Planned updated analysis 
Following primary analysis, at the closure of the study, after the last subject has discontinued 
treatment and study assessments, an updated analysis will be performed. The updated analysis 
will be descriptive only and may consist of listings. 
11. 
Data handling and quality assurance 
11.1 
Data recording 
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the study site.  The study site must implement processes to ensure 
this happens.  A source document checklist will be used at the study site to identify the source 
data for all data points collected and the monitor will work with the study site to complete 
this. 
Data recorded from “only screened subjects (screening failures)” 
Data of “only screened subjects” will be recorded at least as source data, as far as the reason 
for the premature discontinuation is identifiable.  At a minimum, data to be recorded in the 
eCRF are demographic information (subject number, date of birth/age, sex, race [if 
applicable] and ethnicity), the reason for premature discontinuation and date of last visit.  
These data will be transferred to the respective database. 
For screening failures with an SAE, the following additional data should be collected in the 
CRF, in addition to demographic information, primary reason for discontinuation and date of 
last visit: 
• All information about the SAE 


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• All information related to the SAE such as:  
o Concomitant medication 
o Medical history 
o Other information needed for SAE complementary page 
11.2 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the study site prior to the start of the study to review with the study site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
sponsor’s requirements.  When reviewing data collection procedures, the discussion will also 
include identification and documentation of source data items. 
The sponsor/designee will monitor the study site activity to verify that the: 
• Data are authentic, accurate and complete 
• Safety and rights of subjects are being protected 
• Study is conducted in accordance with the currently approved protocol  
(including study treatment being used in accordance with the protocol) 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The Investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
11.3 
Data processing 
The data collection tool for this study will be a validated electronic system.  Subject data 
necessary for analysis and reporting will be transmitted into a validated database or data 
system (e.g., TOSCA; SAS).  Clinical data management will be performed in accordance with 
applicable sponsor’s standards and data cleaning procedures.  This is applicable for data 
recorded on eCRF as well as for data from other sources (e.g., IXRS, laboratory, adjudication 
committees). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used such as the Medical Dictionary for Regulatory Activities and World Health 
Organization Drug Dictionary (WHO-DD). 
11.4 
Missing data 
Every effort should be made to retain subjects who discontinue the treatment period for any 
reason.  These subjects are to be encouraged to remain on the study for follow-up of primary, 
secondary, and exploratory endpoints (i.e., continue in the active follow-up period with or 
without clinic visits). 
The method used for imputation of missing data will be described in the SAP. 
11.5 
Audit and inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 


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Investigator/institution will be informed prior to a sponsor (or designated CRO) audit 
inspections to ensure all required staff are available during the audit process.  The 
Investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory Health Authority representatives and IEC(s)/IRB(s) are 
possible.  The Investigator should notify the sponsor immediately of any such inspection. 
The Investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study. 
11.6 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Subject (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.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period. 
The Investigator/institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership). 
The Investigator Site file is not to be destroyed without the sponsor’s approval. 
The contract with the Investigator/institution will contain all regulations relevant for the study 
site. 
12. 
Premature termination of the study 
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; sites]) at any time, which may be due but not limited to the 
following reasons:  
• If the risk-benefit ratio becomes unacceptable owing to, for example, 
o Results of parallel clinical studies 
o Results of parallel animal studies (e.g., toxicity, teratogenicity, carcinogenicity 
or reproduction toxicity). 
• If the study conduct (e.g., recruitment rate; dropout 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 site at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing. 
• All affected institutions (e.g., IEC(s)/IRB(s); competent authority(ies); study site; head 
of study site) must be informed as applicable according to local law. 


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• All study materials (except documentation that has to remain stored at study site) must 
be returned to the sponsor or (for radium-223 dichloride samples) be destroyed at the 
study site in accordance with the local radioprotection regulations.  The Investigator 
will retain all other documents until notification given by the sponsor for destruction. 
• 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. 
• All ongoing subjects at the time of study termination will finish all study treatments as 
part of the study. 
Details for individual subject's withdrawal can be found in Section 6.3.1. 
13. 
Ethical and legal aspects 
13.1 
Investigators and other study personnel 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the sites will be available in each site’s 
Investigator Site file. 
Whenever the term “Investigator” is noted in the protocol text, it may refer to either the 
Principal Investigator at the study site, or an appropriately qualified, trained and delegated 
individual of the investigational study site. 
The Principal Investigator of each site must sign the protocol signature sheet before subject 
recruitment may start at the respective site.  Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the Principal Investigator before coming into effect at 
the respective site. 
In addition to signing the protocol signature sheet, all ethical and legal aspects (Section 13) 
should be in place prior to any subject recruitment. 
A complete list of all participating sites and their Investigators, as well as all required 
signature documents, will be maintained in the sponsor study file. 
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature page. 
13.1.1 
Independent data monitoring committee  
Not applicable 
13.1.2 
Independent radiological review  
This study will have no central review. 
13.1.3 Independent Data Review Committee (IDRC) 
An independent unblinded data review committee will be established.  
The IDRC will conduct a one-time unblinded review of the data. IDRC review will be 
supported by an independent unblinded statistical analysis center, as further described in the 
IDRC operational plan. 


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13.2 
Funding and financial disclosure 
Funding 
This study will be funded by its sponsor. 
Financial disclosure  
Each Investigator (including principal and/or any sub Investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file. 
13.3 
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 sponsor and Investigator abide by 
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 
sites/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g., 
IEC/IRB, head of the study site/medical institution) must supply to the sponsor, upon request, 
a list of the IEC/IRB members involved in the vote and a statement to confirm that the 
IEC/IRB is organized and operates according to GCP and applicable laws and regulations. 
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.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
Investigator without agreement by both parties.  However, the Investigator or the sponsor 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/sponsor 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/sponsor.  Any deviations from the protocol must be explained and documented by 
the Investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 12. 
13.4 
Subject information and consent 
All relevant information on the study will be summarized in an integrated subject information 
sheet and ICF provided by the sponsor or the study site.  A sample subject information and 
ICF is provided as a document separate to this protocol. 
Based on this subject information sheet, the Investigator or designee will explain all relevant 
aspects of the study to each subject or legal representative or proxy consenter (if the subject is 
under legal protection), prior to her entry into the study (i.e., before any examinations and 
procedures associated with the selection for the study are performed or any study-specific data 
is recorded on study-specific forms). 


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The Investigator will also inform the subject that written approval of the IRB/IEC has been 
obtained. 
Each subject or legal representative or proxy consenter will have ample time and opportunity 
to ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. 
Only if the subject or legal representative or proxy consenter voluntarily agrees to sign the 
ICF and has done so, may she enter the study.  Additionally, the Investigator and other 
information provider (if any) will personally sign and date the form.  The subject or legal 
representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the Investigator Site file or, if locally 
required, in the subject’s note/file of the medical institution. 
A summary of the consenting process, participation in the study, and date of informed consent 
given by the subject should be documented appropriately in the source documentation. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
Investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness. 
For adults under legal protection, consent shall be given by the legal guardian(s).  The consent 
of an adult under legal protection shall also be requested where such a person is able to 
express her own will.  Her refusal or the withdrawal of her consent may not be disregarded. 
The ICF and any other written information provided to subjects or legal representatives or 
proxy consenters will be revised whenever important new information becomes available that 
may be relevant to the subject’s consent, or there is an amendment to the protocol that 
necessitates a change to the content of the subject information and/or the written ICF.  The 
Investigator will inform the subject or legal representative or proxy consenter of changes in a 
timely manner and will ask the subject to confirm her participation in the study by signing the 
revised ICF.  Any revised written ICF and written information must receive the IEC/IRB`s 
approval or favorable opinion in advance of use. 
A summary of any revised written ICF signed by the subject or a legal representative or a 
proxy should be appropriately documented by the study site within the source documents. 
If at any time during the study the subject would like to withdraw consent, the Investigator 
must discuss with the subject the active follow-up period without the clinic visits part of the 
study.  If the subject continues to object to having any study data collected the subject must 
sign the “Declaration of Objection to the Collection of Study Data after Withdrawal of 
Consent” form. 
13.5 
Publication policy and use of data 
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.  


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All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other Investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the Investigator to publish the results upon completion of 
the study.  However, the Investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the Investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
Investigator to reach a mutually agreeable final manuscript. 
13.6 
Compensation for health damage of subjects / insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 
13.7 
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. 
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF.  If the subject name appears on any other document (e.g., pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor.  Study findings 
stored on a computer will be stored in accordance with local data protection laws.  As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The Investigator will maintain a list to enable subjects to be identified. 


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28 Quattrocchio CC, Picucchi S, Sammarra M, Santini D, Vincenzi B, Tonini G, Grasso RF, 
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41 Parker C, et al. Updated analysis of the phase III, double-blind, randomized, multinational 
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superior to megestrol acetate after tamoxifen failure in postmenopausal women with 
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breast cancer in postmenopausal women: the European Organisation for Research and 
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Health-related quality of life among patients with breast cancer receiving zoledronic acid 
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53 Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the NIST 
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Acad Med Singapore. 1994;23:129-38.  
 
 


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15. 
Protocol amendments 
15.1 
Amendment 1 
Amendment 1 (dated 16 MAR 2015) is an amendment to the original protocol dated 
06 MAY 2014.  Changes to the protocol include: 
• Clarified the inclusion criterion of menopausal status 
• Changed the inclusion/exclusion criteria to permit visceral metastases  
• Changed the requirement for baseline scans to be within 3 weeks prior to 
randomization rather than within 6 weeks of randomization.  Increased the screening 
period from 2 to 3 weeks to allow more time for baseline imaging assessments 
• Added an inclusion criterion that subjects must have had progressive disease after 
treatment with a non-steroidal aromatase inhibitor 
• Clarified that all prior SRE-related procedures must be administered prior to 
randomization 
• Clarified that study treatment is radium-223 dichloride/placebo combined with 
exemestane and everolimus 
• Clarified that SSEs should be recorded until the end of active follow-up regardless of 
whether subjects start new anti-cancer therapies 
• Clarified that permanent discontinuation of study treatment is not required for subjects 
who experience bone or non-bone disease progression unless chemotherapy is required 
• Reduced the maximum CTCAE grade required prior to re-dosing with radium-223 
dichloride/placebo after recovery from diarrhea, nausea/vomiting, and constipation 
from Grade ≤2 to Grade ≤1 
• Added plasma collection for biomarker analysis 
• Added triglycerides, glucose, and phosphate to the list of clinical chemistry tests to be 
evaluated 
• Clarified the timing of blood and urine sample collection for biomarker analysis  
• Corrected the calculation of the BPI-SF items from sums to means 
• Added a requirement that all relevant symptoms related to SSEs be recorded as AEs  
• Replaced the GFR formula with a link to the specific GFR calculator using the MDRD 
study equation 
• Added an exclusion criterion for breast-feeding women 
• Replaced bullets with numbering for the lists of inclusion and exclusion criteria  
• Removed reference to monitoring of PSA  
• Updated information on calculation of sample size, including changing total number of 
planned subjects from 310 to 311 
• Added serum albumin as a laboratory assessment 


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• Changed the required duration of bisphosphonate treatment from at least 3 months 
prior to start of study treatment to at least 1 month prior to start of study treatment 
• Updated inclusion criteria to include bone lesions asymptomatic  
• Updated study design to exclude immediate life-threatening visceral disease and 
deleted stratum  
• Added pulse oximetry O2 saturation >92% to inclusion criteria if lung metastases are 
present  
• Added life-threatening visceral disease, lymphangitic carcinomatosis, ascites requiring 
paracentesis, and hypersensitivity to the active substance or to any of the excipients of 
exemestane and everolimus or to other rapamycin derivatives to exclusion criteria  
• Changed the timing of evaluation for radiologic progression from 12 weeks to 8 weeks  
• Changed the timing of the CT/MRI confirmatory scan from 8 weeks to 6 to 8 weeks 
• Updated required interval of coagulation panel testing prior to treatment to ensure 
within proper safety parameters 
• Clarified calculation of determination of sample size per request of the French Ethics 
Committee 
• Removed the inclusion criteria specification that AST and ALT values above the ULN 
could not be related to liver metastases 
• Revised inclusion criteria to allow subjects treated with newly available and other 
anticoagulants to enter the study 
• Added a heading for clarification purposes in dose modifications section 
• Specified methods for determining HER2 status in description of screening period to 
be consistent with the rest of the protocol 
• Provided updated information on dosing used in study DC 109 
• Updated dose adjustment for everolimus as modifications are applicable based on 
product label per country 
• Moved statement regarding subjects already receiving exemestane and everolimus 
from inclusion to exclusion criteria 
• Added FDG PET scan as an adjunct to CT/MRI in line with RECIST 1.1 guidelines 
based on feedback from participating sites and regulatory authorities.  Guidance was 
provided to ensure that this additional imaging modality is used for confirmation of 
new disease only, in compliance with the RECIST 1.1 criteria 
• Revised storage conditions for exemestane and everolimus 
• Clarified definition of soft tissue lesions 
• Updated timing for completion of BPI-SF questionnaire 
• Revised exclusion criterion regarding use of biologic response modifiers to be within 
4 weeks within randomization 


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• Updated inclusion criteria requirements for duration of laboratory assessments prior to 
randomization 
• Revised exclusion criterion regarding platelet transfusions to be within 4 weeks prior 
to randomization 
• Added exclusion criteria for known presence of osteonecrosis of jaw 
• Clarified that if exemestane or everolimus or further standard of care hormonal anti-
cancer therapy are discontinued, radium-223 dichloride/placebo must be discontinued 
• Updated requirement for thrombocytopenia to recover to Grade 1 before restarting 
radium-223 treatment to better ensure patient safety and to align with the dose 
modification guidance for everolimus 
15.1.1 
Overview of changes to the study 
Modification 1 
Clarified the inclusion criterion of menopausal status based on feedback received from the 
sites 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
 
Modification 2 
Changed the inclusion/exclusion criteria to permit visceral metastases based on feedback from 
the sites 
Sections affected include:  
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
• 6.2 Exclusion criteria 
• 9.4.2.3 Exploratory efficacy endpoints 
 
Modification 3 
Changed the requirement for baseline scans to be within 3 weeks prior to randomization rather 
than within 6 weeks of randomization to ensure the time interval between baseline disease 
assessment and start of treatment is in line with RECIST 1.1 guidelines.  Increased the 
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Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
• Table 9-1: Schedule of assessments 
• 9.2.1 Screening period (Visits 0 to 1) 
• 9.2.6 Radiological assessment: tumor and response evaluation 
 
Modification 4 
Added an inclusion criterion that subjects must have had progressive disease after treatment 
with a non-steroidal aromatase inhibitor at the request of the FDA 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion criteria 
 
Modification 5 
Clarified that all prior SRE-related procedures must be administered prior to randomization 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion criteria 
 
Modification 6 
Clarified that study treatment is radium-223 dichloride/placebo combined with exemestane 
and everolimus 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• Synopsis: Methodology 
• 5.1.1 Study periods and duration  
• 6.1 Inclusion criteria 
• 7.1 Treatments to be administered 
• 7.4.5 Dose administration 
• 7.4.6 Dose adjustments, delays, and treatment discontinuations 
• 8.1.2 Permitted concomitant therapy 
• 8.2 Post-study treatment therapy 
• 9.2.3 Treatment period 


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• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 
Modification 7 
Clarified that SSEs should be recorded until the end of active follow-up regardless of whether 
subjects start new anti-cancer therapies 
Sections affected include: 
• Synopsis: Treatment period 
• 5.1.1 Study periods and duration 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.2 Active follow-up without clinic visits 
• 9.2.4.3 End of active follow-up 
 
Modification 8 
Clarified that permanent discontinuation of study treatment is not required for subjects who 
experience bone or non-bone disease progression unless chemotherapy is required.  This 
change was made at the request of the FDA. 
Sections affected include: 
• Synopsis:  Methodology 
• 6.3.1.1 Withdrawal from treatment period (collection of follow-up data) 
 
Modification 9 
Reduced the maximum CTCAE grade required prior to re-dosing with radium-223 
dichloride/placebo after recovery from diarrhea, nausea/vomiting, and constipation from 
Grade ≤2 to Grade ≤1.  Fatigue was also added as a toxicity, which required recovery to 
Grade ≤1 prior to the next study drug administration.  These changes were made at the request 
of the FDA. 
Sections affected include: 
• 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 
Modification 10 
Added plasma to the serum and urine biomarker collection since biomarkers will be assessed 
from plasma in this study 
Sections affected include: 
• Table 9-1: Schedule of assessments 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 


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• 9.7.2.1 Urine and blood based biomarker analysis 
 
Modification 11 
Added triglycerides, glucose, and phosphate to the list of clinical chemistry tests to be 
evaluated.  Glucose and triglycerides need to be monitored per the product labels for 
everolimus.  Phosphate was added to allow a more complete evaluation of Ca+/phosphate 
metabolism as the subjects will receive concomitant bisphosphonates or denosumab. 
Sections affected include: 
• Table 9-1: Schedule of assessments 
• 9.2.1 Screening period (Visits 0 to 1) 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up 
• 9.3.3 Other baseline characteristics 
• 9.6 Safety 
 
Modification 12 
Clarified the timing of the blood and urine sample collection for biomarker analysis to ensure 
consistency 
Sections affected include: 
• Table 9-1: Schedule of assessments 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.7.2.1 Urine, plasma, and serum based biomarker analysis 
 
Modification 13 
Corrected the calculation of the BPI-SF items from sums to means 
Sections affected include: 
• 9.4.2.2 Secondary efficacy endpoints 
 


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Modification 14 
Added a requirement that all relevant symptoms related to SSEs be recorded as AEs.  
Symptomatic skeletal events and the respective CRF (SSE form) requires the Investigator to 
report the symptoms using a dynamic search list.  To be able to select the symptoms in the 
SSEs form the Investigator must have completed an AE form that reports the relevant 
symptom(s).   
Sections affected include: 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.2 Visits 3, 5 and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.2 Active follow-up without clinic visits 
• 9.2.4.3 End of active follow-up 
• 9.6.1.3 Assessments and documentation of adverse events 
 
Modification 15 
Replaced the GFR formula with a link to the specific GFR calculator using the MDRD study 
equation.  The MDRD formula to be used for the calculation of GFR varies depending on the 
method used for serum creatinine assessment (standardized/traceable to isotope dilution mass 
spectrometry method versus non-standardized/non-traceable to isotope dilution mass 
spectrometry method). 
Sections affected include: 
• 16.3 Calculation for glomerular filtration rate 
 
Modification 16 
Added an exclusion criterion for breast-feeding women 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion criteria 
• 6.2 Exclusion criteria 
 
Modification 17 
Replaced bullets with numbering for the lists of inclusion and exclusion criteria for 
consistency with the eCRF 


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Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
• 6.2 Exclusion criteria 
 
Modification 18 
Removed reference to monitoring of PSA because study is being conducted only in women 
Sections affected include: 
• 9.3.3 Other Baseline Characteristics 
 
Modification 19 
Updated information on calculation of sample size, including changing total number of 
planned subjects from 310 to 311 
Sections affected include: 
• Synopsis: Number of subjects 
• Synopsis: Plan for statistical analysis 
• 5.1 Design Overview 
• 6. Studying Population 
• 10.4 Determination of Sample Size 
 
Modification 20 
Added serum albumin >30 g/L as a laboratory assessment 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion Criteria 
 
Modification 21 
Changed the required duration of bisphosphonate treatment from at least 3 months prior to 
start of study treatment to at least 1 month prior to start of study treatment because 1 month is 
sufficient to allow these treatments to have full effect on the bone function 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion Criteria 
• 7.1 Treatments to be administered 


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• 8.1.2 Permitted Concomitant Therapy 
 
Modification 22 
Updated inclusion criteria to include bone lesions asymptomatic 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion Criteria 
 
Modification 23 
Updated study design to exclude immediate life-threatening visceral disease and deleted 
stratum 
Sections affected include: 
• Synopsis: Study objectives 
• 5.1 Design Overview 
• Figure 5-1: Study Design Schematic 
• 7.3 Treatment Assignment 
• 10.1 General Considerations 
• 10.3 Variables and statistical analyses 
• 10.3.3 Exploratory efficacy analysis 
 
Modification 24 
Added pulse oximetry O2 saturation >92% to inclusion criteria if lung metastases are present 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion Criteria 
 
Modification 25 
Added life-threatening visceral disease, lymphangitic carcinomatosis, ascites requiring 
paracentesis, and hypersensitivity to the active substance or to any of the excipients of 
exemestane and everolimus or to other rapamycin derivatives to exclusion criteria 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion criteria 
• Exclusion Criteria 
 


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Modification 26 
Changed the timing of the CT/MRI confirmatory scan from 8 weeks to 6 to 8 weeks 
Sections affected include: 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.4.2 Definition of efficacy variables 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up 
• 16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 
Modification 27 
Changed the timing of evaluation for radiologic progression from 12 weeks to 8 weeks 
Sections affected include: 
• 5.1.1 Study periods and duration 
• Figure 5-1: Study Design Schematic 
• 9.1 Tabular Schedule of Evaluations 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.2 Active follow-up without clinic visits 
• 9.2.5 End of study 
• 9.2.6 Radiological assessment: tumor and response evaluation 
 
Modification 28 
Updated required interval of coagulation panel testing prior to treatment to ensure within 
proper safety parameters 
Sections affected include: 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
 


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Modification 29 
Clarified calculation of determination of sample size per request of the French Ethics 
Committee  
Sections affected include: 
• 10.4 Determination of sample size 
 
Modification 30 
Removed the inclusion criteria specification that AST and ALT values above the ULN could 
not be related to liver metastases  
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria  
• 6.1 Inclusion criteria 
 
Modification 31 
Revised inclusion criteria to allow subjects treated with newly available and other 
anticoagulants to enter the study 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria  
• 6.1 Inclusion criteria 
 
Modification 32 
Added a heading for clarification purposes in dose modifications section 
Section affected includes: 
• 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 
Modification 33 
Specified methods for determining HER2 status in description of screening period to be 
consistent with the rest of the protocol 
Section affected includes: 
• 9.2.1 Screening period (Visit 0 to 1) 
 
Modification 34 
Provided updated information on dosing used in study DC 109 
Section affected includes: 
• 3.3.1.3 Dosing rationale 


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Modification 35 
Updated dose adjustment for everolimus as modifications are applicable based on product 
label per country 
Section affected includes: 
• 7.4.6.1 Radium-223 dichloride dose delays and treatment discontinuations guidance 
 
Modification 36 
Moved statement regarding subjects already receiving exemestane and everolimus from 
inclusion to exclusion criteria 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion criteria 
• 6.1 Inclusion Criteria 
• 6.2 Exclusion Criteria 
 
Modification 37 
Added FDG PET scan as an adjunct to CT/MRI in line with RECIST 1.1 guidelines based on 
feedback from participating sites and regulatory authorities.  Guidance was provided to ensure 
that this additional imaging modality is used for confirmation of new disease only, in 
compliance with the RECIST 1.1 criteria  
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion Criteria  
• 9.1 Tabular schedule of evaluations 
• 9.2.1 Screening period (Visit 0 to 1) 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards)  
• 9.2.3.4 End of treatment visit  
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up 
• 9.2.6 Radiological assessment: tumor and response evaluation  
• Appendix 16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 


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Modification 38 
Revised storage conditions for exemestane and everolimus 
Sections affected include: 
• 7.2.1.3 Study treatment with exemestane and everolimus 
 
Modification 39 
Clarified definition of soft tissue lesion 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion criteria 
• 6.1 Inclusion criteria 
• 16.2 Response Evaluation Criteria in Solid Tumors 
 
Modification 40 
Updated timing for completion of BPI-SF questionnaire 
Sections affected include: 
• 9.2.1 Screening period (Visit 0 to 1) 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit)  
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of Active follow-up 
• 9.4.2.2 Secondary efficacy endpoints 
 
Modification 41 
Revised exclusion criterion regarding use of biologic response modifiers to be within 4 weeks 
within randomization 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion Criteria 
• 6.2 Exclusion criteria 
• 8.1.2 Permitted concomitant therapy 
 
Modification 42 
Updated inclusion criteria requirements for duration of laboratory assessments prior to 
randomization  


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• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Inclusion Criteria 
• 6.1 Inclusion criteria 
 
Modification 43 
Revised exclusion criteria regarding platelet transfusions to be within 4 weeks prior to 
randomization 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion Criteria 
• 6.2 Exclusion criteria 
• 8.1.2 Permitted concomitant therapy 
• 9.2.3 Treatment Period 
 
Modification 44 
Added exclusion criteria for known presence of osteonecrosis of jaw 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion Criteria 
• 6.2 Exclusion criteria 
• 7.4.6.1 Radium-223 dichloride dose delays and treatment discontinuations guidance 
 
Modification 45 
Clarified that if exemestane or everolimus or further standard of care hormonal anti-cancer 
therapy are discontinued, radium-223 dichloride/placebo must also be discontinued 
Sections affected include: 
• Synopsis: Methodology 
• 5.1.1 Design Overview 
• 6.3.1 Withdrawal 
 
Modification 46 
Updated requirement for thrombocytopenia to recover to Grade 1 before restarting 
radium-223 treatment to better ensure patient safety and to align with the dose modification 
guidance for everolimus 
Section affected includes: 
• 7.4.61 Radium-223 dichloride dose delays and treatment discontinuations guidance 
• 7.4.7 Supportive care guidelines 
• 9.2.3 Treatment period 


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15.1.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 1 are provided in Section 15.1.2 of 
integrated protocol Version 2.0. 
15.2 
Amendment 3 
Amendment 3 (dated 29 JUL 2015) is an amendment to global Amendment 1 of the original 
protocol dated 16 MAR 2015.  Changes to the protocol include: 
• Added pain improvement as a secondary endpoint as patients can now be evaluated for 
pain improvement based on revision of exclusion criteria. 
• Changed assessment of bone ALP response from EOT to Week 24.  
• Updated the quantification of radium-223 radioactivity in Xofigo® based on the 
revised primary standardization performed by the US NIST. 
• Added text related to counting of SREs for clarification. 
• Removed exclusion criteria 13 per objection from participating sites that majority of 
subjects with advanced breast cancer and bone disease would not be asymptomatic or 
mildly symptomatic. 
• Changed estimated glomerular filtration rate from 60 to 30 to align with denosumab 
and bisphosphonates labeling and exclude only patients with severe renal impairment. 
• Changed thrombocytopenia from Grade 3 to Grade 2 for consistency. 
• Removed completion of BPI-SF at screening based on revision of exclusion criteria. 
• Changed body weight to be taken within 5 days to allow more time to receive results. 
• Changed blood samples to be taken within 5 days to allow more time to receive 
results. 
• Added collection time period for biomarkers to be within 5 days to allow more 
flexibility. 
• Added text for the collection of scans for retrospective analysis. 
• Added new Appendix to provide detailed guidance for the administration of the BPI-
SF questionnaire. 
• Added 8-week time interval for performance of assessments during active follow-up. 
• Updated screening procedures for consistency. 
• Changed pregnancy test to be taken within 5 days to allow more time to receive 
results. 
• Removed requirement for first dose of study treatment to occur 1 to 3 weeks after 
randomization.  
• Removed requirement that bisphosphonates or denosumab to be administered at least 2 
hours before study treatment. 
• Modified text for clarification. 


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• The list of abbreviations was updated to reflect the usage of abbreviations in the 
amended protocol. 
 
15.2.1 
Overview of changes to the study 
Modification 1 
Added pain improvement as a secondary endpoint as patients can now be evaluated for pain 
improvement based on revision of exclusion criteria. 
Sections affected include: 
• Synopsis: Study objectives 
• 4. Study objectives 
• 5.1.2 Study endpoints 
• 9.4.1 Efficacy variables 
• 9.4.2.2 Secondary efficacy endpoints 
• 10.3 Variables and planned statistical analyses 
 
Modification 2 
Changed assessment of bone ALP response from EOT to Week 24.  The objective of the 
biomarker assessment is to evaluate the effect of radium-223 dichloride on the bone markers.  
The change will allow assessment of bone biomarkers at the end of treatment with 
radium-223, which corresponds to week 24 rather than at EOT which in this study is intended 
as the end of treatment of all study medications (radium-223, everolimus and exemestane).  In 
fact exemestane and everolimus treatment may continue beyond week 24 till the subject 
experiences progression or unacceptable tolerability. 
Sections affected include: 
• Synopsis: Study objectives 
• 4. Study objectives 
• 5.1.2 Study endpoints 
• 9.4.1 Efficacy variables 
• 9.4.2.3 Exploratory efficacy endpoints: 
• 10.3 Variables and planned statistical analyses 
 
Modification 3 
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 


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prepare the NIST traceable radium-223 reference material, which is 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 (52) and current measurements was confirmed and a 
revised NIST primary reference standard has been issued (53).  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 [53]) 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.  A 
respective variation application and substantial amendment to our CTAs have been initiated.   
The current standard (NIST 2010 [52]), dial setting and dose will remain in effect until a 
unique implementation date in Q2 2016 as agreed with FDA and EMA.  All clinical sites 
using radium-223 dichloride will be notified in writing about the exact date of implementation 
prior to the effective date. 
Justification for changing the dose to 55 kBq/kg body weight: 
A systematic approximately 10% error in the radium-223 NIST standardization (NIST 2010 
[52]) means that the current patient dose and the dose documented as safe and efficacious 
throughout development is 55 kBq/kg body weight and not 50 kBq/kg body weight as 
declared during clinical trials and in the marketing authorization application / new drug 
application.  However, as this is a systematic error, the actual dose has been the same all the 
time.  In order to keep the actual dose for patients identical to what has been documented and 
administered so far, also when implementing the new official standard, the nominal value of 
the patient dose will be changed to 55kBq/kg body weight (NIST update [53]). This change 
keeps the same accuracy in the nominal value of the dose.  Thus, there will be no actual 
change in the patient dose (amount of radioactivity), it will be only a change in the dose 
nominal value when corrected according to the new official radium-223 NIST standard.  All 
sites will continue to use the current dial setting (NIST 2010 [52]) for the activity 
measurements until the implementation date in Q2 2016.  
Justification for changing the description of the radioactivity in the vial to 1,100 kBq/mL: 
A systematic approximately 10% error in the radium-223 NIST standard (NIST 2010 [52]) 
means that the Xofigo® solution for injection with a radioactivity concentration claim of 
1,000 kBq/mL, which has been tested in pivotal clinical trials and is currently marketed, 
actually has a concentration of 1,100 kBq/mL. If the drug product concentration is adjusted to 
1,100 kBq/mL, the total activity in the vial (6 mL) must be changed from 6,000 kBq/vial to 
6,600 kBq/vial (changed from 6.0 MBq/vial to 6.6 MBq/vial in many countries). Xofigo® 
solution for injection produced according to the new NIST standardization (NIST update [53]), 
is the same product as before.   NOTE:   All product received by sites will be labeled with the 
current standard activity of 1000 kBq/mL until the implementation date in Q2 2016. 
Now that the new radium-223 standard has been published, Bayer has applied for labeling and 
packaging changes, in accordance with the new standards, with each Health Authority for 
which Bayer holds a marketing application for radium-223 dichloride.  Once all approvals 
have been received, the updated standard will be applied to all active protocols that include 


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radium-223 dichloride, including this one, and the verification of the patient dose in treatment 
sites has to be performed using updated dial-settings of dose calibrators.   
The change in the NIST radium-223 standard has no impact on subjects; subjects are 
receiving, and will continue to receive, the same actual dose that was studied in ALSYMPCA 
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.  Subjects 
who are on-treatment at the time the new NIST calibration standard goes into effect will be 
notified of this change and will be required to sign a Patient Information Sheet to 
acknowledge that they have received information on the updated NIST standard calibration.  
All subjects randomized after the new calibration standard is in effect will sign a revised ICF 
that contains the updated NIST standard calibration. 
Note: throughout this document the dose of radium-223 dichloride is given as 50 kBq/kg, 
which is based on the original NIST standardization (NIST 2010 [52]); however, when NIST 
issues the updated radium-223 dichloride standardization, the dose administered will actually 
be 55 kBq/kg (based on a change to the reference standard (NIST update [53]) only), though 
the volume of radium-223 dichloride given to each subject will remain the same.   
Sections affected include: 
• Synopsis: Dose 
• Synopsis: Methodology 
• 3.3.1.3 Dosing Rationale 
• 5.1.1 Study periods and duration 
• 7.1 Treatments to be administered 
• 7.2.1.1 Radium-223 dichloride 
• 7.4.1 Dose calibration 
• 7.4.3 Radium-223 dose calculation 
• 14. Reference list 
 
Modification 4 
Added text related to counting of SREs for clarification. 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
 
Modification 5 
Removed exclusion criteria 13 as there was doubt if patient's assessment of pain was a proper 
definition in being asymptomatic or mildly symptomatic. 


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Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
 
Modification 6 
Changed estimated glomerular filtration rate from 60 to 30 to exclude patients with severe 
renal impairment. 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
 
Modification 7 
Changed thrombocytopenia from Grade 3 to Grade 2 for consistency. 
Section affected includes: 
• 7.4.6.1 Radium-223 dichloride dose delays and treatment discontinuations guidance 
 
Modification 8 
Removed completion of BPI-SF at screening based on revision of exclusion criteria. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.1 Screening period (Visit 0 to 1) 
 
Modification 9 
Changed body weight to be taken within 5 days to allow more time to receive results. 
Sections affected include: 
• 7.4.3 Radium-223 dose calculation 
• 9.1 Tabular schedule of evaluations 
• 9.2.3 Treatment period 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
 
Modification 10 
Changed blood samples to be taken within 5 days to allow more time to receive results. 


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Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.3 Treatment period 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.3 End of active follow-up 
• 9.7.2.1 Urine and blood based biomarker analysis 
 
Modification 11 
Added collection time period for biomarkers to be within 5 days to allow more flexibility. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
 
Modification 12 
Added text for the collection of scans for retrospective analysis. 
Sections affected include: 
• 9.2.6 Radiological assessment: tumor and response evaluation 
 
Modification 13 
Added new Appendix to provide detailed guidance for the administration of the BPI-SF 
questionnaire. 
Sections affected include: 
• 14. Reference list 
• Appendix 16.7 BPI-SF 
 
Modification 14 


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Added 8-week time interval for performance of assessments during active follow-up. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.4.1 Active follow-up with clinic visits 
 
Modification 15 
Updated screening procedures for consistency. 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion criteria 
 
Modification 16 
Changed pregnancy test to be taken within 5 days of dosing to allow more time to receive 
results. 
Sections affected include: 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
 
Modification 17 
Removed requirement for first dose of study treatment to occur 1 to 3 weeks after 
randomization as some countries will not be able to meet this requirement.  It is not expected 
that the change will affect the safety of the subjects on study because they will undergo safety 
laboratory tests and will be assessed for AEs before first administration of radium-223 
dichloride to ensure they continue to meet the protocol requirements.  
Sections affected include: 
• 6. Study population 
• 9.1 Tabular schedule of evaluations 
 
Modification 18 
Removed requirement that bisphosphonates or denosumab to be administered at least 2 hours 
before study treatment based on feedback from Clinical Pharmacology that any potential risk 
for interaction could be excluded. The change is being implemented across the radium-223 
clinical program. 


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Sections affected include: 
• 7.1 Treatments to be administered 
• 8.1.2 Permitted concomitant therapy 
 
Modification 19 
Modified text for clarification. 
Sections affected include: 
• 6.3.1.1 Withdrawal from treatment period (collection of follow-up data) 
• 7.2.1.3 Study treatment with exemestane and everolimus 
• 9.1 Tabular schedule of evaluations 
• 9.2.4.3 End of active follow-up 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.7.2.1 Urine and blood based biomarker analysis 
 
Modification 20 
• The list of abbreviations was updated to reflect the usage of abbreviations in the 
amended protocol. 
• Sections affected include: 
• List of abbreviations 
 
15.2.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 3 are provided in Section 15.2.2 of 
integrated protocol Version 3.0. 
15.3 
Amendment 5 
Amendment 5 (dated 28 APR 2016) is an amendment to global Amendment 3 of the original 
protocol dated 29 JUL 2015.  Changes to the protocol include: 
• Updated text for estradiol assay as postmenopausal ranges and detection limit for 
serum/plasma estradiol assay vary per laboratory. 
• Updated frequency of bone scans. 
• Deleted text for exclusion of bilateral and 2 distinct breast cancers. 
• Clarified data collection for pain medication in alignment with completion of the 
BPI-SF questionnaire. 
• Clarified language for everolimus dosing. 
• Added text for completion of PRO Questionnaire Information Sheet by study staff for 
when BPI questionnaire is required to be completed. 


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• Clarified the process for unblinded staff members to obtain subject’s treatment 
assignment. 
• Clarified the drug order process at sites in the USA. 
• Clarified radium-223 administration timelines. 
• Changed the SRE definition used for eligibility to make it in line with the SRE 
definition used in prior studies with other bone-targeted agents (Denosumab, 
bisphosphonates). 
• Updated time period for recording of analgesic use in diary. 
• Updated text for independent radiological review to include that all digitized 
images/scans will be collected for retrospective analysis. 
• Added text as biomarkers are to be collected before study drug dosing. 
• Added PRO Questionnaire Information Sheet for completeness. 
• Updated text for clarification. 
• Definition of pain progression was revised. 
• Added separate collection of opiate use to allow calculation of time to opiate use. 
• Removed progression as a separate assessment because progression is assessed 
radiologically as per tumor assessment schedule. 
• Clarified that clinical chemistry assessment will include bone marrow ALP only if that 
testing can be performed locally. 
• Clarified timing of technetium-99m bone scans and CT scans. 
• Updated study medical expert and contact information 
• Added sampling for CTCs, which are believed to represent a surrogate for tumor cells 
and can be used as a surrogate to demonstrate efficacy of the drug by enumeration of 
CTCs but also as a source of tumor molecular characterizations. 
 
15.3.1 
Overview of changes to the study 
Modification 1 
Updated text for estradiol assay as postmenopausal ranges and detection limit for 
serum/plasma estradiol assay vary per laboratory.  
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion Criteria. 
 
Modification 2 
Updated frequency of bone scans.  All bone lesions identified at baseline by bone scan need to 
be scanned by CT or MRI and progression in bone needs to be confirmed by CT/MRI.  The 
CT or MRI scans are to be performed at an interval of every 8 weeks (± 7 days).  Under these 


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circumstances, a bone scan interval of 12 weeks, instead of 8 weeks, is appropriate and is 
more in line with standard clinical practice resulting also in a lower radiation exposure of 
patients. 
Section affected includes: 
• 9.2.6 Radiological assessment: tumor and response evaluation. 
 
Modification 3 
Deleted text for exclusion of bilateral and 2 distinct breast cancers.  Eligible patients for this 
study must have stage IV (Any T, Any N, M1) metastatic disease and be considered 
candidates for second or further line of therapy.  None of the recent studies (i.e. BOLERO, 
PALOMA) in metastatic setting excluded patients with such conditions.   
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.2 Exclusion Criteria. 
 
Modification 4 
Clarified data collection for pain medication in alignment with completion of the BPI-SF 
questionnaire. 
Sections affected include: 
• 8.1.2 Permitted concomitant therapy 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up. 
 
Modification 5 
Clarified language for everolimus dosing. Following input from Investigators, start of 
everolimus at a dose of 5 mg/day is an approach that may be used in some patients as per their 
institutional standard practice. The language in the protocol has been clarified mentioning that 
the dose of 10 mg/day is actually the recommended dose and that the starting dose should be 
in line with the local label and/or local standard of practice.   
Sections affected include: 
• 7.1 Treatments to be administered 
• 7.2.1.3 Study treatment with exemestane and everolimus 
• 7.4.5 Dose administration 


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• 7.4.7 Supportive care guidelines 
• 8.1.2 Permitted concomitant therapy 
• 9.2.3 Treatment period. 
 
Modification 6 
Added text for completion of PRO Questionnaire Information Sheet by study staff for when 
BPI questionnaire is required to be completed. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up. 
 
Modification 7 
Clarified the process for unblinded staff members to obtain subject’s treatment assignment. 
Section affected includes: 
• 7.3 Treatment assignment. 
 
Modification 8 
Clarified the drug order process at sites in the USA. 
Section affected includes: 
• 7.3 Treatment assignment. 
 
Modification 9 
Clarified radium-223 administration timelines. 
Section affected includes: 
• 7.2.1.1 Radium-223 dichloride. 
 
Modification 10 
Changed the SRE definition used for eligibility to make it in line with the SRE definition used 
in prior studies with other bone-targeted agents (Denosumab, bisphosphonates). 
Sections affected include: 


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• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.1 Inclusion Criteria. 
 
Modification 11 
Updated time period for recording of analgesic use in diary. 
Section affected includes: 
• 9.1 Tabular schedule of evaluations. 
 
Modification 12 
Updated text for independent radiological review to include that all digitized images/scans 
will be collected for retrospective analysis. 
Section affected includes: 
• 13.1.2 Independent radiological review. 
 
Modification 13 
Added text as biomarkers are to be collected before study drug dosing. 
Section affected includes: 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit). 
 
Modification 14 
Added PRO Questionnaire Information Sheet for completeness. 
Sections affected include: 
• 16.9 Patient Reported Questionnaire Information Sheet 
 
Modification 15 
Updated text for clarification. 
Sections affected include: 
• Synopsis: Study objectives 
• 4. Study objectives 
• 5.1.2 Study endpoints 
• 6. Study Population 
• 9.1 Tabular schedule of evaluations 
• 9.4.1 Efficacy variables 
• 9.4.2.2 Secondary efficacy endpoints 


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• 9.4.2.3 Exploratory efficacy endpoints 
• 9.6.1.3 Assessments and documentation of adverse events 
• 9.7.2 Biomarker assessments 
• 10.3 Variables and planned statistical analyses 
 
Modification 16 
Definition of pain progression was revised. 
Sections affected include: 
• List of abbreviations 
• 9.4.2.2 Secondary efficacy endpoints. 
 
Modification 17 
Added separate collection of opiate use to allow calculation of time to opiate use. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up. 
 
Modification 18 
Removed progression as a separate assessment because progression is assessed radiologically 
as per tumor assessment schedule. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.2 Visits 3, 5 and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up. 


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Modification 19 
Clarified that clinical chemistry assessment will include bone marrow ALP only if that testing 
can be performed locally. 
Sections affected include: 
• Section 9.1 Tabular schedule of evaluations  
• 9.2.1 Screening period (Visit 0 to 1) 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.2 Visits 3, 5 and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up. 
• 9.3.3 Other baseline characteristics 
 
Modification 20 
Clarified timing of technetium-99m bone scans and CT scans. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.3 Ongoing treatment with exemestane and everolimus (Visits 11, 12 and 
onwards) 
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.3 End of active follow-up 
• 9.2.6 Radiological assessment: tumor and response evaluation 
 
Modification 21 
Updated study medical expert and contact information. 
Section affected includes: 
• Title page 
 


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Modification 22 
Added sampling for CTCs. CTCs are believed to represent a surrogate for tumor cells and can 
be used as a surrogate to demonstrate efficacy of the drug by enumeration of CTCs but also as 
a source of tumor molecular characterizations. 
Sections affected include: 
• List of Abbreviations 
• 9.1 Tabular schedule of evaluations 
• 9.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
• 9.2.3.4 End of treatment visit 
• 9.7.2.2 Collection of Circulating Tumor Cells for Biomarker Analyses 
 
15.3.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 5 are provided in Section 15.3.2 of 
integrated protocol Version 4.0. 
15.4 
Amendment 8 
Amendment 8 (dated 18 MAY 2017) is an amendment to global Amendment 5 of the original 
protocol dated 09 JUL 2015.  Changes to the protocol include: 
• Removed timeframe for prior chemotherapy administered for adjuvant/neo-adjuvant 
disease. 
• Added text to provide tolerance limits for permitted radiation. 
• Text was updated to provide clarity to study sites. 
• Text was added for consistency with Table 9-1: Schedule of assessments. 
• Text was added as it is mandatory to include for studies involving Japanese centers 
where the CSP requires the use of medical devices that are currently non-approved in 
Japan. 
• Clarified sites at which CTCs are collected. 
• Added interim data review. 
• Updated company name. 
• Updated text for independent radiological review. 
• Added text for the establishment of an independent unblinded data review committee.  
• Reformatted page for signature of the sponsor’s medically responsible person. 
15.4.1 
Overview of changes to the study 
Modification 1 
Removed timeframe for prior chemotherapy administered for adjuvant/neo-adjuvant disease.  
More recent data from chemotherapy combination studies with Xofigo shows good safety 
profile of the combination.  In addition, long term safety follow-up data from ALSYMPCA 


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showed good safety profile for patients that received subsequent chemotherapy.  At the time 
of the current study set up, this data was not available. 
Sections affected include: 
• Synopsis: Diagnosis and main criteria for inclusion and exclusion 
• 6.2 Exclusion criteria. 
 
Modification 2 
Added text to provide tolerance limits for permitted radiation. 
Sections affected include: 
• 7.4.4 Study drug dose preparation. 
 
Modification 3 
Text was updated to provide clarity to study sites. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations. 
 
Modification 4 
Text was added for consistency with Table 9-1: Schedule of assessments.  Although monthly 
visits might not be possible for some patients, tumor assessments as per time schedule 
described in Section 9.2.6 might be feasible and will allow collection of data for disease 
response assessment related to some efficacy endpoints (radiological PFS, radiological bone-
specific PFS, etc). 
Sections affected include: 
• 9.2.4.2 Active follow-up without clinic visits. 
 
Modification 5 
Text was added as it is mandatory to include for studies involving Japanese centers where the 
CSP requires the use of medical devices that are currently non-approved in Japan. 
Sections affected include: 
• 9.6.3 Reporting of medical device failures. 
 
Modification 6 
Clarified sites at which CTCs are collected. 
Sections affected include: 
• 9.7.2.2 Collection of circulating tumor cells for biomarker analyses.  
 


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Modification 7 
Added interim data review. 
Sections affected include: 
• 10.5 Planned interim data review.  
 
Modification 8 
Updated company name. Bayer HealthCare AG merged with Bayer AG, an affiliated 
company within the Bayer Group, effective as of 1st July 2016. Thereby, Bayer HealthCare 
AG ceased to exist and Bayer AG became its legal successor and automatically took over all 
of the Bayer HealthCare AG’s rights, obligations and liabilities by law. As a result of the 
above mentioned merger, Bayer AG assumes the role of the sponsor. 
Sections affected include: 
• Header 
• Title page 
 
Modification 9 
Updated text for independent radiological review. 
Sections affected include: 
• 9.2.6 Radiological assessment: tumor and response evaluation  
• 13.1.2 Independent radiological review 
 
Modification 10 
Added text for the establishment of an independent unblinded data review committee. 
Sections affected include: 
• List of abbreviations 
• 13.1.3 Independent Data Review Committee 
 
Modification 11 
Added text for the establishment of an independent unblinded data review committee. 
Section affected includes: 
• Signature of the sponsor’s medically responsible person 
 
15.4.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 8 are provided in Section 15.4.2 of 
integrated protocol Version 5.0. 


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15.5 
Amendment 9 
Amendment 9 (dated 03 APR 2018) is an amendment to Version 5.0 of the protocol, dated 
23 MAY 2017.  Changes to the integrated protocol include: 
• New request that bone fractures and bone associated events (e.g., osteoporosis) need to 
be reported as (S)AEs, including during long-term follow-up, regardless of the 
investigator’s causality assessment. 
• Addition of possibility to transition to long-term follow-up study for subjects who 
have completed at a minimum the end of treatment visit or 30 days from last study 
treatment dose, whichever is latest 
• Updated sponsor’s medically responsible person  
• Clarification to AE and SAE reporting requirements during active follow-up in the 
Schedule of Assessments 
• Minor clarifications 
15.5.1 
Overview of changes 
15.5.1.1 
Modification 1 
Bone fractures and bone associated events (e.g., osteoporosis) need to be reported as (S)AEs, 
including during long-term follow-up, regardless of the investigator’s causality assessment. 
Sections affected include: 
• Synopsis 
• 5.1.1 Study periods and duration 
• 9.1 Tabular schedule of evaluations  
• 9.2.3.4 End of treatment visit 
• 9.2.4.1 Active follow-up with clinic visits 
• 9.2.4.2 Active follow-up without clinic visits 
• 9.2.4.3 End of active follow-up 
• 9.6.1.3 Assessments and documentation of adverse events 
• 9.6.1.4 Reporting of serious adverse events 
Rationale: 
The ERA 223 study, a phase III randomized trial in prostate cancer patients examining 
radium-223 dichloride versus placebo in combination with abiraterone and prednisone (study 
number 15396, NCT02043678) was unblinded based on the IDMC recommendation 
following an ad hoc independent analysis where more treatment-emergent fractures, SSE-FS, 
and total deaths events were observed in the active treatment arm compared with the placebo 
arm. Based on these data European Health Authorities requested that all bone fractures and 
bone associated events (e.g., osteoporosis) occurring during study and in the follow-up period 
should be documented regardless of the investigator’s causality assessment. 


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15.5.1.2 
Modification 2 
Clarification of transition to long-term extension study to allow collection of long term safety 
data 
Sections affected include: 
• Synopsis 
• 5.1.1 Study periods and duration 
• 5.3 End of study 
• 9.2.5 End of study 
Rationale 
To allow collection of long term safety data, subjects who have completed at a minimum the 
end of treatment visit or 30 days from last study treatment dose, whichever is latest, may be 
transitioned into a separate long‐term follow‐up study. Until the transition to the long‐term 
follow-up study, subjects will continue to follow all the protocols required procedures and 
visits in the current protocol. 
15.5.1.3 
Modification 3 
The sponsor’s medically responsible person has changed and signature page was updated to 
reflect this. 
Sections affected include: 
• Signature of the sponsor’s medically responsible person 
15.5.1.4 
Modification 4 
Clarification of footnotes in the schedule of assessment to reflect consistency with the body 
text. The AEs and SAEs reporting requirements during active follow-up apply regardless of 
whether the patient has clinic visits or not.  The footnotes previously indicated these reporting 
requirements applied only in the case without clinic visits, which is inconsistent with the 
active follow up description in Section 9.2.4.1. 
Sections affected include: 
• 9.1 Tabular schedule of evaluations 
15.5.1.5 
Minor clarifications 
For Word-related technical reasons, numbered footnotes have been replaced with a summary 
of changes at the start of each amended section. 
15.5.2 
Changes to the protocol text 
Changes to the protocol text are provided in a separate tracked changes document. 
15.6 
Amendment 10 
Amendment 10 (Version 7.0), dated 04 DEC 2019, is a global amendment to Version 6.0 of 
the integrated protocol.  
15.6.1 
Overview of changes 
Overall rationale for the amendment 


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At the time of the primary analysis, only a limited number of subjects were receiving study 
medication (exemestane and everolimus).  
After implementation of CSP Amendment 9, subjects who completed the EOT visit could be 
transferred to a separate extended safety follow-up study for their remaining follow-up. After 
implementation of CSP Amendment 10, all such subjects will be transferred; only subjects 
on oral treatment will remain on study, and no post-treatment data will be collected beyond 
the 30-day safety follow-up (EOT visit).   
As the key efficacy objectives will have been accomplished, long-term safety transferred, and 
only a limited number of subjects will remain in this study, in order to reduce the burden to 
study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, 
and OS. Accordingly, the updated analysis following the closure of the study will be 
descriptive only and may consist of listings. Once subjects are rolled over, the long-term 
safety will be collected and assessed entirely in the separate extended safety follow-up study. 
High-level descriptions and rationales of the changes and the affected sections are listed 
below. 
Sections 
Description of 
change 
Rationale 
Synopsis 
4. Study objectives 
5.1.1 Study periods and 
duration 
5.1.2 Study endpoints 
9.4.1 Efficacy variables 
9.6   Safety 
9.7 Other procedures and 
variables 
Collection of data will 
be reduced to focus on 
acute safety, SSE and 
OS. 
 
 
Clarified the 
assessment of safety 
endpoints. 
Due to the limited number of patients 
beyond primary analysis and to reduce the 
burden to study subjects, collection of data 
will be reduced and will focus mainly on 
acute safety, SSE, and OS.  
 
 
Synopsis 
5.1.1 Study periods and 
duration 
9.1 Tabular schedule of 
evaluations 
9.2.3.2 Visits 3, 5 and 7 
[…] 
9.2.3.3 Ongoing treatment 
with exemestane and 
everolimus […] 
9.2.3.4 End of treatment 
visit 
9.2.4 Active follow-up 
9.2.6 Radiological 
assessment: tumor and 
response evaluation 
9.6 Safety 
Updated schedule of 
assessments and 
procedures 
To reduce the burden to study subjects, 
the schedule of assessments and 
procedures were modified. 
Updated frequency of visits to every 8 
weeks and imaging according to local 
standard practice, until disease 
progression or treatment discontinuation.  
Pain, QoL assessments and biomarker 
collection are being discontinued as they 
will no longer be analyzed. 
 Laboratory assessments were reduced to 
monitoring of adverse events of study 
drugs. 
ECGs will be performed according to local 
standard practice. 
 


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Sections 
Description of 
change 
Rationale 
Synopsis 
5.1.1 Study periods and 
duration 
5.3 End of study 
6.3.1 Withdrawal 
6.3.1.1 
Withdrawal from 
treatment period […] 
8.2 Post-study treatment 
therapy 
9.1 Tabular schedule of 
evaluations 
9.2.3.3 Ongoing treatment 
with exemestane and 
everolimus […] 
9.2.4 Active follow-up 
9.2.3.4 End of treatment 
visit 
9.2.5 End of study 
10.4 Determination of 
sample size 
Clarification on the 
sample size 
Updated criteria to 
transition subjects to 
separate extended 
safety follow-up study 
Removal of active 
follow-up periods 
Subject enrollment in this trial was 
discontinued in APR 2018, prior to accrual 
of the originally planned sample size. 
By the time of primary analysis, all patients 
in follow-up will be transitioned to the 
separate extended safety follow-up study 
(16996). After primary analysis, subjects 
discontinuing study treatment will be 
directly transitioned to the separate 
extended safety follow-up study (16996). 
Therefore, the active follow-up periods are 
no longer applicable. 
Synopsis 
5.1.1 Study periods and 
duration 
6.3.1.1 
Withdrawal from 
treatment period […] 
7.1 Treatments to be 
administered 
7.4.6.1 Radium-223 
dichloride dose delays […] 
9.2.3 Treatment period 
9.2.3.3 Ongoing treatment 
with exemestane and 
everolimus […] 
Updated criteria for 
discontinuation of 
study drugs 
A clarification in regards to the criteria for 
the discontinuation of the study drugs was 
included to make it aligned with standard 
clinical practice, i.e., subjects presenting 
disease progression (defined as as 
radiological progression, either by RECIST 
or bone progression, clinical progression), 
initiation of new anti-cancer therapy, 
occurrence of unacceptable toxicity or 
discontinuation of treatment for other 
reasons will prompt discontinuation of 
study drugs. 
Synopsis 
5.1.1 Study periods and 
duration 
5.3 End of study 
9.2.5 End of study 
Updated end of study 
criteria 
The definition of EOS was modified to 
reflect the changes in study status. EOS 
will occur at the time the last subject on 
treatment discontinues oral exemestane 
and/or everolimus treatment and completes 
end of treatment visit or discontinues from 
this study for another reason. 
In addition, guidance on reporting of safety-
related events after primary analysis for 
sites/subjects not transitioning to extended 
safety follow-up study was included. 
Synopsis 
7.5 Blinding 
10.5 Planned interim data 
review 
Clarification on the 
blinding of the study 
and on the analysis 
performed after last 
subject last visit. 
Following the primary analysis, the study 
will be fully unblinded. 
After the last subject has discontinued 
treatment and study assessments, an 
updated analysis will be performed. 


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Sections 
Description of 
change 
Rationale 
10.1 General 
considerations 
Clarification on the 
further analysis of data 
from patients who 
were transferred  
Data from patients who are transferred to 
the separate extended safety follow-up 
study may be pooled and analyzed 
together with the data from this study. 
10.3.2 Secondary efficacy 
analysis 
Removal of 80% CI 
from the secondary 
efficacy time-to-event 
endpoints.  
Per Sponsor decision, there is no need to 
report 2 different confidence intervals for 
every endpoint in a study that is being 
terminated. The 95% CI was retained as it 
is the most commonly used CI in the 
literature. Of note, both CIs will be retained 
for the primary endpoint.  The 80% value 
corresponds to the 10% 1-sided 
hypothesis test (equivalent to 20% 2-
sided) used as the basis of study power. 
Title page 
Signature of the sponsor’s 
medically responsible 
person 
Sponsor’s medical 
expert and sponsor’s 
medically responsible 
person were changed. 
Role of signatory was 
changed.   
Administrative change. 
15. Protocol amendments 
and 15.1.2, 15.2.2, 15.3.2 
and 15.4.2 Changes to the 
protocol text 
 
Throughout 
The detailed old vs. 
new text comparisons 
for protocol 
amendments 1, 3, 5, 
and 8, and 
descriptions on how 
those comparisons 
were detailed, were 
replaced with a 
reference to the 
respective protocol 
amendment. 
Old annotations from 
previous amendments 
were removed. 
To improve readability, and to reduce 
complexity of the protocol. 
 
15.6.2 
Changes to the protocol text 
Changes to the protocol text are provided in a separate tracked-changes version. 
 


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16. 
Appendices 
16.1 
National Cancer Institute-Common Terminology Criteria, version 4.03 
This study will utilize the NCI-CTCAE v4.03 for toxicity and SAE reporting.  A copy of the 
CTCAE v4.03 can be downloaded from the website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.  All 
appropriate treatment areas should have access to a copy of the CTCAE v4.03. 
16.2 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Disease response and progression will be evaluated in this study using a modified version of 
RECIST version 1.1.(51)  The modification refers to bone lesions assessment: all bone lesions 
are considered non-measurable and new bone lesions identified by bone scan will need to be 
confirmed by further imaging (CT/MRI).  
Definitions: 
Bone lesions: malignant findings in skeleton.  
Soft tissue lesions:  Malignant finding in soft tissue: skin, subcutaneous, muscle, fat, lymph 
nodes. 
Visceral lesions:  Malignant finding in visceral organs: lung, liver, brain, etc.  
Measurable lesions:  Lesions that, at baseline, meet the requirements for being reproducibly 
quantifiable (see section below for detailed definition of measurable lesions).  
Non-measurable lesions:  Lesions that, at baseline, do not meet the below-described 
requirements.  These lesions cannot be chosen for quantitative assessment, and must be 
assessed qualitatively only. 
Target lesions:  Lesions that are chosen at baseline (from the set of measurable lesions) for 
quantitative assessment throughout the trial, using rules outlined below.  A lesion that has 
been selected as a target lesion remains a target lesion for the rest of the trial. 
Non-target lesions:  Lesions that are not chosen at baseline for quantitative assessment, and 
must be assessed qualitatively throughout the trial.  A lesion that has been selected as a non-
target lesion remains a non-target lesion for the rest of the trial. 
Methods of Measurement: 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
All measurements must be recorded in millimeters (or decimal fractions of centimeters). 
For measurements of tumors other than lymph nodes, the longest unbroken diameter seen on 
an axial slice is recorded.  
Lymph nodes must always be measured in the short axis (the longest measurement on an axial 
slice perpendicular to the longest diameter of the lymph node).  Lymph nodes less than 10 mm 
in short axis diameter are defined as normal. 
CT/MRI of chest/abdomen/pelvis and any additional sites of disease (if clinically indicated) 
will be performed for all patients.  


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In addition, all patients will have their bone disease assessed by technetium-99m bone scan 
with careful identification of all disease-related hotspots.  
If FDG PET/CT or FDG PET scan is performed as part of the standard of practice imaging, 
the results of the FDG PET scan can be used as a complement to CT scanning in the 
assessment of disease progression – based on occurrence of new lesions – as per the RECIST 
1.1 algorithm (See section on New lesions in this appendix). 
The CT component of the FDG PET/CT scan, as per RECIST 1.1, can be used for tumor 
measurements only if the site can document that the CT performed as part of a FDG PET/CT 
scan is of identical diagnostic quality to a diagnostic CT. 
FDG PET/CT or 18F-sodium fluoride positron emission tomography (PET)/CT scan is 
acceptable as an alternative to technetium-99m bone scintigraphy if it is the standard of care at 
the institution, provided the same bone imaging modality is used throughout the study. 
Clinical lesions might be assessed clinically only as per the following rules: clinical lesions 
will only be considered measurable when they are superficial (e.g., skin nodules, palpable 
lymph nodes) and ≥10mm diameter as assessed using calipers.  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. 
Baseline Assessment: 
Identifying measurable disease: 
Non-nodal malignant lesions: Measurable lesions are those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI.  If scans 
with slice thickness greater than 5mm are used, the minimum size should be twice the 
slice thickness. 
• 10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
Malignant lymph nodes: To be considered pathologically enlarged, a lymph node must be ≥ 
10 mm in short axis when assessed by CT scan.  To be considered measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan.  
Tumor lesions situated in a previously irradiated area are not considered measurable unless 
there has been demonstrated progression in the lesion. 
Identifying non-measurable disease: 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with short axis 10-14 mm) are considered non-measurable disease.  
Bone lesions: 
All bone lesions (blastic, lytic, mixed type) will be considered non-measurable lesions.   
Selection of target and non-target lesions:  
At baseline, lesions are divided into those that will be followed quantitatively (target lesions) 
and those that will be followed qualitatively (non-target lesions). 


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Target lesions: 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and be recorded and 
measured at baseline.  These lesions should be selected on the basis of their size (lesion with 
the longest diameter/short axis for lymph nodes), be representative of all involved organs and 
should be suitable for reproducible repeated measurements.  
For the purposes of this selection, all lymph nodes should be regarded as a single organ.  If 
there are multiple chains/regions, consider selecting one from each. 
The sum of the diameters (longest diameter for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated by adding all target lesion diameters/short axis (for 
lymph nodes) and reported as the baseline sum of diameters.  The baseline sum of diameters 
will be used as the reference measurement when looking for evidence of objective response at 
later visits. 
If there are more than 5 measurable lesions, those not selected as target lesions will be 
considered together with non-measurable disease as non-target lesions. 
Non-target lesions: 
Non-target lesions include all non-measurable lesions, plus any measurable lesions over and 
above the maximum 5 listed as target lesions.  
Bone lesions are considered non-measurable and therefore should all be classified as non-
target lesions.   
Post-baseline assessment: 
At every response assessment visit after baseline, the Investigator will assess the following:  
• target lesions selected at baseline, and  
• non-target lesions selected at baseline, and   
• search for new lesions.  
The lesion assessments are then combined into an assessment of the entire subject at that visit 
(called the visit response or the overall response). 
Target lesion assessment: 
The Investigator will measure each target lesion in the same manner as at baseline.  
Malignant lymph nodes will be measured in short axis diameter.  
If a lesion decreases in size to the point where it is still present, but cannot be measured 
accurately, a default value of 5 mm should be recorded for its diameter.  
If a lesion has disappeared, a value of 0 mm should be recorded for its diameter. 
If a lesion has split into distinct fragments, the longest diameter of each fragment should be 
measured, and the diameters added together.  
If 2 lesions have merged, the longest diameter of the entire resulting lesion should be 
measured. 
The sum of diameters will be calculated by adding all target lesion diameters/short axis (for 
lymph nodes).  


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The sum of diameters is always compared to 2 reference points: the baseline sum of 
diameters, and the smallest sum of diameters seen during the trial (also called the nadir).  The 
baseline may actually be the nadir, if there has been no reduction in the sum of diameters 
during the trial.  The target lesion response is then classified as follows in Table 16–1. 
Table 16–1:  Target lesion response 
Response 
Response characteristics 
Complete response (CR) 
Complete disappearance of target lesions 
All target lymph nodes <10 mm 
Partial response (PR) 
At least a 30% decrease in the sum of diameters 
from baseline 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters 
from the smallest value seen during the trial 
(including baseline), with at least a 5 mm absolute 
increase in the sum 
Stable disease (SD) 
Neither enough shrinkage to qualify as PR, nor 
enough growth to qualify as PD 
Non-evaluable (NE) 
One or more target lesions not evaluated because 
of imaging issues, coverage, or change in imaging 
technique 
Please note that when lymph nodes are included as target lesions, a CR may occur even when 
the sum of diameters is not zero, since a normal lymph node will have a diameter greater than 
zero but less than 10 mm. 
Non-target lesion assessment: 
Non-target lesions are assessed as a whole.  After examining each non-target lesion, the 
Investigator will classify the non-target lesion response as follows in Table 16–2. 
Table 16–2:  Non-target lesion response 
Response 
Response characteristics 
Complete response (CR) 
Complete disappearance of all non-target lesions  
All non-target lymph nodes <10 mm 
Progressive disease (PD) 
Unequivocal progression of non-target lesions as 
a whole. 
• 
Subjective call by expert reviewer 
• 
Evaluated as a group, not lesion by lesion 
Non-CR/Non-PD 
Non-target lesions still present, without 
unequivocal progression 
Non-evaluable (NE) 
One or more non-target lesions not evaluated 
because of imaging issues, coverage, or change 
in imaging technique 
To achieve unequivocal progression in patients with measurable disease on the basis of the 
non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal progression. 
New lesions: 
Any new lesion that is considered unequivocally malignant is evidence of progression, with 
no minimum size requirement.  


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An individual radiological event will be adjudicated in retrospect as progression at the time it 
was first detected by imaging techniques, even if strict criteria were fulfilled only on 
subsequent radiological testing.  This means that if a new lesion is not unequivocal at the time 
of initial detection, but later becomes unequivocal, the date of progression will be the date it 
was first detected. 
Specific considerations for new bone lesions and for unequivocal progression of existing 
bone lesions: 
The finding of a new bone lesion or progression of existing bone lesions should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor:  some new bone lesions 
or unequivocal increase in size of existing lesions may be simply healing or flare of pre-
existing lesions. 
The following rules will apply: 
• A new bone lesion or progression of existing bone lesion/s initially identified on a 
Tc99m bone scan must be confirmed by CT or MRI.  If confirmed by CT/MRI, the 
date of occurrence of the new lesion or of progression of existing bone lesion/s will be 
the date it was initially detected (by Tc99m bone scan) even if the confirmation by 
CT/MRI was done at a subsequent scan.   
• A new bone lesion or progression of existing bone lesions initially identified by 
CT/MRI (and not visible on a Tc99m bone scan) will not need further confirmation by 
CT/MRI unless not considered unequivocal at time of initial documentation.  The date 
of occurrence of new lesion or progression of existing lesions will be the date it was 
initially detected by CT/MRI. 
New lesions and FDG PET imaging 
New lesions on the basis of FDG PET imaging can be identified according to the following 
algorithm: 
• (-) FDG PET at baseline and (+) FDG PET at follow-up = Progressive Disease (PD) 
based on a new lesion 
• No FDG PET at baseline and (+) FDG PET at follow-up = PD if the new lesion is 
confirmed on CT. If a subsequent CT confirms the new lesion, the date of PD is the 
date of the initial FDG PET scan. 
• No FDG PET at baseline and (+) FDG PET at follow-up corresponding to a pre-
existing lesion on CT that is not progressing is not PD 
Note: A ‘positive’ FDG PET scan lesion means one with uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image 
Visit response: 
The response of the target lesions, the response of the non-target lesions, and the presence or 
absence of new lesions are combined into the visit response for the entire subject at this visit, 
using the tables below. 
 


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Table 16–3:  Visit Response:  Patients with target lesions (with or without 
non-target lesions) 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease. 
The following text descriptions of the visit response are logically equivalent to the tables 
above.  
Complete Response (CR):  Disappearance of all clinical and radiological evidence of tumor 
(both target and non-target).  Any pathological lymph nodes (whether target or non-target) 
must have a reduction in short axis to <10 mm. 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum, no unequivocal progression of existing non-target 
lesions and no appearance of new lesions. 
Stable Disease (SD):  Steady state of disease.  Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target 
lesions and no appearance of new lesions. 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target lesions 
from the smallest sum on-study (this includes the baseline sum if that is the smallest on-
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  Unequivocal progression of existing non-target lesions or the 
appearance of one or more new lesions also constitutes progressive disease.  Ascites or pleural 
effusion will be recorded as disease progression only if proven malignant. 
In the absence of target disease, the following will apply (Table 16–4). 
 


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Table 16–4:  Time Point Response:  Patients with non-target lesions only 
Non-Target Lesions 
New Lesionsa 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD b 
Not all evaluated 
No 
NE 
Unequivocal PDc 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a New lesions must be unequivocal (see bone lesions specifications). 
b “Non-CR/non-PD” is preferred over “stable disease”. 
c “Unequivocal PD”:  Subjective call by expert reviewer.  Evaluated as a group, not lesion by lesion 
 
16.3 
Calculation for glomular filtration rate 
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated glomerular filtration rate 
(GFR), calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) study 
formula.  
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older.  The formula can 
be found at the following web site:  http://www.kidney.org/professionals/kdoqi/gfr_calculator. 
16.4 
New York Heart Association Functional Classification 
Class 
NYHA Functional Classification 
I 
Subjects have cardiac disease but without the resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
II 
Subjects have cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
III 
Subjects have cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest.  Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
IV 
Subjects have cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort is 
increased. 
 


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16.5 
ECOG performance status  
Grade 
Description 
0 
Fully active, able to carry on all pre-diseases performance without restriction.  
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work).  (Karnofsky 
70-80) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours.  (Karnofsky 50-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.  (Karnofsky 30-40) 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.  (Karnofsky 10-20) 
16.6 
Interaction of everolimus with other medicinal products 
Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and 
P-glycoprotein are listed in Table 16–5 below. 
Table 16–5:  Effects of other active substances on everolimus  
Active substance by 
interaction 
Interaction – Change in 
Everolimus AUC/Cmax  
Geometric mean ratio 
(observed range)  
Recommendations 
concerning co-administration  
Potent CYP3A4/P-glycoprotein inhibitors  
Ketoconazole  
AUC ↑15.3-fold  
(range 11.2-22.5) 
 
Cmax ↑4.1-fold  
(range 2.6-7.0)  
Concomitant treatment of 
everolimus and potent inhibitors 
is not recommended.  
Itraconazole, posaconazole, 
voriconazole 
Not studied.  Large increase in 
everolimus concentration is 
expected. 
None 
Telithromycin, clarithromycin 
Not studied.  Large increase in 
everolimus concentration is 
expected. 
None 
Nefazodone 
 
Not studied.  Large increase in 
everolimus concentration is 
expected. 
None 
Ritonavir, atazanavir, 
saquinavir, darunavir, indinavir, 
nelfinavir 
Not studied.  Large increase in 
everolimus concentration is 
expected. 
None 
Moderate CYP3A4/PgP inhibitors  
Erythromycin  
AUC ↑4.4-fold  
(range 2.0-12.6)  
 
Cmax ↑2.0-fold  
(range 0.9-3.5)  
Use caution when co-
administration of moderate 
CYP3A4 inhibitors or P-gp 
inhibitors cannot be avoided.  If 
patients require co-
administration of a moderate 
CYP3A4 or P-gp inhibitor, dose 
reduction to 5 mg daily or 5 mg 
every other day may be 
considered.  However, there are 


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Table 16–5:  Effects of other active substances on everolimus  
Active substance by 
interaction 
Interaction – Change in 
Everolimus AUC/Cmax  
Geometric mean ratio 
(observed range)  
Recommendations 
concerning co-administration  
no clinical data with this dose 
adjustment.  Due to between 
subject variability the 
recommended dose 
adjustments may not be optimal 
in all individuals, therefore close 
monitoring of side effects is 
recommended.  
Verapamil 
AUC ↑3.5-fold  
(range 2.2-6.3)  
 
Cmax ↑2.3-fold  
(range1.3-3.8) 
None 
Ciclosporin oral 
AUC ↑2.7-fold  
(range 1.5-4.7)  
 
Cmax ↑1.8-fold  
(range 1.3-2.6) 
None 
Fluconazole  
Not studied.  Increased 
exposure expected. 
None 
Diltiazem 
 
Not studied.  Increased 
exposure expected. 
None 
Amprenavir, fosamprenavir 
Not studied.  Increased 
exposure expected. 
None 
Grapefruit juice or other food 
affecting CYP3A4/PgP  
Not studied.  Increased 
exposure expected (the effect 
varies widely).  
Combination should be 
avoided.  
Potent CYP3A4 inducers  
Rifampicin  
AUC ↓63%  
(range 0-80%)  
 
Cmax ↓58%  
(range 10-70%)  
Avoid the use of concomitant 
potent CYP3A4 inducers.  If 
patients require co-
administration of a potent 
CYP3A4 inducer, an everolimus 
dose increase from 10 mg daily 
up to 20 mg daily should be 
considered using 5 mg 
increments applied on Day 4 
and 8 following start of the 
inducer.  This dose of 
everolimus is predicted to 
adjust the AUC to the range 
observed without inducers.  
However, there are no clinical 
data with this dose adjustment.  
If treatment with the inducer is 
discontinued, the everolimus 
dose should be returned to the 
dose used prior to initiation of 
the co-administration.  


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Table 16–5:  Effects of other active substances on everolimus  
Active substance by 
interaction 
Interaction – Change in 
Everolimus AUC/Cmax  
Geometric mean ratio 
(observed range)  
Recommendations 
concerning co-administration  
Corticosteroids (e.g., 
dexamethasone, prednisone, 
prednisolone) 
Not studied.  Decreased 
exposure expected.  
None 
Carbamazepine, phenobarbital, 
phenytoin 
Not studied.  Decreased 
exposure expected. 
None 
Efavirenz, nevirapine 
Not studied.  Decreased 
exposure expected. 
None 
St John’s Wort (Hypericum 
perforatum)  
Not studied.  Large decrease in 
exposure expected.  
Preparations containing St 
John’s Wort should not be used 
during treatment with 
everolimus  
Abbreviations:  AUC = area under the concentration curve; Cmax = maximum concentration; 
CYP = cytochrome P450; P-gp = P-glycoprotein. 
16.7 
BPI-SF 
The severity of pain and its impact on daily functions will be self-assessed by the study 
subjects using the BPI-SF (54) measure. 
The BPI-SF allows subjects to rate the severity of their pain and the degree to which their pain 
interferes with common dimensions of feeling and function (e.g., general activity, walking, 
work, mood, enjoyment of life, relations with others, and sleep). The BPI-SF is an 11-item, 
self-administered, clinically valid, reliable, and responsive measure developed to assess pain 
related to cancer. The instrument is available in validated multilingual versions; on average, it 
requires less than 10 minutes to complete the questionnaire. 
All BPI items are scored using rating scales. Four items measure pain intensity (pain now, 
average pain, worst pain, and least pain) using 0 (no pain) to 10 (pain as bad as you can 
imagine) numeric rating scales, and 7 items measure the level of interference with function 
caused by pain (general activity, mood, walking ability, normal work, relations with other 
people, sleep, and enjoyment of life) using 0 (no interference) to 10 (complete interference) 
rating scales. It has a 24-hour recall period. 
The BPI-SF will be self-administered by the subject at Dose 1, Day 1 (before the start of study 
treatment), at each treatment visit, at the end of treatment visit and follow-up clinic visits. At 
the beginning of each scheduled visit, before meeting with the Investigator, subjects will be 
asked to complete the BPI-SF, with the exception of Question 2 (locating areas of pain on a 
diagram) and Question 7 (regarding use of pain medication). Subjects will not be asked to 
answer Question 2 because the information will not be used for the score. Subjects will not be 
asked to answer Question 7 because pain medication used is captured elsewhere in the eCRF. 
The items are aggregated into 2 dimensions: (1) Pain Severity Index, using the sum of the 4 
items on pain intensity and (2) Function Interference Index, using the sum of the 7 pain 
interference items. The Function Interference Index is scored as the mean of the item scores 
multiplied by 7, given that more than 50% (or 4 of 7), of the items have been completed. 
The BPI-SF should be self-administered by the subject alone during her scheduled visit at the 
site. The instrument should be administered at the start of the visit, before the subject sees the 
physician so that any interaction between the subject and physician will not influence the 


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subject’s responses to the questionnaire. The questionnaire should also be administered before 
the subject is asked about AEs and concurrent illnesses, again so that any discussions of 
health problems do not influence the subject’s responses. 
A quiet place should be provided for the subject to complete the BPI-SF. It is important that 
the subject completes the BPI-SF alone, without any advice from family members or friends 
who may accompany her. 
How should the Questionnaire be introduced?  
A sample script for introducing the questionnaire is given below.  
“Your doctor would like to better understand how you feel, how well you are able to do your 
usual activities, and how you rate your health. To help us better understand these things about 
you, we will ask you to complete this questionnaire about your health on the day of each 
clinic visit. Remember that this is not a test and there are no right or wrong answers. Choose 
the answer that best describes the way you feel. I will quickly review the questionnaire when 
you are done to make sure that all the questions have been answered. You should answer these 
questions by yourself. Your spouse or other family members should not help you when you 
answer the questionnaire. I will be nearby in case you want to ask me any questions. Please let 
me know when you have finished the questionnaire.”  
What to do if the subject asks for clarification?  
Some subjects may ask the meaning of specific questions. If this happens, the staff member 
can assist the subject by re-reading the question for them verbatim. If the subject asks what 
something means, do not try to explain what the question means, but tactfully suggest that the 
subject use her own interpretation of the question. All subjects should answer the questions 
based on what they think the questions mean, or the study results may be biased. 
Questionnaire completion and review of worst pain score over the previous 7 days  
At the beginning of each visit, please check that the subject has completed the questionnaire, 
check that all of the questions have been answered. If the questionnaire is not complete, point 
out to the subject that some of the questions were not answered. If the subject does not 
quickly volunteer to answer these items, ask her whether she had any difficulty completing the 
questionnaire. If the subject says that she had trouble understanding a question, ask her why 
she had difficulty with that item. Re-read the question for her verbatim, but do not attempt to 
explain or reword the question, as explained before. If the subject is still unable to answer the 
question, accept the questionnaire as is.  
Some subjects may be confused by the response choices. They may want to respond with “I 
don’t know” or some other response choice that is not available. If this happens, try to help 
the subject choose one of the response categories by saying something like: “I know that it 
may be difficult for you to choose an answer, but which of these answers do you think comes 
closest to the way that you are thinking or feeling?” If the subject still cannot select an 
answer, accept the questionnaire as is.  
Occasionally, subjects may not report having difficulty with a question or the response 
choices, but still may hesitate or refuse to answer an item or items. If this happens, accept the 
questionnaire as is. 
 
 


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16.8 
Resource utilization questionnaire 
 
 


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16.9 
Patient Reported Questionnaire Information Sheet 
Subject Number   ___ ___ ___ ___ ___/___ ___ ___ ___ 
Visit: _____________ 
Instructions: 
• 
This information sheet is to be completed by the study nurse/investigator. 
• 
This information sheet must be competed for all patients at each visit in which the 
protocol requires the questionnaire to be administered, whether or not the 
questionnaire was completed by the patient. 
• 
When the patient returns the questionnaire 
o Please complete this information sheet. 
o Please check that the patient has answered all the questions and no question 
has more than one answer. 
1. Was the questionnaire provided to the patient at this  
    visit? 
     1 No  
 
      2 Yes 
If YES, please continue 
If NO, please go to question 5 
 
2. Date questionnaire completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d d m m y y y y 
 
3. Was the questionnaire provided prior to clinical  
    examination? 
     1 No  
 
        2 Yes 
 
4. Were all questions answered? 
     1 No  
 
        2 Yes 
 
If YES, please STOP 
 
If NO, please continue 
 
5. If No, specify reason questionnaire/questions was not answered: 
Patient felt too ill 
 
Patient refused to complete questionnaire for reason other than illness 
 
Patient did not keep appointment 
 
Questionnaire not administered due to institution error 
 
Questionnaire not available in the appropriate language 
 
 
Other, please specify: 
 
 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan and supplement 
Official Title: 
A phase II randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with exemestane and 
everolimus versus placebo in combination with exemestane and 
everolimus when administered to metastatic HER2 negative 
hormone receptor positive breast cancer subjects with bone 
metastases 
NCT Number: 
NCT02258451 
Document Date: 
14 Feb 2020 
24 Jun 2020 
 


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 17096
Page:
1 of
36
Title Page
A phase II randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with exemestane and 
everolimus versus placebo in combination with exemestane and 
everolimus when administered to metastatic HER2 negative 
hormone receptor positive breast cancer subjects with bone 
metastases
Short title: Study of radium-223 dichloride in combination with exemestane and everolimus 
versus placebo in combination with exemestane and everolimus in subjects with bone 
predominant HER2 negative hormone receptor positive metastatic breast cancer
BSP Study drug
BAY 88-8223 / Radium-223 dichloride / Xofigo®
Study purpose:
This is a randomized, double-blind, placebo-controlled phase II study to 
evaluate the clinical benefit of radium-223 dichloride in combination 
with exemestane and everolimus versus placebo in combination with 
exemestane and everolimus when administered to metastatic HER2 
negative hormone receptor positive breast cancer subjects with bone 
metastases
Clinical study 
phase:
II
Date:
14 FEB 2020
Study No.:
BAY 88-8223 / 
17096
Version:
V4.0
Author:
Bayer HealthCare Pharmaceuticals
Whippany, NJ  07981
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 sponsor 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.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 17096
    Page: 2 of 36
Table of Contents
Title Page ...................................................................................................................................1
Table of tables ...........................................................................................................................3
Abbreviations ............................................................................................................................4
Definitions of terms...................................................................................................................5
1.
Introduction........................................................................................................................6
2.
Study Objectives ................................................................................................................8
3.
Study Design.......................................................................................................................9
4.
General Statistical Considerations.................................................................................11
4.1
General Principles ......................................................................................................11
4.2
Handling of Withdrawal.............................................................................................11
4.3
Handling of Missing Data ..........................................................................................11
4.4
Data Rules ..................................................................................................................12
4.4.1
Interim Analyses ........................................................................................................12
4.4.2
Data Monitoring .........................................................................................................13
4.5
Primary and updated Analyses...................................................................................13
4.5.1
Primary Analysis ........................................................................................................13
4.5.2
Updated Analysis .......................................................................................................14
4.6
Validity Review..........................................................................................................14
5.
Analysis Sets.....................................................................................................................14
6.
Statistical Methodology ...................................................................................................14
6.1
Population characteristics...........................................................................................15
6.1.1
Disposition of subjects ...............................................................................................15
6.1.2
Demographic and baseline characteristics .................................................................15
6.1.3
Medical history...........................................................................................................16
6.1.4
Prior, concomitant and post-treatment medications...................................................16
6.2
Efficacy Analysis .......................................................................................................16
6.2.1
Primary efficacy variables..........................................................................................16
6.2.2
Secondary efficacy variables......................................................................................19
6.2.3
Exploratory efficacy variables ...................................................................................24
6.2.4
Subgroup analyses......................................................................................................27
6.2.5
Brief Pain Inventory-Short Form (BPI-SF)................................................................28
6.2.6
Other variables ...........................................................................................................28
6.3
Safety Analysis...........................................................................................................28
6.3.1
Extent of exposure......................................................................................................29
6.3.2
Adverse events ...........................................................................................................29
6.3.3
Deaths.........................................................................................................................31
6.3.4
Clinical laboratory evaluations...................................................................................31
6.3.5
Other safety measures ................................................................................................32
6.4
Pharmacokinetics .......................................................................................................32
6.5
Biomarker analyses ....................................................................................................32
6.6
Sample size estimation...............................................................................................32
6.7
Additional analyses planned to be reported outside the main report .........................33


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6.8
Change of analysis .....................................................................................................33
6.8.1
Efficacy endpoints......................................................................................................33
6.8.2
Other endpoints ..........................................................................................................34
7.
Document history and changes in the planned statistical analysis..............................34
8.
References.........................................................................................................................35
9.
Appendices........................................................................................................................35
9.1
Overall tumor response ..............................................................................................35
Table of tables
Table 6–1: Symptomatic Skeletal Event Free Survival (SSE-FS) censoring rules. .................17
Table 6–2: Radiological progression-free survival (rPFS) censoring rules..............................22
Table 6–3:  Time to first on-study SSE censoring rule.............................................................25
Table 6–4:  Time to first visceral metastases onset censoring rule...........................................26
Table 9–1: Overall tumor response...........................................................................................35


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Abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
BHA
Denosumab or bisphosphonates
BMI
Body Mass Index
BPI-SF
Brief Pain Inventory – Short Form 
CT
Computed tomography
CTCAE 
Common Terminology Criteria for Adverse Events; version 4.03
EBRT
External beam radiation therapy
ECOG
Eastern Co-operative Oncology Group 
ECOG PS
Eastern Co-operative Oncology Group Performance Status
eCRF
Electronic case report form
EOT
End of Treatment
EOXT
End of Xofigo Treatment
GCP
Good Clinical Practice
HR
Hazard ratio
ICF
Informed consent form
IDMC
Independent data monitoring committee
ITT
Intent-to-treat
IV
Intravenous
IXRS
Interactive Voice/Web Response System
kBq
KiloBecquerel; SI unit of radioactivity
kg
Kilogram
mCi
Millicuries
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
OS
Overall survival
PD
Progressive disease
PS
Performance status
rPFS
Radiological progression-free survival
RECIST
Response Evaluation Criteria in Solid Tumors
TEAE
Treatmemt-emergent adverse event
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis software
SSE
Symptomatic skeletal event
SSE-FS
Symptomatic skeletal event-free survival
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPS
Worst pain subscale


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Definitions of terms
Radium-223 
dichloride 
The investigational product, a targeted alpha particle emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous injection 
containing the drug substance radium-223 dichloride. The active moiety is the 
alpha particle emitting nuclide radium-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 radium-223 
administered.


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1. Introduction
Study Background
Presence of estrogen receptor (ER) and/or progesterone receptor (PR) is one of the most 
important prognostic/predictive factors in breast cancers. Patients with hormone receptor positive 
disease and HER2-negative disease are candidates for endocrine therapy. Bone is a frequent site 
of metastatic spread with approximately 65% to 75% of patients with metastatic breast cancer 
having skeletal involvement [[1]]. Due to the disrupted bone remodeling process, patients with 
metastatic bone lesions are at risk of increased morbidity including skeletal-related events (SRE), 
such as bone pain requiring intervention (i.e., radiotherapy or surgery), pathologic fractures, 
spinal cord compression, as well as symptomatic hypercalcemia and bone marrow infiltration. 
These events will ultimately impair the patient’s quality of life (QoL) and functional 
independence.
Radium-223 dichloride solution for injection is a novel alpha particle-emitting 
radiopharmaceutical. The bone targeting property of radium-223 is similar to that of other earth 
alkaline elements, like calcium or strontium-89. However, the radiation characteristics of an 
alpha particle-emitting radionuclide appear to be more advantageous than of a beta-emitting 
radionuclide. The alpha particle range from radium-223 dichloride is less than 100 micrometers 
(less than 10 cell diameters), which limits damage to the surrounding normal tissue.
In the phase III, double-blind, randomized, BC1-06, ALSYMPCA (Alpharadin in Symptomatic 
Prostate Cancer) study, a total of 922 subjects with CRPC and symptomatic bone metastases 
were randomized to receive 6 injections of radium-223 dichloride (50 kBq/kg IV, based on NIST 
2010 standardization [[2]]) or matching placebo every 4 weeks. Based on data of an interim 
analysis (n=809), radium-223 dichloride significantly improved overall survival (OS compared 
to placebo (the median OS was 14.0 versus 11.2 months, respectively; Hazard ratio [HR]= 0.695; 
p=0.00185). Symptomatic skeletal events (SSE) were lower in the radium-223 dichloride arm, 
and time to first SSE was significantly delayed (the median time to SSE was 13.6 months, versus 
8.4 months, respectively; HR=0.610; p=0.00046). Adverse events of any grade were reported in 
88% of the subjects who received radium-223 dichloride versus 94% in the placebo arm (Grade 
3/4 AEs were reported for 51% and 59% of subjects, respectively).
In an open-label, multicenter, single-arm, phase IIa study (BC1-09), 23 subjects with metastatic 
breast cancer with bone dominant disease were administered 4 injections of radium-223 
dichloride (50 kBq/kg IV, based on NIST 2010 standardization[[2]]) every 4 weeks. The primary 
efficacy endpoints were the change in urine levels of N-terminal telopeptide (NTX) and bone 
alkaline phosphatase (ALP) from baseline at Week 16. Median urine NTX levels were reduced 
by 20% (from 36 to 29 nmo1 bone collagen equivalents [BCE]/mmo1 creatinine; p=0.03) and 
33% (from 36 to 23 nmo1 BCE/mmo1 creatinine; p=0.0124) at Week 8 and Week 16, 
respectively; 17/23 and 9/13 subjects (for whom data were available) had a decrease in urine 
NTX at Week 8 and Week 16, respectively. Median bone ALP levels were reduced by 33% 
(from 22.1 to 12.1 ng/mL; p=0.0001) at Week 8 and 42% (from 22.1 to 10.94 ng/mL; p=0.04) at 
Week 16. Bone ALP levels were reduced in 20/22 subjects at Week 8 and in 10/12 subjects (for 


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Protocol No.: BAY 88-8223 / 17096
    Page: 7 of 36
whom data were available) at Week 16. Radium-223 dichloride was found to be safe and well 
tolerated.
The treatment options for patients with bone dominant metastasis of breast cancer are still 
limited. 
Radium-223 dichloride has shown significant anti-tumor activity in a phase III study in subjects 
with bone predominant metastatic CRPC and in a phase II metastatic breast cancer study. The 
safety profile and tolerability for radium-223 dichloride appear to be acceptable in this study 
population.
Recently, a phase III BOLERO-2 study showed that the addition of everolimus to exemestane 
significantly improved progression-free survival (PFS) compared with single-agent exemestane 
in estrogen receptor positive (ER+), HER2-negative patients whose metastatic disease was
refractory to prior treatment with letrozole or anastrozole.[[3]]  This led to the recent marketing 
approval of everolimus by the FDA and EMA for the treatment of hormone receptor-positive, 
HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal 
women without symptomatic visceral disease after recurrence or progression following a NSAI. 
At the time of final analysis with a median follow-up of 18 months, the median PFS (as per 
Investigator review) was 7.8 months for everolimus and exemestane versus 3.2 months for 
placebo and exemestane (hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.38 to 0.54; 
log-rank p<0.0001).[[4]]
For a more detailed introduction, refer to the clinical study protocol.
This Study
This study is a phase II, randomized, double-blind, placebo-controlled, parallel group trial of 
radium-223 dichloride versus placebo administered with exemestane and everolimus and 
supportive care in subjects with HER2 negative hormone receptor positive breast cancer with 
bone metastases. The primary endpoint is skeletal event-free survival. At study start the study 
had a single-stage design with no interim analysis. Protocol Amendment 8 added an unblinded 
administrative review, which was performed on 05 DEC 2017. Subsequent to the review, and 
prior to the primary analysis, Protocol Amendment 10 curtailed post-treatment follow-up and 
permitted patients to be transferred to a long-term follow-up study following their end-of-
treatment visit. 
This Statistical Analysis Plan
This statistical analysis plan (SAP) describes the analyses to be performed for the final primary 
analysis of study 17096, to be performed at primary endpoint maturation and included in the 
Clinical Study Report. In addition, it describes the analyses to be performed for the interim 
administrative review and for the exploratory updated analyses to be performed after study 
closure. This document is version 4.0 (amendment 3) of the SAP. It is based on the SAP version 
1.0, dated 25 OCT 2016, the version 2.0 (amendment 1), dated 25 OCT 2017, the version 3.0 
(amendment 2), dated 04 JAN 2019 and the integrated clinical study protocol version 7.0 


Statistical Analysis Plan
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(amendment 10), dated 04 DEC 2019.1 The original protocol, version 1.0, is dated 06 MAY 
2014. Detailed descriptions of the Tables, Listings, and Figures (TLFs) to be created will be 
described in a separate TLF specification document.   
This SAP excludes any biomarker analyses, which will be described in a separate document and 
reported in a separate report.
2. Study Objectives
The objective of this study is to assess efficacy and safety of radium 223 dichloride in 
combination with exemestane and everolimus in subjects with human epidermal growth factor 
receptor 2 (HER2) negative, hormone receptor positive breast cancer with bone metastases.
The primary endpoint is:

symptomatic skeletal event-free survival (SSE-FS). 
The secondary endpoints are:

OS; 

time to opiate use for cancer pain; 

time to pain progression; 

time to cytotoxic chemotherapy; 

radiological progression free survival (rPFS);

pain improvement rate; 

Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy. 
The exploratory endpoints are:

time to first on-study SSE; 

time to bone-ALP progression; 
                                                
1 As of Amendment 3.


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
bone-ALP response at Week 12 and 4 weeks (± 7 days) after last radium-223 
dichloride/placebo dose; 

bone-specific rPFS;

resource utilization; 

biomarker assessments, 

time to visceral metastases onset. 
3. Study Design
This study is a phase II, randomized, double-blind, placebo-controlled, parallel group trial of 
radium-223 dichloride versus placebo administered with exemestane and everolimus and 
supportive care in subjects with HER2 negative hormone receptor positive breast cancer with 
bone metastases. Randomization will be stratified by:

Geographical regions (Europe/North America [including Israel] versus Asia)

Previous lines of hormone therapy in metastatic setting (1 versus 2 or more): for the 
purpose of counting the number of prior lines of hormone therapy, only a change of the 
hormone agent due to progression is counted as a new line of therapy.  A switch of 
hormone therapy from one agent to another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of progressive disease (PD) at the time of switch will be 
counted as one line, although 2 different agents have been administered.

Visceral disease: Yes versus No  
This study will be conducted at approximately 160 investigative study sites and approximately 
311 subjects will be enrolled.
Prior to the primary analysis, the study is comprised of 4 periods: screening, randomization, 
treatment, and the follow-up period (active follow-up with clinic visits and active follow-up 
without clinic visits).
Investigational treatment consists of up to 6 cycles of radium-223 dichloride 55 kBq/kg body 
weight (based on updated 2015 NIST standardization[[5]]1) (Arm A) or placebo (Arm B) each 
separated by an interval of 4 weeks. All subjects will start treatment with exemestane and 
                                                
1 Updated dose per revised NIST standardization. The amount of radioactivity in the 
administered dose is unchanged from the 2010 standardization; only the numerical value of the 
dose changed due to the revised standard.


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everolimus, after randomization, either before or simultaneously to the first injection of radium-
223 dichloride/placebo. Treatment with exemestane and everolimus will continue after 
completion of radium-223 dichloride until disease progression, initiation of new anti-cancer 
therapy, unacceptable toxicity occurs , discontinuation of study treatment for other reasons, or 
study is terminated, whichever occurs first.  All subjects receive supportive care, as per local 
standard of practice.
During the treatment period, subjects will be assessed for safety at each treatment visit, every 8 
weeks, and will be evaluated for radiological progression according to local standard practice.
Symptomatic skeletal events should be recorded until end of treatment visit, independent of 
whether the subject starts a new anti-cancer therapy (i.e., chemotherapy, other).Subjects will 
receive an end-of treatment clinic safety visit 30 days +7 following their last treatment. 
Prior to Protocol Amendment 9, subjects who discontinued or completed the treatment phase will 
enter an active follow-up phase. Following Protocol Amendment 9, the active follow-up phase 
became optional. For subjects who have not experienced an SSE. active follow-up visits will 
occur every 4 weeks ± 7 days, with clinic visits where feasible, otherwise by telephone. For 
subjects who have experienced an SSE, active follow-up will occur by telephone every 8 weeks 
± 7 days. Per Protocol Amendment 10, the active follow-up phase will be discontinued entirely 
following the cutoff for the primary analysis. 
This study will end, and the updated analysis will be performed, after the last 4 weeks follow up 
visit by the time last subject on treatment discontinues oral exemestane and/ or everolimus 
treatment and completes end of treatment visit or discontinues from this study for another reason 
(e.g., death, consent withdrawn and active objection for further data collection, lost to follow-
up).
Changes to Study Design
Protocol Amendment 8, dated 18 May 2017, provided for an unblinded administrative interim 
data review of efficacy and safety, with efficacy focusing on rPFS, to be performed when a 
minimum of 80 rPFS events is reached. The administrative data review took place on 5 Dec 
2017.
Protocol Amendment 9, dated 3 Apr 2018, permitted subjects who completed the later of end of 
treatment visit or 30 days from last study treatment to transfer into a separate long-term follow-
up study, whether or not an SSE had been observed. In addition, enrollment was discontinued in 
April 2018. 
Protocol Amendment 10, dated 4 Dec 2019, removed the active follow-up period from this study 
following the primary analysis. After the primary analysis, subjects who complete the later of 
end of treatment visit or 30 days from last study treatment will be required to transfer into a 
separate long-term follow-up study.
A schematic of the study design is presented in protocol Section 5.  


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4. General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS version 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). Unless otherwise noted, data will be analyzed by 
descriptive statistical methods: The number of data available and missing data, mean, standard 
deviation, minimum, quartiles, median, and maximum will be calculated for continuous data. 
Frequency tables will be generated for categorical data.
Definition of efficacy and safety endpoints, analysis strategies, structure of analysis datasets and 
layout of analysis data displays are following Bayer Healthcare Pharmaceuticals (BHP) 
standards: Xofigo Project Standards, the Therapeutic Area Oncology Standards (TAS) and the 
Global Medical Standards (GMS), respectively, with more specific standards controlling over 
more global ones. Where needed for study-specific reasons, study-specific departures from 
standards may be specified
4.2
Handling of Withdrawal
A 
“withdrawal” from treatment is defined as a subject who has been randomized and 
discontinues study treatment for any reason. Subjects withdrawn from study treatment will not be 
replaced. Refer to Section 6.3 in the study protocol for withdrawal of subjects from study.
A “screen failure” is defined as a subject who enrolled in the study but was not randomized.
All efficacy analyses are based on the ITT population, which comprises all randomized subjects, 
including subjects who withdraw regardless of the reason for withdrawal. See following chapters 
for more details on deriving efficacy endpoints in case of missing data.
Subjects who were lost to follow-up will be handled in time to event analyses per the applicable 
censoring rules.
4.3
Handling of Missing Data
In order to achieve the goal of a well conducted clinical trial according to ICH Good Clinical 
Practice (ICH-GCP), every effort should be made to collect all data. However, despite best 
efforts, it may be inevitable that missing or incomplete data are reported. All missing or partial 
data will be presented in the subject data listing, as they are recorded on the eCRF. Except as 
noted, missing data will not be imputed or carried forward in any statistical analysis.
No imputation will be performed for missing lesion assessment and tumor response, unless 
otherwise specified. 


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The partial missing date used for derivation of time to event will be imputed and the imputation 
rule will be specified in the analysis dataset specifications.
Specific statistical methods, such as handling of censoring for time-to-event methods (e.g. 
Kaplan-Meier and the log-rank test), address loss to follow-up and other missing data situations
through statistical assumptions established in the literature. 
4.4
Data Rules
Safety baseline value is defined as the last non-missing value on or prior to first administration 
date of  any study medication (Radium-223 dichloride/placebo or exemestane or everolimus).
Investigator determine the baseline for tumor assessments based on protocol rules. For other 
efficacy endpoints except pain endpoints, the baseline is defined as the last available value prior 
to or on the date of randomization. For pain efficacy endpoints baseline is defined as last 
available value prior to first administration of radium-223 dichloride/ Placebo since the data are 
not collected at screening visit.
The duration for the time-to-event variables is calculated by event/censoring date – reference 
date + 1. Time-to-event analysis reference date is randomization date except for time to opiate 
use for cancer pain, time to pain progression, pain improvement rate. Interim Analyses and Data 
Monitoring
4.4.1
Interim Analyses
Protocol Amendment 8, dated 18 May2017, added an administrative interim data review, to be 
performed when a minimum of 80 rPFS events is reached. The interim data review is to be 
primarily focused on the rPFS, with the interim data review results to inform future radium-223 
clinical development plans in this indication. The review was to be conducted by an independent 
unblinded review committee..
No formal statistical testing was specified for either SSE-FS or rPFS at the time of this interim 
review. Both summary statistics and hazard ratio will be produced. The number of patients 
randomized,  number censored, number of events, median rPFS and its 80% and 95% CI, and 
rPFS event rate at 6, 9 and 12 months will be presented. A Kaplan-Meier curve will be generated 
for each treatment group. The hazard ratio (radium-223 dichloride / placebo) for rPFS and its 
80% and 95% confidence intervals (CIs) will be calculated using a univariate Cox model, 
stratified by stratification factors: geographical regions (Europe/North America [including Israel] 
vs. Asia), previous lines of hormone therapy (1 vs. ≥2), and visceral disease (yes vs. no). 
Sensitivity analyses will be conducted for rPFS with Cox model stratified by prior SREs (1 vs. 
2), visceral disease (yes vs. no), and non-stratified Cox model, respectively.
No adjustment to the original single-stage operating characteristics is planned as a result of this 
interim analyis. As there was no plan to stop the trial due to superior efficacy, no alpha 
adjustment is applied for this interim look at the primary endpoint of SSE-FS. In addition, as at 
the time this interim analysis was planned, there was no plan to stop the study for futility, no beta 


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spending or power adjustment is planned. As an interim analysis may nonetheless affect study 
operating characteristics, some caution in interpretation may be warranted. The study will remain 
blinded after the interim data review. 1
The planned interim efficacy analysis focused on rPFS and included summary statistics, Kaplan-
Meier estimates, and hazard ratios with confidence intervals for rPFS and SSE-FS. The planned 
interim safety analysis included treatment-related AEs, study drug-related TEAEs, TE, AEs of 
interest, serious AEs, and lab toxicities.Details are described in the separate administrative 
review analysis specifications document.2
4.4.2
Data Monitoring
An Independent Data Monitoring Committee (IDMC) will not be applied to this study. 
4.5
Primary and updated Analyses
After implementation of CSP Amendment 9, subjects who completed the EOT visit could be
transferred to a separate extended safety follow-up study for their remaining follow-up, whether 
or not they had experienced an SSE or radiological progression. In face of the enrollment 
discontinuation on Apr/2018 and potentially curtailed active follow-up introduced by CSP 
Amendment 9, the sponsor decided to conduct the primary analysis, independent of the number 
of SSE-FS achieved, with a cutoff date of 22JAN2020. Therefore, there will be 2 analyses in the 
study: the primary analysis will encompass all data from study start until cutoff date of 
22JAN2020, and an exploratory updated analysis (after implementation of CSP Amendment 10) 
will be performed after the last subject discontinues treatment discontinues oral exemestane 
and/or everolimus treatment and completes end of treatment visit or discontinues from this study 
for another reason (e.g., death, consent withdrawn and active objection for further data collection,
lost to follow-up) .
4.5.1 Primary Analysis
Following the enrollment discontinuation on Apr/2018 and observation of curtailed active 
follow-up introduced by CSP Amendment 9, the sponsor decided to conduct the primary 
analysis, independently of the number of SSE-FS achieved, with a cutoff date of 22JAN2020. 
This analysis will include all of the items described in Section 6 below and include all of the 
planned tables, figures, and listings for this study. It will include all data from the treatment 
period for each subject and all follow-up data up until the date that the last subject who 
completes his End of Treatment visit are transferred to a separate extended safety follow-up 
study.
                                                
1 As of SAP Amendment 1.
2 As of SAP Amendment 1.


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4.5.2 Updated Analysis
A follow-up analysis will be conducted when all treated subjects discontinue oral treatment and 
are transferred to or decline the separate extended safety follow-up study. This analysis will 
include the following items:

Disposition;

Adverse events: related adverse events, related serious adverse events (including deaths), 
new primary malignancies, new symptomatic skeletal event-related adverse events, 
deaths and adverse events of interest;

Efficacy: symptomatic skeletal event free-survival, overall survival.
4.6
Validity Review
The results of validity review meetings will be documented in the Validity Review Reports. 
5. Analysis Sets
Intent-to-treat analysis (ITT) population
The primary population for all efficacy analyses is the Intent-to-treat analysis (ITT) population, 
which is defined as all randomized subjects. Subjects will be analyzed as randomized. 
Safety analysis (SAF) population
The safety analysis (SAF) population is comprised of all randomized subjects who received at 
least one dose of any study medication (Radium-223 dichloride or placebo or exemestane or
everolimus) and will be used for all safety analyses. Subjects will be analyzed as treated. Using a 
conservative approach, subjects randomized to the placebo arm will be analyzed under the 
Radium-223 dichloride arm if the subject received at least one dose of Radium-223 dichloride
treatment whereas subjects randomized to the Radium-223 dichloride arm will still be analyzed 
under the Radium-223 dichloride arm regardless of receiving at least one dose of placebo. Only 
in a case where a subject randomized to the Radium-223 dichloride arm received only placebo 
treatment would the subject be analyzed under the placebo arm. 
6. Statistical Methodology
The formal statistical analyses will be both descriptive and inferential. Summaries will be 
provided for each of the treatment groups.


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6.1
Population characteristics
For this analysis, only descriptive statistics will be provided (no testing performed). The results 
will be displayed by treatment group for the ITT population.
6.1.1
Disposition of subjects
The number of subjects enrolled and included in each of the ITT and safety populations will be 
tabulated by region, country, and center. A summary table will also be presented for the number 
of subjects enrolled and the number and percentage of subjects in each of the defined 
populations. The reasons for subjects excluded from each of the analysis populations will also be 
tabulated. In addition, the number of subjects who were screened, randomized, treated and 
discontinued will be summarized by treatment group. Reasons for discontinuation of study 
treatment will be tabulated.
6.1.2
Demographic and baseline characteristics
All demographic and baseline characteristics will be summarized for the ITT population using 
descriptive statistics such as frequency and proportion (for categorical variables), mean, median 
and standard deviation (for continuous variables).
These will include, but may not be limited to:

Demographics and baseline characteristics:                                                                      
Sex, race, ethnicity, age calculated at the date of randomization using date of birth, age 
categories ( ≥55, <55) 1, Geographical region (Europe/North America [including Israel] 
versus Asia), baseline weight, height, systolic blood pressure (BP), diastolic BP, heart 
rate, respiration rate.

Baseline cancer characteristics:                                                                                  
Eastern Cooperative Oncology Group (ECOG) performance status, menopausal status, 
histology, stage at initial diagnosis (TNM), Nottingham combined histologic grading at 
initial diagnosis, status of primary tumor at study entry, TNM classification of breast 
cancer at study entry, progesterone receptor status, estrogen receptor status, HER2/neu 
status (Immunohistochemistry[IHC]), HER2/neu status (Fluorescence in situ 
hybridization[FISH])/( Chromogenic in situ hybridization[CISH])/( HER2 gene 
amplification ISH (other validated assay)), time since initial diagnosis to metastatic 
disease, time since initial diagnosis to bone metastases, time since first progression, time 
since most recent progression, previous lines of hormone therapy in metastatic setting (1 
                                                
1 As of Amendment 1.


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versus 2 or more), and prior SREs (1 versus 2), visceral disease (yes versus no), cancer 
pain assessment
6.1.3
Medical history
The dictionary for coding is MedDRA version 19 or most recent version. By treatment-group 
summary statistics (frequency and percentage) will be provided by system organ class and 
preferred term for ITT analysis set. 
6.1.4
Prior, concomitant and post-treatment medications
The dictionary used for coding medications is World Health Organization Drug Dictionary 
(WHO-DD). The following categories of medications will be summarized

Systemic anti-cancer therapies: frequency of subjects for each drug category, prior and 
post study medication. 

Diagnostic and Therapeutic Procedures: frequency of subjects by procedure, prior, during 
and post study medication. 

Radiotherapies: frequency of subjects by field and intent, prior, during therapy and post
study medication.

Myelosupressive systemic anti-cancer therapy during follow up: frequency of subjects for 
each drug category.

Analgesics: frequency of subjects for each drug category, prior and post study medication.

Denosumab or bisphosphonates (BHA): frequency of subjects for each drug category, 
prior study medication.

Other prior and concomitant medications: frequency of subjects for each drug category. 
6.2
Efficacy Analysis
All comparisons of the treatment groups with respect to the primary and secondary efficacy 
variables will be based on the ITT population. 
6.2.1
Primary efficacy variables
6.2.1.1 Definition of SSE-FS:
The primary efficacy endpoint is symptomatic skeletal event-free survival (SSE-FS). It is defined 
as the time from date of randomization to occurrence of one of the following, whichever happens
earlier:
(1) An on-study SSE, which is defined as:


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a.
the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms
b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral)
c.
the occurrence of spinal cord compression
d. a tumor related orthopedic surgical intervention.
(2) Death from any cause 
Note: Any EBRT or orthopedic surgery related to a prior skeletal related event but 
administered after signature of the informed consent form (ICF) will not be counted as an on-
study SSE.
To demonstrate SSEs, one or more associated symptoms need to be recorded on the 
applicable AE CRF and linked to an associated procedure (e.g. EBRT, imaging, surgery, 
etc.). For event date, the procedure date instead of the dates of symptom(s) will be used 
to calculate the SSE-FS.
The censoring rules for SSE-FS are summarized in Table 6–1.
Table 6–1: Symptomatic Skeletal Event Free Survival (SSE-FS) censoring rules.
Situation
End Date 
Censored
Reason for 
Censoring
No post-baseline SSE 
assessment and no death
Date of 
Randomization
Yes
No post-baseline 
SSE assessment and 
no death
Subject had an SSE event
Date of first SSE
No*
N/A
Death without prior SSE
(<9 weeks between last SSE 
assessment and death) #
Date of death
No*
N/A
Death without prior SSE (≥
9 weeks between last SSE
assessment and death) #
Last SSE assessment 
before the missing 
SSE assessments#
Yes
≥ 9 weeks between 
last SSE
assessments
immediately prior to 
death
Neither SSE nor death at data 
cutoff 
Last SSE assessment Yes
Neither SSE nor
death
Symptomatic Skeletal Event Free Survival (SSE-FS) = End Date – Date of Randomization +1 
*The earliest end date in the table is used in calculating the SSE-FS
#: use randomization date instead of last SSE assessment date if no post-baseline SSE assessment.
SSE events immediately after missing SSE assessments are still counted as events in the analysis of SSE-FS.
6.2.1.2 Analysis of SSE-FS:
Per protocol, the primary analysis of SSE-FS was to be performed when approximately 160
subjects have SSE-FS. 


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Following the enrollment discontinuation on APR 2018 and observation of curtailed active 
follow-up introduced by CSP Amendment 9, the sponsor decided to conduct the primary 
analysis, independently of the number of SSE-FS achieved, with a cutoff date of 22JAN2020.
Since differences are expected between the values of the stratification variables entered by the 
investigator at the time of randomization (IxRS) and those derived from information collected on 
the eCRF, the analysis will be performed using both assignments to the strata. However, the 
primary stratified analyses for the efficacy endpoints will be based on the stratification 
information entered in IxRS. Stratification factors collected on the eCRF will be used for 
sensitivity analyses. In rare circumstances, if eCRF data are not available, then IxRS data will be 
used.
The null hypothesis that both treatment with radium-223 dichloride dose not result in superior 
SSE-FS to treatment with placebo in subject population was tested against the alternative 
hypothesis that the treatment with radium-223 dichloride results in superior SSE-FS time to 
treatment the placebo. 
H0: SSE-FSRadium-223+ Exemestane/Everolimus ≤SSE-FS Placebo+ Exemestane/Everolimus, versus
HA: SSE-FSRadium-223+ Exemestane/Everolimus > SSE-FS Placebo+ Exemestane/Everolimus
The SSE-FS will be compared using a stratified log-rank test with a one-sided alpha of 0.1 (2-
sided alpha of 0.2), stratified by the same stratification factors as randomization: geographical 
regions, previous lines of hormone therapy in metastatic setting and visceral disease, based on 
the stratification data in IxRS. 
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to event (median and its 
95% CI, 25th and 75th percentile, range), probability of event-free survival at pre-specified 
months. A Kaplan-Meier curve will be generated for each treatment group.
The hazard ratio (radium-223 dichloride / placebo) for SSE-FS and its 80% and 95% confidence 
intervals (CIs) will be calculated using a univariate Cox model, stratified by the same factors as 
stated above.
The Kaplan-Meier (KM) estimates for SSE-FS and KM curves will also be presented for each 
treatment group. The median and SSE-FS rates at time points such as 3 months, 6 months, etc., 
together with corresponding 95% CIs will also be calculated by treatment group. 
The contribution of each component of the composite SSE between the arms will be evaluated. 
Descriptive statistics will be presented.


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Sensitivity analyses will be conducted for the following scenarios1 if the primary analysis of 
SSE-FS result is significant:

SSE-FS will be re-evaluated considering initiation of anti-cancer therapies (excluding 
standard of care anti-cancer hormonal treatments). SSE-FS will be censored at the last 
SSE assessment before the start of new anti-cancer therapies (excluding standard of care 
anti-cancer hormonal treatments). 

SSE-FS will be evaluated considering all deaths as events, regardless duration of 9 weeks 
between last SSE assessment and death.

SSE-FS will be evaluated with an unstratified log-rank testSSE-FS will be evaluated 
using stratification factors derived from the information collected on the eCRF.
6.2.2
Secondary efficacy variables
The secondary efficacy variables are specified below: 

Overall survival (OS)

Time to opiate use for cancer pain

Time to pain progression

Pain improvement rate

Time to cytotoxic chemotherapy

rPFS
6.2.2.1 Definition
Overall survival is defined as the time from the date of randomization to the date of death due to 
any cause.  The OS time for subjects alive at the time of analysis (or database cut-off date) will 
be censored at their last known alive date. For subjects whose last date of follow-up confirms the 
subject was alive at the data cut-off (i.e., based on the formal survival sweep), the subject will be 
censored at the data cut-off date. If a subject is lost to follow up and there was no contact after 
randomization, this subject will be censored at randomization date (OS = 1 day). 
Time to opiate use for cancer pain is defined as the interval from the date of radium-223 
dichloride treatment start to the date of start of opiate use.  Subjects who have no opiate use at 
the time of analysis (or database cut-off date) will be censored at the last opiate use assessment 
date.  Subjects with no on study assessment or no baseline assessment will be censored at
radium-223 dichloride treatment start date (day 1). Subjects who have opiate use prior to radium-
223 dichloride treatment start will be censored at radium-223 dichloride treatment start date. 
                                                
1 As of Amendment 3.


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Time to opiate use for cancer pain will be analyzed based on the information collected on the 
analgesic concomitant medication, analgesics use 24 hour page and opiate use eCRF pages, 
whichever is the earliest.
Time to pain progression is defined as the interval from radium-223 dichloride treatment start
to the first date a subject experiences pain progression based on worst pain subscale (WPS) and 
analgesic use.  Time to pain progression will be evaluated in subjects with baseline WPS ≤ 8. 
Pain progression is defined as an increase of 2 or more points in the “worst pain in 24 hours” 
score from baseline observed at 2 consecutive evaluations ≥4 weeks apart
OR
an increase in pain management with respect to baseline, whichever occurs first.
An increase in pain management (IPM) is defined as.

For subjects taking no analgesics or a non-opioid at baseline, the initiation of any opioid 
would be considered an IPM.

For subjects taking a weak opioid at baseline, the initiation of any strong opioid would be 
considered an IPM.

For subjects taking a strong opioid at baseline, the initiation of an additional strong 
opioid would be considered an IPM

For subjects taking a weak opioid at baseline, the initiation of an additional weak opioid 
would be considered an IPM.1
Pain intensity (worst pain score [WPS]) assessments will occur on the day of visit. Subjects who 
have not experienced pain progression at the time of analysis (or database cut-off date) will be 
censored at the last post-baseline pain assessment date .  Subjects with no on-study assessment or 
no baseline assessment will be censored at radium-223 dichloride  treatment start date.
The increase in pain management is based on the analgesic use information collected on all 
eCRF pages including analgesic concomitant medication, 24-hour analgesic use page and opiate 
use eCRF page.
Pain improvement is defined for subjects evaluable for pain improvement, i.e. subjects with 
baseline WPS≥ 2, as a 2-point decrease or more in WPS from baseline over 2 consecutive
measurements conducted at least 4 weeks apart, without an increase in pain management.
                                                
1 As of Amendment 3.


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Pain improvement rate is defined as the number of subjects with pain improvement as defined 
above, divided by the total number of subjects evaluable for pain improvement (i.e., subjects 
with baseline WPS≥ 2). 
Time to cytotoxic chemotherapy is defined as the time from the date of randomization to the 
date of the first cytotoxic chemotherapy during follow up. Subjects who have not started 
cytotoxic chemotherapy during the study will be censored at last assessment for systemic anti-
cancer therapy.  
Radiological progression-free survival (rPFS) is defined as the time from the date of 
randomization to the date of first radiological progression or death (if death occurs before 
progression).  For subjects without documented radiological progression or death at the time of 
analysis (or database cut-off date), the rPFS time will be censored at the date of the last evaluable 
tumor assessment. Every effort will be made to obtain radiological scans for documentation of 
progression.
The radiological progression will be derived using algorithm in Table 9–1: Overall tumor 
response in appendix. Table 6–2 shows the end date and censoring rules for rPFS.
Subjects with baseline superscan will continue to have post-baseline bone imaging by either 
anatomically limited or full body CT/MRI, and the CT/MRI imaging will be used for rPFS 
analysis for these subjects. If no confirmed  radiological progression is detected by bone imaging 
full-body CT/MRI at post-baseline and no death, then these subjects will be censored at the last 
full-body CT/MRI assessment date with clear radiological non-PD. Anatomically limited 
CT/MRI assessments identify results unknown.


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Table 6–2: Radiological progression-free survival (rPFS) censoring rules
Situation
End Date 
Censored
Reason for Censoring
Subject had a radiological 
assessment of PD (no missed 
radiological assessment)
Date of first PD
No
N/A
Death during the study (no 
missed radiological 
assessment) or before first 
radiological PD assessment
Date of death
No
N/A
Subjects with baseline 
superscan, then either 
radiological PD(regardless 
by anatomically limited or 
full body CT/MRI) or death 
at post-baseline
Date of first PD or death
No
N/A
Subjects with baseline 
superscan, then radiological 
non-PD (by full body 
CT/MRI) and no death at 
post-baseline
Date of last full-body 
CT/MRI assessment with 
radiological non-PD(by 
full body CT/MRI)
Or 
Date of randomization if 
no full body CT/MRI at 
post-baseline
Yes1
Radiological non-PD 
(by full body CT/MRI) 
and no death at post-
baseline
Subjects without any 
evaluable post-baseline 
radiological tumor 
assessment.
The randomization date
Yes
No baseline or post-
baseline tumor 
assessment.
Subjects who had a death or 
disease progression 
immediately after two or more 
consecutive missed 
radiological assessments. 
Date of last radiological 
assessment before missed 
assessments.
Yes
Death or disease 
progression immediately 
after two or more 
consecutive missed 
radiological 
assessments.
New protocol new systemic 
anticancer treatment* started 
prior to radiological PD or 
death
Date of last radiological 
assessment prior to the 
change of therapy
Yes
New protocol new
systemic anticancer 
treatment* started prior 
to radiological PD or 
death
                                                
1 As of SAP Amendment 1.


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Table 6–2: Radiological progression-free survival (rPFS) censoring rules
Subjects who discontinue or 
withdraw early from the study 
without documented 
radiological disease 
progression.
Date of last evaluable 
radiological assessment
Yes
Discontinue or withdraw 
early from the study 
without documented 
radiological disease 
progression
Radiological Progression Free Survival (rPFS) = End Date – Start Date +1
Two consecutive missing radiological assessments are defined if the time interval between two consecutive radiological 
assessments is more than 18 weeks (2 × (8 +1 week)). 1
# For patients with baseline superscan, radiological non-PD has to be identified by bone imaging full-body CT/MRI. 
Anatomically limited CT/MRI assessments identify results unknown.
* Excluding standard of care anti-cancer hormonal treatments
The prohibited concomitant therapies during the treatment phase of study include: 

Chemotherapy

Radiopharmaceuticals, such as strontium-89, samarium-153, rhenium-186, or rhenium-
188

Hemibody external radiotherapy

Other investigational drugs

All medications that are prohibited as per the local label instructions for exemestane and 
everolimus and the supportive treatment.  
6.2.2.2 Analysis of secondary efficacy endpoints
Time to event efficacy analysis will be performed to compare two treatment groups using a 
stratified log-rank test stratified by the same stratification factors as randomization. The hazard 
ratio (radium-223 dichloride / placebo) and its 95% CIs will be estimated from the Cox model, 
stratified by the same factors as for SSE-FS analysis. No alpha adjustment for multiplicity will 
be applied for secondary endpoints.
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to event (median and its 
95% CI, 25th and 75th percentile, range), probability of event-free survival at pre-specified 
months, such as 6, 12, 18, etc. months for OS. A Kaplan-Meier curve will be generated for each 
treatment group.
                                                
1 As of SAP Amendment 1.


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The pain improvement rates will be calculated by treatment group with their exact binomial 
Clopper-Pearson 95% CI as well as the differences of pain improvement rates between treatment 
groups and the corresponding exact binomial Clopper-Pearson 95% CIs. Pain improvement rate 
at week 12, EOXT and any visit will be considered.
Due to inaccuracies in German translation of BPI-SF, the primary analyses of pain progression 
and pain improvement rates will be conducted with cleaned BPI-SF data only, excluding the mis-
translated data from German sites. Sensitivity analyses will be conducted for pain progression 
and pain improvement rates with all BPI-SF data, including uncleaned BPI-SF data.1
The comparison of pain improvement rate for all visits between the two treatment groups will be 
performed by using the “general association Cochran-Mantel-Haenszel statistic” stratified by the 
same stratification factors used in the SSE-FS analysis.

The following sensitivity analyses will be conducted for rPFS if the primary analysis of 
rPFS result is significant :rPFS will be evaluated with an unstratified log-rank test.

rPFS will be evaluated using stratification factors derived from information collected on 
the eCRF.
6.2.3
Exploratory efficacy variables
The exploratory efficacy variables are specified below: 

Time to first on-study SSE

Time to bone ALP progression

Bone ALP response at week 12 and EOXT 

Bone specific rPFS

Time to visceral metastases onset
6.2.3.1 Definition
Time to first on-study SSE is defined as the time from the date of randomization to the date of 
the first on-study SSE. For subjects without SSE at the time of analysis, time to first on-study 
SSE will be censored at the date of last assessment of SSE. 
The conventions for calculation of time to first on-study SSE are the same as for SSE-FS in 
section 6.2.1.1 except without considering death as an SSE event. The censoring rules for time to 
first on-study SSE are summarized in Table 6–3.
                                                
1 As of Amendment 3.


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Table 6–3: Time to first on-study SSE censoring rule
Situation
End Date 
Censored
Reason for Censoring
No post-baseline SSE 
assessment
Randomization date
Yes
No post-baseline SSE 
assessment
Subject had an SSE event
Date of first SSE
No
N/A
No SSE and no death at 
data cutoff
Last SSE assessment 
Yes
No SSE
No SSE prior to death
Last SSE assessment 
Yes
No SSE prior to death
SSE events immediately after missing SSE assessments are still counted as events in the analysis of Time to 
first on-study SSE.
Time to bone ALP progression is defined as the time from the date of randomization to the date 
of first bone ALP progression.  Bone ALP progression is defined as a 25% increase from the 
baseline value, at least 12 weeks from baseline in subjects with no bone ALP decline from 
baseline; or a 25% increase above the nadir value, which is confirmed by a second value 
obtained 3 or more weeks later in subjects with an initial bone ALP decline from baseline. 
Confirmation visit does not have to be adjacent to first visit with increase from nadir. Subjects 
without bone ALP progression at the time of analysis (or database cut-off date) will be censored 
at last bone ALP assessment. Subjects without baseline or without any post-baseline bone ALP 
values will be censored at date of randomization. 
For subjects who had a bone ALP progression immediately after two or more consecutive missed 
ALP assessments, time to bone ALP progression will be censored at the date of last bone ALP 
assessment before missed assessments. Two consecutive missing assessments is defined if the 
time interval between two consecutive ALP assessments is more than 10 weeks (2 × (4 weeks +1
week)) during the treatment period, or 17 weeks (2 × 8 weeks +1 week) during the active follow-
up period1.
Bone ALP response at week 12 and EOXT is defined as a ≥30% reduction of the blood level at 
Week 12 and EOXT, compared to the baseline value.  Confirmed bone ALP response is defined 
as a ≥30% reduction of the blood level, compared to the baseline value, confirmed by a second 
bone ALP value 4 or more weeks later.
Bone specific rPFS is defined as the time from the date of randomization to the date of 
confirmed radiological progression detected by bone imaging or death (if death occurs before 
progression).  Subjects without confirmed radiological progression or death at the time of 
analysis (or database cut-off date) will be censored at their last evaluable radiological bone
imaging assessment. If a new bone lesion or unequivocal increase in size of bone lesions is 
                                                
1 As of Amendment 3.


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identified on bone scan, the lesion must also be confirmed by computed tomography/magnetic 
resonance imaging (CT/MRI).  If a new bone lesion or unequivocal increase in size of bone 
lesions is only visible on a CT/MRI and not visible on a technetium 99m bone scan, progression 
will be declared without further confirmation. The conventions for calculation of bone specific 
rPFS are the same as for rPFS in section 6.2.2.1 except that bone progression or death (if death 
occurs before progression) is considered as a bone specific rPFS event and bone tumor 
assessment is used to determine the event/censoring. 
Subjects with baseline superscan will continue to have post-baseline bone imaging by either 
anatomically limited or full body CT/MRI, and the CT/MRI imaging will be used for bone 
specific rPFS analysis for these subjects. If no confirmed  radiological progression is detected by 
bone imaging full-body CT/MRI at post-baseline, then these baseline superscan subjects will be 
censored at the last full-body CT/MRI assessment date with clear radiological non-PD. Baseline 
superscan subjects will be censored at date of randomization if no full body CT/MRI at post-
baseline. Anatomically limited CT/MRI assessments identify results unknown.
Time to visceral metastases onset (in subjects with no visceral disease at baseline) is defined as 
the time from the date of randomization to the date of the first scan showing visceral metastatic 
disease. 
The censoring rules for time to visceral metastases onset are summarized in Table 6–4.
Table 6–4: Time to first visceral metastases onset censoring rule
Situation
End Date 
Censored
Reason for Censoring
Subject had a visceral metastases at 
post-baseline
Date of the first scan 
showing visceral 
metastatic disease
No
N/A
Subjects without any evaluable 
post-baseline non-bone tumor 
assessment.
The randomization 
date
Yes
No post-baseline tumor
assessment.
Subjects who didn’t have visceral 
metastases at the time of analysis.
Date of last evaluable 
non-bone tumor 
assessment
Yes
Subjects who didn’t 
have visceral metastases 
at the time of analysis.
6.2.3.2 Analysis of exploratory efficacy endpoints
Similar to the primary efficacy endpoint, time to event efficacy analysis will be performed to 
compare two treatment groups using a stratified log-rank test stratified by the same stratification
factors as randomization. The hazard ratio (radium-223 dichloride / placebo) and its 95% CIs 
will be estimated from the Cox model, stratified by the same factors as for SSE-FS analysis. 
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to event (median and its 
95% CI, 25th and 75th percentile, range), rate of subjects who did not yet develop an event at pre-
specified months. A Kaplan-Meier curve will be generated for each treatment group.


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Sensitivity analysis of Time to bone ALP progression will be performed by dropping the 12 
week restriction in the definition.
The bone ALP response at Week 12 and EXOT will be calculated by treatment group with their 
exact binomial Clopper-Pearson 95% CI as well as the differences of bone ALP response 
between treatment groups and the corresponding exact binomial Clopper-Pearson 95% CIs. 
The comparison of bone ALP response at Week 12 and EOXT between two treatment groups 
will be done using the “general association Cochran-Mantel-Haenszel statistic” stratified by the 
same stratification factors used in the SSE-FS analysis.  
The change from baseline in WPS at Week 12 visit and EOXT visit will be calculated. The 
missing values at Week 12 and /or EOXT will remain missing (the previous value will not be 
carried forward).
6.2.4 Subgroup analyses
Descriptive statistics and hazard ratio estimates with 95% CIs will be provided for SSE-FS and 
rPFS at least within each category of the following variables, provided there are a sufficient 
number of events in total within the subgroup across the treatment groups. 
The list used for subgroup analyses for SSE-FS were updated and provided as below:

Age (≥55, <55) 1

Race

Geographical region (Europe/North America [including Israel] versus Asia)

Baseline ECOG performance status 

Previous lines of hormone therapy in metastatic setting, 

Visceral disease

Prior SREs, 

Baseline total body weight

Baseline ideal body weight

BMI

Opiate use
The subgroup analyses for rPFS will be performed as below2:

Age (≥55, <55)

Geographical region (Europe/North America [including Israel] versus Asia)

Baseline ECOG performance status 
                                                
1 As of Amendment 1.
2 As of Amendment 3.


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
Previous lines of hormone therapy in metastatic setting

Visceral disease

BMI

Baseline total body weight
6.2.5 Brief Pain Inventory-Short Form (BPI-SF)
The BPI-SF is an 11-item, self-administered, clinically valid, reliable, and responsive measure 
developed to assess pain related to cancer. All BPI items are scored using rating scales. Four 
items measure pain intensity (pain now, average pain, worst pain, and least pain) using 0 (no 
pain) to 10 (pain as bad as you can imagine) numeric rating scales, and 7 items measure the level 
of interference with function caused by pain (general activity, mood, walking ability, normal 
work, relations with other people, sleep, and enjoyment of life) using 0 (no interference) to 10 
(complete interference) rating scales. 
The items are aggregated into 2 dimensions: (1) Pain severity index, and (2) Function 
interference index, using the mean of the 7 pain interference items. All 4 severity items must be 
completed for aggregating the pain severity index. The function interference index is scored as 
the mean of the item scores multiplied by 7, given that more than 50% or 4 of 7 of the items have 
been completed. 
Descriptive statistics for observed data will be presented at each assessment time point and for 
change from baseline by treatment group. 
6.2.6 Other variables
6.2.6.1 Resource utilization
Resource utilization data will be presented in the listing.1
6.3
Safety Analysis
The summaries of the safety data will be completed for the Safety analysis population (SAF). No 
formal statistical test will be performed for the safety variables.
                                                
1 As of Amendment 3


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6.3.1 Extent of exposure
Study medication and single standard of care hormonal treatment will be summarized for the 
SAF by treatment group, using descriptive statistics such as frequency and proportion (for 
categorical variables), mean, median, and standard deviation (for continuous variables).
Summaries will include, but may not be limited to:

Duration of treatment Radium-223 dichloride: overall duration of study treatment, 
number of injections of study treatment, time between two consecutive injections, 
average time between injections.

Overall duration of exemestane and/or everolimus treatment in study medication 
treatment period, respectively and together.

Dosage of Radium-223 dichloride: total activity injected, total activity injected per 
body weight. 

Actual dosage per day of exemestane and everolimus treatment will be summarized
for safety population.

Dose modifications of Radium-223 dichloride: number of injections delayed, 
number of injection delays due to AE, and reasons other than AE.

Dose modification of exemestane and everolimus treatment: number of delays, 
number of delays due to AE, and reasons other than AE.
6.3.2
Adverse events
All adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19 or most recent version. The intensity of an AE will be 
documented using National Cancer Institute (NCI) Common Terminology Criteria Adverse 
Event (CTCAE), version 4.03.
A treatment-emergent AE is defined as any event started or worsen between first dose date of 
any study medication (Radium-223 dichloride/placebo or exemestane or everolimus) and last 
dose date of any study medication + 30 days, inclusive.
Summary statistics (frequency and percentage of subjects, not of events) will be presented by 
treatment group using MedDRA for the following:

Incidence rate of pre-treatment AEs. 

Incidence rate of treatment-emergent AEs.

Incidence rate of treatment-emergent drug-related AEs, with respect to Radium-223 
dichloride/placebo, Exemestane and Everolimus, respectively.

Incidence rate of treatment-emergent AEs with grades 3 or 4.


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
Incidence rate of treatment-emergent AEs leading to death.

Incidence rate of treatment-emergent AEs leading to permanent withdrawal of medication
of Radium-223 dichloride/placebo, Exemestane and Everolimus, respectively. 

Incidence rate of treatment-emergent AEs leading to dose interruptions of Radium-223 
dichloride/placebo, Exemestane and Everolimus, respectively.

Incidence rate of treatment-emergent AEs leading to dose reductions (applies to 
background treatment and concomitant medication of interest) for Radium-223 
dichloride/placebo, Exemestane and Everolimus, respectively.

Incidence rate of treatment-emergent AEs of concomitant medication of interest. 1

Incidence rate of treatment-emergent serious adverse events.

Incidence rate of treatment-emergent drug-related serious adverse events , with respect to 
Radium-223 dichloride/placebo, Exemestane and Everolimus, respectively.

The maximum severity of the TEAEs will be summarized according to the NCI-CTCAE 
toxicity criteria. For each subject, multiple occurrences of the same event will be counted 
once at their maximum severity within a system organ class and preferred term. TEAE 
will also be summarized by NCI-CTCAE toxicity criteria and relationship to study 
medication.

Listing of treatment-emergent AEs leading to withdrawal: subject ID, investigator AE 
term, start and stop date of study drug administration, start and stop date of AE, drug 
related (yes/no), serious (yes/no), worst grade, outcome.

Listing of treatment-emergent serious AEs: subject ID, investigator AE term, worst 
grade, start and stop dates of study treatment, start and stop date of AE , drug related 
(yes/no), outcome, action taken. 

In addition, descriptive summaries will be provided for long term safety endpoints 
including new primary malignancies and hematopoietic reserve for tolerability of
subsequent chemotherapy. 

Bone fractures and bone associated events will be reported, including during long-term 
follow-up, regardless of the investigator’s causality assessment.2

Time to fracture is defined as the time (months) from the first dose date to the date of first 
fracture. Subjects without fractures are censored at the last visit date before or on the end
of active follow-up period. Time to fracture will be summarized using Kaplan-Meier 
                                                
1 As of SAP Amendment 1.
2 As of SAP Amendment 2.


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estimates.  Median survival time together with the 25th and 75th percentiles and 
associated 95% confidence intervals (CI) will be presented by treatment arm.
Corresponding Kaplan-Meier curves will be generated by treatment arm.

Competing risks for time to fracture is defined fracture as the primary event, death as 
competing risks. Patients who had fracture will be counted as primary event. Patients 
who died without fracture will be counted as competing risk.
6.3.3
Deaths
Deaths reported during the study period will be tabulated by treatment group.

Summary table of deaths (all deaths, all deaths during treatment period, all deaths during 
active follow up)

Listing of subjects who died during treatment period: subject ID, start and stop date of 
study medication, date of death, and cause of death.
6.3.4
Clinical laboratory evaluations
Worst grades for hematological and biochemical toxicities will be calculated according to 
CTCAE, version 4.03 based on laboratory measurements. Summary statistics (frequency and 
percentage of subjects, not of events) will be presented by treatment group and NCI CTC worst 
grade for the following:

Hematological and Biochemical Toxicities: treatment-emergent events by worst CTCAE 
grade.

Change in worst grade from baseline for hematological and biochemical toxicity (worst 
grade under treatment- latest pre-treatment value). 

Shift table from baseline to worst grade post-baseline for hematological and biochemical 
toxicity (worst grade under treatment- latest pre-treatment value).

By-subject listing of subjects with abnormal laboratory values.
If more than one assessment occurred at any post-baseline visit (repeated measures at same visit), 
the last valid (non-missing) value will be used in the summaries. Unscheduled laboratory data 
will be listed but will not be included in the summary tables. CTC grading of some laboratory 
parameters require clinical information in addition to the laboratory values. However, laboratory 
CTC grades presented in the CSR will be based only on the numerical lab results.


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6.3.5 Other safety measures
The last pre-treatment safety measurement, i.e., SBP, DBP, weight, body temperature, heart rate, 
respiration rate and electrocardiogram (ECG) will be used as “baseline value.”
When more than one value is collected at the same visit, the value retained at that particular visit 
for summary statistics will be the average of the different measures reported for that visit.
For each treatment group, vital signs will be tabulated and summarized by visit for observed 
values and changes from baseline using descriptive statistics, as appropriate. 
Summary statistics of ECG data will be reported at each visit for raw data and for changes from 
baseline. In addition, incidence rates of treatment-emergent ECG findings will be reported.
The number and percentage of subjects in each ECOG category will be presented by visit. 
Changes from baseline in ECOG will be summarized in shift tables by treatment group and visit.
6.4
Pharmacokinetics 
No pharmacokinetic (PK) measurements will be performed in this study.
6.5
Biomarker analyses 
Biomarker analyses planned within this study may include predictive, prognostic, and 
pharmacodynamic biomarkers analyzed from serum and urine. Summary statistics for 
biomarkers and their changes from baseline may be presented by visits and treatment depending 
on the availability of data. 
Biomarker analyses will be described in a separate analysis plan. 
6.6
Sample size estimation
The sample size is based on the primary efficacy endpoint, SSE-FS. 
Assuming 1-sided alpha of 0.1 (2-sided alpha of 0.2), power of 90%, and a randomization ratio 
of 1:1 between the experimental and control arms, 160 events are required to detect a 50% 
increase in SSE-FS. The expected study duration is 26.9 months assuming subjects enroll at a 
rate of 20 subjects per month, an enrollment ramp-up time of 6 months, a dropout rate of 15% for 
the primary endpoint, exponentially distributed event time, 8.3 month median time for the 
control group and a 12.45 month long, enrollment for a total of 311 patients in the two treatment 
groups combined.
The power calculation does not take into account the administrative interim analysis, which was 
added in Protocol Amendment 8 (dated 18 MAY 2017).  No alpha and no beta spending 


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adjustment is performed. There was no plan to stop the study for futility or superiority. However, 
an interim analysis may affect the operating characteristics. 
The power calculation does not take into account the Sponsor decisions to discontinue 
enrollment in April 2018, and to curtail the study and conduct the primary analysis, 
independently of the number of SSE-FS achieved, with a cutoff date of 22JAN2020. Because the 
study is being ended and the primary analysis performed with less than the originally planned 
number of patients and events, the actual power of this study is expected to be less than planned. 
6.7
Additional analyses planned to be reported outside the main report
Biomarker analyses if any will be reported in a separate report and specified in a separate 
document.
6.8
Change of analysis1
After the unblinded administrative data review, conducted on 05 DEC 2017, the IDRC
recommended discontinuing enrollment on 30 NOV 2017. Protocol Amendment 9, dated 
03 APR 2018, allowed subjects who completed the EOT visit to be transitioned to the separate 
long-term follow-up study (BAY 88-8223 Study 16996 / NCT02312960), without further follow-
up in the 17096 study.
The premature enrollment discontinuation, with subsequent reduced sample size, and the 
potentially reduced follow-up period limited the number of SSE-FS events observed. Therefore, 
the sponsor decided to conduct the primary analysis, independently of the number of SSE-FS 
achieved, with a cutoff date of 22JAN2020.
6.8.1 Efficacy endpoints
The planned sensitivity analyses for all efficacy endpoints in previous sections will not be 
performed due to the study early termination, except for SSE-FS will be evaluated using 
stratification factors derived from the information collected on the eCRF. All confidence 
intervals for time to event results specified in previous sections are calculated for 95%% CI only. 
A hazard ratio with 2-sided 95% CI from a stratified Cox proportional hazards model will be 
performed as planned. The use of 80% CIs specified in the protocol will be limited to the 
primary endpoint main analysis. 
The list used for subgroup analyses for SSE-FS were updated and provided as below:

Age (≥55, <55)
                                                
1 As of Amendment 4.


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
Race 

Geographical region (Europe/North America [including Israel] versus Asia)

Baseline ECOG performance status 

Previous lines of hormone therapy in metastatic setting

Visceral disease

Prior SREs, 

Baseline total body weight

Baseline ideal body weight

BMI
The subgroup analyses for rPFS will be performed as below:

Age (≥55, <55)

Geographical region (Europe/North America [including Israel] versus Asia)

Baseline ECOG performance status 

Previous lines of hormone therapy in metastatic setting

Visceral disease

BMI
6.8.2 Other endpoints
The following planned analysis will not be performed due to the study early termination.

Resource utilization (will be included in listing only)

Biomarker analyses

Area under curve (AUC) for pain severity index and function interference index

Analysis of impact of baseline ideal body weight and total body weight on AEs
7. Document history and changes in the planned statistical analysis

Signed SAP version 1.0 dated 25 October 2016, according to protocol version 1.0 up to 
amendment 5.0, integrated protocol version 5.0, and dated 11 MAR 2016.

Signed SAP version 2.0 dated 25 OCT 2017, according to protocol version 1.0 up to 
amendment 8, integrated protocol version 4.0, and dated 23 May 2017.

Signed SAP version 3.0 dated 04 JAN 2019, according to protocol version 1.0 up to 
amendment 9, integrated protocol version 6.0, and dated 03 APR 2018.

Signed SAP version 4.0 dated 14 FEB 2020, according to protocol version 1.0 up to 
amendment 10, integrated protocol version 7.0, and dated 04 DEC 2019.


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8. References
[1]. Rubens RD, Coleman RE. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE. 
Clinical oncology. New York: Churchill Livingstone, 1995:643-65. 
[2]. Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation 
counting. Appl Radiat Isot. 2010;68(7-8):1523-8. 
[3]. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. 
Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl 
J Med. 2012;366(6):520-9. http://dx.doi.org/10.1056/NEJMoa1109653. Epub 2011 Dec 7.
[4]. Yardley et al. Everolimus plus exemestane in postmenopausal patients with HR+ breast 
cancer: BOLERO-2 final progression-free survival. AnalysisAdv Ther. 2013;30:870-84.
[5]. Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the NIST 
standard for 223Ra: new measurements and review of 2008 data. Journal of Research of 
the National Institute of Standards and Technology. 2015;120:37-57.
9. Appendices
9.1
Overall tumor response
Table 9–1: Overall tumor response
Overall non-bone 
response according 
to modified 
RECIST 1.1 
Response of non-target 
bone lesions
(including new bone 
lesions)
Overall response 
(consider both non-
bone and bone 
response)
The scan date used for 
censoring if overall response is 
non-PD (1st or last date)
Complete response
Complete response
CR
Partial response
Complete response
PR
Stable disease
Complete response
SD
Non CR/Non PD
Complete response
Non CR/Non PD
Progressive disease
Complete response
PD
Last assessment date prior to PD
Not evaluable/Missing
Complete response
NE
Complete response
Non CR/Non PD
PR
Partial response
Non CR/Non PD
PR
Stable disease
Non CR/Non PD
SD
Non CR/Non PD
Non CR/Non PD
Non CR/Non PD
Progressive disease
Non CR/Non PD
PD
Last assessment date prior to PD
Not evaluable/Missing
Non CR/Non PD
NE
Complete response
Unequivocal progression
PD
Bone response date
Partial response
Unequivocal progression
PD
Bone response date
Stable disease
Unequivocal progression
PD
Bone response date
Non CR/Non PD
Unequivocal progression
PD
Bone response date
Progressive disease
Unequivocal progression
PD
Bone response date


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    Page: 36 of 36
Table 9–1: Overall tumor response
Overall non-bone 
response according 
to modified 
RECIST 1.1 
Response of non-target 
bone lesions
(including new bone 
lesions)
Overall response 
(consider both non-
bone and bone 
response)
The scan date used for 
censoring if overall response is 
non-PD (1st or last date)
Not evaluable/Missing
Unequivocal progression
PD
Bone response date
Complete response
Not (all) evaluated/Missing
NE
Partial response
Not (all) evaluated/Missing
NE
Stable disease
Not (all) evaluated/Missing
NE
Non CR/Non PD
Not (all) evaluated/Missing
NE
Progressive disease
Not (all) evaluated/Missing
PD
Last assessment date prior to PD
Not evaluable/Missing
Not (all) evaluated/Missing
NE/Missing
Not applicable 
Complete response
CR
Bone response date
Not applicable
Non CR/Non PD
Non CR/Non PD
Bone response date
Not applicable
Unequivocal progression
Unequivocal progression
Bone response date
Not applicable
Not (all) evaluated
Not (all) evaluated
Bone response date
Definitions:
1. Not applicable = No non bone lesions at baseline and no new non bone lesions (no PD)
2. Not evaluated = not all evaluated = Missing (new lesion must be absent)
3. As per RECIST 1.1 paper: ""When no imaging/measurement is done at all at a particular time point, the patient is 
not evaluable (NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually the 
case is also considered NE at that time point"" (unless other arguments for PD)"


Supplement Statistical Analysis Plan
BAY 88-8223/17096
Page: 1 of 14
Title page
A phase II randomized, double-blind, placebo-controlled trial of radium-
223 dichloride in combination with exemestane and everolimus versus 
placebo in combination with exemestane and everolimus when 
administered to metastatic HER2 negative hormone receptor positive 
breast cancer subjects with bone metastases
Short title: Study of radium-223 dichloride in combination with exemestane and 
everolimus versus placebo in combination with exemestane and everolimus in subjects with 
bone predominant HER2 negative hormone receptor positive metastatic breast cancer
Bayer study drug
BAY no. 88-8223 / Radium-223 dichloride / Xofigo
[Study purpose:]
Efficacy and Safety
Clinical study 
phase:
II
Date:
24 JUN 2020
Study No.:
BAY 88-8223 / 
17096
Version:
1.0
Author:
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 
sponsor 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.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Supplement Statistical Analysis Plan
Protocol No.: BAY 88-8223/17096
Page: 2 of 14
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 2
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 3
4.
General Statistical Considerations .................................................................................. 4
4.4
Data Rules........................................................................................................................ 4
5.
Analysis Sets ...................................................................................................................... 4
6.
Statistical Methodology .................................................................................................... 4
6.1
Population characteristics ................................................................................................ 4
6.2
Efficacy............................................................................................................................ 4
6.2.1
Primary efficacy variables............................................................................................ 5
6.2.2
Secondary efficacy variables........................................................................................ 5
6.2.3
Exploratory efficacy variables...................................................................................... 6
6.3
Safety ............................................................................................................................. 13
6.4
Pharmacokinetics........................................................................................................... 13
6.5
Biomarker analyses........................................................................................................ 13
6.6
Sample size estimation................................................................................................... 13
6.7
Additional analyses planned to be reported outside the main report............................. 13
6.8
Change of analysis ......................................................................................................... 13
7.
Document history and changes in the planned statistical analysis............................. 13
8.
References ........................................................................................................................ 14
9.
Appendices....................................................................................................................... 14
Abbreviations
ALP
Alkaline Phosphate
CSR
Clinical Study Report
FAS
Full Analysis Set
rPFS
Radiological progression-free survival
SAP
Statistical Analysis Plan


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1.
Introduction
The statistical analysis plan (SAP), version 4.0, dated 14 FEB 2020, was considered the main 
SAP applied for analysis. Its analyses were pre-hoc, specified and applied prior to database 
lock of the study.  
This Supplemental SAP version 1.0 describes analyses that were not included in the main 
SAP but may be used for clinical study report (CSR) or other submission documents. Changes 
to planned analyses in the main SAP are also described in this Supplemental SAP.
This Supplemental SAP version 1.0 is a supplement to SAP version 4.0 dated 14 FEB 2020.  
Unless otherwise indicated in this supplemental SAP, the analyses described in this 
supplemental SAP should be considered post-hoc and may have been specified after database 
lock. 
2.
Study Objectives
The primary endpoint is: 

symptomatic skeletal event-free survival (SSE-FS). 
The secondary endpoints are:

OS; 

time to opiate use for cancer pain; 

time to pain progression; 

time to cytotoxic chemotherapy; 

radiological progression free survival (rPFS);

pain improvement rate; 

Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy. 
The exploratory endpoints are:

time to first on-study SSE; 

time to bone-ALP progression; 

bone-ALP response at Week 12 and 4 weeks (± 7 days) after last radium-223 
dichloride/placebo dose; 

bone-specific rPFS;

resource utilization; 

biomarker assessments, 

time to visceral metastases onset. 
3.
Study Design
Refer to the main SAP v4.0 dated 14 FEB 2020.


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4.
General Statistical Considerations
Refer to the main SAP v4.0 dated 14 FEB 2020.
4.4
Data Rules
Refer to the main SAP v4.0 dated 14 FEB 2020.
For the survival assessment-related main analysis of time-to-event endpoints which 
incorporate survival information, including primary endpoint SSE-FS, secondary endpoints 
OS and rPFS, and exploratory endpoint bone-specific rPFS, 17096 subjects who transferred 
to the 16996 study will have survival information from the 16996 study incorporated in 
determining the death date. Accordingly, subjects whose deaths were recorded in the 16996 
study will have death events recorded at their respective death dates as documented in the 
16996 study , In addition, for secondary endpoint OS, which incorporates last known alive 
date (LKAD) for censoring purposes, subjects who were still alive and followed up in 16996
as of the cutoff date will be censored at the last known alive date prior to or on the cutoff 
including survival assessments performed and documented in in 16996, 
The above data rule for the above endpoints was implemented prior to database lock. 
Accordingly, it does not change the pre-hoc nature of the analyses of these endpoints as 
otherwise described in the main SAP. 
Analyses of three supplemental exploratory endpoints defined in this supplemental SAP will 
also use data from 16996, including competing risks for time to radiological bone 
progression, competing risks for time to radiological non-bone progression, and summary of 
death events. For these endpoints. 17096 subjects who transferred to the 16996 study will 
have survival information from the 16996 study incorporated in determining the death date. 
Accordingly, subjects whose deaths were recorded in the 16996 study will have death events 
recorded at their respective death dates as documented in the 16996 study. These endpoints, 
and this data rule for them, are considered post hoc. 
5.
Analysis Sets
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.
Statistical Methodology
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.1
Population characteristics
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.2
Efficacy
Refer to the main SAP v4.0 dated 14 FEB 2020.


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Subjects who completed the EOT visit were eligible to be transitioned to the separate long-
term follow-up study (BAY 88-8223 Study 16996 / NCT02312960), without further follow-
up in the 17096 study. For primary analyses (described in the main SAP v4.0 dated 14 FEB 
2020) as well as post-hoc analyses described in the present SAP, the survival data, including 
death date and last-known alive date, obtained in 16996 will be extracted and merged to the 
17096 data.
6.2.1
Primary efficacy variables
Refer to the main SAP v4.0 dated 14 FEB 2020.The primary analysis of SSE-FS, and any 
associated sensitivity, supplemental, and/or subgroup analyses specified in the main SAP, 
will be performed incorporating data from study 16996 as specified in Section 4.4 Data Rules.
These analyses will otherwise be performed as specified in main SAP V4.0, Section 6.2.1. As 
the data rule was implemented prior to database lock, these analyses are considered pre-hoc.
In addition, a sensitivity analysis for SSE-FS will be performed using data from study 17096 
only. All data from study 16996 will be excluded from this sensitivity analysis. This 
sensitivity analysis will otherwise be performed in the same manner as the primary analysis of 
SSE-FS as specified in main SAP V4.0, Section 6.2.1.2. This sensitivity analysis is 
considered post-hoc. 
6.2.2
Secondary efficacy variables
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.2.2.1 Definition
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.2.2.2
Analysis of secondary efficacy endpoints
The primary analyses of OS and rPFS, and any associated sensitivity, supplemental, and/or 
subgroup analyses specified in the main SAP,  will be performed incorporating data from 
study 16996 as specified in Section 4.4 Data Rules, These analyses will otherwise be 
performed as specified in main SAP V4.0, Section 6.2.1. As the data rule was implemented 
prior to database lock, these analyses are considered pre-hoc.
In addition, sensitivity analyses for OS and rPFS respectively will be performed using data 
from study 17096 only. All data from study 16996 will be excluded from these sensitivity 
analyses. These sensitivity analyses will otherwise be performed in the same manner as the 
primary analyses of OS and rPFS, respectively, as specified in main SAP V4.0, Section 
6.2.1.2. These sensitivity analyses are considered post-hoc. 
Time to pain progression was evaluated in subjects with baseline WPS ≤ 8. However, subjects 
with baseline WPS score >8 will also be included in the analysis by censoring at radium-223 
dichloride or placebo treatment start date. Pain improvement rate was summarized with safety 
subjects with baseline WPS ≥ 2 as denominator. These analyses are considered pre-hoc, in 
which the analysis populations were not clearly specified in main SAP V4.0, but included in 
this supplement SAP.


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6.2.3
Exploratory efficacy variables
6.2.3.1 Definition
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.2.3.2
Analysis of exploratory efficacy endpoints defined in the main SAP
The primary analyses of bone-specific rPFS, and any associated sensitivity, supplemental, 
and/or subgroup analyses specified in the main SAP,  will be performed incorporating data 
from study 16996 as specified in Section 4.4 Data Rules, These analyses will otherwise be 
performed as specified in main SAP V4.0, Section 6.2.1. As the data rule was implemented 
prior to database lock, these analyses are considered pre-hoc.
In addition, a sensitivity analysis for bone-specific rPFS respectively will be performed using
data from study 17096 only. All data from study 16996 will be excluded from this sensitivity 
analysis. This sensitivity analysis will otherwise be performed in the same manner as the 
primary analyses of bone-specific rPFS, respectively, as specified in main SAP V4.0, Section 
6.2.1.2. This sensitivity analysis is considered post-hoc. 
For analysis of time to bone ALP progression, two consecutive missing assessments is 
defined if the time interval between two consecutive ALP assessments is more than 10 weeks 
(2 × (4 weeks +1 week)) during the treatment period, or 18 weeks (2 × (8 weeks +1 week))
during the active follow-up period. The time window for active follow-up period is mis-
specified in main SAP V4.0 section 6.2.3.1, but corrected in this supplement SAP.
6.2.3.3 Definition of additional exploratory efficacy variables
The additional exploratory efficacy variables are specified below: 

Time to radiological bone progression (Kaplan-Meier)

Time to radiological non-bone progression (Kaplan-Meier).

Competing risks for time to radiological bone progression (death and radiological non-
bone progression as competing risks)

Competing risks for time to radiological non-bone progression (death and radiological 
bone progression as competing risks)

Summary of death events with radiographic bone and non-bone progression as 
competing risks

Summary of visceral disease
Derivation of three out of the above six variables, including competing risks for time to 
radiological bone progression, competing risks for time to radiological non-bone progression, 
and summary of death events, will also include the addition of 16996 data as described in 
Section 4.4 Data Rules.
Time to Radiological Bone Progression (Kaplan-Meier) is defined as the time (months) 
from randomization date to the date of radiological bone progression (according to the 


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mRECIST1.1 criteria), as documented by the investigator. Radiological bone progression 
occurs when progression by bone scan is detected.
Time to Radiological Bone progression = (End Date – Randomization Date +1)/30.44
Table 6–1: Time to Radiological Bone progression censoring rules (Kaplan-Meier 
analysis)
Situation
End Date 
Censored
Reason for Censoring
No baseline or post-baseline 
radiological bone assessment
(bone scan)
Randomization Date
Yes
No baseline or post-
baseline bone radiological 
assessment.
Superscan at baseline
Randomization Date
Yes
Superscan at baseline
Subject had a radiological bone 
assessment of PD (no two 
consecutive missed radiological 
bone assessments)
Date of first bone PD
No
N/A
PD immediately after two or more 
consecutive  missed radiological  
bone assessments
Date of last radiological bone 
assessment before missed 
assessments
Yes 
Missed two or more 
consecutive bone scan 
assessments
Subject discontinuation from 
study for other than PD 
Last radiological bone 
assessment date  
Yes
Subject discontinued 
from study due to a 
reason other than bone  
PD
Death during the study before first 
radiological bone PD assessment
Randomization Date  
Yes
No radiological bone 
progression observed
Subjects discontinued from 
study due to PD, but no 
documented date of bone 
PD
Date of last radiological 
bone assessment
Yes
Subjects discontinued 
from study due to 
PD, but no 
documented date of 
bone PD
Subjects still on study at the 
time of data cutoff without 
bone PD
Last radiological bone 
assessment before data 
cutoff
Yes
Subject is still alive 
without bone PD
New systemic anticancer 
treatment started
Date of last radiological 
bone assessment before 
starting new systemic 
anticancer treatment
Yes 
New systemic 
anticancer treatment 
started


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Time to Radiological non-Bone Progression (Kaplan-Meier) is defined as the time (months) 
from randomization date to the date of radiological non-bone (soft-tissue or visceral lesions) 
progression (according to the mRECIST1.1 criteria), as documented by the investigator.
Radiological non-bone progression occurs when progression by non-bone scan is detected.
Time to Radiological non-Bone progression = (End Date – Randomization Date +1)/30.44
Table 6–2: Time to Radiological non-Bone progression censoring rule (Kaplan-
Meier analysis)
Situation
End Date 
Censored
Reason for 
Censoring
No baseline or post-baseline 
radiological non-bone 
assessment (non-bone scan)
Randomization Date
Yes
No baseline or post-
baseline non-bone 
radiological 
assessment.
Subject had a radiological 
non-bone assessment of PD 
(no two consecutive missed 
radiological non-bone 
assessments)
Date of first non-bone 
PD
No
N/A
Non-bone PD immediately 
after two or more 
consecutive missed 
radiological non-bone 
assessments
Date of last radiological 
non-bone assessment 
before missed 
assessments
Yes 
Missed two or more 
consecutive non-
bone scan 
assessments
Subject discontinuation 
from study for other than 
non-bone PD 
Last radiological bone 
assessment date  
Yes
Subject discontinued 
from study due to a 
reason other than 
non-bone PD
Death during the study 
before first radiological non-
bone PD assessment
Randomization date  
Yes
No radiological non-
bone progression 
observed
Subjects discontinued from 
study due to non-bone PD, 
but no documented date of 
non-bone PD
Date of last radiological 
non-bone assessment
Yes
Subjects 
discontinued from 
study due to PD, but 
no documented date 
of non-bone PD


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Table 6–2: Time to Radiological non-Bone progression censoring rule (Kaplan-
Meier analysis)
Situation
End Date 
Censored
Reason for 
Censoring
Subjects still on study at the 
time of data cutoff without 
non-bone PD
Last radiological non-
bone assessment before 
data cutoff
Yes
Subject is still alive 
without non-bone 
PD
New systemic anticancer 
treatment started
Date of last radiological 
non-bone assessment 
before starting new 
systemic anticancer 
treatment
Yes 
New systemic 
anticancer treatment 
started
Competing risks for time to radiological bone progression and competing risks for time 
to radiological non-bone progression
Once time to radiological bone progression and time to radiological non-bone progression
event and Kaplan-Meier censoring rules are defined above. 
Competing risks for time to radiological bone progression is defined radiological bone 
progression as the primary event, death and radiological non-bone progression as two 
competing risks. Subjects who experienced radiological bone progression before or on the 
first occurrence of radiological non-bone progression or death will be counted as primary 
event. Subjects who died or had radiological non-bone progression without radiological bone 
progression will be counted as competing risks. Subjects with neither a primary nor a 
competing risk event will be censored. Censoring rules, including rules addressing missing 
assessments, are described below.
Competing risks for time to radiological non-bone progression is defined radiological 
non-bone progression as the primary event, death and radiological bone progression as two 
competing risks. Subjects who experienced radiological non-bone progression before or on 
the first occurrence of radiological bone progression or death will be counted as primary event. 
Subjects who died or had radiological bone progression without radiological bone progression 
will be counted as competing risks. Subjects with neither a primary nor a competing risk 
event will be censored. Censoring rules, including rules addressing missing assessments, are 
described below.
The competing risks are defined with combination the outcome of different type of 
events/censoring. The outcome combination 
logic is as below:


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(1) Rules for addressing subsequent therapy and missing assessments  (missing 
assessment windowing):

If there was a new anti-cancer therapy, then all tumor assessments and any 
death event following the date of the first anti-cancer therapy (both bone and 
non-bone) are discarded.

For each type of tumor assessment (bone and non-bone), considered separately, 
if there are two consecutive missing assessments (gap between 2 assessments 
of  > 18 weeks) for that assessment type prior to the PD (PD is > 18 weeks 
after last non-PD assessment) for the type, then the PD is discarded.

For each type of tumor assessment (bone and non-bone), considered separately, 
if there are two consecutive missing assessments (gap of  > 18 weeks) for that 
assessment type prior to a death event with no prior progression of that type, 
then the death event is discarded for purposes of evaluating the progression 
type (Note: the death event may count for the other progression type if 
assessments did not result in a gap).

After applying the above rules, if a PD event occurs >18 weeks after the last-
dated assessment of the other tumor type, and the other tumor type has no PD, 
then the PD is discarded. 
(2) Rules for addressing simultaneity: . After applying the above rules, if the last-dated 
remaining bone scan is within ±7 days of the last-dated remaining non-bone tumor 
assessment  (either assessment occurred 7 or fewer days after the other), then the two 
assessments will be regarded as effectively occurring simultaneously. This 
simultaneity windowing concept addresses the potential for tumor assessments of 
different types to occur on different dates even though they are effectively part of the 
same tumor assessment visit, and to reduce the possibility of minor scheduling 
anomalies biasing the outcomes. To implement this, the following table (Table 6–3)
determines the outcome and date of each endpoint:
Table 6–3: Rules for addressing simultaneity
Endpoint
Earlier of Last 
Assessments
(Bone or non-
Bone)
Earlier 
Assessment
Outcome
Later 
Assessment 
Outcome
Outcome
Date
TT Bone 
Progression
Bone 
Assessment
PD
PD
Event
Bone Assessment
Bone 
Assessment
PD
Non-PD
Event
Bone Assessment
Bone 
Assessment
Non-PD
PD
Competing Risk 
Event
Non-Bone 
Assessment
Bone 
Assessment
Non-PD
Non-PD
Censor
Bone Assessment


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Table 6–3: Rules for addressing simultaneity
Endpoint
Earlier of Last 
Assessments
(Bone or non-
Bone)
Earlier 
Assessment
Outcome
Later 
Assessment 
Outcome
Outcome
Date
Non-Bone 
Assessment
PD
PD
Event
Bone Assessment
Non-Bone 
Assessment
PD
Non-PD
Competing Risk 
Event
Non-Bone 
Assessment
Non-Bone 
Assessment
Non-PD
PD
Event
Bone Assessment
Non-Bone 
Assessment
Non-PD
Non-PD
Censor
Bone Assessment
TT Non-Bone 
Progression
Bone 
Assessment
PD
PD
Event
Non-Bone 
Assessment
Bone 
Assessment
PD
Non-PD
Competing Risk 
Event
Bone Assessment
Bone 
Assessment
Non-PD
PD
Event
Non-Bone 
Assessment
Bone 
Assessment
Non-PD
Non-PD
Censor
Non-Bone 
Assessment
Non-Bone 
Assessment
PD
PD
Event
Non-Bone 
Assessment
Non-Bone 
Assessment
PD
Non-PD
Event
Non-Bone 
Assessment
Non-Bone 
Assessment
Non-PD
PD
Competing Risk 
Event
Bone Assessment
Non-Bone 
Assessment
Non-PD
Non-PD
Censor
Non-Bone 
Assessment
(3) Rules for addressing precedence (after applying both windowing rules above): Rules 
are based on the following table (Same for time to bone progression/bone assessments 
and time to non-bone progression/non-bone assessments respectively). The window 
refered to in the table below (i.e., Table 6–4) is a ±7 day window: 
Table 6–4: Rules for addressing precedence
Last Endpoint 
Last Other 
Other
Death
Outcome
Date


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(Bone or
Non-Bone)
Assessment 
(Non-Bone
or Bone)
Assessment
Precedence
PD
PD
Before, outside 
window 
After or none
Competing Risk 
Event (Other)
Other Assessment
Any
Any
Window
After or none
See Table 6–3
3
PD
PD 
After, outside 
window
After or none
Event
Endpoint 
Assessment
PD
Non-PD 
After, outside 
window
After or none
Event
Endpoint 
Assessment
PD
Non-PD
Before, outside 
window 
After or none
Event
Endpoint 
Assessment
Non-PD
PD
Before, Outside 
Window
After or none
Competing Risk 
Event (Other)
Other Assessment
Non-PD
PD
After, Outside 
window
After or none
Censored
Endpoint 
Assessment
Non-PD
Non-PD
Any, outside 
Window
After
Competing Risk
Event (Death)
Death
Non-PD
Non-PD
Any, outside 
Window
none
Censored
Endpoint 
Assessment
6.2.3.4 Analysis of additional exploratory efficacy endpoints
For Kaplan-Meier time to radiological bone progression and time to radiological none-bone 
progression, analysis will be performed similarly to the primary endpoint. To compare the 
two treatment groups, a stratified log-rank test will be performed, stratified by the same 
stratification factors as randomization. The hazard ratio (radium-223 dichloride / placebo) and 
its 95% CIs will be estimated from the Cox model, stratified by the same factors as for SSE-
FS analysis. The product-limit estimates of the survival distribution functions (Kaplan-Meier) 
will be presented for each treatment group: N, total censored, total failed, time to event 
(median and its 95% CI, 25th and 75th percentile, range), rate of subjects who did not yet 
develop an event at pre-specified months. A Kaplan-Meier curve will be generated for each 
treatment group.
For competing risks variables, competing-risk time to radiological bone progression and 
competing-risk time to radiological none-bone progression, the hazard ratio (radium-223 
dichloride / placebo) for and its 95% CIs for time to event with competing risks will be 
estimated from the subdistribution proportional hazard model, stratified by the same factors as 
for SSE-FS analysis. Time to event with competing risks efficacy analysis will be performed 
to compare two treatment groups using Gray’s test[1] stratified by the same stratification 
factors as randomization. The estimates of the nonparametric cumulative incidence functions 


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will be presented for each treatment group: N, total censored, total event, total competing 
risks, rate of subjects who developed an event at pre-specified months. The cumulative 
incidence function curves will be generated for each treatment group.
Due to the small number of death events with radiological bone and non-bone progression ask 
competing risks, summary of death events with radiographic bone and non-bone progression 
as competing risks will be provided. No time to event analysis will be performed.
The number of subjects (N and percenatages) with visceral disease will be summarized with 
bone rPFS, death and non-bone rPFS events, respectively. 
6.3
Safety
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.4
Pharmacokinetics
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.5
Biomarker analyses 
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.6
Sample size estimation
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.7
Additional analyses planned to be reported outside the main report
Refer to the main SAP v4.0 dated 14 FEB 2020.
6.8
Change of analysis
Refer to the main SAP v4.0 dated 14 FEB 2020.
Additional change of analysis:
Due to the limitation of data collection, overall duration of single standard of care hormonal 
treatment in follow up period and dosage of hormonal treatment, which were pre-hoc analyses  
specified in main SAP V4.0, will not be summarized in CSR.
7.
Document history and changes in the planned statistical analysis
Refer to the main SAP v4.0 dated 14 FEB 2020.


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8.
References
Refer to the main SAP v4.0 dated 14 FEB 2020.
[1] Gray, R. J. (1988). “A Class of K-Sample Tests for Comparing the Cumulative Incidence 
of a Competing Risk.” Annals of Statistics 16:1141–1154.
9.
Appendices
Refer to the main SAP v4.0 dated 14 FEB 2020.