BrUOG L301: Xofigo Following Frontline-Line Chemotherapy For Patients With Non-Small Cell Lung Cancer and Bone Metastases
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer With Bone Metastatses
Sponsor: Angela Taber MD

  
5/31/14, 8/25/14, 8/26/14, 9/2/14, 9/5/14, 9/10/14, 10/21/14, 12/2/14 IND Exemption, 12/8/14, 12/17/14,1/8/15, 
Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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BrUOG  L301  
 
 
 
 
 
 
IND EXEMPT 124745 
 
BrUOG L301: Xofigo Following Frontline-Line Chemotherapy For Patients  
With Non-Small Cell Lung Cancer and Bone Metastases 
 
Angela Taber, MD 
Brown University Oncology Group 
 
Humera Khurshid, MD 
Richard Noto, MD 
Don Yoo, MD 
 
 
Thomas Dipetrillo, MD 
 
Howard Safran, MD 
Director, Brown University Oncology Research Group 
The Rhode Island Hospital and Miriam Hospital 
 
 
Coordinating Center 
Kayla Rosati, EdM 
Brown University Oncology Research Group 
233 Richmond Street Box G-R001 
Providence, Rhode Island 02903 
Phone: (401) 863-3000 
Fax: (401) 863-3820 
Email: Kayla_rosati@brown.edu 
 
 
This study is supported in part by the Joan DeCotis Foundation 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law 
or regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
The values in this protocol have been revised as per the United States (US) National Institute of 
Standards and Technology (NIST) standardization update (agreed on 17 MAR 2015) 
Original protocol 5/21/14 
Amendment #1 5/19/15 
Amendment # 2, 2/19/16 
Amendment # 3 3/3/16 
Amendment #4 11/30/16

  
5/31/14, 8/25/14, 8/26/14, 9/2/14, 9/5/14, 9/10/14, 10/21/14, 12/2/14 IND Exemption, 12/8/14, 12/17/14,1/8/15, 
Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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TABLE OF CONTENTS 
Section  
 
 
 
 
 
 
 
 
Page 
1.0 
OBJECTIVES  
 
 
 
 
 
 
3 
2.0 
BACKGROUND 
 
 
 
 
 
 
3 
3.0 
PATIENT ELIGIBILITY 
 
 
 
 
 
4 
 
 
4.0 
TREATMENT 
 
 
 
 
 
 
6 
 
5.0 
TOXICITIES AND DOSE MODIFICATIONS 
                         8 
                                              
6.0 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
10 
                          
7.0      RESPONSE ASSESSMENT  
 
 
 
 
12 
 
 
8.0 
PATIENT REGISTRATION  
 
 
 
 
13 
9.0 
PHARMACEUTICAL INFORMATION                                           
13 
10.0 
AGENT ACCOUNTABILITY     
 
 
 
 
21 
 
11.0 
ADVERSE DRUG REACTION REPORTING 
 
 
22 
 
12.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
30 
13.0 
FOLLOW UP    
 
 
 
 
 
 
30 
   
14.0 
REGULATORY CONSIDERATIONS   
 
                          31 
15.0 
DATA MONITORING/QUALITY ASSURANCE/ 
 
 
32 
RECORD RETENTION 
 
 
 
 
 
 
 
16.0 
DATA SAFETY AND MONITORING BOARDS 
 
 
34 
 
17.0 
STATISTICAL CONSIDERATIONS  
 
 
    
35 
18.0 
REFERENCES                                                                        
36 
 
APPENDIX SECTION: 
 
 
 
 
 
APPENDIX A INFORMED CONSENT 
 
 
 
 
 
APPENDIX B ELIGIBILITY CHECKLIST  
 
 
 
 
APPENDIX C COMMON TOXICITY CRITERIA  
 
 
APPENDIX D ECOG PERFORMANCE STATUS   
 
 
APPENDIX E CASE REPORT FORMS 
 
APPENDIX F TREATMENT GUIDELINES PRE- NIST CHANGES 
APPENDIX G TREATMENT GUIDELINES POST-NIST CHANGES  
 

  
5/31/14, 8/25/14, 8/26/14, 9/2/14, 9/5/14, 9/10/14, 10/21/14, 12/2/14 IND Exemption, 12/8/14, 12/17/14,1/8/15, 
Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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1.0  OBJECTIVES 
1.1 PRIMARY OBJECTIVE: 
1.1.1 To evaluate if Xofigo can reduce symptomatic skeletal events (SSE) in patients with 
NSCLC and bone metastases who have had stable or responding disease following initial 
systemic chemotherapy. 
 
1.2 SECONDARY OBJECTIVES: 
1.2.1 To evaluate toxicity of Xofigo in patients with NSCLC and bone metastases following 
front-line chemotherapy. 
 
1.2.2 To evaluate time to symptomatic skeletal events.  
 
1.2.3 To evaluate changes in health-related quality of life, using the EORTC QLQ-C30 and QOL-
BM22 questionnaires, in patients with NSCLC and bone metastases treated with Xofigo.  
 
1.2.4 To evaluate the impact of treatment with Xofigo on alkaline phosphatase levels in patients 
with NSCLC and bone metastases.  
 
1.2.5 To measure progression-free survival and overall survival of patients with NSCLC and bone 
metastases and stable or responding disease after front-line chemotherapy treated with Xofigo.   
 
2.0  BACKGROUND 
Non-Small Cell Lung Cancer (NSCLC): Lung cancer is the most common cause of cancer 
death worldwide, with an estimated 1,600,000 new cases and 1,380,000 deaths per year.1 In the 
United States, there are an estimated 228,000 new cases of lung cancer and 159,500 deaths, 
yearly.2  
Bone Metastases from NSCLC: Approximately 50% of patients with advanced lung cancer will 
develop progressive bone metastases during the course of their illness.3 Bone metastases from 
NSCLC are frequently symptomatic leading to significant morbidity due to pain, pathologic 
fracture and neural compression. Primary treatment has relied upon radiation therapy.3-6 Local 
external-beam radiation can be effective in patients with a small number of metastases, but its 
clinical utility in patients with disseminated metastatic bone disease is limited by the number of 
sites that can be treated. The potential for toxicity to neighboring tissues at an effective radiation 
dose can also limit retreatment to certain sites. Chemotherapy can be helpful until the disease 
becomes refractory.3 
Bisphosphonates and Denosumab in NSCLC and Bone Metastases: Bisphosphonates have  a 
modest impact in reduction of skeletal related events in NSCLC and other solid tumors.7-9 In the 
phase III study of zoledronic acid for patients with bone metastases from solid tumors, the time to 
a skeletal related event was increased from 163 days to 230 days with zoledronic acid versus 

  
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Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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placebo. In this study, approximately 40% of patients with bone metastases from NSCLC had a 
new skeletal related event within 4 months.7,8 
The monoclonal antibody denosumab also demonstrates a modest benefit in reduction of skeletal 
events in NSCLC.9,10 Denosumab binds to RANKL inhibiting osteoclast formation. 
Bisphosphonates and denosumab act primarily on osteoclasts and do not treat metastases directly. 
Furthermore, they each are associated with osteonecrosis of the jaw.7-10 
Radium-223 (Xofigo): Xofigo is an alpha-particle emitting radiotherapeutic drug (radium-223 
dichloride) which mimics calcium and forms complexes with hydroxyapatite at areas of increased 
bone turnover, such as bone metastases.11 Xofigo targets bone metastases by delivering high-
energy, short-range (<100 um) alpha-particles. These alpha particles can potentially provide 
greater dose to the exact site of bone metastases while also reducing marrow toxicity due to their 
shorter path length. 12 The phase III, double blind ALSYMPCA study randomized patients 2:1 to 
receive Xofigo, 6 injections every 4 weeks or placebo. Xofigo significantly improved overall 
survival in patients with castrate resistant prostate cancer (median overall survival 14.9 versus 
11.3 months; P < 0.001).11  Xofigo significantly delayed time to first symptomatic skeletal events 
including reducing pathologic bone fracture, spinal cord compression, need for surgical 
intervention for a bone metastasis, and time to external beam radiotherapy. Xofigo also reduced 
pain and opioid use.  
Standard Front-line Treatment of NSCLC and Optimal Role for Xofigo: The initial 
treatment for patients with metastatic NSCLC who do not have a driver mutation (EGFR or ALK 
mutation) involves combination chemotherapy for 4-6 cycles with agents such as cisplatin, 
carboplatin, paclitaxel, pemetrexed. 13,14 For patients with stable or responding disease, 
maintenance chemotherapy with pemetrexed or docetaxel may be utilized. 15 After initial front-
line chemotherapy, patients with stable or responding disease are often given a treatment break 
from chemotherapy and followed symptomatically and radiographically. In patients with bone 
metastases, denosumab or zoledronic acid are commonly administered to reduce symptomatic 
skeletal events but their effects are on osteoclasts and do not directly treat metastases. Their 
effectiveness is very limited with approximately half of all patients expected to have new 
symptomatic skeletal  events within the next 4 months.7,8 It is within this period following 
completion of front-line chemotherapy that this protocol will investigate Xofigo. 
 
3.0 PATIENT ELIGIBILITY 
3.1 Conditions for Patient Eligibility 
3.1.1 
Age ≥ 18 years.  
3.1.2 
Advanced non-small cell lung cancer with bone metastases.  
3.1.3  Stable or responding disease after completion of initial systemic chemotherapy as defined 
by RECIST criteria. “Initial systemic treatment,” is to include all treatment and therapy given 
before a patient progresses. Therefore, a patient may receive different agents, including radiation, 
as part of their initial treatment as long as they have not and do not progress at any point prior to 
BrUOG 301 enrollment. However, patient must have received chemotherapy. Site to submit pre-
treatment scan with post treatment scan for RECIST and confirmation to BrUOG. Document 

  
5/31/14, 8/25/14, 8/26/14, 9/2/14, 9/5/14, 9/10/14, 10/21/14, 12/2/14 IND Exemption, 12/8/14, 12/17/14,1/8/15, 
Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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blastic or lytic lesions (and for lytic soft tissue or no soft tissue component. Soft tissue component 
requires measurements for RECIST). 
3.1.4 
At least 3 weeks must have elapsed since completion of last chemotherapy and 4 weeks 
since last radiation, prior to first dose of Xofigo. Patients are not permitted to receive any form of 
‘maintenance’ chemotherapy or biologic/targeted anticancer therapy while being treated on this 
study  
3.1.5 
Life expectancy of at least 12 weeks (3 months). 
3.1.6 
Patients with treated brain metastases are allowed, but must have brain imaging showing 
evidence of stability since most recent treatment for brain mets, prior to first dose of Xofigo. For 
patients with brain metastases only, brain imaging is required as per section 6 and scan must be 
sent to BrUOG with registration information before patient is registered on study. Patients who 
do not have brain metastases or symptoms of potential brain metastases are not required to have 
baseline brain imaging, but this must be confirmed in writing to BrUOG at time of registration. 
3.1.7 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 – 1. 
3.1.8 
Required entry laboratory parameters within 14 days of study entry: White Blood Cell 
 
Count (WBC) ≥ 3,000/mm3; Absolute Neutrophil Count (ANC) ≥ 1,500/mm3; Platelet 
 
(PLT) count ≥ 100,000/mm3; Hemoglobin (Hgb) > 9g/dl, Total bilirubin level ≤ 1.5 x 
institutional upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 x ULN ; Creatinine ≤ 1.5 x ULN; Albumin > 2.5 g/dL. 
3.1.9 
Concurrent treatment with bisphosphonates and denosumab is allowed. Information on 
start and stop date and drug with dose to be sent to BrUOG if patient to be treated 
concurrently. 
3.1.10  Prior skeletal related events (pathologic fracture, radiation or surgery to bone, or spinal 
 
cord compression) are allowed if they have been managed and now patient is stable for 4 
weeks prior to study entry. Must submit how events managed to BrUOG for documentation to 
confirm eligibility criterion. (For example, if a patient experienced a SSE and had radiation for 2 
weeks they must then be stable for 4 weeks after the completion of radiation prior to study entry) 
3.1.11 Subjects must be able to understand and be willing to sign the written informed consent 
 
form.   
3.1.12 All acute toxic effects related to prior treatment(s) must have resolved to NCI-CTCAE v4  
Grade 1 or less at the time of registration except for alopecia. Please note blood 
transfusion is allowed at baseline to bring HGB within study requirements, see section 
5.2 
3.1.13 Women of childbearing potential must have a negative serum pregnancy test performed 
 
within 7 days prior to the start of study drug.  Post-menopausal women (defined as no 
 
menses for at least 1 year) and surgically sterilized women are not required to undergo a 
 
pregnancy test. 
3.1.14 Subjects (men and women) of childbearing potential must agree to use adequate 
 
contraception beginning at the signing of the ICF until at least 30 days after the last dose 
 
of study drug.  The definition of adequate contraception will be based on the judgment of 
 
the treating physician. 

  
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Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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3.1.15 Willing and able to comply with the protocol, including follow-up visits and 
 
examinations 
3.2 Conditions for Patient Ineligibility 
3.2.1 
Received systemic therapy with radionuclides (e.g., strontium-89, samarium-153, 
 
rhenium-186, or rhenium-188, or Radium Ra 223 dichloride) for the treatment of bony 
 
metastases   
3.2.2 
No prior invasive malignancy within the prior two years. However, patients with an early 
 
stage malignancy that is not expected to require treatment in the next 2 years (such as 
 
early stage, resected breast cancer or asymptomatic prostate cancer) are eligible 
3.2.3 
Untreated brain metastases. 
3.2.4 
Any other serious illness or medical condition that in the investigator’s opinion would 
interfere with protocol treatment, such as but not limited to: Any active infection ≥ 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4 Grade 2 or Cardiac failure New York Heart Association (NYHA) III 
or IV 
3.2.5 
Women who are pregnant or breast-feeding. 
3.2.6 
Inability to comply with the protocol and/or not willing or who will not be available for 
follow-up assessments. 
3.2.7 
Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial 
 
participation. 
3.2.8 
Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
 
immunotherapy, biologic therapy, or tumor embolization) other than Ra 223 dichloride. 
3.2.9    Major surgery within 28 days of starting study drug. Central venous catheter placement is 
not considered major surgery. 
 
4.0 TREATMENT 
Schema: 
                                                      Primary Endpoint after 4 cycles of treatment 
   Register                         No SSEs 
 
 
 
 
 
 
 
Xofigo, 50 kBq/kg body weight (55kBq/kg body weight after NIST implementation), will be 
administered in the nuclear medicine department as a bolus intravenous (IV) injection (up to 1 
minute) at intervals of every 4 weeks for up to 6 cycles. (Treatment should be administered 
Pts with bone 
metastases & 
stable or 
responding 
disease after 1st 
line treatment 
Xofigo x 6 cycles. 
Assess every 4 
weeks    

  
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Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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within +/- 3 days of cycle due date). Treatment delays of up to 14 days due to patient, physician 
or facility scheduling issues should be reported but will not constitute a deviation. Weight used 
for drug order is to be from pre-cycle assessment (done within 7 days prior to cycle start). 
Patients are to be dosed based on drug order weight and weight collected the day of dosing, prior 
to dosing, is to only be used to confirm patient’s weight has not changed by more than 10% (see 
section 5.1). Patient’s dose is not to be adjusted based on day of weight. 
For dosing please refer to appendices F and G  
 
Filling of the syringe should take place in a safety bench or similar in the radiopharmacy/Nuclear 
Medicine department. Personnel should wear medical gloves and eye protection during syringe 
filling to prevent contamination of the radioactive solution to skin and eyes. The individual 
responsible for study drug preparation will draw the correct volume of study drug into a syringe. 
 
The syringe should be handed over to the nuclear medicine personnel who will perform the 
injection. There is no need for shielding from alpha particle radiation during preparation and 
administration of the patient doses. (Alpha particles from radioactive decay of radium-223 and 
progeny are easily stopped by the thickness of a sheet of a paper or the walls of a glass vial.) 
 
Aseptic technique should be used in the administration of Xofigo. The agent is administered as a 
slow bolus intravenous injection. After administration, the equipment used in connection with the 
preparation 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.  
 
In general, the administration of radioactive drugs involves a potential risk for third parties, due 
to radiation from the patient and due to possible contamination by spilling urine or feces. When 
Xofigo has been injected intravenously into a patient, 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 very 
low portion of beta and gamma radiation. For these reasons the product can be administered on an 
outpatient basis.  
 
Patients are informed to practice good hygiene for at least 1 week after study administration 
including washing hands, flushing the toilet several times after each use and washing clothes that 
are soiled with stool or urine promptly and separately from other clothes. 
 
4.1 Duration of Treatment 
Xofigo will be administered every 4 weeks for a maximum of 6 treatments. See 5.2 for reasons 
for study discontinuation. (Treatment should be administered within +/- 3 days). Treatment 
delays of up to 14 days due to patient, physician or facility scheduling issues should be reported 
but will not constitute a deviation.  
5.0 TOXICITIES, DOSE MODIFICATIONS, AND MANAGEMENT 

  
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Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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5.1   
 
If labs are re-drawn post enrollment and prior to cycle 1 day 1 dosing, the following criteria are 
required to be met before dosing cycle 1: 
 
ANC must be > 1.5 prior to day 1 dose of treatment (cycle 1) 
 (PLT) count must be ≥ 100,000/mm3 prior to day 1 dose of treatment (cycle 1) 
 Hemoglobin (Hgb) must be  > 9g/dl prior to day 1 dose of treatment (cycle 1) 
 
A new course (cycle 2-6) of treatment should not begin until the following criteria are met: 
 
Platelets > 50,000x109/L 
 
Granulocytes >1000x109/L (1000/mm3) 
 
Recovery from other treatment related, non-hematologic toxicities to < Grade 2    
 
Diarrhea < grade 2 
 
Nausea or vomiting < grade 2 or to baseline levels 
 If the patient does not meet these criteria delay day 1 until these requirements are met.  
Patients who require a treatment delay of more than 4 weeks from the scheduled treatment 
day due to toxicity will be removed from protocol treatment. 
 
**Weight prior to cycles 2-6 can be taken up to7 days prior to dosing each cycle. Weight within 7 
days of each cycle to be used for drug order and drug dosing for that cycle. Weight must again be 
assessed the day of drug administration, but this weight is only to be used to confirm  patient’s 
weight  has not changed by > 10% since the prior assessment pre-dosing (for example 7 days 
prior). If weight has not changed by >10% then, the patient is considered okay to treat. See 
section 6 subscript K for more details** 
 
5.2   Dose Modification/Study Discontinuation  
Toxicity: NCI common toxicity version 4 will be utilized to assess toxicity.  
Every effort should be made to administer the full dosing regimen of Radium Ra 223 dichloride.  
Adjustment of dose level is not permitted.   
•  Blood transfusion at baseline is acceptable to obtain baseline value of  >9 and between 
study drug administrations, but not on the same day as Xofigo administration. Use of 
biologic myeloid growth factors such as G-CSF, is allowed in the management of acute 
toxicity. 
Gastrointestinal events: 
Diarrhea should be treated as per local institutional practices.  The next cycle should not begin 
before diarrhea is recovered to CTCAE v4 Grade 2 or less.  
Nausea or vomiting should be treated as per local practice.  A further dose of study medication 
should not be given before nausea or vomiting is recovered to CTCAE v.4 Grade 2 or baseline 
levels. 
Xofigo will be permanently discontinued for the following: 
 

  
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Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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 
Symptomatic Skeletal Event: 
- Pathologic fracture:  Pathologic fractures are to be treated in a manner that attempts to 
maintain the best functional status and quality of life. Study treatment should be 
discontinued if the pathologic fractures are due to disease.  
- Spinal cord compression: If the patient experiences spinal cord compression during the 
treatment period, the patient should be treated for the event, and may not receive further 
study drug administration.  
- Radiation therapy to bone 
- Surgery to bone 
 
 
Patients with lung cancer progression requiring treatment with chemotherapy, radiation 
or surgery.  
 
Unacceptable toxicity (see section 5) 
 
Surgical Intervention: If surgery is required, and not due to disease progression, the 
patient may continue with study treatment, following a period of at least 4 weeks, if this 
is considered safe in the treating Investigator’s opinion.  
 
Non-pathological fractures: For traumatic fractures in weight-bearing bones during 
treatment phase, the study drug administration should be discontinued.  
 
Incidental, asymptomatic new or worsening bone metastases will not require 
discontinuation of Xofigo.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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6.0 SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
Parameter 
Pre-study (to be sent to 
BrUOG prior to 
registration) 
 Prior to 
each Day 
1 of Each 
Cycle 
(within 7 
days) 
(Every 4 
weeks) CK 
At study 
completion 
for all 
patients(30 
days- 5 
weeks post 
last dose 
of Xofigo) 
FUH 
Informed Consent 
(within 30 days of day 
1) *pts are to be re-
consented if ICF will be 
outside 30 day window 
X 
 
 
 
History , Demographics 
(baseline only) 
X 
 
 
 
Physical examination  
X 
X 
X 
 
Weight 
X 
XK 
X 
 
Vital signs 
X 
XK 
X 
 
Toxicity Assessment 
X 
XE 
XEF 
 
QOL questionnairesA 
X 
X 
X 
 
Performance 
Status  
X 
X 
X 
 
CBC, diff, platelet 
countC 
X (within 14 days) 
X 
X 
 
Alk phos C 
X (within 14 days) 
X 
X 
 
T. bili, AST, ALT, Cr, 
albumin C 
X (within 14 days) 
 
 
 
Serum PregnancyB,C 
X (within 7 days of drug) 
 
 
 
CT scan of  
Chest/abd/pelvisDG 
XD(within 28 days) 
Per 
treating 
physician 
Per 
treating 
physician  
Per treating 
physician 
Bone Scan 
XJ 
 
 
 
Brain imaging (CT or 
MRI)- contrast to be 
used unless 
documented allergy or 
inadequate renal 
function 
XI 
 
 
 
Survival and Disease 
status  
 
 
X 
XH 
A See Appendix F for EORTC QLQ-C30 and QOL-BM22 questionnaires. Quality of life to be at baseline, 
after completion of cycles 2, 4, and 6, and end of treatment.  If patients complete 6 cycles, end of cycle 6 
questionnaire to count for end of treatment questionnaire as well.   
B Post-menopausal women (surgical menopause or lack of menses >12 months) do not need to have a 
pregnancy test, document status. 
C It is appropriate to use labs from screening for cycle 1 day 1, if labs are within 14 days (pregnancy must 
be within 7 days as noted above for applicable patients). It is required that if labs are re-drawn prior to day 
1 cycle 1 that ANC must be > 1.5, PLT >100k, HGB >9 prior to cycle 1 dosing or dosing must be delayed 

  
5/31/14, 8/25/14, 8/26/14, 9/2/14, 9/5/14, 9/10/14, 10/21/14, 12/2/14 IND Exemption, 12/8/14, 12/17/14,1/8/15, 
Amendment #1 5/19/15 approved Bayer, Amendment # 2 2/19/16, Amendment # 3 3/3/16, Amendment # 4 
11/30/16 
 
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until criteria are met. It is appropriate to use physical, weight, vitals, toxicity assessment and PS from 
screening for cycle 1 day 1 if within 14 day screening window. 
D CT Scan for disease assessment should be performed within 28 days of study entry. A PET scan may 
substitute for a CT scan. Report required.  
E All patients removed from the study for any reason, including completion will have toxicity assessments 
performed at time of removal from study. 
F Adverse event evaluation, inclusive of SAE evaluation, and Performance status assessment will be done 
30 days (+1 week) post last dose of drug. SAEs occurring outside this 30 day window must be reported if 
the event is considered to be possibly related to the drug. If a patient begins a new treatment, AE evaluation 
will be stopped unless the patient experiences an event that is thought to be possibly related to the study 
treatment. SAEs will continue to be captured even if patient begins a new treatment within the 30 day 
window if event thought to be possibly related to Xofigo.. 
 GAlthough it is not a study requirement, it is suggested that CT scans be completed approximately every 2 
months (approximately every 2 cycles) or per treating physician.  
H The time to first progression and the time to first SSE is to be reported to BrUOG on a 2-3 month basis.  
Overall survival is to be reported every 2-3 months. Follow-up will be for 1 year. 
IFor patients with treated brain metastases must have brain imaging showing evidence of stability prior to 
first dose of Xofigo. Scan must be sent to BrUOG with registration information before patient is registered 
on study.  
J: A bone scan is required to have been done or to be done on each patient prior to registration. Bone scan 
results required to be sent to BrUOG for registration. However, the bone scan is not required to be positive 
as long as other imaging or pathology/cytology is positive for bone metastases. Documentation to be sent to 
BrUOG. 
K: It is required that weight and vitals be captured the day of infusion, prior to drug administration and 
these values be reported to BrUOG even if patient already had weight and vitals done pre-cycle within 7 
day window. If patient has weight done 7 days before dosing and then again pre-drug administration (day 
of), unless patient’s weight changed by > 10% (since the +7 day assessment) then drug can be 
administered. Pre-cycle weight to be used for drug ordering and drug dosing. Day of weight is only to be 
used to confirm % of weight change if applicable. 
**Any radiographic scans or tests, such as MRIs, PETs, CTs, Bone Scans (etc) that are performed 
before, during or after study treatment (up to 1 year) , to be submitted to BrUOG 
6.1 Patient Assessments:  
Patients will undergo a baseline radiographic assessment with either a CT scan or PET scan after 
completion of 1st-line treatment as per institutional standard of care. Patients meeting study 
eligibility may be entered on the study. Patients will have a physical monthly prior to each Xofigo 
treatment. Patients with new signs or symptoms suggesting bone metastases, or other sites of 
disease progression, will have additional radiographic assessment for evaluation as per 
institutional standards. The primary endpoint will be the assessment of how many patients 
develop an SSE during the study treatment and in particular during the first 4 cycles 
(approximately 4 months) on study.  Following completion of all 6 treatments, patients will 
undergo restaging radiographic studies as per institutional standard of care.  
 
6.2 Alkaline Phosphatase Assessment:  

  
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11/30/16 
 
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Alkaline phosphatase was found to be an important biomarker in the ALSYMPCA trial.16 
Alkaline phosphatase levels will be assessed at study entry and prior to each dose of Xofigo. We 
will secondarily assess the following: 1. Time to an increase in alkaline phosphatase by ≥ 25% 
from baseline, 2. Alkaline phosphatase response (reduction of ≥ 30% from baseline value), and 3. 
Normalization of the alkaline phosphatase level (defined as a return to normal range in patients 
with an elevated level at baseline). 
6.3 Quality of Life Assessments:  
The EORTC QLQ-C30 and BM22 questionnaires will be performed monthly prior to each 
administration of Xofigo, and at study completion. The EORTC QLQ-30 assesses quality of life 
in patients with cancer, and the BM22 assesses quality of life in patients with bone metastases.17 
7.0 DEFINITION OF PROGRESSION: 
Progression 
 
7.1 Progression of bone metastases Symptomatic Skeletal Event: 
- Pathologic fracture:  Pathologic fractures are to be treated in a manner that attempts to 
maintain the best functional status and quality of life. Study treatment should be 
discontinued if the pathologic fractures are due to disease.  
- Spinal cord compression: If the patient experiences spinal cord compression during the 
treatment period, the patient should be treated for the event, and may not receive further 
study drug administration.  
- Radiation therapy to bone 
- Surgery to bone 
 
Incidental, asymptomatic new or worsening bone metastases will not require 
discontinuation of Xofigo.  
 
7.2 Progression of lung cancer will be evaluated in this study using the international criteria 
proposed in the Revised Response Evaluation Criteria in Solid Tumors (RECIST) Guideline 
version 1.1  
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray, as ≥10 mm 
with CT scan, or ≥10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis).  
 
Patients with lung cancer progression requiring treatment with chemotherapy, radiation 
or surgery will be removed from the study. Patients not requiring treatment with 
chemotherapy, radiation, or surgery may continue on study at physician discretion.  
 

  
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11/30/16 
 
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8.0 
PATIENT REGISTRATION  
All patients will be registered through the Brown University Oncology Research Group Central 
Office. Eligibility Checklist with supporting documentation, On Study Form and the signed 
Patient Consent Form must be faxed to the BrUOG Central Office, Fax: (401) 863-3820, at the 
time of registration and prior to patient treatment. 
Details of patient’s study participation should be documented in clinic/file notes. The Brown 
University Oncology Research Group will provide case report forms, included in the appendix, 
for the recording and collection of data. In the event of corrections, each correction will be 
initialed and dated by the person making the correction. The investigator will sign the case reports 
to indicate that, to his/her knowledge, they are complete and accurate. Case report forms, flow 
sheets, off-study forms and follow-up forms should be mailed / faxed to:  
Kayla Rosati 
Director, BrUOG 
Brown University Oncology Research Group, 
Brown University 
Box G-R 001 
Providence, RI 02912 
Fax: 401-863-3820 
Phone: 401-863-3000 
All support data must be sent in with the corresponding BrUOG forms. It is the treating 
physician’s responsibility to review all data submitted to the BrUOG Central Office for accuracy 
and completeness and he/she must sign the off study form.  
9.0  
PHARMACEUTICAL INFORMATION 
 
9.1  
(Xofigo) Radium Ra 223 dichloride 
9.1.1 
Description 
Radium Ra 223 dichloride is an alpha particle emitter with a physical half-life of 11.4 days. The 
product is isotonic and has a pH of 6.0-8.0.  
The radioactive concentration at the reference date is 1,000 kBq/mL (1,100 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 accompanying each shipment.  
Progressive Disease 
(PD): 
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
 

  
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11/30/16 
 
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Radium Ra 223 dichloride, is manufactured by Bayer Healthcare LLC  contract manufacturer 
Algeta’s Institute for Energy Technology, Isotope laboratories, Kjeller, Norway. The product is 
produced according to Good Manufacturing Practice (GMP). The product will be delivered in a 
glass vial, ready-to-use with a certified activity. Radium Ra 223 dichloride is shipped in a lead 
container and Type A radioactive package according to international transportation guidelines for 
radioactive materials.  
 
The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after implementation of 
NIST update) at the reference day. Radium Ra 223 dichloride has a shelf life of 28 days from 
production day, when stored at ambient temperature. The shelf life has been demonstrated for 
temperatures from cold storage (2-8°C) up to 40°C. In addition, it has been shown that the 
product quality is not jeopardized upon freezing. 
 
All study drugs will be labeled according to the requirements of local law and legislation. For all 
study drugs, a system of numbering in accordance with all requirements of GMP will be used, 
ensuring that each dose of study drug can be traced back to the respective bulkware of the 
ingredients 
9.1.2 
Mechanism of Action  
The active moiety of Radium Ra 223 dichloride is the alpha particle-emitting isotope radium-223 
(as radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone 
mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high 
linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of double-
strand DNA breaks in adjacent cells, resulting in an anti-tumor 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. 
 
9.1.3  Instructions for use/handling  
9.1.3.1 General warning 
Radium 223 dichloride should be received, used and administered only by authorized persons in 
designated clinical settings. The receipt, storage, use, transfer and disposal Radium 223 dichloride 
are subject to the regulations and/or appropriate licenses of the competent official organization. 
Radium 223 dichloride should be handled by the user in a manner which satisfies both radiation 
safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. 
 
9.1.3.2 Radiation protection  
The administration of Radium Ra 223 dichloride is associated with potential risks for other 
persons (e.g. medical staff, care givers and members of the patient’s family) from radiation or 
contamination from spills of body fluids such as urine, feces, or vomit. Therefore, radiation 
protection precautions must be taken in accordance with national and local regulations. 
 
 
 
For drug handling 
Follow the normal working procedures for the handling of radiopharmaceuticals and use 
universal precautions for handling and administration such as gloves and barrier gowns when 
handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the 
affected area should be flushed immediately with water. In the event of spillage of Radium Ra 

  
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11/30/16 
 
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223 dichloride, the local radiation safety officer should be contacted immediately to initiate the 
necessary measurements and required procedures to decontaminate the area. A complexing agent 
such as 0.01 M ethylene-diaminetetraacetic acid (EDTA) solution is recommended to remove 
contamination. 
 
For patient care 
Whenever possible, patients should use a toilet and the toilet should be flushed several times after 
each use. When handling bodily fluids, simply wearing gloves and hand washing will protect 
caregivers. Clothing soiled with Radium Ra 223 dichloride or patient fecal matter or urine should 
be washed promptly and separately from other clothing. 
 
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-
particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-
radiation is 1.1%. The external radiation exposure associated with handling of patient doses is 
considerably lower in comparison to other radiopharmaceuticals for therapeutic purposes as the 
administered radioactivity will usually be below 8 MBq (0.216 mCi) 8.8MBq(0.238mCi  after 
implementation of  NIST. In keeping with the As Low As Reasonably Achievable (ALARA) 
principle, for minimization of radiation exposure, it is recommended to minimize the time spent 
in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. 
Any unused product or materials used in connection with the preparation or administration are to 
be treated as radioactive waste and should be disposed of in accordance with local regulations. 
The gamma radiation associated with the decay of radium-223 and its daughters allows for the 
radioactivity measurement of Radium Ra 223 dichloride and the detection of contamination with 
standard instruments. 
 
9.1.4 Dose calibration 
 A table with decay correction factors will be provided with each vial of Xofigo. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Decay Correction Factor Table 

  
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The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To 
determine the decay correction factor, count the number of days before or after the reference date. 
The Decay Correction Factor Table includes a correction to account for the 7 hour time difference 
between 12 noon Central European Time (CET) at the site of manufacture and 12 noon US CST, 
which is 7 hours earlier than CET. 
Immediately before and after administration, the net patient dose of administered radium-223 
should be determined by measurement in an appropriate radioisotope dose calibrator that has 
been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-
223 standard (a new reference vial will be sent to each center corresponding to the updated NIST 
reference material) and corrected for decay using the date and time of calibration. The dose 
calibrator must be calibrated with nationally recognized standards, carried out at the time of 
commissioning, after any maintenance procedure that could affect the dosimetry and at intervals 
not to exceed one year. 
As of December 2015, Bayer visited the Nuclear Medicine department located at the Miriam 
Hospital to provide to them the new 2015 NIST standard reference material for establishing the 
revised dial setting on the dose calibrator. The Nuclear medicine department was informed that 
the new dial setting is not to be used until  Bayer has obtained approval from the FDA of an  
activation date in the 2nd quarter of 2016.  Additionally Bayer has agreed to send notification via 
memo to BrUOG of the implementation date and the memo has been approved at the hospital’s 
IRB.  Radium Ra 223 dichloride can be measured in a normal dose calibrator instrument. 
Different clinical study centers possess dose calibrators from various suppliers; thus, the isotope 
calibration factor may differ from center to center. Consequently, each center must perform the 
Radium Ra 223 dichloride dial setting on their relevant dose calibrator(s). For dial setting, the 
clinical study center will receive a sealed vial containing a Radium Ra 223 dichloride solution for 
calibration only. The vial is identical to the vials used for study treatment. The amount of Radium 
Ra 223 dichloride in the vial will be stated on the label. Instructions for the dial setting, including 
the calibration log form, will be enclosed with the dispatch of the calibration sample. 

  
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11/30/16 
 
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9.1.5  NIST Standardization Update 
 
The quantification of radium-223 radioactivity in Xofigo (radium-223 dichloride; BAY 88-8223) 
is based on the primary standardization performed by the US NIST. National Institute of 
Standards and Technology prepares the standard reference material (SRM) using an official dial 
setting (primary standardization) as published (17).The NIST SRM is used to calibrate the 
instruments in production and quality control for both the drug substance and drug product. 
Additionally, the NIST SRM is used to prepare the NIST traceable Ra-223 reference materials 
which are then sent to the end-users (e.g., nuclear medicine laboratory physicians or technicians) 
for dial-setting of their dose calibrators, to allow verification of the patient dose.  
In 2014, NIST performed a re-assessment of the primary standardization based on preliminary 
information suggesting a potential discrepancy of approximately 8-10% between the published 
NIST primary standardization (17) and results obtained by other national metrology institutes 
(United Kingdom, Germany, Japan). After completion of there-assessment, NIST reported their 
findings (18) and had issued a revised NIST SRM in 2015.The discrepancy in the NIST 
standardization was determined to be −9.5% between activity values obtained using the old 
reference standard relative to the new primary standardization. Consequently the current 
numerical values need to be corrected by approx. + 10.5%. 
 
The current (NIST(NIST 2010) standard for radium-223 dichloride will remain in effect until the 
FDA has fully approved the regulatory variation submitted  for Xofigo and is anticipated in the 
2nd quarter of 2016. Sites are not able to implement the new NIST standards and are not to use the 
new dial settings until the site IRB has received and approved the Bayer activation memo 
documenting the implementation date for the change.  
The change in the numerical description of the patient’s dose, product strength and labeled vial 
activity does not impact the safety or efficacy of Xofigo. The change in the NIST radium-223 
standard has no impact on subjects; dose subjects are receiving, and will continue to receive. 
Subjects will receive the same actual dose and volume that was studied in Study 15245 (BC1-06 
dosimetry study) and is associated with the proven safety and efficacy of radium-223 dichloride, 
though the stated nominal radiation dose received is being updated to reflect the new standard. 
The formula for the calculation of the volume to be administered has to be changed respectively. 
(see dosing section 9.1.8) 
 
9.1.6 
Dosimetry 
The absorbed radiation dose calculation was performed based on clinical biodistribution data. 
Calculations of absorbed doses were performed using OLINDA/EXM (Organ Level INternal 
Dose Assessment/EXponential Modeling), a software based on the Medical Internal Radiation 
Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting 
radionuclides. For radium-223, which is primarily an alpha emitter, additional assumptions were 
made for the intestine, red marrow and bone/osteogenic cells to provide the best possible 
absorbed dose calculations for Radium Ra 223 dichloride, considering its observed 
biodistribution and specific characteristics. 
 
For an administered activity of 3.65 MBq (0.0987 mCi) (50 kBq (0.00135 mCi) (55kBq (.0015 
after NIST update)  per kg body weight to a 73-kg adult), the calculated absorbed doses to the 
bone (osteogenic cells) is 4.2050 Gy (420.5 rad) and to the red marrow is 0.5066 Gy (50.66 rad). 

  
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The calculated absorbed doses to the main excretory organs are 0.0265 Gy (2.65 rad) for the 
small intestine wall, 0.1180 Gy (11.8 rad) for the upper large intestine wall and 0.1696 Gy (16.96 
rad) for the lower large intestine wall.  
The calculated absorbed doses to other organs are low, e.g. heart wall (0.0063 Gy, 0.63 rad), lung 
(0.0003 Gy, 0.03 rad), liver (0.0109 Gy, 1.09 rad), kidneys (0.0117 Gy, 1.17 rad), urinary bladder 
wall (0.0147 Gy, 1.47 rad), testes (0.0003 Gy, 0.03 rad), and spleen (0.0003 Gy, 0.03 rad).  
 
The hematological adverse drug reactions observed in the clinical studies with Ra-223  are much 
lower in frequency and severity than what could be expected from the calculated absorbed doses 
to the red marrow. This may be related to spatial distribution of alpha particle radiation resulting 
in non-uniform radiation dose to the red marrow. 
 
9.1.7 
Dose handling 
Radium-223 has an 11.4-day half-life allowing sufficient time for its distribution, preparation, 
and administration 
 
The Radium Ra 223 dichloride vials must be stored inside their lead container in a secure facility. 
The study drug should be used within 28 days of production. The shelf life of the drug in the 
patient ready dose syringe that is drawn by Cardinal is 4 days.  When delivered, the syringe will 
be labeled with the expiration date on the prescription reflecting this 4-day shelf-life.  
Radium Ra 223 dichloride is an alpha-pharmaceutical and should be handled by individuals who 
are qualified by training and experience in the safe handling of radionuclides. One dedicated 
person and a back-up designee will have responsibility as assigned from the Primary Investigator 
for handling and storage of Radium Ra 223 dichloride. All administrations of Radium Ra 223 
dichloride are based on the certified activity of Radium Ra 223 dichloride at the calibration date. 
 
9.1.8 
Dose calculation 
Please see appendix F regarding pre- new NIST changes and Appendix G post new NIST change 
implementation which is contingent upon IRB approval of the Bayer activation memo and which 
cannot be implemented prior to Bayer activation date as indicated in the Bayer activation memo. 
 
9.1.9 Dose preparation 
Personnel should use appropriate protective clothing and equipment during syringe filling and 
application to prevent contamination with the radioactive solution (medical gloves / protective 
glasses). 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. Radium Ra 223 dichloride should not be diluted or 
mixed with any solutions. Do not store above 40°C (104°F). If the vials have been stored in a 
refrigerator, they should be left at room temperature for 1 hour prior to use, since cold material 
should not be injected in a patient. Store Radium Ra 223 dichloride in the original container or 
equivalent radiation shielding. This preparation is approved for use by persons under license by 
the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. 
 
9.1.10 Dose administration 
Before administration of study drug, the patient must be well hydrated; the patient should be 
instructed to drink ad libitum. Aseptic technique should be used in the administration of Radium 
Ra 223 dichloride. The syringe should be handed over to the individual who will perform the 

  
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11/30/16 
 
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injection. The study medication will be administered as a bolus intravenous (IV) injection (up to 1 
minute). After administration, the equipment used in connection with the preparation and 
administration of drug is to be treated as radioactive waste and should be disposed in accordance 
with local procedure for the handling of radioactive material. The short penetration of the alpha 
particles allows for the use of standard radiation protection measures during shipping and 
administration. Standard dose calibrators and regular contamination monitors are used during 
drug handling Radium-223 becomes non-active after ten half-lives (approximately 4 months), 
thus waste can be stored for 4 months, then discarded as normal clinical waste, or as according to 
standard operating procedures of the institutions nuclear medicine department.  
Patients will receive radium-223 as outpatients and there is no restriction to public or family 
contact afterwards. 
 
9.1.11 Toxicities 
The most common adverse reactions (≥ 10%) in patients receiving Radium Ra 223 dichloride 
were nausea, diarrhea, vomiting, and peripheral edema. Grade 3 and 4 adverse events were 
reported among 57% of Radium Ra 223 dichloride-treated patients and 63% of placebo treated 
patients. The most common hematologic laboratory abnormalities in Radium Ra 223 dichloride-
treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and 
neutropenia. Treatment discontinuations due to adverse events occurred in 17% of patients who 
received Radium Ra 223 dichloride and 21% of patients who received placebo.  
 
The most common hematologic laboratory abnormalities leading to discontinuation for Radium 
Ra 223 dichloride were anemia (2%) and thrombocytopenia (2%). 
 
Table 1 below shows adverse reactions occurring in ≥ 2% of patients and for which the incidence 
for Radium Ra 223 dichloride exceeds the incidence for placebo. 
 
Table 1 Adverse Reactions in the Randomized Trial 
System/Organ Class 
Preferred Term  
Radium Ra 223 dichloride 
(n=600)  
Placebo (n=301)  
Grades 1-4 %  
Grades 3-4 %  
Grades 1-4 %  
Grades 3-4 %  
Blood and lymphatic system disorders  
Pancytopenia  
2  
1  
0  
0  
Gastrointestinal disorders  
Nausea  
36  
2  
35  
2  
Diarrhea  
25  
2  
15  
2  
Vomiting  
19  
2  
14  
2  
General disorders and administration site conditions  
Peripheral edema  
13  
2  
10  
1  
Renal and urinary disorders  
Renal failure and 
impairment  
3  
1  
1  
1  
Laboratory Abnormalities 
Table 2 shows hematologic laboratory abnormalities occurring in > 10% of patients and for 
which the incidence for Radium Ra 223 dichloride exceeds the incidence for placebo. 
Table 2: Hematologic Laboratory Abnormalities 
Laboratory values were obtained at baseline and prior to each 4-week cycle. 

  
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As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on 
Radium Ra 223 dichloride and in 2% of patients on placebo. Among patients who received 
Radium Ra 223 dichloride, the laboratory abnormality grade 3-4 thrombocytopenia occurred 
in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. 
Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who 
have received prior docetaxel. 
 
Fluid Status 
Dehydration occurred in 3% of patients on Radium Ra 223 dichloride and 1% of patients on 
placebo. Radium Ra 223 dichloride increases adverse reactions such as diarrhea, nausea, and 
vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status 
carefully and promptly treat patients who display signs or symptoms of dehydration or 
hypovolemia. 
 
Injection Site Reactions 
Erythema, pain, and edema at the injection site were reported in 1% of patients on Radium Ra 
223 dichloride. 
 
Secondary malignant neoplasms 
No cases of radiation-induced cancer have been reported in reported in clinical trials with 
radium-223 dichloride in follow-up of up to three years. However, the radiation dose 
resulting from therapeutic exposure may result in higher incidence of cancer (e.g. sarcomas of 
the bone, or leukemia), mutations and a potential for development of hereditary defects. 
 
Bone Marrow Suppression 
In the randomized trial, 2% of patients on the Radium Ra 223 dichloride arm experienced 
bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. 
There were two deaths due to bone marrow failure and for 7 of 13 patients treated with 
Radium Ra 223 dichloride, bone marrow failure was ongoing at the time of death. Among the 
13 patients who experienced bone marrow failure, 54% required blood transfusions. Four 
percent (4%) of patients on the Radium Ra 223 dichloride arm and 2% on the placebo arm 
permanently discontinued therapy due to bone marrow suppression. 
In the randomized trial, deaths related to vascular hemorrhage in association with 
myelosuppression were observed in 1% of Radium Ra 223 dichloride-treated patients 
compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths 
(2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients 
treated with Radium Ra 223 dichloride and placebo. 
Hematologic  
Xofigo (n=600)  
Placebo (n=301)  
Laboratory  
Grades 1-4  
Grades 3-4  
Grades 1-4  
Grades 3-4  
Abnormalities  
%  
%  
%  
%  
Anemia  
93  
6  
88  
6  
Lymphocytopenia  
72  
20  
53  
7  
Leukopenia  
35  
3  
10  
<1  
Thrombocytopenia  
31  
3  
22  
<1  
Neutropenia  
18  
2  
5  
<1  

  
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Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; 
has been reported in patients treated with Radium Ra 223 dichloride. In the randomized trial, 
complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir 
CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 
study of Radium Ra 223 dichloride, neutrophil and platelet count nadirs occurred 2 to 3 
weeks after Radium Ra 223 dichloride administration at doses that were up to 1 to 5 times the 
recommended dose, and most patients recovered approximately 6 to 8 weeks after 
administration  
 
Hematologic evaluation of patients must be performed at baseline and prior to every dose of 
Radium Ra 223 dichloride. Before the first administration of Radium Ra 223 dichloride, the 
absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L 
and hemoglobin ≥ 9 g/dL. Before subsequent administrations of Radium Ra 223 dichloride, 
the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. Patients with evidence of 
compromised bone marrow reserve should be monitored closely and provided with 
supportive care measures when 
clinically indicated. Discontinue Radium Ra 223 dichloride in patients who experience life-
threatening complications despite supportive care for bone marrow failure. 
 
The safety and efficacy of concomitant chemotherapy with Radium Ra 223 dichloride have 
not been established. Outside of a clinical trial, concomitant use with chemotherapy is not 
recommended due to the potential for additive myelosuppression. If chemotherapy, other 
systemic radioisotopes or hemibody external radiotherapy are administered during the 
treatment period, Radium Ra 223 dichloride should be discontinued. 
 
10.0 
AGENT ACCOUNTABILITY 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all agents received from 
manufacturer using a Drug Accountability Record Form. The nuclear medicine department will 
maintain records of drug receipt drug preparation, and dispensing, including the applicable lot 
numbers. Any discrepancy between the calculated dose and dose administered and the reason for 
the discrepancy must be recorded in the source documents. 
It is required that each drug order form and drug destruction form be sent to the BrUOG office for 
tracking and record keeping. 
 
Destruction and Return 
At the end of the study, unused supplies of Ra 223 dichloride and other investigational agents 
should be destroyed appropriately and according to institutional policies, but only after BrUOG is 
sent the accountability logs outlining all drug shipments, receipts, each time patients are dosed 
and only after BrUOG obtains approval from Bayer, to have site destroy drug. 
 

  
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22
 Destruction will be documented in the Drug Accountability Record Form. The certificate of 
destruction for Ra 223 dichloride should be sent to BrUOG each time. 
   
10.1 Treatment Compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted. 
 
All drugs will be administered to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  The nuclear medicine department will maintain records of drug 
receipt drug preparation, and dispensing, including the applicable lot numbers. Any discrepancy 
between the calculated dose and dose administered and the reason for the discrepancy must be 
recorded in the source documents. 
 
11.0 ADVERSE DRUG REACTION (ADR) REPORTING 
BrUOG considers the SAE reporting period to begin when the subject signs the study specific 
informed consent. 
 
This study will utilize the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4 for grading all adverse events. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4. A copy of the 
CTCAE version 4can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have to 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of Xofigo ® whether or not considered related to Xofigo ®. This includes 
any newly occurring event or previous condition that has increased in severity or frequency since 
the administration of drug. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, subjects 
should not be questioned regarding the specific occurrence of one or more adverse events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial medication. All AEs 
considered related to trial medication will be followed until resolution even if this occurs post-
trial. 
 
11.1 Definitions 
An adverse event is any new, undesirable medical experience or change of an existing condition 
that occurs during or after treatment, whether or not considered product-related. 
 
Serious adverse event (SAE) 

  
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An adverse event occurring at any dose that results in any of the following outcomes (CFR 
312.32): 
 
death 
 
is life-threatening  
 
inpatient hospitalization or prolongation of existing hospitalization excluding  those for study 
drug administration, transfusional support, disease staging/re-staging procedures, 
concomitant radiotherapy, thoracentesis / paracentesis, or placement of an indwelling 
catheter, unless associated with other serious events. 
 
persistent or significant disability or incapacity, 
 
congenital anomaly / birth defect.  
 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. A new diagnosis 
of cancer during the course of treatment should be considered an important medical event. 
 
The definition of “related” being that there is a reasonable possibility that the drug caused the 
adverse experience. 
 
Unexpected adverse event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the investigator's brochure or package 
insert. 
 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred.  It does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 
 
11.2 Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.  All SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). 
 
11.3 BRUOG ADVERSE EVENT REPORTING REQUIREMENTS  
Investigators are required by Federal Regulation to report adverse drug reactions. Question 
regarding drugs as used in this study should be directed to the Brown University Oncology 
Research Group (BrUOG) Central Office, Phone: (401) 863-3000 Fax (401) 863-3820, which 
will in turn notify the Principal Investigator. 
 

  
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Intensity for each adverse event will be scored using CTCAE Version 4.  A copy of the CTCAE 
Version 4can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  All 
appropriate treatment areas have access to a copy of the CTCAE Version 4.  All adverse clinical 
experiences, whether observed by the investigator or reported by the patient, must be recorded, 
with details about the duration and intensity of each episode, the action taken with respect to the 
test drug, and the patient’s outcome.  The investigator must evaluate each adverse experience for 
its relationship to the test drug and for its seriousness. 
 
11.3.1 Pregnancies 
Pregnancies occurring while the subject is on study drug or within 4 weeks after the subject’s last 
dose of study drug are considered expedited reportable events.  If the subject is on study drug, the 
study drug is to be discontinued immediately.  The pregnancy must be reported to the Brown 
University Oncology Research Group with 24 hours and BrUOG will in turn report to Bayer 
within 24 hours (1 working day) of the Investigator’s knowledge of the pregnancy by email 
and/or facsimile using the SAE Form. Pregnancies and suspected pregnancies (including a 
positive pregnancy test regardless of age or disease state) of a female subject occurring while the 
subject is on IP, or within 4 weeks (30 days) of the subject’s last dose of IP, are considered 
immediately reportable events. IP is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Bayer Drug Safety immediately by 
facsimile, or other appropriate method (to be done by BrUOG), using the Medwatch3500A form 
(MedWatch 3500A-to be completed by site). 
 
The Investigator will follow the subject until completion of the pregnancy, and must notify Bayer 
(by informing BrUOG) of the outcome as specified below.  The Investigator will provide this 
information as a follow-up to the initial report .If the outcome of the pregnancy meets the criteria 
for immediate classification as a SAE (i.e., spontaneous abortion [any congenital anomaly 
detected in an aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting SAEs (i.e., report the event 
to BrUOG who will then report to Bayer by facsimile within 24 hours (1 working day) of being 
made aware of the event). 
 
Any suspected fetal exposure to Xofigo ® must be reported to BrUOG within 24 hours who will 
then report to Bayer within 1 working day of being made aware of the event.  The patient should 
be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects to be 
related to the in utero exposure to the study drug should also be reported. In the case of a live 
“normal” birth, Bayer should be advised as soon as the information is available. 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. 
 
11.3.2 Serious Adverse Event Reporting Procedures  

  
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All pregnancies or suspected pregnancies, including suspected fetal exposure or neonatal deaths 
must be reported to the Brown University Oncology Research Group within 24 hours. BrUOG 
will report all pregnancies to Bayer within 1 working day of being made aware of the event.  
 
All other SAEs are to be documented via email to BrUOG within 24 hours. Sites will have 5 
business days to send the written report (Medwatch 3500A) to BrUOG (from date of being 
notified of event), who will then report the SAE to Bayer product safety within 1 working day 
when possible of discovery or notification of the event Initial SAE information and all 
amendments or additions must be recorded on an SAE Form and faxed to Bayer.  
 
 
Bayer Drug Safety Contact Information: (to be reported to by BrUOG) 
Electronic Mailbox:   
DrugSafety.GPV.US@bayer.com  
 
Facsimile:   
 
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare  
 
 
 
 
P.O. Box 915 
 
 
 
 
Whippany, NJ 07981-0915  
 
Address:   
 
 
100 Bayer BLVD., Whippany, NJ 07981  
FDX or UPS only   
 
67 Whippany Road, Whippany, NJ 07981  
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept:  
 
Phone:  
 
1-888-842-2937 
 
The principal investigator has the obligation to report all serious adverse events to the Brown 
University Oncology Research Group’s (BrUOG) office who in return will report to the FDA, 
Bayer, and all sites participating in the trial.  All SAE reports will be forwarded to Bayer Product 
Safety by BrUOG. All events reported to the FDA by the investigator are to be filed utilizing the 
Form FDA 3500A (MedWatch Form).  Sites must alert BrUOG to SAEs within 24 hours via 
email, and will then have 5 business days to submit formal notification via the 3500A (5 days 
from date of being notified of event). BrUOG will then alert Bayer within 1 business day when 
possible. BrUOG will submit the SAE memo, and Medwatch 3500A to the FDA within 7 days. 
 
Expedited Reporting by Investigator to Bayer 
Serious adverse events (SAE) are defined above.  All events must be reported, by FAX or email, 
to the Brown University Oncology Research Group who must inform Bayer in writing using a 
MEDWATCH 3500A form of any SAE within 1 business day (when possible) of being aware of 
the event.  The written report must be completed and it will then be supplied by BrUOG to Bayer 
by facsimile within 24 hours/1 business day (when possible) of BrUOG being made aware of the 
event.  The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 

  
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26
values received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE (such as discharge from hospital) is required.  The Bayer 
tracking number (ONC-2014-099) and the institutional protocol number should be included on 
SAE reports (or on the fax cover letter) sent to Bayer.  A copy of the fax transmission 
confirmation of the SAE report to Bayer should be attached to the SAE and retained with the 
study records at BrUOG. (Bayer does NOT send a confirmation so BrUOG will have to use 
documentation from their fax that it was sent) 
All adverse events and special reporting situations, whether serious or non-serious, related or 
unrelated, will be reported from the time a signed and dated ICF is obtained until 30 days after 
the last dose of Xofigo, or until the subject withdraws consent from study participation (declines 
participation) or at the time patient becomes a screen failure, whichever occurs first. 
All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported to BrUOG within 5 business days or as soon as the investigator is made aware 
of the event. If the death is thought to be related to the study drug, deaths must be reported to 
BrUOG within 24 hours of the investigator being made aware of the event. 
 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks (30 days +1 week) after the patient has stopped study participation must be reported. This 
includes the period in which the study protocol interferes with the standard medical treatment 
given to a patient (e.g. treatment withdrawal during washout period, change in treatment to a 
fixed dose of concomitant medication). If a patient begins a new therapy AE evaluation is to stop 
but SAEs are to continue if SAE is thought to be possibly related to Xofigo. 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Bayer study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
11.4 Reporting requirements and procedures depend upon: 
1. Whether investigational agents are suspected of causing toxicity; 
2. Whether the possibility of such a toxicity was reported in the protocol, consent form, or 
manufacturer’s literature (Expected toxicity); and  
3. The severity of grade of the toxicity.   
 
11.5 Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that treatment caused 
or contributed to an adverse event.  The following general guidance may be used: 
 
Yes: if the temporal relationship of the clinical event to treatment administration makes a  
causal relationship possible, and other drugs, therapeutic interventions or underlying conditions 
do not provide a sufficient explanation for the observed event. 
 
No:if the temporal relationship of the clinical event to treatment administration makes a  
causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions 
provide a sufficient explanation for the observed event. 

  
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11.6 Types of Report: For sites: 
Telephone report:  For SAE’s initial or follow-up, contact BrUOG Central Office (401) 863-
3000 (or via email), immediately upon learning of the event (within 24 hours). 
 
Written report: Send the copy of the Medwatch 3500A form within 5 business days of being 
made aware of the event to the BrUOG Central Office by email, scan or Fax: 
 
Brown University Oncology Research Group 
Phone: (401) 863-3000, Fax: (401) 863-3820 
Emails: Kayla_rosati@brown.edu and Kristen_Mitchell@brown.edu 
 
All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported to BrUOG within 5 business days or as soon as the investigator is made aware 
of the event. If the death is thought to be related to the study drug, deaths must be reported to 
BrUOG within 24 hours of the investigator being made aware of the event. 
 
MedWatch 3500A Reporting Guidelines: The following information is a requirement to be 
included in the initial SAE report, sites please be aware: 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of 
the MedWatch 3500A form: 
 
Name and contract information of reporter 
 
Patient identification such as initials, study number, age, sex, weight 
 
Treatment regimen ( name of study drug, dosing frequency, combination therapy) 
 
Date and time of administration of study drug 
 
Concomitant medications 
 
Protocol description (and number, if assigned) 
 
Description of event, severity (grade) , treatment, and outcome, if known 
 
Supportive laboratory results and diagnostics- medical treatment provided 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
**It is required that you put the following numbers on the Medwatch form for 
tracking: 
o BrUOG 301 and ONC-2014-099 
 
Sites should also be sure to include the following when possible at initial if known: 
 date of onset 
 time from administration to start of event 
 any possibly etiology for event 
 final diagnosis or syndrome 
 action taken 
 
A final report to document resolution of the SAE (such as discharge from hospital) is 
required. 

  
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The investigator is responsible for evaluating all adverse events to determine whether criteria for 
“serious” as defined above are present.  The Brown University Oncology Research Group is 
responsible for reporting serious adverse events to Bayer as described above. 
 
Follow-up information:   
Additional Info may be added to a previously submitted report by any of the following methods. 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. 
D.O.B. initial, subject number), protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new information is added to the 
correct initial report). 
 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy.   
 
11.7 BrUOG Responsibility Regarding Reporting:  
The BrUOG Central Office will notify by phone and/or fax all drug reaction reports to the FDA, 
the Principal Investigator, and the participating sites (who will in turn notify their local IRBs) as 
soon as possible but no later than 7 calendar days after initial receipt of the information. BrUOG 
will alert Bayer to a SAE within 1 business day (when possible) of being made aware of the event 
via documentation. SAEs will be reported as an amendment to the IND (if applicable) within 15 
days of sponsor notification. They will all receive a simultaneous copy via facsimile of all 
adverse events filed with the FDA(which will be sent to the Medwatch fax line for IND 
exemption or to the division fax if there is an IND). A copy of the form will be kept by the 
BrUOG Central Office.   
 
 
 
Fax: 1-800-FDA-0178 (1-800-332-0178) For IND exempt study or for IND study the SAE 
will be sent to Center Drug Evaluation Division fax line that has responsibility for review of 
IND) 
 
Mail: For IND studies BrUOG will send the SAE as an amendment to the IND as well 
 
All SAEs that are serious and reasonably or probably related to the use of Xofigo ®  will be 
faxed to: Bayer 
 
11.8 Safety Reporting for IND Holders 
In accordance with 21 CFR 212.32, Sponsor-Investigator of the study conducted under an IND 
must comply with following safety-reporting requirements:  
 
a. Expedited IND Safety Reports: 
BrUOG will fax reports to the FDA for IND Safety Reports: 1 (800) FDA – 0178, unless per 
the IND status BrUOG is to submit the SAEs to the Division Fax instead. 

  
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All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
faxed to Bayer as well as any pregnancy occurring in association with use of a Bayer product to:  
 
BrUOG will send to: Bayer via Email: DrugSafety.GPV.US@bayer.com 
 
b. IND Annual Reports, for IND study only 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 
provides the data elements that are to be submitted in the report.  The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to Bayer Corporation as a supporter of 
this study as follows. 
11.9 Adverse event updates/IND safety reports 
Bayer shall notify the Brown University Oncology Research Group (BrUOG) via an IND Safety 
Report of the following information: 
 
Any AE associated with the use of study drug in this study or in other studies that is both 
serious and unexpected. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
BrUOG will then notify the sites who shall notify their IRB/EC promptly of these new serious 
and unexpected AE(s) or significant risks to subjects. 
 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
 
12.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Extraordinary medical circumstances or withdrawal of consent by the patient: If, at any time, the 
constraints of this protocol are detrimental to the patient's health, and/or the patient no longer wishes 
to continue protocol therapy, the patient shall be withdrawn from protocol therapy.  Patients will also 
be withdrawn from study for the following reasons: 
1. Disease Progression: Any patient with disease progression should be removed 
from study as per section 7.1 and 7.2.  Details and tumor measurements should 
be documented on flow sheets. 
2. Patient is unable to tolerate the toxicity resulting from the study treatment, even with 
optimal supportive care, in the opinion of the Treating Physician. Adverse event(s) that, in the 
judgment of the investigator, may cause severe or permanent harm or which rule out 
continuation of study drug.  
3. The physician feels it is in the best interest of the patient to stop the treatment. 
4. Inter current illness that would, in the judgment of the Investigator, affect assessment of 
clinical status to a significant degree or require discontinuation of study treatment 

  
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5. Non protocol chemotherapy or immunotherapy is administered during the study 
6. Noncompliance with protocol or treatment—major violation 
7. Pregnancies or Suspected Pregnancies(including positive pregnancy test) 
8. Patient is lost to follow-up 
9. Patient refuses to continue treatment (patient will continue to be followed for disease-free 
survival and overall survival) 
10. Death 
 
In this event notify: 
Brown University Oncology Research Group (BrUOG) Central Office, 
Phone:  (401) 863-3000 
Fax:  (401) 860-3820 
 
The BrUOG Central Office will in turn notify the Principal Investigator. 
*Document the reason(s) for withdrawal on flow sheets.  Follow the patient for survival 
with follow-up forms as dictated by the protocol 
13.0 FOLLOW-UP  
All Subjects that discontinue treatment early for any reason as well as patients who complete 
therapy will be followed for time to disease progression at any site, time to SSE, and overall 
survival (up to 1 year).  Information will be sent to BrUOG central office every 2-3 months. At 
treatment discontinuation, subjects will undergo adverse event evaluation and again 
approximately 30 days post the last dose of study drug (+1 week). If a patient begins a new 
treatment AEs do not need to be captured but SAEs must continue to be captured for the 30 day 
period and post 30 days if the event is thought to be potentially related to Xofigo. In addition off 
study evaluations will be done when treatment is discontinued -Section 6.0.   
14.0 REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Angela Taber, in collaboration 
with Brown University Oncology Research Group (BrUOG), which will serve as the central 
coordinating office for the study. This study is supported by Bayer (the makers of Xofigo ®). 
14.1 Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
14.2 Compliance with the Protocol and Protocol Revisions: 
The study must be conducted as described in this approved protocol.   

  
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All revisions to the protocol must be provided to Brown University Oncology Research Group, 
and Bayer.  The Investigator should not implement any deviation or change to the protocol 
without prior review and documented approval/favorable opinion from the IRB/IEC and Bayer of 
an Amendment, except where necessary to eliminate an immediate hazard(s) to study patients. 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to Brown University Oncology Research Group, and Bayer.  If the revision is an 
Administrative Letter, Investigators must inform their IRB(s)/IEC(s).  
The Investigator must ensure that patients or their legally acceptable representatives are clearly 
and fully informed about the purpose, potential risks and other critical issues regarding clinical 
trials in which they volunteer to participate.  Preparation of the consent form is the responsibility 
of the Investigator and must include all elements required by CFR 21 Part 50.25 and the local 
IRB. 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s). 
 
14.3 Protocol amendments or changes in study conduct:  
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed and approved by Brown University Oncology Research Group, 
Bayer and the investigator before implementation. Amendments significantly affecting the safety 
of subjects, the scope of the investigation or the scientific quality of the study require additional 
approval by the IRB at each study center.  A copy of the written approval of the IRB must be 
provided to Brown University Oncology Research Group, and Bayer. 
 
Examples of amendments requiring such approval  
 
Increases in drug dose or duration of exposure of subjects 
 
Significant changes in the study design (e.g. addition or deletion of a control group) 
 
Increases in the number of invasive procedures 
 
Addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Brown University Oncology Research Group and Bayer in the 
interests of preserving the safety of all patients included in the trial.  If an immediate change to 
the protocol is felt to be necessary by the investigator and is implemented for safety reasons 
Brown University Oncology Research Group and Bayer must be notified and the IRB at the 
center must be informed immediately. Amendments affecting only administrative aspects of the 
study do not require formal protocol amendments or IRB approval but the IRB must be kept 
informed of such administrative changes.  

  
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Examples of administrative changes not requiring formal protocol amendments and IRB approval 
include: 
 
Changes in the staff used to monitor trials (Bayer considers a change in Principal 
Investigator or the addition of sub-site(s) to be substantial and requires Bayer approval 
prior to implementation) 
 
Minor changes in the packaging or labeling of study drug. 
 
15.0 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION 
15.1 Good Clinical Practice: The study will be conducted in accordance with the International 
Conference on Harmonisation (ICH) for Good Clinical Practice (GCP) and in the US Code of 
Federal Regulations.  The investigator will be thoroughly familiar with the appropriate use of the 
drug as described in the protocol and Investigator’s Brochure.  Essential clinical documents will 
be maintained to demonstrate the validity of the study and the integrity of the data collected.  
Master files should be established at the beginning of the study, maintained for the duration of the 
study and retained according to the appropriate regulations.   
15.2 Patient Confidentiality: In order to maintain patient privacy, all data capture records, drug 
accountability records, study reports and communications will identify the patient by initials and 
the assigned patient number.  The investigator will grant monitor(s) and auditor(s) from Bayer or 
its designees and regulatory authority (ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection process.  
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
15.3 Protocol Compliance: The investigator will conduct the study in compliance with the 
protocol given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies).  Changes to the protocol will require approval from Bayer and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory 
authority (ies) permit, expedited review and approval/favorable opinion for minor change(s) in 
ongoing studies that have the approval /favorable opinion of the IRB/IEC.  The investigator will 
submit all protocol modifications to Bayer and the regulatory authority (ies) in accordance with 
the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
15.4 On-site Audits: Regulatory authorities, the IEC/IRB and/or Bayer clinical quality assurance 
group may request access to all source documents, data capture records, and other study 
documentation for on-site audit or inspection.  Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 

  
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15.5 Drug Accountability: Accountability for the drug at all study sites is the responsibility of 
the principal investigator.  The investigator will ensure that the drug is used only in accordance 
with this protocol.  Drug accountability records indicating the drug’s delivery date to the site (if 
applicable), inventory at the site (if applicable), use by each patient, and return to Bayer for 
disposal of the drug (if applicable and if approved by Bayer) will be maintained by the clinical 
site.  Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers.   
All material containing Xofigo ® will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
15.6 Premature Closure of the Study: This study may be prematurely terminated, if in the 
opinion of the investigator or Bayer, there is sufficient reasonable cause.  Written notification 
documenting the reason for study termination will be provided to the investigator or Bayer by the 
terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to patients 
 
Failure to enter patients at an acceptable rate 
 
Insufficient adherence to protocol requirements 
 
Insufficient complete and/or evaluable data 
 
Plans to modify, suspend or discontinue the development of the drug 
 
Should the study be closed prematurely, all study materials must be returned to Bayer. 
 
15.7 Record Retention:  
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
The Brown University Oncology Research Group, as coordinator of this study, is responsible for 
ensuring proper conduct of the study with regard to protocol adherence and the validity of the 
data recorded on the case report forms. The Principle Investigator (Angela Taber, M.D.) and 
Brown University Oncology Research Group Manager of Operations (Kayla Rosati) will monitor 
this study. The case report forms will be monitored against the submitted documents every 3 
months for accuracy, completeness, adherence to the protocol and regulatory compliance.  
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consents 
forms, laboratory test results and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the investigation is discontinued and the FDA and the 
applicable local health authorities are notified. Bayer will notify the Principle Investigator if an 
application is filed.  
16.0 DATA SAFETY AND MONITORING BOARDS 

  
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All trials initiated by the Brown University Oncology Research Group (BrUOG) are subject to 
oversight by the Data Safety Monitoring Board (DSMB).  This board meets two times per year 
with any additional meetings scheduled when needed.  The responsibilities are as follows: 
 
Familiarize themselves with the research protocol (s)  
 
The DSMB reviews trial performance information such as accrual information.   
 
Review interim analyses of outcome data and cumulative toxicity data summaries to 
determine whether the trial should continue as originally designed, should be changed, or 
should be terminated based on these data.   
 
The DSMB also determines whether and to whom outcome results should be released 
prior to the reporting of study results. 
 
All adverse events are reviewed by the committee, with assurances that these have been 
in fact sent for review to all pertinent IRBs. 
 
Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 
 
Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, 
increasing target sample size). 
 
Following each DSMB meeting, provide the study leadership with written information 
concerning findings for the trial as a whole related to cumulative toxicities observed and 
any relevant recommendations related to continuing, changing, or terminating the trial.  
 
The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s. 
 
17.0 STATISTICS 
This protocol will evaluate the effect of Ra 223 on patients with NSCLC who had stable to 
responding disease after completion of first line chemotherapy. The primary end point is the 
proportion of patients who experience their first symptomatic skeletal event (including pathologic 
bone fracture, spinal cord compression, need for surgical intervention for a bone metastasis, and 
time to external beam radiotherapy) during study treatment. A second primary endpoint is to 
evaluate the reduction of SSEs after 4 cycles of treatment (approximately 4 months) following the 
first Ra 223. The control is a historic experimental arm consisting of 257 patients (the majority 
having advanced NSCLC) from a study by Rosen et al 7,8 who received zoledronic acid 4mg q 3 
weeks with concomitant antineoplastic therapy. Approximately 40% patients experienced their 
first symptomatic skeletal event by 4 months in that study. 
 We hypothesize that the addition of Ra 233 to standard chemotherapy would reduce the 
proportion of patients with first symptomatic skeletal event at 4 months by half, i.e., to 20% 
compared to historic controls who received zoledronic acid. Using Fisher's exact test, we 
calculated a sample size of 36 patients to detect this 20% difference in the proportion of patients 

  
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having their first symptomatic skeletal event at 4 months with power of 75% and two sided α 
error probability of 0.1. 
Progression-free survival (PFS) and overall survival (OS): PFS and OS will be determined from 
the time of study entry. 
Time to symptomatic skeletal events: Will be determined from the time of study entry.  
 
 
 
 
 
 
18.0 REFERENCES 
1. 
Jemal A, Bray F, Center MM, et al. Global cancer statistics, CA Cancer J Clin 2011, 
61 (2):69-90. 
2. 
Jemal A, Siegel R, Xu J et al. Cancer statistics. CA Cancer J Clin 2010;60(5):277-
300. 
3. 
Bone Metastasis: Monitoring and Treatment. Stoll BA and Parbhoo S. (eds) Raven 
Press New York 1983. 
4. 
Twycross RG Management of pain in skeletal metastases. Clin Ortho. 1995;312:187-
196. 
5. 
Janjan NA. Radiation for bone metastases: conventional techniques and the role of 
systemic pharmaceuticals. Cancer. 1997;80:1628-1645. 
6. 
Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous 
metastases; final results of the study by the radiation therapy oncology group. 
Cancer. 1982;50:893-899. 
7. 
Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the 
treatment of skeletal metastases in patients with lung cancer and other solid tumors: 
A phase III, double blind, randomized trial - The zoledronic acid lung cancer and 
other solid tumors study group. J Clin Oncol 21:3150-3157, 2003. 
8. 
Rosen LS, Godron D, Tchekmedyian NS et al. Long-term efficacy and safety of 
zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell 
lung cancer and other solid tumors: a randomized, phase III double-blind placebo-
controlled trial. Cancer 100:2613-2621, 2004. 
9. 
Fizazi K, Carducci M, Smith M, et al, Denosumab Versus Zoledronic Acid for 
Treatment of Bone Metastases in Men With Castration-Resistant Prostate Cancer: A 
Randomised, Double-Blind Study,” Lancet, 2011, 377(9768):813-22. [PubMed 
21353695] 

  
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36
10. 
Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with 
lung cancer and bone metastases treated with denosumab versus zoledronic acid. 
Subgroup analysis from a randomized phase 3 study. J Thoracic Oncology 7: 1823-
1829, 2012. 
11. 
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter Radium-223 and survival in 
metastatic prostate cancer. N Engl J Med 2013;369:213-23.  
12. 
Jadvar, H, Quinn, DI. Targeted alpha-particle therapy of bone metastases in prostate 
cancer. Clin Nucl Med, 2013; 38:966-971 
13. 
NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to 
supportive care improves survival in advanced nonsmall cell lung cancer: a systemic 
review and meta-analsyis of individual patient data from 16 randomized controlled 
trials. J Clin Oncol 2008: 26:4617. 
14. 
Azzoli CG, Bakder S, Temin S, et al. American Society of Clinical Oncology 
Clinical Practice Guideline update on chemotherapy for stage IV non-small cell lung 
cancer. J Clin Oncol 2009; 27; 6251 
15. 
Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival 
results of the phase III study of maintenance pemetrexed versus placebo immediately 
after induction treatment with pemetrexed cisplatin for advanced nonsquamous non-
small lung cancer. J Clin Oncol 2013; 31:2895. 
16. 
Chow, E, Nguyen J, Zhang L, et al. International field testing of the reliability of the 
EORTC QLQ-BM22 module to assess health related quality of life in patients with 
bone metastases. Cancer 118:1457-1465, 2012. 
17. 
Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation 
counting. Appl. Radiat. Isot. 2010;68:1523-8. 
18. 
Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R. Revision of the NIST 
Standard for 223Ra: New Measurements and Review of 2008 data.J Res Natl 
InstStand Technol. 2015;120:37-57. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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37
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A  
 
Agreement to Participate in a Research Study And Authorization for Use and Disclosure of 
Information 
 
BrUOG L301: Xofigo Following Frontline-Line Chemotherapy For Patients  
With Non-Small Cell Lung Cancer and Bone Metastases 
 
You are being asked to take part in a research study.  All research studies at <INSERT 
HOSPITAL NAME> hospital follow the rules of the state of <INSERT STATE>, the United 
States government and <INSERT HOSPITAL NAME>.  Before you decide whether to be in the 
study, you and the researcher will engage in the “informed consent” process.   During this 
process, the researcher will explain the purpose of the study, how it will be carried out, and what 
you will be expected to do if you participate.  The researcher will also explain the possible risks 
and benefits of being in the study, and will provide other information.  You should feel free to ask 
any questions you might have.  The purpose of these discussions is for you to decide whether 
participating in the study is the best decision for you. 
If you decide to be in the study, you will be asked to sign and date this form in front of the person 
who explained the study to you.  This form summarizes the information you discussed.  You will 
be given a copy of this form to keep.   
Nature and Purpose of the Study      

  
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Your doctors are participating in this research study sponsored by the Principal Investigator, Dr. 
Angela Taber, in collaboration with Brown University Oncology Research Group (BrUOG), 
which will serve as the central coordinating office for the study.  
You are being asked to take part in this study because you have been diagnosed with advanced 
lung cancer which has spread to your bones. You have already received standard chemotherapy 
for your lung cancer.  
In this study you will receive the medicine Xofigo which is a radioactive drug that is FDA 
approved to treat prostate cancer that has spread to the bones. Cancer that has spread to the bones 
can cause pain and increase the risk of a broken bone (fracture) by weakening the bone. If the 
cancer has spread to the bones of your spine there is a risk that a damaged bone could put 
pressure on your spinal cord, causing paralysis. In patients with prostate cancer that had spread to 
the bones, treatment with Xofigo reduced the risks of bone pain and fractures and prolonged 
survival.  Xofigo has not previously been tested to treat lung cancer that has spread to the bones. 
Your doctors are studying the effects, good and bad, of Xofigo when used to treat lung cancer 
that has spread to the bones. 
This study is supported by Bayer, the makers of Xofigo. 
How Many People will take part in the Study?  
We expect to enroll approximately 36 subjects into this study. The study is sponsored by the 
Principal Investigator Angela Taber, MD. 
Explanation of Procedures   
What will happen if I take part in this research study?  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures, while on the study.  They are part of 
regular cancer care.  
Baseline 
 
CT scan of your chest, abdomen, and pelvis or PET scan prior to starting treatment. You may 
also need to have a bone scan if you have not had one since your diagnosis. 
 
History and Physical examination prior to starting treatment inclusive of vital signs, weight, 
toxicity assessment, performance assessment. 
 
Blood tests prior to starting treatment (about 3 tablespoons) 
 
Pregnancy test if you are a female of childbearing potential 
 
Quality of life questionnaires  
 
On study 
 
 Physical examination prior to treatment  every 4 weeks inclusive of vital signs, weight, 
toxicity assessment, performance assessment. 
 
Blood tests prior to treatments every 4 weeks (about 3 tablespoons) 
 
Quality of life questionnaires every 8 weeks 

  
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Xofigo is administered IV over 1 minute in the nuclear medicine department approximately every 
4 weeks for up to 6 treatments (about 6 months.) 
You should drink plenty of fluids (at least 2 liters/day) the day that you receive Xofigo. 
How long will I be in the study?  
You will receive Xofigo for up to six months (6 treatments) or as long as your cancer does not 
grow or spread or cause worsening bone pain or a fracture for which you require surgery or 
radiation and you do not have severe side effects from Xofigo. After completion of Xofigo, you 
will be followed for up to 1 year for survival. 
 
 
Off study and follow-up: 
 
 
Your physician may decide to order CT scans of your chest, abdomen, and pelvis or PET 
scans in follow-up as necessary 
 
Physical examination inclusive of vital signs, weight, toxicity assessment, performance 
assessment. 
 
Toxicity assessment again approximately 30 days after the last dose of Xofigo 
 
Blood tests (about 3 tablespoons) 
 
Quality of life questionnaires  
 
Follow-up for disease status and survival information every 2-3 months for 1 year 
 
Can I stop being in the study?  
Yes. You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.   
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
discontinuation of treatment can be evaluated by your doctor.  Another reason to tell your 
doctor that you are thinking about stopping is to discuss what follow-up care and testing 
could be most helpful for you.  
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.  
Costs for participating in this study  
Some of the services you will receive are being performed only because you are participating in 
this research study.  Examples of these ‘research only’ services include: the investigational drug: 

  
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Xofigo.  The drug will be paid for by the study and will be provides by Bayer, the maker of the 
drug at no charge; the cost will not be billed to you or your health insurance company. 
Other services you will receive during this research study are considered "routine clinical 
services" that you would have received even if you were not in the research study. Examples are 
all study doctor visits, blood tests, drugs used to reduce side effects and CT scans.   
These services will be billed to your health insurance company, but you will be responsible for 
paying any deductibles, co-payments, or co-insurance that are a normal part of your health 
insurance plan.  If you do not have health insurance, you will be responsible for those costs. 
  
Contact Information: If you have any questions regarding this study, you may contact the 
Principal Investigator, <INSERT SITE PI NAME AND CONTACT> 
 
Discomforts and Risks 
You may have side effects while on this study.  We will monitor everyone in the study for any 
side effects. Contact your study doctor if you experience a side effect or have any questions about 
possible side effects. 
 
Side effects may be mild or serious.  We may give you medicines to help lessen side effects.  
Some side effects will go away as soon as you stop taking the drug.  In some cases, side effects 
can be serious, long-lasting, or may never go away. Taking part in this study may lead to time 
away from work. 
 
Xofigo 
The following side effects are expected to occur in less than 20% of patients 
 Nausea 
 Diarrhea 
 Vomiting 
 Swelling in the hands and legs 
 Low red blood cells (which can cause fatigue) 
 Low white blood cells (which can increase the risk of infection). 
 Low platelets (which can increase the risk of bleeding). 
 Inflammation and pain at the injection site. 
 Kidney damage 
 Dehydration. 
 
Risk of Secondary Cancers or Leukemia: Xofigo may increase the risk of other cancers or 
leukemia (a blood cancer). 
 

  
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In general, when a person is given a radioactive drug, there is a potential risk for the people 
around you, due to radiation from your body and due to possible contamination by spilling urine 
or feces. When Xofigo has been injected into a patient, the risk for external radiation exposure to 
other people is extremely low, due to the short range of the radiation particles in Xofigo (less than 
1mm, which is less than one-twenty-fifth of an inch). For these reasons the product can be 
administered on an outpatient basis. However, you should practice good hygiene including 
washing hands, flushing  the toilet several times after each use and washing clothes that are soiled 
with stool or urine promptly and separately from other clothes, for _7__ days after each Xofigo 
treatment. 
 
Reproductive Risks 
Xofigo may decrease sperm count. This is usually temporary but is infrequently permanent, 
which would result in sterility. Because the drugs in this study can affect an unborn baby, you 
should not become pregnant while on this study Ask your study doctor for more information 
regarding preventing pregnancy during the study treatments. You should not nurse your baby 
while on this study. If you are premenopausal, your periods are likely to stop temporarily and 
may stop permanently due to the study treatments, which may lead to symptoms of menopause, 
such as hot flashes, and the inability to become pregnant, which may be permanent. If you are 
concerned about this, ask your study doctor about options for preserving your reproductive 
choices, which may include referral to a specialist in this field.   
By signing this document you are acknowledging that you understand and agree to the 
information presented in this Reproductive Risks section. 
Antiemetics (anti-nausea medications): Various medications used to prevent and treat nausea 
and vomiting may cause drowsiness, dry mouth, diarrhea, constipation, headache, restlessness, 
agitation, anxiety, dizziness, involuntary tremors, skin rash, and possible allergic reaction. 
 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 
When you receive Xofigo by vein, there is a slight risk that some of the drug may leak out around 
the needle at the injection site. A skin burn may result. Most skin burns are treatable and heal 
well. 
In order to monitor the side effects, your physician will examine you frequently and obtain 
laboratory tests (blood tests, chest x-rays, or CT scans as needed) to determine the effects of your 
treatment. 
Risk of CT imaging: CT imaging uses x-rays. The radiation dose associated with this procedure 
is estimated to be a small fraction of the annual permissible dose to an x-ray technologist. 
There may be other side effects that have not been reported. If you have any unusual symptoms, 
you should report them immediately to your doctor or nurse. 
 
Benefits 

  
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Taking part in this study may or may not make your health better. While doctors hope that Xofigo 
will be active against the lung cancer that has spread to your bones and that the side effects are 
not too severe, this is not yet known. We do know that the information from this study will help 
doctors learn more about Xofigo as a treatment for lung cancer that has spread to the bones. This 
information could help future cancer patients. 
Alternative Therapies 
What other choices do I have if I do not take part in this study?  
You have just finished receiving standard chemotherapy for lung cancer. You may already be 
taking another medicine to reduce the risk of bone pain or fracture. Other options may include 
 
Additional chemotherapy 
 
Radiation 
 
Observation 
 
Taking part in another study 
 
Getting no treatment 
 
Getting comfort care, also called palliative or supportive care. This type of care helps reduce 
pain, tiredness, appetite problems, and other problems caused by the cancer. It does not treat 
the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Refusal/Withdrawal 
It is up to you whether you want to be in the study.  You are not required to enroll or participate.  
If you decide to participate, you can always change your mind and quit at any time.  If you decide 
not to be in the study, or if you quit later, you will still be able to get the health care services you 
normally get.  If you join, but later on the researcher or your doctor feels being in the study is no 
longer good for you, they may choose to take you out of the study before it is over.  If new 
information becomes available that might change your mind about whether you want to stay in 
the study the researcher will share this information with you as soon as possible. 
Follow-up after Withdrawal of Consent  
If you leave the study, it would still be useful for us to know how you do over the next year. We 
would appreciate if you would permit us to get follow-up information about your health from 
your doctor or your medical record. 
____ If I withdraw from the study, you have my permission to collect information about my 
health from my doctor or medical record. 
_____ I do not give my permission for you to continue to collect information about me if I stop 
participating in the study. 

  
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Signature of study volunteer 
 
 
 
Date 
 
You have the right to change your mind at any time regarding follow-up after withdrawal.  If you 
decide to quit the study please tell the head researcher <INSERT NAME AND CONTACT> 
Medical Treatment/Payment in Case of Injury 
A research injury is any physical or mental injury or illness caused by being in the study. If 
you are injured by a medical treatment or procedure you would have received even if you 
were not in the study that is not a research injury. To help avoid research injury and added 
medical expenses, it is very important to follow all study directions carefully. If you do 
experience a research injury, <INSERT HOSPITAL NAME>  or the study doctor can arrange 
medical treatment for you. Such treatment will be paid for as described below.  
 
Medical treatment will be available if you suffer a research related injury; however, you 
and/or your health insurance company will be charged for this treatment. The study will not 
pay for this medical treatment. Neither Dr. Angela Taber, the sponsor of the study, nor 
BrUOG, the coordinating center, nor Bayer, the maker of the drug Xofigo, have money set 
aside to reimburse you for medical bills from treatment of a research related injury or 
otherwise compensate you in the event of a study-related injury.  
 
If you have insurance and have a research injury that is not covered by the study, it is 
possible that some or all of the cost of treating you could be billed to your insurer. If your 
health insurance will not cover such costs, it is possible you would have to pay out of pocket. 
In some cases, <INSERT HOSPITAL NAME>  might be able to help you pay if you qualify 
for free care under <INSERT HOSPITAL NAME>  policy. However, <INSERT HOSPITAL 
NAME>  has no policy to cover payment for such things as lost wages, expenses other than 
medical care, or pain and suffering. 
Rights and Complaints 
Signing this form does not take away any of your lawful rights. If you have any complaints 
about this study, or would like more facts about the rules for research studies, or the rights of 
people who take part in research studies you may contact <INSERT IRB CONTACT AND 
NUMBER> 
Confidentiality 
Your research records will be treated as private health care records and will be protected 
according to <INSERT HOSPITAL NAME>  privacy practices and policies that are based on 
state and federal law. In particular, federal law requires us to get your permission to use or 
disclose (release your information to someone outside of <INSERT HOSPITAL NAME>) your 
health information for research purposes. If you sign this form you agree to be in this research 
study and you permit the use and disclosure of your health information for the purpose of 

  
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44
conducting the research, providing treatment, collecting payment and running the business of the 
hospital. This permission has no expiration date. You may withdraw from the study at any time. 
However, if you do not want the researchers to use or disclose any further information in this 
study you must cancel permission in writing and may do so at any time. If you cancel your 
permission, you will stop taking part in the study and no new information will be collected about 
you. However, if you cancel your permission, it will not apply to actions already taken or 
information already collected about you by the hospital or the researchers before you canceled 
your permission.  
 
Generally, the entire research record and any medical records held by the hospital may be used 
and released for research purposes. The following people or businesses/companies might use, 
release, or receive such information:  
 The researcher and their support staff;  
 The study sponsor, BrUOG, The Brown University Oncology Research Group and Bayer 
(maker of the drug being used on this study and financial supporter of this study);  
 Doctors, nurses, laboratories and others who provide services to you in connection with this 
study;  
 The company or section of the U.S. government that is paying for the study and others they 
hire to oversee, administer, or conduct the research;  
 The United States Food and Drug Administration, the Department of Health and Human 
Services, the Office of Inspector General, and the Office of Civil Rights;  
 People who volunteer to be patient advocates or research volunteer protectors;  
 Members of the hospital's administrative staff responsible for reviewing, approving and 
administering clinical trials and other healthcare or research activities.  
 
There are times when the law might require or permit <INSERT HOSPITAL NAME> to release 
your health information without your permission. For example, <INSERT STATE> law requires 
researchers and health care workers to report abuse or neglect of children to the Department of 
Children, Youth and Families (DCYF) and to report abuse or neglect of people age 60 and older 
to the Department of Elderly Affairs. 
 
All researchers and health care providers are required to protect the privacy of your health care 
information. Other people and businesses/organizations that are not health care providers are not 
required by law to do that so it is possible they might re-release your information.  
 
You have the right to refuse to sign this form and not participate in the research. Your refusal 
would have no affect on your treatment, charges billed to you, or benefits at any <INSERT 
HOSPITAL NAME>  health care site. If you do not sign, you will not be able to enroll in the 
research study and will not receive treatment as a study participant.  
 
If you decide to quit the study after signing this form (as described in Section 6) no new 
information will be collected about you unless you gave us permission to do so. However, the 
hospital or the researchers may continue to use information that was collected before you quit the 
study to complete analysis and reports of this research. 
 

  
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45
Additionally, a description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time.  
 
For more detail about your privacy rights see the<INSERT HOSPITAL NAME> Joint Privacy 
Notice which has or will be given to you. 
 
Research authorization for use and disclosure of information.   
The purpose of this section of the document is to provide you with some more information about 
how the information learned about you during the study will be used and shared. 
We understand that your medical information is very personal and we will work hard to keep it 
private. If you sign this form you consent to participate in this research study and are giving us 
permission to use and share your personal health information in the ways described in this form.   
Understandings and notifications 
The main purpose of permitting the use and release of your information is to allow the research 
project to be conducted and to ensure that the information relating to that research is available to 
all parties who may need it for research purposes.  Your information may also be used as 
necessary for your research-related treatment, to collect payment for your research-related 
treatment (when applicable), and to run the business operations of the hospital. 
All health care providers are required to protect the privacy of your information.  However, most 
persons or entities (i.e., businesses, organizations) that are not health care providers are not bound 
by law to protect the privacy of your information.  You understand that if the person or entity that 
receives your information is not a health care provider bound to protect your privacy, such person 
or entity might re-release your health information.  
You have the right to refuse to sign this form.  If you do not sign this form, none of your health 
care outside the study, or the payment for your health care, or your health care benefits will be 
affected.  However, if you do not sign this form, you will not be able to enroll in the research 
study described in this form, and you will not receive treatment as a study participant.  
If you sign this consent form, you may withdraw from the study at any time.  However, if you do 
not want the researchers to use or disclose any further information in this study you must cancel 
permission in writing and may do so at any time. If you cancel your permission, you will stop 
taking part in the study and no new information will be collected about you.  However, if you 
cancel your permission, it will not apply to actions already taken or information already collected 
about you by the hospital or the researchers before you canceled your permission.  This 
information or action may be needed to complete analysis and reports of this research. This 
permission will never expire unless you cancel it.  To cancel this permission, please write to 
Angela Taber, MD c/o the Medical Oncology Clinical Research Office at Rhode Island Hospital, 
593 Eddy Street, APC Building Rm. 131, Providence, RI 02903. 
If after you have signed this form you have any questions relating to your rights, please contact 
<INSERT IRB CONTACT WITH PHONE NUMBER>  

  
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46
Uses and releases covered by this authorization (permission) 
Who will release, receive, and/or use your information?  This form will allow the following 
person(s), class(es) of persons, and/or organization(s)* to release,  use, and receive the 
information listed below in connection with this Study, or as required by law: 
 
Every research site for this study, including this hospital, and including each site's 
research staff and medical staff 
 
Health care providers who provide services to you in connection with this study 
 
Laboratories and other individuals and organizations that analyze your health information 
in connection with this study, in accordance with the study’s protocol 
 
The following research sponsors or supporters and the people and companies that they 
use to oversee, administer, or conduct the research: BrUOG, the group coordinating the study, 
and Bayer (maker of the drug being used on this study and financial supporter of this study) 
 
The United States Food and Drug Administration, the Department of Health and Human 
Services, the Office of Inspector General, and the Office of Civil Rights 
 
The members and staff of the Institutional Review Board(s) or Ethics Committee(s) that 
approves this study 
 
Principal Investigator and other Investigators 
 
Study Coordinator 
 
Additional members of the Research Team 
 
The Patient Advocate or Research Volunteer Protector: _____________________ 
 
Members of the hospital's administrative staff responsible for administering clinical trials 
and other research activities 
 
Contract Research Organization (A contract research organization is an independent 
organization that agrees to oversee and make possible, various aspects of the clinical research 
process for the research sponsor.) 
 
Data and Safety Monitoring Boards and others that monitor the conduct of the Study, for 
example a Clinical Events Committee 
 
The members and staff of the hospitals affiliated Privacy Board (if such a board is used) 
 
Others:  
 
 
 
 
_____________________________ 
* If, during the course of the research, one of the companies or institutions listed above merges 
with or is purchased by another company or institution, this permission to use or release protected 
health information in the research will extend to the new company or institution.  
 
 The entire research record and any medical records held by the hospital may be used and 
released.   
 The following information: _____________________________________________ 
 
 
SIGNATURE 
 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE 
BEEN ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 

  
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47
 
By signing below, I give my permission to participate in this research study and for the described 
uses and releases of information.  I also confirm that I have been now or previously given a copy 
of the<INSERT HOSPITAL NAME> Privacy Notice 
 
 
 
 
 
The Researcher is required to provide a copy of this consent to you.  
 
_________________________________________ 
________          ____________ 
Signature of study volunteer/authorized representative* Date         and    Time when signed 
 
 
I was present during the consent PROCESS AND signing of this agreement by the study 
volunteer or authorized representative 
__________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
Signature of Translator  
 
 
 
 
Date 
___________________________________________ 
________          __________ 
Signature of researcher or designate 
 
 
 
Date         and    Time when 
signed 
 
* If signed by agent other than study volunteer, please explain below. 
______________________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
This informed consent document expires on _________________.   

  
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48
 
 
 
APPENDIX B: Checklist 
BrUOG L301: Xofigo Following Frontline-Line Chemotherapy For Patients  
With Non-Small Cell Lung Cancer and Bone Metastases 
 
Inclusion Criteria 
________(y/n) Advanced non-small cell lung cancer with bone metastases 
________(y/n) Stable or responding disease after completion of initial systemic chemotherapy as 
defined by RECIST criteria. Site to submit pre-treatment scan with post treatment scan for 
RECIST and confirmation to BrUOG. Document blastic or lytic lesions (and for lytic soft tissue 
or no soft tissue component. Soft tissue component requires measurements for RECIST). 
________(y/n) At least 3 weeks have elapsed since prior chemotherapy and 4 weeks since 
radiation prior to first dose of Xofigo. Patients are not permitted to receive any form of 
‘maintenance’ chemotherapy or biologic/targeted anticancer therapy while being treated on this 
study  
________(y/n) Voluntary, signed written informed consent, Date signed_____________ 
________(y/n) Age >18  
___________(y/n) Must be willing to consent to use effective contraception while on treatment 
and for at least 30 days afterwards.  
___________(y/n) CT scan of chest/abdomen prior to registration (PET scan can substitute), 
report to be submitted to BrUOG 
_________(y/n) Labs within 14 days of study registration: Date:_____________ 
________(y/n) serum pregnancy test negative within 7 days of beginning study drug for women 
of childbearing potential: Date if applicable: if not applicable because patient is male document 
with N/A. If post-menopausal female (defined as no menses for at least 1 year) then document 
here with N/A and write in note to submit to BrUOG 
_________(y/n) Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 30 days after the last dose of study 

  
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drug.  The definition of adequate contraception will be based on the judgment of  the treating 
physician. 
__________(y/n) Absolute neutrophil count ≥ 1,500/ul, Date_________  
_________(y/n) WBC ≥ 3,000/mm3; date:___________ 
___________(y/n) Platelet ≥ 100,000/uL,  Date_________ 
__________(y/n) HGB  > 9g/dl: Date:_________ 
___________(y/n) Total bilirubin ≤ 1.5 x ULN, Date_________ 
___________(y/n) AST≤  2.5x ULN, ALT < 2.5x ULN, albumin > 2.5g/dl Institution 
Date_________     
___________(y/n) creatinine < 1.5xULN  Date:______________ 
 
___________(y/n) All acute toxic effects related to prior treatment(s) must have recovered to < 
grade 1 except for alopecia at time of registration. 
___________(y/n) ECOG 0-1 
______(y/n) Life expectancy of at least 12 weeks: treating investigator to document and confirm 
in note  
_________(y/n)Is patient going to be treated with concurrent bisphosphonates or denosumab? if 
yes, please send BrUOG the information on drug, start date and dose 
_________(y/n) Prior skelteal events (pathologic fracture, radiation or surgery to bone, or spinal 
cord compression)?? allowed if stable and managed prior and now patient is stable for 4 weeks 
prior to study entry. Must submit how events managed to BrUOG for documentation to confirm 
eligibility criterion. (For example, if a patient experienced a SSE and had radiation for 2 weeks 
they must then be stable for 4 weeks after the completion of radiation prior to study entry) 
______(y/n) Willing and able to comply with the protocol, including follow-up visits and 
 
examinations 
________(y/n) Bone scan baseline 
Exclusion Criteria: 
__________(y/n) No prior invasive malignancy within the prior two years. However, patients 
with an early stage malignancy that is not expected to require treatment in the next 2 years (such 
as early stage, resected breast cancer or asymptomatic prostate cancer) are eligible. 

  
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50
__________ (y/n) Patients with untreated brain metastases ** if patient has treated bone mets, 
must have brain imaging showing evidence of stability prior to first dose of Xofigo.  
 
_________(y/n)  Received systemic therapy with radionuclides (e.g., strontium-89, samarium-
153, rhenium-186, or rhenium-188, or Radium Ra 223 dichloride) for the treatment of bony 
 
metastases   
___________(y/n) Patients on concurrent anticancer therapy (chemotherapy, radiation therapy, 
surgery, immunotherapy, biologic therapy, or tumor embolization) other than Ra 223 dichloride. 
___________(y/n) major surgery within 28 days of study treatment start date. Central venous 
catheter placement is not considered major surgery.See eligibility for more details 
 
__________(y/n) Any other serious illness or medical condition that would interfere with 
protocol treatment, such as but not limited to: Any active infection ≥ National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 2 or Cardiac 
failure New York Heart Association (NYHA) III or IV;  
 
________(y/n): Inability to comply with the protocol and/or not willing or not available for 
follow-up assessments. 
__________(y/n): Any condition which, in the investigator’s opinion, makes the subject 
unsuitable for trial participation. 
 
___________(y/n) Pregnant or breastfeeding. Women of child bearing potential must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
within 7 days prior to beginning of treatment. Post-menopausal women (surgical menopause or 
lack of menses >12 months) do not need to have a pregnancy test, please document status in note. 
Signed informed consent: The patient must be aware of the neoplastic nature of his/her disease 
and must willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and 
discomforts. 
The support documentation, per the requirements under the study parameters section of this 
study, as well as the consent form and this checklist, must be faxed to the BrUOG Central Office 
at the time of registration.  Please check if “Enclosed”, state reason when “Not Enclosed,” or 
check if "Not Applicable."  
 
1) Eligibility Form  
 
Enclosed __Not Enclosed   
___ Not Applicable  __ 

  
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2) Heme/Onc initial note 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
3) Pathology Report(s)         
Enclosed __Not Enclosed   
___ Not Applicable  __ 
4) MRI/CT Report(s)   
Enclosed __Not Enclosed   
___ Not Applicable  __ 
5) Lab Source Document        Enclosed __Not Enclosed   
___ Not Applicable  __ 
6) ICF signature page 
7) Other documents, please list________________________ 
 
IRB approval date of protocol:   
  
Hospital where patient will be treated with Oncologist:    
 
 
 
 
 
Date patient will begin treatment:  
 
  Primary Physician: 
  
 
 
 
Nuclear Medicine physician:________________ 
Your signature:  
 
 
 
 
 
 
 
 

  
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APPENDIX C 
1.1 NCI CTC Version 4 
 
Toxicity will be scored using NCI CTC Version 4 for toxicity and adverse event reporting.  A 
copy of the NCI CTC Version 4 can be downloaded from the CTEP homepage: 
(http://ctep.info.nih.gov).  All appropriate treatment areas have access to a copy of the CTC 
Version 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX D 
 ECOG PATIENT PERFORMANCE STATUS 
STATUS 
KARNOFSKY 
ZUBROD-ECOG-
WHO 
Description 
No complaints 
100 
0 
Normal activity 
 
Able to carry on 
normal activities 
90 
1 
Symptoms, but fully 
ambulatory 
 
Normal activity with 
effort 
 
80 
 
 
 
Cares for self.  Unable 
to carry on normal 
activity or to do active 
work 
 
70 
2 
Symptomatic, but in 
bed <50% of the day 
Requires occasional 
assistance, but able to 
care for most of his 
needs 
 
60 
 
 
Requires considerable 
assistance and 
frequent medical care 
 
50 
3 
Needs to be in bed 
>50% of the day, but 
not bedridden 
Disabled, requires 
special care and 
assistance 
 
40 
 
 

  
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Severely disabled.  
Hospitalization 
indicated though 
death non imminent 
 
30 
4 
Unable to get out of 
bed 
Very sick.  
Hospitalization  
Necessary.  Active 
support treatment 
necessary 
 
20 
 
 
Moribund 
 
10 
 
 
Dead 
0 
 
 
From: Minna J.D., Higgins G.A and Glapstein E.J.  Cancer of the lung:  In: DeVita V, Hellman 
S., Rosenberg S., (Eds.).  Cancer: Principles and Practice of Oncology, Lippincott, Philadelphia, 
1984, p. 536

  
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APPENDIX E 
CASE REPORT FORMS 
Attached separately are the BrUOG Case Report Forms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX F: 
Treatment for use pre-Bayer activation memo for NIST standards: 
 
The current dose calibration is referenced to the 2010 NIST standard and corresponds to 
50KBq/kg. 
 
 
The volume to be administered to a given patient should be calculated using the: 
 
– 
Patient’s body weight (kg) 
– 
Dosage level 50 kBq/kg body weight  or 1.35 microcurie/kg body weight–
 
Radioactivity concentration of the product (1,000 kBq/mL; 27 microcurie/mL  at the 
reference date 
– 
Decay correction factor to correct for physical decay of radium-223. 
 
The total amount (volume to be drawn into the syringe) to be administered to a patient should be 
calculated as follows:  
 
Volume to be administered (mL) = Body weight (kg) x dose (50 kBq/kg b.w) 
                                                          DK factor x 1,000 kBq (0.027 mCi)/mL 
 
 
A table with decay correction factors will be provided with each vial of Xofigo. 
 
 
 
 
 
 
 
Weight used for drug order is to be from pre-cycle assessment (done within 7 days prior to cycle start). 
Patients are to be dosed each cycle based on drug order weight and weight collected the day of dosing 
(prior to dosing), is to only be used to confirm patient’s weight has not changed by more than 10% (see 
section 5.1). Patient’s dose is not to be adjusted based on day of weight. 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX G:   

  
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Treatment:  
The revised  dose  55kBq/kg  corresponds to the new NIST standard reference material (NIST 
2015), which is to be used upon IRB approval of Bayer activation memo but cannot be used prior 
to the date indicated in Bayer activation memo expected in 2Qof 2016. 
 
 
 
The volume to be administered to a given patient should be calculated using the: 
 
– 
Patient’s body weight (kg) 
– 
Dosage level 55 kBq/kg body weight or 1.49 microcurie /kg body weight–
 
Radioactivity concentration of the product 1,100 kBq/mL;29.7 microcurie/mL at the 
reference date 
– 
Decay correction factor to correct for physical decay of radium-223. 
 
The total amount (volume to be drawn into the syringe) to be administered to a patient should be 
calculated as follows:  
 
Volume to be administered (mL) = Body weight (kg) x dose (55 kBq/kg b.w) 
                                                          DK factor x 1,100 kBq (29.7 microcurie)/mL 
 
 
 
A table with decay correction factors will be provided with each vial of Xofigo. 
 
 
Weight used for drug order is to be from pre-cycle assessment (done within 7 days prior to cycle 
start). Patients are to be dosed each cycle based on drug order weight and weight collected the 
day of dosing (prior to dosing), is to only be used to confirm patient’s weight has not changed by 
more than 10% (see section 5.1). Patient’s dose is not to be adjusted based on day of weight.