Conditions: Sarcoma
Keywords: Sarcoma Osteosarcoma recurrent or metastatic Ra-223 dichloride Radium-223 chloride Alpharadin
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 18
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to find the highest tolerable dose of radium-223 dichloride that can be given to patients with osteosarcoma.

Radium-223 chloride is designed to work like radiation therapy in cells that are actively making bone. It is designed to target new bone growth in and around bone cancer and may kill cancer cells.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 3 groups of 3 participants will be enrolled in the Phase I portion of the study, and up to 6 participants will be enrolled in Phase II.

If you are found to be eligible to take part in this study, you will be assigned to a dose level of radium-223 dichloride based on when you join this study. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of radium-223 dichloride is found.

If you are enrolled in the Phase II portion, you will receive radium-223 dichloride at the highest dose that was tolerated in the Phase I portion.

Study Drug Administration:

You will receive radium-223 chloride by vein over several minutes on Day 1 of each 4-week cycle.

You should drink plenty of fluids before each study drug dose.

You and your caregivers will receive spoken and written instructions about safety precautions after receiving this drug.

Study Visits:

At all study visits, you will be asked about any drugs you may be taking and if you have had any side effects from them.

On Day 1 of Cycle 2-6:

* You will have a physical exam, including measurement of your vital signs
* You will complete a brief questionnaire about any pain that you may be experiencing. This questionnaire should take about 5-10 minutes to complete.
* Your performance status will be recorded.
* Blood (about 1 tablespoon) will be drawn for routine tests.
* If you can become pregnant, you will have a urine or blood pregnancy test. If the doctor thinks it is needed, you will also have an ultrasound to check for pregnancy. To take part in this study, you cannot be pregnant.

Within 1-3 weeks after Cycle 3:

* You will have scans such as a bone scan and CT or MRI scan to check the status of the disease.
* Blood (about 1 tablespoon) will be drawn for routine tests.

You may have other routine tests done, including a pregnancy test, if the study doctor thinks it is needed.

Length of Study Drug Dosing:

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

Your participation in this study will be over once you have completed the end-of-dosing visit (and follow-up visits if applicable).

End-of-Dosing Visit:

About 30 days after your last study drug dose:

* You will be asked about any drugs you may be taking and if you have had any side effects from them.
* You will have a physical exam, including measurement of your vital signs.
* You will complete a brief questionnaire about any pain that you may be experiencing. This questionnaire should take about 5-10 minutes to complete.
* Your performance status will be recorded.
* Blood (about 1 tablespoon) will be drawn for routine tests.
* You will have scans such as a bone scan and CT or MRI scan to check the status of the disease.

Follow-Up Visits:

If you are younger than 18 years old, your height and weight will be measured 1 time a year until you turn 21. These measurements may stop earlier if your height stays about the same for 2 years in a row.

Information about your health status and any side effects (especially related to your bones) will be collected and reported to the study staff every year.

This is an investigational study. Radium-223 dichloride is commercially available and FDA approved for the treatment of certain types of prostate cancer. It is currently being used for research purposes only.

Up to 20 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Phase I Starting Dose of Ra-223 Dichloride: 50 kBq/kg by vein over several minutes on Day 1 of each 4-week cycle.

Phase II Starting Dose of Ra-223 Dichloride: MTD from Phase I.

Up to 3 groups of 3 participants will be enrolled in the Phase I portion of the study, and up to 6 participants will be enrolled in Phase II.

Interventions: intervention 1: Ra-223 Dichloride
Intervention descriptions: intervention 1: Phase I Starting Dose of Ra-223 Dichloride: 50 kBq/kg by vein over several minutes on Day 1 of each 4-week cycle.

Phase II Starting Dose of Ra-223 Dichloride: MTD from Phase I.

Protocol document:
Prot_SAP_000.pdf: 
 
 
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Phase I Dose Escalation of Monthly Intravenous Ra-223 dichloride in Osteosarcoma 
Test drug(s): 
Ra-223 dichloride  (BAY 88-8223)  
Study purpose: 
Proof of concept of targeted Ra-223-dichloride therapy for 
osteosarcoma, a bone-forming cancer 
Clinical study phase: 
I/II 
Version no.: 
6 
Date: 
13-Oct-2014 
Amendment no.: 
6 
Date: 
 13-Oct-2014 
Bayer Study no.: 
ONC-2012-66 
Institution Study no.: 
 
Primary Investigator: Vivek Subbiah MD. Investigational 
Cancer Therapeutics 1515 Holcombe, Unit 455 Houston TX 
77030-4009; 713-563-0393; vsubbiah@mdanderson.org   
 
Eric Rohren MD. Nuclear Medicine 1515 Holcombe Unit 1264 
ACB6.1720 Houston TX 77030-4009  713-792-6345 
eric.rohren@mdanderson.org  
 
Research Coordinator:    Joanna Grace Fernandez 
Data Manager:  Anna Lui, Research Data Coordinator, Investigational Cancer 
Therapeutics 713-792-4843; pager 713-606-3743; alui@mdanderson.org 
Statistician:  Kenneth R. Hess 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable regulatory 
requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 


 
 
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Synopsis 
 
Title 
Phase I Dose Escalation of Monthly Intravenous Ra-223 dichloride in 
Osteosarcoma 
Clinical study phase 
Phase I/II 
Study objective(s) 
Primary objective: Determine maximum tolerated or 
recommended dose of monthly 223-radium dichloride in patients 
with recurrent or metastatic osteosarcoma. Comparison of safety 
and toxicity of 50, 75, and 100 kBq 223-radium dichloride /kg will 
be made.  
Secondary Objective: compare alkaline phosphatase reduction 
to quantitative imaging techniques (99mTc-MDP, 18FDG-PET-CT, 
18FNa PET-CT scans to determine objective response of 
osteosarcoma indicator lesions to 223-radium dichloride  
Name of active ingredient 
Dose(s)  
Route of administration 
Ra-223 dichloride 
 
50, 75 or 100  kBq/kg body weight 
Intravenous 
Indication 
Osteosarcoma recurrence or  metastatic (bone-forming tumors) 
Diagnosis and main criteria 
for inclusion 
Osteosarcoma with  
1)  metastatic or recurrent disease and 
 2) indicator lesion(s) avid on 99mTc-MDP bone scan.  
Study design 
The study design is a 3+3 Phase I dose escalation (N=3/cohort) with 
expansion at highest safe dose (N=6); if 75kBq is 2/3 DLT, the dose -1 
(50kBq/kg) is the MTD 
Type of control 
Uncontrolled study (i.e. no placebo or control group) 
Number of subjects 
Dose escalation N=14; dose expansion N=6 ;total= 20 
Plan for statistical analysis 
Primary objective: Determine maximum tolerated or recommended 
dose of monthly 223-radium dichloride in patients with recurrent or 
metastatic osteosarcoma. Comparison of safety and toxicity of 50, 75, 
and 100 kBq 223-radium dichloride /kg will be made.   
Secondary Objectives: Analysis change in objective measurements of 
alkaline phosphatase pre , before dose 4 (mid study)  and at end of 
study (after dose 6) vs change in SUV of for PET- scans (18FDG and 
/or 18FNa)  and of SPECT CT for 99mTc-MDP. Changes in uptake will 
be analyzed for dose response effects (between groups) and pre vs mid 
study and end of study (within group) 
 


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


 
 
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Definitions of terms 
 
Ra-223 dichloride      
The investigational product, a targeted alpha-pharmaceutical (a 
radiopharmaceutical emitting alpha radiation), is a ready-to-use solution for 
intravenous injection containing the drug substance radium chloride. The 
active moiety is the alpha particle emitting nuclide Ra-223, present as a         
divalent cation (223Ra2+). 
Dose                                  
Doses are given as kiloBecquerel (kBq) per kilogram body weight, with the 
corresponding dose given in millicurie (mCi) per kilogram in parenthesis. The 
term “dose” is used to describe the quantity of radioactivity from Ra-223 
dichloride administered. 
 
1. Introduction 
1.1 Background 
Ra-223 dichloride is potentially a very low toxicity and high efficacy targeted agent 
for osteosarcoma, an osteoblastic bone-forming tumor. Because of low marrow 
toxicity of this radiopharmaceutical, knowledge of the MTD in this patient population 
is needed to develop future protocols. Use of Ra-223 dichloride in osteosarcoma 
should reduce the morbidity of therapy and mortality from metastases. The goal of 
this initial study is to determine the safety of escalating doses of monthly 223RaCl2 in 
osteosarcoma patients with osteoblastic bone-forming metastases until MTD or a 
dose 100 kBq/kg dose is reached (whichever is first).  Ra-223 dichloride will be given 
monthly and side effects of this bone-targeted therapy on monthly blood counts and 
alkaline phosphatase will be determined. After 3 and 6 doses patients will have 
imaging to compare 99mTcMDP uptake to baseline and other imaging as clinically 
indicated including 18F-FDG PET-CT , Na18F and/ chest CT.  Evaluations will include 
anatomic imaging (CT or MRI) of all sites of disease along with chest CT at baseline 
and restaging for all patients to allow for assessment of RECIST progression.  
RECIST progression will determine progressive disease regardless of other imaging. 
If well tolerated at the MTD, an additional 6 patients will be studied to better define 
toxicity and obtain data to support future investigation of Ra-223 dichloride with other 
agents and modalities (e.g. other drugs, surgery or external beam RT) for improved 
treatment of osteosarcoma. 
1.2 Rationale of the study 
Patients with osteosarcoma recurrence or metastases after initial therapy have 5 
year overall survival of 16%. The median survival after 1st, 2nd, 3rd, or 4th recurrence 
was about 1 year [1] Although chemotherapy may possibly contribute to longer 
overall survival after first relapse, surgery is critical to prevent subsequent relapses. 
Thus for patients with axial, recurrent, or metastatic osteosarcoma, more effective 
treatments are needed.   Ra-223 dichloride is an alpha-emitting radiopharmaceutical 
developed by Oyvind Bruland at the Norwegian Radium Hospital in Oslo (figure 1).  
 


 
 
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The intrinsic bone targeting property of Ra-223 dichloride is similar to calcium and 
other alkaline earth elements. Tables 2 and 3 show how the 223Ra alpha-particle 
emitting radiopharmaceutical has different radiation dose characteristics than the 
current FDA approved beta-emitting radiopharmaceuticals such as 89SrCl2 and 
153Sm-EDTMP [2]. Despite experience with 153Sm-EDTMP for treatment of high-risk 
osteosarcoma [3-8], Radium-223 dichloride may have very significant advantages 
(less marrow toxicity and repeated dosing without stem cell support possible) 
compared to 153Sm-EDTMP.  Radium-223 dichloride emits alpha-particles with high 
energy and high linear energy transfer (LET) radiation with a range limited to less 
than 100 micrometers. These radiation characteristics have the advantages of 
generating highly localized and effective radiation kill zones via the high probability of 
the dense alpha particles inducing double-strand breaks to the DNA of cancer cells.  
 
In contrast, the 89Sr and 153Sm emit beta-particles (electrons) that have much lower 
energy and lower LET. Beta radiation mainly induces single-strand breaks to DNA 
which are more easily repaired. In addition, beta-particles typically have 30-80 times 
longer radiation range compared to alpha-particles. Thus, nearby tissues are more 
subject to collateral damage from beta-emitters. For example after radiation from 
beta-emitters, nearby marrow and stem cells are damaged resulting in anemia, 
leucopenia, and thrombocytopenia.   
 
Rationale for dose level being studied 
 
Ra-223 has been extensively studied in prostate cancer, with a median age of > 65. 
Osteosarcoma occurs in adolescent and young adults and for this type of disease, 
an osteoblastic bone-forming tumor, perhaps a higher dose would have a better 
efficacy in terms of its direct bone targeting properties.  Because of low marrow 
toxicity of this radiopharmaceutical, knowledge of the recommended dose in this 
patient population is needed to develop future protocols. 


 
 
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Figure 2. Decay cascade of Ra-223. The initial ejection of the high LET alpha 
particle takes a relatively long time (t=11.4 days). Subsequent quick decay of radon 
daughters provide additional alpha particles quickly with for increased  therapeutic 
effectiveness at target location of emission (bone-forming tumor cell in the case of 
osteosarcoma) and little changece for diffusion of radon daughters to other 
locations/tissues for non-target effects.   
 
1.3 Ra-223 dichloride 
1.3.1 Preclinical 
In single and repeated dose toxicity studies in rats, the main findings were 
reduced body weight gain, hematological changes, reduced serum alkaline 
phosphatase and microscopic findings in the bone marrow (depletion of 
hematopoietic cells, fibrosis), spleen (secondary extra-medullary hematopoiesis) 
and bone (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous 
lesions, disruption/disorganization of the physis/growth line). These findings were 
related to radiation-induced impairment of hematopoiesis and a reduction of 
osteogenesis and occurred beginning in the dose range of 20 (0.00056 mCi) – 80 
kBq (0.0022 mCi) per kg body weight, with the exception of body weight 
decreases. 1 2  


 
 
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Dose-limiting myelotoxicity was seen in dogs after single administration of 450 
kBq (0.012 mCi) Ra-223 dichloride per kg body weight (9 times the clinically 
recommended dose).   
Osteosarcomas, a known effect of bone-seeking radionuclides, were observed at 
clinically relevant doses in rats 7 – 12 months after start of treatment. 
Osteosarcomas were not observed in dog studies. No case of osteosarcoma has 
been reported in clinical studies with Ra-223 dichloride. The risk for patients to 
develop osteosarcomas with exposure to Ra-223 dichloride is unknown at 
present.3 4 5  
 
Studies on reproductive and developmental toxicity have not been performed. 
Since Ra-223 dichloride binds to bone, the potential risk for toxic effects in the 
male gonads in cancer patients with castration-resistant prostate cancer is very 
low, but cannot be excluded. Studies on the mutagenic and carcinogenic 
potential of Ra-223 dichloride have not been performed 
. 
No histological changes were observed in organs involved in the excretion of Ra-
223 dichloride. No significant effects were seen on vital organ systems, i.e. 
cardiovascular (dog), respiratory or central nervous systems (rat), after single 
dose administration of 450 to 1000 kBq (0.012  to 0.027 mCi) per kg body weight 
(9 (dog) to 20 (rat) times the clinically recommended dose. 
 
1.3.1 Pharmacokinetics / pharmacodynamics  
No PK or PD studies are proposed. See Investigator’s brochure. 
1.3.2 Clinical Experience Summary 
The clinical development of Ra-223 dichloride, to date, includes nine studies in 
patients with prostate cancer or breast cancer with bone metastases. The Phase 
I program consisted of three studies to establish the safety, dose limiting 
toxicities, dosimetry, biodistribution and PK in patients with bonemetastases 
mainly from prostate cancer; and it included some patients with MBC with bone 
metastases. The Phase II program included three completed studies of Ra-223 
dichloride in patients with prostate and breast cancer, who have bone 
metastases. The results of the completed studies indicated that safety and 
tolerability of Ra-223 dichloride in CRPC/HRPC patients with bone metastases 
was well tolerated, and that there was evidence of dose related efficacy against 
bone markers and other markers of disease. In addition there was an effect on 
median overall survival in a Phase II (BC1-02) placebo-controlled study. These 
studies enabled the initiation of the Phase III ALSYMPCA (ALpharadin in 
SYMptomatic Prostate CAncer) study. 
 


 
 
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The clinical safety and efficacy of Ra-223 dichloride have been evaluated in a 
double-blind, randomized, multiple dose, phase III multicenter study 
(ALSYMPCA) in castration-resistant prostate cancer patients with bone 
metastases. The primary efficacy endpoint was Overall Survival (OS).  
At the cut-off date of the pre-planned interim analysis, a total of 809 patients 
were randomized 2:1 to receive Ra-223 dichloride 50 kBq (0.0014 mCi)/kg 
intravenously every 4 weeks for 6 cycles (N=541) plus best standard of care or 
matching placebo plus best standard of care (N=268). Best standard of care 
included e.g. local external beam radiotherapy, corticosteroids, antiandrogens, 
estrogens, estramustine or ketoconazole.  
An updated descriptive analysis of safety and of OS was performed in 921 
randomized patients prior to implementing crossover (i.e. offering patients in the 
placebo group to receive Ra-223 dichloride treatment). 
The results of both, interim and updated analysis, revealed that OS was 
significantly longer in patients treated with Ra-223 dichloride plus best standard 
of care compared to patients treated with placebo plus best standard of care. For 
the updated analysis, an increase in median overall survival of 3.6 months was 
seen with Ra-223 dichloride plus best standard of care compared to placebo plus 
best standard of care (HR =0.695 (95% CI 0.581/0.832), median OS 14.9 months 
versus 11.3 months, respectively). 
The results of the interim analysis and the updated analysis showed also a 
significant improvement in all main secondary endpoints in the Ra-223 dichloride 
arm compared to the placebo arm: 
Time to SRE ( to be update based on final results) - As with good practice, 
the sponsors have conducted further verification of the ALSYMPCA SRE 
data in preparation for the US FDA NDA regulatory submission. This has 
resulted in changes in the numbers previously reported for SRE data in the 
ASCO 2012 abstracts (Abstract #4551, LBA #4512). Though 
discrepancies were noted, the overall interpretation of the results has not 
changed. The SRE data will be disclosed once all additional data 
verification and analyses activities are completed.” 
Prolonging the time to total ALP progression (defined as ≥ 25% increase 
compared to baseline/nadir) (Interim analysis: HR = 0.163, 95% CI 0.121 – 
0.221; p < 0.00001, median number of months not estimable since median 
was not reached at the time of data cut-off; updated analysis: HR = 0.167, 
95% CI 0.129 – 0.217; median number of months = 7.4 months for Ra-223 
dichloride versus 3.8 months for placebo).  
Time to PSA progression (defined as a ≥ 25% increase and an increase in 
absolute value of ≥ 2 ng/mL compared to baseline/nadir ) was also 


 
 
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significantly prolonged in patients receiving Ra-223 dichloride compared to 
patients receiving placebo (Interim analysis: HR = 0.671, 95% CI 0.546 – 
0.826; p = 0.00015, median number of months = 3.6 months for Ra-223 
dichloride versus 3.4 months 
Total ALP response (confirmed ≥ 30% reduction compared to baseline) at 
week 12 compared to the placebo group (Interim analysis: 43.3% in the 
Ra-223 dichloride group, 2.5% in the placebo group, p < 0.001; updated 
analysis: 46.9% in the Ra-223 dichloride group, 3.3% in the placebo 
group). 
Most common non-hematologic all grades adverse events occurring in more than 
15% of patients were: bone pain (43% vs. 58%), diarrhea (22% vs. 13%), nausea 
(34% vs. 31%), vomiting (17% vs. 13%) and constipation (18% vs. 18%).  Most 
common hematologic all grades adverse events were anemia (27% vs. 27%), 
neutropenia (4% vs. 1%) and platelets (8% vs. 6%). 
Subgroup survival analysis 
Subgroup survival analysis showed a consistent survival benefit for treatment 
with Ra-223 dichloride, independent of total alkaline phosphatase (ALP), current 
use of bisphosphonates, prior use of docetaxel and baseline ECOG status.  
 
Pain relief 
The results from the phase III ALSYMCA study regarding time to external beam 
radiation therapy (EBRT) for pain relief and fewer patients reporting bone pain as 
an adverse event in the Ra-223 dichloride group indicate a positive effect on 
bone pain. This is further supported by the effects seen on bone pain using 
specific pain measures in a single dose Phase II study. 
2. Study objectives 
2.1 Primary Objective: Determine maximum tolerated or recommended 
dose of monthly Ra-223 dichloride in patients with recurrent or 
metastatic osteosarcoma. Comparison of safety and toxicity of 50, 
75, and 100 kBq Ra-223- dichloride /kg will be made. 
2.2 Secondary Objectives: compare alkaline phosphatase reduction to 
quantitative imaging techniques (99mTc-MDP, 18FDG-PET-CT, 18FNa 
PET-CT scans to determine objective response of osteosarcoma 
indicator lesions to 223-radium dichloride  
3. 
Investigator[s] and other study participants 
 


 
 
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PI 
Vivek Subbiah MD 
MDACC Assistant Professor,  
Investigational Cancer Therapeutics, Unit 455 
713-563-0393; Pager 713-606-5368 
vsubbiah@mdanderson.org 
 
Co- PI and Ra-223 dichloride license holder: Eric Rohren  MD 
MDACC Associate Professor 1515 Holcombe, Unit 1483. ACB 6.1720 
Houston TX 77030-4009; 713-792-6345 pager 713-404-4080  
Eric.rohren@mdanderson.org 
 
 
Other key personnel: William Erwin   Senior Medical Physicist 
CPB5.3319, Box 1352 713-794-4256; pager 713-404-6992 
werwin@mdanderson.org 
 
Kenneth Hess, Professor, Biostatistics 713-794-4157. FTC4.6028, Unit 1141 
 khess@mdanderson.org  
4. Study design 
The goal of this initial study is to determine the safety of escalating doses of monthly 
Ra-223 dichloride in osteosarcoma patients with osteoblastic bone-forming 
metastases until MTD or a dose 100 kBq/kg dose is reached (whichever is first).  
Radium-223 dichloride will be given monthly for up to 6 cycles and side effects of this 
bone-targeted therapy on monthly blood counts and alkaline phosphatase will be 
determined. After 3 and 6 doses patients will have imaging to compare 99mTcMDP 
uptake to baseline and other imaging as clinically indicated including 18F-FDG PET-
CT , Na18F and/ chest CT.  Anatomic imaging (CT or MRI) of all sites of disease 
along with chest CT at baseline and restaging for all patients will be done to allow for 
assessment of RECIST progression. RECIST progression will determine progressive 
disease regardless of other imaging. 
Table 1. Ra-223 dichloride Dose Escalation scheme (N=3/cohort) 
Dose level:  
kBq/kg 
 
N 
-1 
 
 
25 
 
-- 
0 (starting dose) 
50 
 
3 
1 
 
 
75 
 
3 
2 
 
 
100 
 
8 
Expansion cohort MTD   
6 
Anticipated Total N = 9- 20 (N= 20 assumes reaching 100 mBq/kg MTD) 


 
 
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Table 2.  Decay and Marrow/Bone Ratios Clinically Useful Bone-seeking 
Isotopes  
 
 
 
Half-life *Ratio of Surface  
 
MeV particle      Range 
 
 
 
Days Bone : red marrow  Particle 
Emission energy   (mm) 
153Sm-EDTMP 
2  
 
  4.4  
Beta  
0.66 max 
 
0.6 
 
 
 
 
 
 
 
 
 
0.22 average 
 
89SrCl2 
 
50.5  
  1.6  
Beta  
0.58  
 
2.4 
223RaCl 
 
11.4  
10.3  
Alpha   
27.4  
 
<0.1
 
 
* Bone surface to red bone marrow radioactivity dose ratio 
 
Table 3. Comparison of Alpha and Beta Particles from Bone-Seeking Cancer 
Drugs 
Characteristic 
 
 
 
 
Alpha  
 
Beta  
Range 
(um)  
 
 
 
40-90  
 
50-6000 
Linear Energy Transfer* 
 
 
 
60-230 
 
0.015-0.4 


 
 
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Relative mass 
 
 
 
 
7000** 
 
 
1** 
DNA hits to kill a cell 
 
 
 
1-5 
 
 
100-3000 
Cytotoxic against G0  cells  
 
 
Yes 
 
 
No 
Effective against “radio-resistant” cells  
Yes 
 
 
No 
 
*(LET; keV/µm) 
**Alpha particles are dense particles (i.e. like a helium nucleus); beta particles are 
electrons 
Preclinical work showed that mice had significantly less marrow toxicity from Ra-223 
dichloride than after the beta-emitting radiopharmaceutical strontium-89 chloride [9, 
10]. Alpharadin has shown promising marrow-sparing properties in patients with 
bone metastases of hormone refractory prostate cancer [2, 11, 12]. In a placebo 
controlled trial, patients with hormone refractory prostate cancer bone metastases 
had no significant effects on blood counts after repeated monthly Ra-223 dichloride 
doses (50kBq/kg) [12].   
 
Bone marrow suppression from Ra-223 dichloride has been minimal. Alkaline 
phosphatase in patients with prostate cancer bone metastases after 223Ra 
decreased was 66% versus increase of 9% in placebo treated patients (p=0.001) 
[12]  Time to PSA progression was 26 versus 8 weeks (p=0.048).  A large phase III 
multicenter, randomized, double blinded, placebo controlled trial in prostate cancer is 
underway and includes centers in Europe and the USA [13]. Results of Alpharadin 
against prostate cancer bone metastases in two randomized phase II studies were 
reviewed at ASCO 2011 by Nielsson et al. [14]. Alkaline phosphatase normalization 
was dose-related in trial BC1-04: 5/29 (17% in 25 kBq/kg group, 10/25 (40%) in the 
50kBq/kg group, and 10/21 (48%) in the 80 kBq/kg group. Alkaline phosphatase 
normalization was associated with significantly improved median survival (58 weeks 
vs 102 weeks (log rank p=0.0086).   
 
Alkaline phosphatase is a marker not only of bone formation associated with 
metastases to bone in osteosarcoma, but also the intrinsic bone forming activity by 
the osteoblastic osteosarcoma neoplastic cells. Mialou et al. found that not only 
bone (vs lung) metastases, but also high alkaline phosphatase (>500 IU) was 
significantly associated with a worse outcome in metastatic osteosarcoma [15].  An 
alpha-emitting targeted radiopharmaceutical located in osteosarcoma target tissue 
will deliver the radiation to a much more localized tumor volume than a beta-emitter, 
thereby reducing exposure of surrounding normal tissues and leading to less toxicity.  
 
Thus a dose finding study to determine best dose for monthly Alpharadin dosing in 
osteosarcoma is proposed. This information can then be used to develop potential 
“game-changing” strategies against osteosarcoma to improve pain in metastatic 
patients, make surgery better (fewer amputations, better function), and reduce the 
considerable morbidity of current therapy, 
 


 
 
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5. Study population 
5.1 Eligibility 
 
5.1.1 Inclusion criteria 
• Patients with progressive, locally recurrent, or metastatic osteosarcoma 
(i.e. high-risk only) with no standard curative options available with at least 
one indicator lesion avid on 99mTc-MDP scan or a Sodium Fluoride (Na F) 
Bone PET scan will be eligible. In addition, subjects with extremely rare 
bone forming osteosarcoma-like tumors that behave like osteosarcoma 
phenotypically and are clinically treated like osteosarcoma (eg. Malignant 
Fibrous Histiocytoma of Bone or malignant transformation of giant cell 
tumor of bone) may be included if they satisfy all of the inclusion criteria. 
• Anatomic imaging (CT or MRI) of all sites of disease along with chest CT 
at baseline and restaging for all patients will be done to allow for 
assessment of RECIST progression. RECIST progression will determine 
progressive disease regardless of other imaging. 
• Indicator lesion that has uptake of 99mTc-MDP on bone scan or a Sodium 
Fluoride ( Na F) Bone PET scan and can be subjected to quantitative 
assessment by this scans and possibly other means  
• Age 15 and above and >40 kg. 
• ECOG=2 or better  
• Subjects or their guardians must be able to understand and be willing to 
sign the written informed consent form.  A signed informed consent form 
must be appropriately obtained prior to the conduct of any trial-specific 
procedure. 
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE 
v4.0 Grade 1 or less at the time of signing the Informed Consent Form 
(ICF). 
• Women of childbearing potential must have a negative serum or urine 
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. 
• 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 


 
 
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contraception will be based on the judgment of the principal investigator 
or a designated associate. 
• Acceptable hematology and serum biochemistry screening values: 
 White Blood Cell Count (WBC) ≥ 1500/mm3 
 Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 
 Platelet (PLT) count ≥ 75,000/mm3 
 Hemoglobin (HGB) ≥ 8 g/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 > 25 g/L 
• Willing and able to comply with the protocol, including follow-up visits and 
examinations  
5.1.2 Exclusion criteria 
 
• Diagnosis other than osteosarcoma 
• 
99mTc-MDP bone scan with no significant uptake (i.e. “nothing” for a bone-
seeking isotope to target/ i.e.  indicator lesion that would be expected to 
have the bone-seeking targeted uptake of 223-radium dichloride) 
•  Other malignancy treated within the last 3 years (except non-melanoma 
skin cancer or low-grade superficial bladder cancer)  
• Any other serious illness or medical condition, such as but not limited to: 
o Any active  infection ≥ National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 
Grade 2  
o Cardiac failure New York Heart Association (NYHA) III or IV 
o Fecal incontinence (this is because of Ra-223 elimination in feces) 
• Women who are pregnant or breast-feeding. 
• Inability to comply with the protocol and/or not willing or not available for 
follow-up assessments. 


 
 
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• 
Any condition which, in the investigator’s opinion, makes the subject 
unsuitable for trial participation. 
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy,     
surgery, immunotherapy, biologic therapy, or tumor embolization)  
• Patients on oxygen 
5.2 Withdrawal of subjects from study 
5.2.1 Withdrawal 
Subjects must be withdrawn from the trial (treatment and procedures) for the 
following reasons:  
• Subject withdraws consent from study treatment and study procedures.  A 
subject must be removed from the trial at his/her own request or at the 
request of his/her legally acceptable representative.  At any time during 
the trial and without giving reasons, a subject may decline to participate 
further.  The subject will not suffer any disadvantage as a result. 
• Progressive disease and dose limiting toxicity (DLT) 
• Subject is lost to follow-up. 
• Death. 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug, trial procedures, or both; 
including the use of anti-cancer therapy not prescribed by the study 
protocol. 
• Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who 
have been withdrawn from treatment with study drug because of 
pregnancy should not undergo CT scans [with contrast]/MRI or bone 
scans while pregnant.) 
• If, in the investigator's opinion, continuation of the trial would be harmful to 
the subject's well-being. 
• The development of a second cancer.  
• Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, significantly affect assessments of clinical 
status and trial endpoints. 


 
 
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• Deterioration of ECOG performance status to 4. 
• Use of illicit drugs or other substances that may, in the opinion of the 
investigator, have a reasonable chance of contributing to toxicity or 
otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until 
discharge or transfer is medically acceptable. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the 
subject's medical records. 
5.2.2 Screen Failures/Dropouts 
A subject who discontinues study participation prematurely for any reason is 
defined as a “dropout” if the subject has already been assigned to treatment and 
administered at least one dose of study drug. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), 
terminates the study before the time point used for the definition of “dropout” (see 
above) is regarded a “screening failure”. 
5.2.3 Replacement 
 
Subjects/patients who discontinue from the study for reasons unrelated to the 
study (e.g., personal reasons or disease progression) will be replaced as required 
for the study to meet its objectives. The decision to remove a subject/patient and 
to replace dropouts will be made by the study investigator. Both the replacement 
and originally allocated number will be unique numbers. 
 
6. Treatment 
6.1 Treatments to be administered:  
Monthly doses of Radium-223-dichloride 
6.2 Treatment assignment 
Patients will be screened with clinically appropriate tests for study inclusion.  A 
patient number (a unique identification number from CORe in MD Anderson) will 
be assigned after a patient is evaluated for inclusion into the study and signs 
informed consent after successful screening. 


 
 
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6.2.1 Radium-223 dichloride 
6.2.2 Treatments to be administered 
Ra-223 dichloride will be administered as a slow bolus IV injection at intervals 
of every 4 weeks for up to 6 cycles. 
 
 
• Dose (50, 75, or 100 kBq/kg) will be assigned in cohorts of 3 after study 
registration in CORe. 
• Dose #1 should be given within 30 days of study registration   
• At least 3 patients will be required to successfully complete 6 weeks of 
therapy before advancing to the next cohort.   
• Patients will receive the same Ra-223-dichloride dose as dose #1 for all 
subsequent doses. 
• Monthly dosing (q 4 weeks +/- 6 days) as slow iv bolus for up to a total of 6 
doses  
• Monthly doses will be delayed, but no more than 2 weeks from scheduled 
dose for any grade 3 hematologic toxicity.  
 
Criteria for subsequent doses (i.e. doses 2-6):  
 
• Hematologic Toxicity (if present): Hb, ANC, and platelets- resolved to grade 2 
or less within 6 weeks of prior dose. Since lymphopenia may be chronic, this 
will not be a criteria for subsequent doses 
• All toxicities must be resolved to grade 2 or less in order to begin subsequent 
cycles 
• Performance status ECOG 0 to 2  
• Alkaline phosphatase stable or improving at the discretion of the treating 
physician  
• Not on oxygen  
• Not pregnant 
• After dose #3 and before dose #4: stable disease or better in indicator lesions 
as determined by quantitative nuclear medicine imaging (18FDG PET-CT, 
quantitative 99mTc-MDP SPECT/CT, or Na18F PET/CT) or RECIST criteria on 
anatomic imaging (note: often osteosarcoma “indeterminate” lesions 1-9 mm 
remain stable or have minimal change depending on chest CT technique). 
• Anatomic imaging (CT or MRI) of all sites of disease along with chest CT at 
baseline and restaging for all patients will be done to allow for assessment of 
RECIST progression.  
• RECIST progression will determine progressive disease regardless of other 
imaging. 
 


 
 
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For the Phase I aspect of the protocol, prior to advancing/changing dose levels, a 
cohort summary must be completed and submitted to the Clinical Research 
Monitor in the IND Office. 
6.2.3 Identity of study treatment 
The alpha-pharmaceutical Ra-223 dichloride is a ready-to-use, sterile, non-
pyrogenic, clear and colorless aqueous solution of Ra-223 dichloride for IV 
administration. Ra-223 dichloride is an alpha particle emitter with a physical 
half-life of 11.4 days. The product is isotonic and has a pH of 6.0-8.0. The 
radioactive concentration at the reference date is 1000 kBq/mL. 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. 
 
Bayer Corporation will provide Ra-223 dichloride, which will be manufactured 
by the contract manufacturer: Institute for Energy Technology, Isotope 
laboratories, Kjeller, Norway. The product is produced according to Good 
Manufacturing Practice (GMP). The product will be delivered in a glass vial, 
ready-to-use with a certified activity. Ra-223 dichloride is shipped in a lead 
container and Type A radioactive package according to international 
transportation guidelines for radioactive materials.  
 
The volume per vial is 6 mL, corresponding to 6 MBq at the calibration day. Ra-
223 dichloride has a shelf life of 28 days from production day, when stored at 
ambient temperature. The shelf life has been demonstrated for temperatures 
from cold storage (2-8°C) up to 40°C. In addition, it has been shown that the 
product quality is not jeopardized upon freezing. 
 
All study drugs will be labeled according to the requirements of local law and 
legislation. For all study drugs, a system of numbering in accordance with all 
requirements of GMP will be used, ensuring that each dose of study drug can 
be traced back to the respective bulkware of the ingredients.  
 
6.2.4 
Dosage and administration  
Written information about Ra-223 dichloride and instruction about handling 
and injection of radioactive material will be provided to study personnel.  
 
In general, the administration of radioactive drugs involves a potential risk for 
third parties, due to radiation from the patient and due to possible 
contamination by spilling urine or feces. When Ra-223 dichloride 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 low portion of beta and gamma radiation. For these 


 
 
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reasons the product can be administered on an out-patient basis. To minimize 
the risk of contamination, the patient and his caregivers will receive oral and 
written instructions regarding hygiene precautions to abide by after receiving 
the radioactive drug. 
6.2.5 Dose calibration 
Ra-223 dichloride can be measured in a normal dose calibrator instrument. 
When written approvals for the use of Ra-223 dichloride from the Radiation 
Protection Agency for the specific center have been received by the sponsor, a 
vial of Ra-223 dichloride for technical use will be sent to the study center. 
 
Different clinical study centers possess dose calibrators from various suppliers; 
thus, the isotope calibration factor may differ from center to center. 
Consequently, each center must perform the Ra-223 dichloride dial setting on 
their relevant dose calibrator(s). For dial setting, the clinical study center will 
receive a sealed vial containing a Ra-223 dichloride solution for calibration 
only. The vial is identical to the vials used for study treatment. The amount of 
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. 
 
6.2.6 Dose handling 
The Ra-223 dichloride vials must be stored inside their lead container in a 
secure facility. The study drug should be used within 28 days of production. 
Ra-223 dichloride is an alpha-pharmaceutical and should be handled by 
individuals who are qualified by training and experience in the safe handling of 
radionuclides. One dedicated person and a back-up designee will have 
responsibility as assigned from the Primary Investigator for handling and 
storage of Ra-223 dichloride. Control measurements of both the Ra-223 
dichloride vial (before and after dispensing) and syringes (before and after 
administration) are performed as part of the clinical trial documentation. All 
administrations of Ra-223 dichloride are based on the certified activity of Ra-
223 dichloride at the calibration date. 
6.2.7 Dose calculation 
The dosage of Ra-223 dichloride is 50, 75, or 100 kBq/kg body weight. The 
total activity to be injected will be calculated volumetrically using the patient’s 
body weight on the day of injection (kg), the 50 kBq/kg body weight dosage 
level, and the decay correction factor (DK) to correct for physical decay of Ra-
223 dichloride. A table with DKs according to physical decay of the study 
medication will be provided with each vial of Ra-223 dichloride. The total 
amount (volume to be drawn into the syringe) to be administered to a patient 
should be calculated as follows: 


 
 
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Body weight (kg) x50 kBq/kg = volume to be injected (mL)    
DK x 1000 kBq/mL   
 
Data regarding activity should be recorded on the appropriate electronic case 
report form (eCRF) page. 
6.2.8 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 usage of shielded syringes 
is strongly recommended; however, this decision will be dictated by the 
individual guidelines of the respective nuclear medicine department. Filling of 
the syringe should take place in a safety bench or similar cabinet in the 
Radiopharmacy/ Nuclear Medicine department. The individual responsible for 
study drug preparation will draw the correct volume of study drug into a 
syringe. The size of the syringe should be chosen according to the applied 
volume to reach the required dosing accuracy. Ra-223 dichloride should not be 
diluted or mixed with any solutions. If the vials have been stored in a 
refrigerator, they should be left at room temperature for 1 hour prior to use, 
since cold material should not be injected in a patient. 
6.2.9 Dose administration 
Before administration of study drug, the patient must be well hydrated; the 
patient should be instructed to drink ad libitum. Aseptic technique should be 
used in the administration of Ra-223 dichloride. The syringe should be handed 
over to the individual who will perform the injection. The study medication will 
be administered as a slow bolus intravenous (IV) injection. 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 hospital procedure for the handling of radioactive 
material. Written information about Ra-223 dichloride and instruction about 
handling and injection of radioactive material will be given to study personnel 
 
Radiation Safety Considerations  
Radiation Risk Management for Patients 
Biodistribution of 223Ra in the body 
Pharmacokinetics, biodistribution and dosimetry in man have been previously 
investigated 
(see 
also 
ATI-BC-1: 
blood 
pharmacokinetics; 
BC1-05: 
pharmacokinetics, biodistribution and radiation dosimetry; Algeta ASA). After 
intravenous injection of 2Ra-223 dichloride, then radiopharmaceutical is quickly 
eliminated from blood, taken up in bone and excreted via the small intestine. The 
major route of elimination is through the gut with the feces; at 48 hours only 1-5% 
was excreted in urine and the rate of urinary excretion was decreasing. Thus, the 
kidneys, urinary bladder, and urethra are exposed to a minimal amount of radiation. 


 
 
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Gamma scintigraphy images show early activity in the gut, decreasing at the later 
images. It is not possible to determine the relative activity within gut wall versus gut 
contents from the scan, but it is assumed that the activity is mainly confined to the 
gut contents (i.e. fecal stream). This is a reasonable assumption since the activity in 
the scans is seen to move along the gut. No specific uptakes were seen in any other 
normal organs such as the heart, the liver, the kidney, the gallbladder, stomach and 
the spleen. The highest absorbed doses were measured in the bone with lesser 
amounts in the red marrow.  
 
Biosampling (blood tests)  
In the first week after injection of Ra-223 dichloride, there may be radioactivity in 
body fluids. A considerable fraction of the study drug is eliminated via feces, and to a 
lesser degree via urine. Blood clearance after injection is very rapid (<1% remaining 
24 hours post injection). To ensure radiation protection for hospital personnel, 
special attention should be directed to ensure that only necessary samples of blood, 
urine and feces should be handled during the first week after administration. In case 
of necessary unforeseen blood samples, laboratory personnel should be notified in 
order to avoid contamination. All patients in clinical trials with Ra-223 dichloride 
receive a card stating that they have received a radioactive drug and that special 
care should be taken during unforeseen contact with medical or public health 
services. 
 
Restrictions for patients 
Unlike many other radiopharmaceuticals, there are no restrictions on family contact 
after administration of Ra-223 dichloride. The range of α-particles in human tissue is 
£ 0.1 mm. Once injected, both α- and β-particles emitted from Ra-223 are stopped 
by the patient’s tissue. Due to attenuation in the patient’s body mass, the radiation 
outside the patient’s body is extremely low and there should be no safety issues 
related to homeland security/airport travel.  Nevertheless patients should have a 
letter or card indicating recent treatment with a radioisotope in case of detection in 
by radiation detectors while traveling (advice: wear clean underpants!). Dose rates 
(µSv/h per MBq injected) measured outside the body are ~200 at one centimeter  
and 0.02 at one meter[16] 
 
Ra-223 dichoride can be given on an out-patient basis, and there are no restrictions 
on normal interactions with friends or relations.  Patients are provided with written 
instructions describing simple steps to be followed at home in connection with vomit, 
blood, urine or stools for a period of one week after dosing.  
 
Burial and Cremation risks 
After burial 223Ra will decay naturally and has essentially no health risk to others 
after 3 months. Cremation of a body containing 223Ra does not present a significant 
risk to the local population or to the crematorium workers themselves, even if the 
worst case scenarios are assumed. When crematorium workers receive a body that 
contains any type of radioactivity, they should be suitably trained, informed 


 
 
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beforehand and given suitable personal protection equipment (i.e. universal blood 
and body fluid precautions - especially when handling ashes containing potentially 
radioactive bone fragments.  Calculations and the rationale for radiation dose 
estimates are available upon request (see investigators Brochure). 
 
Definition of Dose-Limiting Toxicities (DLTs): 
 
Toxicities will be graded in severity according to the guidelines outlined in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (publish date 
28-May-2009). Dose-limiting toxicities include all adverse experiences that are 
related to study medication, and clearly not related to disease progression or 
intercurrent illness.  
 
Based on prior experience with other bone seeking radiopharmaceuticals and Ra-
223 dichloride in prostate cancer patients, the expected dose limiting toxicity (DLT) 
will be hematologic.  Lymphopenia is common in patients with bone metastases and 
will be monitored, but not considered a DLT in this protocol. Any grade 4 anemia, 
any grade 4 neutropenia for >7 days or grade 4 neutropenia with fever (a single 
temperature greater than 38.3˚C or a sustained temperature of ≥ 38˚C for more than 
one hour) and grade 3 or 4 thrombocytopenia with clinically significant bleeding will 
be dose limiting.  Grade 3 non-hematologic toxicities except for nausea, emesis or 
diarrhea that are controlled with maximal medical management within 72 hours will 
be considered dose-limiting. DLTs will only be monitored during the first 6 weeks of 
treatment. Ongoing toxicity that causes a delay of more than 2 weeks in starting the 
next cycle will also be dose-limiting if it occurs during the first cycle. 
 
Dose Modification and Escalation  
Every effort should be made to administer the full dosing regimen of Ra-223 
dichloride.  Adjustment of dose level is not permitted.   
• 
A minimum of 3 patients initially will be enrolled at the first dose level. 
• 
If at least 2 patients are observed to have a dose-limiting toxicity (DLT), the 
MTD will have been exceeded and no further patients will be enrolled at this 
dose level or at any higher dose level.  The prior dose level is defined as the 
MTD (unless only 3 patients have been treated at that level, in which case it is 
the tentative MTD). 
• 
If 0 of the 3 patients are observed to have DLT during the DLT assessment 
period, the dose level is escalated one step for the next cohort of 3 patients, 
and the process continues as above. 


 
 
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• 
If exactly 1 of the 3 patients treated show DLT during the DLT assessment 
period, 3 additional patients are treated at the current dose level. 
• 
If none of these additional 3 patients show DLT during the DLT assessment 
period, the dose level is escalated for the next cohort of 3 patients, and the 
process continues as above; otherwise, the prior dose level is defined as the 
MTD (unless only 3 patients have been treated at that level, in which case it is 
the tentative MTD). 
• 
A tentative MTD becomes final when a total of 6 patients are treated with less 
than 2 showing DLT. 
• 
If 2 of the first 3 patients have hematologic DLT, then next cohort will be dose 
level -1. 
Study visits during the treatment period should occur at 4 weeks intervals 
(within a window of +/- 7 days).  Dosing delays may be instituted under the 
following circumstances: 
Disease progression: 
The Investigator should delay cytotoxic chemotherapy, other systemic 
radioisotope, hemibody external radiotherapy or other investigational drug until 
the follow-up period.  If such treatments have to be given during the treatment 
period, further study drug administrations must be discontinued.  Patients with 
disease progression may continue other treatment at the Investigator’s 
discretion.  
Myelosuppression:   
Treatment-related changes in hematology parameters may occur. 
• 
Blood transfusion is acceptable between study drug administrations.  
Use of biologic response modifiers, such as G-CSF or GM-CSF, is allowed in 
the management of acute toxicity. 
• 
If myeloid growth factors are required for the management of acute 
toxicity this event should be considered a DLT. 
Gastrointestinal events: 
Diarrhea should be treated as per local practice.  A further dose of study 
medication should not be given before diarrhea is recovered to CTCAE v4.03 
Grade 2 or baseline levels.  


 
 
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Nausea or vomiting should be treated as per local practice.  A further dose of 
study medication should not be given before nausea or vomiting is recovered 
to CTCAE v.4.03 Grade 2 or baseline levels. 
For any grade 3 hematologic toxicity for >14 days, study drug administrations 
must be discontinued (grade 4 events of anemia and neutropenia >7 days are 
dose-limiting). 
Spinal Cord Compression: 
If the patient experiences spinal cord compression during the treatment period, 
the patient should be treated for the event, and this will be considered disease 
progression. 
Surgical Intervention: 
If surgery is required, the patient should continue with study treatment, if this is 
considered safe in the treating Investigator’s opinion.  The surgeon needs to 
be notified that the patient has been given radioactive drug, and needs to 
follow the guidelines for radioactive protection.   
Non-pathological fractures: 
For traumatic fractures in weight-bearing bones during treatment phase, the 
study drug administration should be delayed for 2-4 weeks from the time of 
fracture.  
Pathological fractures: 
Pathological fractures may occur as the result of either progressive disease or 
increased physical activity associated with significant pain palliation.  
Pathologic fractures are to be treated in a manner that attempts to maintain 
the best functional status and quality of life. Study treatment may continue as 
planned. 
Any Other Toxicity:  Local practice will apply. 
 
6.3 Drug logistics and accountability 
All study drugs will be stored at the investigational site in accordance with 
Good Clinical Practice (GCP) and Good Manufacturing Practices (GMP) 
requirements and the instructions given by the clinical supplies department of 
the Institution and will be inaccessible to unauthorized personnel. 


 
 
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6.3.1 Accountability 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the agent 
(investigational or free of charge) using the NCI Drug Accountability Record or 
another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the 
drug accountability form.) 
6.3.2 Destruction and Return 
At the end of the study, unused supplies of alpharadin should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. The certificate of destruction should be sent to 
Bayer. 
6.4 Treatment compliance 
An adequate record of receipt, distribution, and return of all study drugs must 
be kept in the form of a Drug Accountability Form.  
Subject compliance with the treatment and protocol includes willingness to 
comply with all aspects of the protocol, and to have blood collected for all 
safety evaluations.  At the discretion of the principal investigator, a subject 
may be discontinued from the trial for non-compliance with follow-up visits or 
study drug. 
6.5 Prior and concomitant therapy- 
During treatment, all concomitant medications (including start/stop dates and 
indication) must be recorded in the patient's medical record and case report 
form ( DMI) 
Permitted  
• Treatment with non-conventional therapies (e.g., herbs [with the exception 
of St. John’s Wart], acupuncture) and vitamin/mineral supplements is 
acceptable provided that, in the opinion of the investigator, such treatment 
will not interfere with the trial endpoints. 
• Subjects may receive standard of care for any underlying illness. 
• In the event of neutropenia, anemia, or thrombocytopenia, subjects may 
receive appropriate supportive care (e.g., transfusion, biologic response 


 
 
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modifiers such as G-CSF or GM-CSF, prophylactic antibiotics, antifungals 
and/or antivirals, hematopoietic growth factors).  This supportive care 
should not substitute a recommended dose modification. 
• Blood transfusions and erythropoietin are allowed during the study period  
• If surgery is required during study drug treatment, the surgeon needs to be 
notified that the patient has been treated with a radioactive product and 
adequate precautions for radioactive protection should be applied during 
the surgical procedure.  The patient should continue with study treatment if 
considered safe in the treating Investigator's opinion. 
7. Procedures and variables 
7.1 
Schedule of procedures 
Labs and imaging are to be done no more than 28 days prior to registration and <30 
days before dose#1 of study drug.  
CBC every 2 weeks for the first 2 cycles (±7 days), then monthly or more frequently 
as clinically indicated. Monitoring of hematologic toxicity will be done with monthly 
cbc from that point on. Weekly testing will be recommended for any patients on a 
clinically indicated basis if they have symptoms suggesting anemia (e.g. increased 
fatigue or headaches), thrombocytopenia (e.g. petechiae, bruising) or neutropenia 
(fevers or infection). If clinically indicated (e.g. grade 3 or higher anemia, neutropenia 
or thrombocytopenia, hematologic monitoring may be done more frequently. 
Alkaline phosphatase will be monitored monthly.  Laboratory monitoring and imaging 
are summarized in table 4.  
Blood counts may be done by local physician as clinically indicated and also week 
before anticipated dosing and communicated to study team to make sure patient is 
ready for dosing prior to travel to MD Anderson Cancer Center. 
Pregnancy test will be required when applicable prior to every cycle. 
7.1.1 Tabulated overview  
Table 4 summarizes required labs and imaging. 
 
 
Table 4: Ra-223 dichloride for Osteosarcoma: observations/monitoring 
 
Test/Procedure 
Before entry 
Doses 2-6 
After dose 3+ 
imaging 
1 month after dose 
(end of study±7 days) 


 
 
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Physical exam 
(including vital 
signs and 
performance 
status+BPS$) 
x 
x 
 
x 
CT/MRI Scans+ 
x 
 
x 
x 
Nuclear Scans* 
x 
 
x 
x 
CBC** w diff 
x 
x 
x 
x 
Creatinine 
x 
 
x 
x 
Bilirubin 
x 
 
x 
x 
ALT 
x 
 
x 
x 
Alk Phos 
x 
x 
x 
x 
HCG** 
x 
        x 
 
 
 
OSTEO1 
x 
x 
x 
x 
BONE ALK2 
x 
x 
x 
x 
CTX3 
x 
x 
x 
x 
Pathology 
x 
 
 
 
 
Nuclear scans: *bone scan required, Other imaging of indicator lesion(s): best study 
or studies for quantitative comparison after dose 3 and after dose 6 (e.g. LD of bone 
forming lesion on CT/MRI, or SUV on 18FDG-PET-CT, or SPECT with 99mTc-MDP 
bone scan, or Na18F PET). 
$Brief Pain Survey. 
+Evaluations to include anatomic imaging (CT or MRI) of all sites of disease along 
with chest CT at baseline and restaging for all patients will be done to allow for 
assessment of RECIST progression. RECIST progression will determine progressive 
disease regardless of other imaging. 
HCG: Urine pregnancy test must be done within 7 days prior to start of study drug 
and when applicable prior to every cycle. Note serum HCG can be a false positive 
marker occasionally in osteosarcoma. For patients with a positive test result, 
pregnancy will be excluded by ultrasound. 
**CBC w/diff: CBC every 2 weeks (±7 days) for the first 2 cycles, then monthly or 
more frequently as clinically indicated 
1 Osteoclacin 
2 Bone specific alkaline phosphatase 
3 Serum CTX 
 
Timing of assessments 
Assessments are to be done monthly as indicated in table 4. 
7.1.2 Medical history 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting 
all criteria listed below will be collected: 


 
 
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• Not pertaining to the study indication 
• Start before signing of the informed consent  
• Considered relevant to the study. 
Detailed instructions on the differentiation between (i) medical history and 
(ii) adverse events can be found in Section 7.4.1.1. 
7.2 Efficacy 
Efficacy will be determined by 
A) Trends comparing measurements of the indicator lesions using quantitative 
nuclear medicine scan will be used as exploratory end points.  RECIST progression 
will determine progressive disease regardless of other imaging.   
B) Alkaline phosphatase trends comparing before, after 3 doses and after 6 doses of 
Ra-223 dichloride 
 
7.3 Pharmacokinetics / pharmacodynamics 
7.4 Safety and Toxicity Monitoring 
All subjects who receive at least one dose of study treatment will be valid for the 
safety analysis.  
All observations pertinent to the safety of the study treatment will be recorded and 
included in the final report. Serious Adverse Events and/ any unexpected and 
clinically significant grade 3 or 4 toxicities will be reported to the MD Anderson IRB 
and Bayer. This trial will use the NCI-CTCAE v4.0 criteria for assessment of toxicity 
and SAE reporting with regard to toxicity grade. 
7.4.1 
Adverse events 
Investigators should refer to the Safety Information section of the current IB for 
radium-223-dichloride, including the DCSI (development core safety information), for 
the expected side effects of Radium-223 dichloride.  As with any agent, there is 
always the potential for unexpected AEs, including hypersensitivity reactions.  The IB 
will be updated if any new relevant safety data are obtained. 
All concomitant medications must be recorded in the subject’s medical record at 
each clinic visit (ClinicStation) . 
Subjects must be carefully monitored for AEs.  This monitoring also includes clinical 
laboratory tests.  Adverse events should be assessed in terms of their seriousness, 
intensity, and relationship to the study drug, or other chemotherapy/treatment. 


 
 
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7.4.1.1 Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any 
unfavorable and unintended sign [including abnormal laboratory findings], 
symptom or disease) in a patient or clinical investigation subject after providing 
written informed consent for participation in the study.  Therefore, an AE may or 
may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician 
treating the subject should not be recorded as AE (however, the condition for which 
the surgery is required may be an AE if the condition worsens compared to 
baseline). 
 
• Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are 
recorded as medical history (e.g. seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which 
symptoms or treatment are present after signing of informed consent, at 
unchanged intensity, are recorded as medical history (e.g. phantom pain). 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any 
of the following criteria (a – f): 
a. Results in death. 
b. Is life-threatening. 
The term ‘life-threatening’ in the definition refers to an event in which the 
patient was at risk of death at the time of the event, it does not refer to an 
event which hypothetically might have caused death if it were more severe. 


 
 
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c. Requires inpatient hospitalization or prolongation of existing hospitalization. 
A hospitalization or prolongation of hospitalization will not be regarded as an 
SAE if at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours. 
- The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
- The admission is not associated with an AE. 
(e.g. social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization 
may fulfill the criterion of ‘medically important’ and as such may be reportable 
as an SAE dependent on clinical judgment.  In addition, where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedence. 
d. Results in persistent or significant disability / incapacity. 
Disability means a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
e. Is a congenital anomaly / birth defect. 
f. Is another medically important serious event as judged by the investigator. 
7.4.1.2 Classifications for adverse event assessment 
 
• Study treatment action 
 
• Other specific treatment of AE 
 
• Causal relationship to protocol-required procedures(s) 
 
• Outcome 
All unexpected and related grade 3 and 4 AEs will be assessed and documented in 
the MDACC AE log by the investigator according to the categories detailed below. 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial. 
 
7.4.1.2.1 Seriousness 


 
 
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An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
• Death 
• A life-threatening adverse drug experience 
• Any adverse experience that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse experience as it 
occurred.  It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• A congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
 
Important medical events as defined above may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND 
Sponsor, IND Office. 
 
All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for investigators on Reporting Serious 
Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
 


 
 
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• 
All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.   
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, unless 
the participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
 
• 
Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
 
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.4.1.1. 
7.4.1.2.2 Intensity 
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to 
the severity (intensity) of the AE: 
CTCAEv4 Grade 3: Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization is indicated; 
disabling; limiting to self care ADL (self care ADL refers to bathing, dressing 
and undressing, feeding self, using the toilet, taking medications, and not 
bedridden). 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is 
indicated. 


 
 
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CTCAEv4 Grade 5: death due to an AE. 
7.4.1.2.3 Causal relationship  
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information. 
The causality assessment should be done separately for each study treatment. 
The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. 
Possible answers are “yes” or “no”. 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at 
surgical site. 
or 
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; 
cancer developing a few days after the first drug administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is 
associated with the use of the study treatment. 
Factors to be considered in assessing the relationship of the AE to study treatment 
include: 
- The temporal sequence from drug administration:  The event should occur after 
the drug is given.  The length of time from drug exposure to event should be 
evaluated in the clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-
introduction (re-challenge): 
- Subject’s response after de-challenge or subjects response after re-challenge 
should be considered in the view of the usual clinical course of the event in 
question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course 
of the disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should 
be examined to determine whether any of them may be suspected to cause the 
event in question. 


 
 
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- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and 
excretion) of the study treatment, coupled with the individual subject’s 
pharmacodynamics should be considered. 
[Causal relationship to protocol-required procedure(s)] 
The assessment of a possible causal relationship between the AE and protocol-
required procedure(s) is based on the question whether there was a “reasonable 
causal relationship” to protocol-required procedure(s). 
Possible answers are “yes” or “no”. 
7.4.1.2.4 Action taken with study treatment  
Any action on study treatment to resolve the AE  may be documented using the 
categories listed below. 
 ־Drug withdrawn 
 ־Drug interrupted 
 ־Dose reduced 
 ־Dose not changed 
 ־Dose increased 
 ־Not applicable 
 ־Unknown 
7.4.1.2.5 Other specific treatment(s) of adverse events 
 ־None 
 ־Remedial drug therapy 
 ־Other 


 
 
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7.4.1.2.6 Outcome 
The outcome of the AE  may be documented as follows:  
 ־Recovered/resolved 
 ־Recovering/resolving 
 ־Recovered/resolved with sequelae 
 ־Not recovered/not resolved 
 ־Fatal 
 ־Unknown 
7.4.1.3 Assessments and documentation of adverse events 
7.4.1.4 Reporting of serious adverse events 
The definition of serious adverse events (SAEs) is given in Section 7.4.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports to the designated person. An isolated laboratory 
abnormality that is assigned grade 4, according to CTC definition, is not reportable 
as an SAE; unless the investigator assesses that the event meets standard ICH 
criteria for an SAE.  CTC grade 4 baseline laboratory abnormalities that are part of 
the disease profile should not be reported as an SAE, specifically when they are 
allowed or not excluded by the protocol inclusion/exclusion criteria.   
 
When required, and according to local law and regulations, serious adverse events 
must be reported to the Ethics Committee and Regulatory Authorities.  
 
All serious and unexpected adverse events should be reported to MD Anderson IRB 
and Bayer within 24 hours.  In the event of such an event, the investigator should 
refer to the Pharmacovigilance section of the contract for reporting procedures. 
 
The Investigator may report serious adverse drug reactions (SADRs) using 
either: 
 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
 
OR 
  
 A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be sent electronically to:  
 


 
 
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Electronic Mailbox:  
 
DrugSafety.GPV.US@bayer.com  
 
Facsimile:    
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare  
P.O. Box 1000  
Montville, NJ 07045-1000  
 
Address:    
 
340 Changebridge Road  
FDX or UPS only    
Pine Brook, NJ  07058  
 
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept:  
 
Phone:  
 
 
1-888-842-2937 
 
7.4.1.5 Expected adverse events 
For this study, the applicable reference document is the most current version of the 
investigator’s brochure (IB) / summary of product characteristics. 
Overview listings of frequent events that have occurred so far in the clinical 
development are shown in the current IB.  If relevant new safety information is 
identified, the information will be integrated into an update of the IB and distributed 
to all participating sites. 
The expectedness of AEs will be determined by the study physician according to the 
applicable reference document and according to all local regulations. 


 
 
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7.4.1.6 Adverse events of special safety interest:  
Since radium 223 dichloride is eliminated in the feces, but is an alpha emitter, 
feces containing the radiopharmaceutical can be safely disposed of by flushing 
down the toilet. If however there is ever an incident of placing the subjects excreta 
in the food of another person and the radiopharmaceutical is ingested (e.g. an 
alpha particle emitting special sandwich), this should be reported to the principal 
investigator and the principal investigator or designate should then determine 
whether the oral ingestion poses any safety risk (probably not) using gamma 
camera imaging to quantitate whether any significant bone absorption has 
occurred.  
Long-term growth monitoring (<18 years only)  
Patients with growth potential (e.g. epiphysis has significant uptake on the screening 
99mTcMDP scan) will have yearly growth monitored (and compared to weight and 
height vs weight percentile) for age until age 21 or no significant change of height is 
seen for 2 consecutive years- whichever is first.  
 
Any secondary malignancies or potential long-term (i.e. > 2 months) grade 3 or 
greater hematologic toxicities will also be reported to MD Anderson IRB and Bayer.  
 
Survival data will be reported yearly as long as MD Anderson Cancer Center IRB 
continuing review and yearly IND reporting is done.  Data concerning any expected 
unexpected or unusual bone toxicities (e.g. hardware failure, pathologic fracture of 
limb salvage bones) will be collected and reported annually. 
 
7.4.2 
Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject, or 
in his partner, during the subject’s participation in this study.  The report should be 
submitted within the same timelines as an SAE, although a pregnancy per se is not 
considered an SAE.   
For a study subject, the outcome of the pregnancy should be followed up carefully, 
and any abnormal outcome of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain 
similar information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 


 
 
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7.4.3 
Further safety 
Progressive disease 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE 
(i.e., hospitalization, disability, death, or important medical event), the signs and 
symptoms should be reported as an SAE and not the underlying progressive 
disease. 
Death 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the 
investigator will inform MD Anderson IRB and Bayer and record the cause of death 
in detail (using the SAE Form) within 1 working day. 
7.5 Other procedures and variables 
7.6 Appropriateness of procedures / measurements 
The assessments described in the previous sections are widely used and generally 
recognized as reliable, accurate, and relevant for determining the safety and efficacy 
of therapies in osteosarcoma. 
8. Statistical methods and determination of sample size 
8.1 Analysis sets 
 
Safety monitoring rule 
• Should DLTs occur in more than two patients at any time during the dose 
expansion phase clinical personnel and study investigators will meet and 
assess the attribution, severity and nature of the DLTs. No additional patients 
will be accrued until the data is reviewed and a decision is made to continue 
at the current dose or to de-escalate the prior dose as the dose for the 
expansion phase. This review and decision will be documented in writing. 
 
 
Monitoring of alkaline phosphatase 
• Alkaline 
phosphatase, 
a 
biomarker 
associated 
with 
osteosarcoma 
metastases, will be determined monthly before administration of each dose of 
Ra-223 dichloride.  The trend of improvement (or not) will be analyzed for a 
particular patient and number of patients in a cohort with improvement as a 
function of dose # will be analyzed.   
 
Imaging 


 
 
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• Nuclear 
Medicine 
Studies 
will 
use 
commercially 
available 
99mTc, 
18Flurodeoxyglucose and sodium 18Fluoride to image indicator lesions.  The 
trend of improvement (or not) in 99mTc-MDP on SPECT CT, 18FDG-PET-CT 
SUV, or Na18F SUV will be compared for study entry vs after dose #3 and 
study entry vs after dose #6 and after dose #3 vs after dose #6 will analyzed 
for a particular patient and number of patients in a cohort with improvement 
after dose #3 and dose #6 will be analyzed.   
 
• Analysis of lung metastases. Up to 3 measurable (1 cm or larger) indicator 
lesions seen on chest CT may be described at study entry and compared 
after dose #3 and dose #6. RECIST criteria (>20% increase in size) will be 
used as criteria for progression. Any change <20% or if size is <1 cm will not 
be used for “off study” progression criteria. 
 
• RECIST progression will determine progressive disease regardless of other 
imaging.  
 
 
8.2 Variables 
Hematologic data 
Alkaline phophastase (total) 
Quantitative imaging data 
8.3 Statistical and analytical plans: as above 
8.4 Planned interim analyses: yearly at time of IND review 
.  
8.5 Determination of sample size 
Dose escalation phase: 3 dose levels using standard 3+3 design (N=9) 
Cohort expansion N=6 


 
 
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9. Data handling and quality assurance 
9.1 Data recording 
It is the expectation that all data has source documentation available at the site.  The 
site must implement processes to ensure this happens.   
 DMI/CORe will be used as the electronic case report form for this protocol.  Protocol 
specific data will be documented in the medical record and then entered into the 
case report form.  
9.2 Monitoring : Data will be reviewed at each dose level, yearly when 
IND yearly review and IRB continuing review is submitted, and at 
completion of the cohort expansion  
9.3 Data processing: As per Biostatistics 
9.4 Audit and inspection 
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) 
are possible.  The investigator should notify Bayer immediately of any such 
inspection. 
9.5 Archiving 
Essential documents shall be archived safely and securely in such a way that 
ensures that they are readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in 
accordance with the maximum period of time permitted by the hospital, institution or 
private practice. 
10. 
 Premature termination of the study 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
- Safety findings from this study (e.g. SAEs) 
- Results of any interim analysis 
- Results of parallel clinical studies 
- Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 


 
 
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• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a 
reasonable time frame. 
The principal investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties. 
• All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study 
center; head of study center) must be informed as applicable according to 
local law. 
• In case of a partial study closure, ongoing subjects, including those in post 
study follow-up, must be taken care of in an ethical manner. 
Details for individual subject's withdrawal can be found in Section 5.2.1. 
11. 
 Ethical and legal aspects: IND  
11.1Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the investigator abide by 
Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in 
the Declaration of Helsinki.  The study will also be carried out in keeping with 
applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all 
participating centers before start of the study, according to GCP, local laws, 
regulations and organizations.  When necessary, an extension, amendment or 
renewal of the EC/IRB approval must be obtained and also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all 
aspects of study conduct; the investigator may not modify or alter the procedures 
described in this protocol.   
Modifications to the study protocol will not be implemented by the investigator 
without discussion and agreement by Bayer.  However, the investigator may 
implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior IEC/IRB/Bayer approval/favorable 
opinion.  As soon as possible, the implemented deviation or change, the reasons for 
it and if appropriate the proposed protocol amendment should be submitted to the 
IEC/IRB/head of medical institution.  Any deviations from the protocol must be 
explained and documented by the investigator. 


 
 
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The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and properly documented.  
Since this is an investigator initiated IND study at MD Anderson, Bayer will provide a 
letter of to authorize the FDA to cross-reference of its current IND and well as 
agreement to supply Ra-223 dichloride for the purposes of this study. The MD 
Anderson IND Office will assist the PI and study personnel in providing yearly IND 
update/submissions to the FDA also. 
11.2Subject information and consent 
Each subject / legal representative or proxy consenter will have ample time and 
opportunity to ask questions and will be informed about the right to withdraw from 
the study at any time without any disadvantage and without having to provide 
reasons for this decision. Subjects <18 years old will provide written assent. 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign 
the informed consent form and has done so, may he/she enter the study.  
Additionally, the investigator and other information provider (if any) will personally 
sign and date the form.  The subject / legal representative or proxy consenter will 
receive a copy of the signed and dated form.  
The signed informed consent statement is to remain in the investigator site file or, if 
locally required, in the patient’s medical record 
In the event that informed consent is obtained on the date that baseline study 
procedures are performed, the study record or subject’s clinical record must clearly 
show that informed consent was obtained prior to these procedures. 
 
1. If the patient is not capable of providing a signature, a verbal statement of 
consent can also be given in the presence of an impartial witness (independent of 
Bayer and the investigator).  This is to be documented by a signature from the 
informing physician as well as by a signature from the witness. 
2. For minors or adults under legal protection, consent shall be given by the legal 
guardian(s).  The consent of a minor or adult under legal protection shall also be 


 
 
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requested where such a person is able to express his/her own will.  His/her 
refusal or the withdrawal of his/her consent may not be disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the 
consent of the patient’s legal representative(s) or proxy consenter, if present, 
should be requested.  The patient should be informed about the study as soon as 
possible and his/her consent to continue the study should be requested. 
The informed consent form and any other written information provided to subjects / 
legal representatives or proxy consenters will be revised whenever important new 
information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of 
the subject information and / or the written informed consent form.  The investigator 
will inform the subject / legal representative or proxy consenter of changes in a 
timely manner and will ask the subject to confirm his/her participation in the study by 
signing the revised informed consent form.  Any revised written informed consent 
form and written information must receive the IEC/IRB`s approval / favorable opinion 
in advance of use. 
11.3Publication policy 
Bayer recognizes the right of the investigator to publish results upon completion of 
the study.  However, the investigator must send a draft manuscript of the publication 
or abstract to Bayer at least thirty days in advance of submission in order to obtain 
approval prior to submission of the final version for publication or congress 
presentation.  This will be reviewed promptly and approval will not be withheld 
unreasonably.  In case of a difference of opinion between Bayer and the 
investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties. All relevant aspects regarding data reporting 
and publication will be part of the contract between Bayer and the 
investigator/institution 
The Principal Investigator should ensure that the information regarding the study be 
publicly available on the internet at www.clinicaltrials.gov. 
11.4 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. 
Should direct access to medical records require a waiver or authorization separate 
from the subject’s statement of informed consent, it is the responsibility of the 
Investigator to obtain such permission in writing from the appropriate individual. 


 
 
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12. 
Reference list 
1. 
Bielack, S.S., et al., Second and subsequent recurrences of osteosarcoma: 
presentation, treatment, and outcomes of 249 consecutive cooperative 
osteosarcoma study group patients. J Clin Oncol, 2009. 27(4): p. 557-65. 
2. 
Bruland, O.S., et al., High-linear energy transfer irradiation targeted to skeletal 
metastases by the alpha-emitter 223Ra: adjuvant or alternative to 
conventional modalities? Clin Cancer Res, 2006. 12(20 Pt 2): p. 6250s-6257s. 
3. 
Anderson, P.M., et al., High-dose samarium-153 ethylene diamine 
tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with 
osteosarcoma and bone metastases. J Clin Oncol, 2002. 20(1): p. 189-96. 
4. 
Anderson, P.M., et al., Gemcitabine radiosensitization after high-dose 
samarium for osteoblastic osteosarcoma. Clin Cancer Res, 2005. 11(19 Pt 1): 
p. 6895-900. 
5. 
Anderson, P., Samarium for osteoblastic bone metastases and osteosarcoma. 
Expert Opin Pharmacother, 2006. 7(11): p. 1475-86. 
6. 
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13. 
Amendments 
13.1.1 So far none 
13.1.2 Overview of Changes 
13.1.3 Changes to the Protocol Text 
 
 
 
 
 
14. 
 Appendices- see PDOL 
15. Other References- in Section  1.3.1 and can be provided by Bayer  
                                                 
  1Report R-8662 
  2Report R-8663 
  3Int J Radiation Oncology 1991;21:361-367 
  4Cancer 2005;104:856-863 
  5Raabe C Health Phys 2010;98:515-536 


 
 
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