Clinical trial NCT01886105
Conditions: Metastatic Osteosarcoma
Keywords: Osteosarcoma Osteogenic Sarcoma Sarcoma Bone Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2013-08-19; Completion date: 2017-06-11
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary goal of this study will be to examine tumor response after radiation treatment via a combination of Samarium-153 EDTMP and external beam radiotherapy.

Detailed description:
Samarium tracer infusion of 1 mCi/kg administered. SPECT images wil be used to determine the distribution of dose delivered to the tumor. This information will be used to determine target doses of external beam radiotherapy. The treatment infusion of Samarium, 30 mCi/kg, will be administered and dosimetry will confirm total dose delivered, and information will be used to finalize doses of external beam radiotherapy. Approximately 14 days after treatment infusion, autologous stem cells infusion is administered. Radiotherapy will be delivered according to the judgement of the treating radiation oncologist.

Arms: arm 1: DAY 1 Tracer dose 153Sm-EDTMP administration (1 mCi/kg) SPECT/High-resolution CT at 4 hours. SPECT/CT (low resolution) at 24 and 48 hrs

DAY 7 Individualized treatment dose 153Sm-EDTMP administration (max 30 mCi/kg) SPECT scans at 4, 24 and 48 hours

DAY 21 (2 weeks following treatment dose) Auto-Stem cell infusion

DAY 40 (approx. two weeks after stem cell rescue) Initiate EBT upon count recovery

1 MONTH following completion of all therapy Response assessment with repeat imaging (CT/MRI, Tc-99m bone scan) 18F-MISO/FDG PET
Interventions: intervention 1: Sm-EDTMP intervention 2: Autologous Stem Cell Infusion intervention 3: External Beam Radiotherapy
Intervention descriptions: intervention 1: Subjects receive a "tracer" infusion of Samarium-153 EDTMP at 1 mCi/kg. 3D dosimetry using SPECT images are obtained post "tracer" infusion to determine the distribution of dose delivered to the tumor and surrounding normal tissues. "Tracer" activity will be applied to development of the external beam radiation (EBT) planning. Second "treatment" infusion of Samarium will then be implemented. Maximum activity administered will be 30 mCi/kg. intervention 2: Administered 14 days after "Treatment" infusion of Samarium-153 EDTMP. intervention 3: The radiotherapy portion of the combined plan will be delivered according to the judgement of the treating radiation oncologist. The total dose to be used will be modified based on surrounding tissue tolerances as evidenced by Samarium infusion and SPECT image planning.

After the "treatment" infusion, SPECT scans will again be performed to confirm the total dose delivered and subsequently adjust the EBT portion of the treatment plan, as necessary.

Protocol documents:
Prot_SAP_000.pdf: 
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Combination of External Beam Radiotherapy with 153Sm-EDTMP to Treat High Risk 
Osteosarcoma and Patients with Solid Tumors Metastatic to Bone 
 
Brian Ladle, MD, PhD 
Sidney Kimmel Comprehensive Cancer Center at 
Johns Hopkins University 
1650 Orleans St. 
Room 205 
Baltimore, MD 21287 
(443) 287-3534 
(410) 614-0549 (Fax) 
E-mail: bladle@jhmi.edu 
 
 
Co-investigators: 
George Sgouros, PhD 
Robert Hobbs, PhD 
Allen Chen, MD, PhD 
Stephanie Terezakis, MD 
Christian Meyer, MD, PhD 
Gary Rosner, ScD 
Marianna Zahurak, MS 
Christine Pratilas, MD 
 
 
IND: Exempt 
Coordinating Center: 
Johns Hopkins Medical Institution 
550 N. Broadway Room 409B 
Baltimore, MD 21205 
443-287-9377/ (F) 410-502-9933 
crocc@jhmi.edu 
 
Participating Sites: 
Dr. Cindy Schwartz, MD 
MD Anderson Cancer Center 
Division of Pediatrics 
1515 Holcombe Blvd 


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Houston, Tx 77030 
clschwartz@mdanderson.org 
 
Dr. Andreza Senerchia, MD 
GRAACC (Support Group for Children and Adolescents with Cancer) 
Rua Botucatu, 743- 
Vila Clementino-SP-CEP 04023-062 
andrezasenerchia@graacc.org.br 
 
 
 


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Table of Contents 
 
1.0      Title  
 
2.0      Schema 
 
3.0      Objectives 
 
4.0       Introduction 
 
5.0       Eligibility Criteria 
 
6.0       Treatment Program 
 
7.0       Toxicity and Complications 
 
8.0       Agent Information 
 
9.0       Treatment Evaluation 
 
10.0 
Serial Measurements 
 
11.0 
Statistical Considerations 
 
12.0 
Data Recording, Management, and Monitoring 
 
13.0 
Multicenter Guidelines 
 
14.0 
References 
 
 
 


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2.0 SCHEMA 
Study Screening/Consent/Enrollment 
H&P, labs, EKG, completion of standard imaging (Tc-99m bone scan, CT/MRI) 
18F-MISO/FDG PET (pre-treatment baseline) 
Radiation planning CT simulation 
 
Day 1 
Tracer dose 153Sm-EDTMP administration (1 mCi/kg) 
SPECT/High-resolution CT at 4 hours post dose 
SPECT/CT (low resolution) at 24 and 48 hrs post dose 
       
 
Day 8 
Individualized treatment dose 153Sm-EDTMP administration (max 30 mCi/kg)  
153Sm planar imaging of abdomen at 1 and 2 hours post dose 
SPECT scans at 4, 24 and 48 hours post dose 
 
 
Between Days 15-22 
Initiate external beam radiation therapy 
 
 
Day 24 Hematopoietic stem cell (HSC) infusion  
 
 
 
One month following completion of all therapy 
Response assessment with repeat imaging (CT/MRI, Tc-99m bone scan) 
18F-MISO/FDG PET 
This study will have 2 strata:  Stratum 1 is for patients with osteosarcoma.  Stratum 2 is for patients with 
other high risk solid tumors metastatic to bone. 
 


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3.0 OBJECTIVES 
3.1 PRIMARY OBJECTIVES 
 
3.1.1 (Stratum 1 Only)  
To assess the clinical response of high-risk osteogenic sarcoma to high-dose 153Sm-
EDTMP and external beam adiotherapy. 
 
3.1.2 (Stratum 2 Only) 
To estimate the response rate of diseases other than osteosarcoma to the combination of 
high-dose 153Sm-EDTMP and external beam radiotherapy. 
 
3.2 SECONDARY OBJECTIVES 
 
3.2.1 To describe the toxicity and long-term effects of combined infusional 153Sm-EDTMP and 
external beam radiation therapy.   
 
3.2.2 To image tumors using [18F]Fluoromisonidazole (18F-MISO) PET scanning before and 
after treatment, and compare with clinical response as measured by radiographic imaging 
and/or histology.   
 
3.2.3 To describe the distribution of absorbed doses delivered to each targeted lesion and the 
distribution of lesion equivalent uniform dose delivered to each patient. 
 
3.2.4 To determine dosimetry measurements after initial tracer dosing, predict target total 
radiation exposure to tumor based on linear kinetics previously described, and calculate a 
subsequent combined treatment dose. 
 
3.2.5 Stratum 1 Only 
To observe overall survival and time to progression in patients treated with combined 
infusional 153Sm-EDTMP and external beam radiation therapy, and model any relationship 
between total absorbed dose and progression.   
 
 
 
4.0 INTRODUCTION 
4.1 GENERAL BACKGROUND 
Cure of osteogenic sarcoma relies on both definitive control of gross tumor masses and 
on effective treatment of micrometastatic disease. While systemic chemotherapy can be effective 
in the control of micrometastases, surgery is usually required to treat gross disease.  Osteogenic 
sarcoma is relatively resistant to radiation therapy, limiting the utility of this treatment modality 
for local control.  A mechanism to deliver radiation therapy at a high enough dose to be 
tumoricidal while sparing surrounding normal tissue would allow the incorporation of radiation 


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into the therapeutic armamentarium when up-front surgery is not feasible. In the event of good 
tumor shrinkage, this might allow for subsequent surgical intervention or other localized therapy 
such as cryoablation. 
Studies of radiation therapy in osteogenic sarcoma were performed prior to 1980, and 
demonstrated that doses in the range of 66-80 Gy are required for a therapeutic response. Several 
studies point out that administration of less than 60 Gy is associated with only transient tumor 
control, and viable tumor has been found in amputation specimens even after treatment with 80 
Gy or more (1-3).  These doses are quite difficult to deliver using standard external beam 
radiation without exceeding the tolerance of surrounding normal tissue.  Because of this, 
standard treatment regimens for osteogenic sarcoma do not incorporate radiation therapy.  Even 
modern conformal techniques, such as intensity-modulated radiation therapy (IMRT) are of 
limited utility in the setting of multiple metastases, and are unable to treat micrometastatic 
disease. This is a hindrance to the cure of patients with multiple sites of metastatic disease or 
with unresectable tumors for which surgery will not provide complete control of gross disease. 
Targeted radioisotope delivery has been pursued as an alternative to external beam 
radiotherapy for osteogenic sarcoma or to supplement external beam radiotherapy. One of the 
most promising agents being developed for this purpose is 153Samarium 
ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP). This compound localizes to 
sites of new bone formation similar to technetium-99m methylene diphosphonate (99mTc-MDP) 
bone scintigraphy.  The EDTMP moiety is structurally related to the chelating agent methylene 
diphosphonate that is complexed to technetium-99 for conventional bone imaging.  This allows 
the delivery of radiotherapy to osseous metastatic lesions visible on conventional bone scan (4). 
A medium energy photon given off by the 153Sm-EDTMP allows for standard scintigraphic 
scanning to monitor the delivery of radiation to the tumor.   
Other characteristics of 153Samarium that make it of interest in the treatment of 
osteogenic sarcoma are the emission of tumoricidal beta radiation and a relatively short half-life. 
The tumoricidal beta radiation of 153Samarium is emitted at maximum energies of 640, 710, and 
810 keV (32.2%, 49.6%, and 17.5% respectively) with an average beta particle energy of 233 
keV. These particles penetrate tissue only over a relatively short distance of 1-2 mm, allowing 
the delivery of high doses of radiation to the tumor while sparing surrounding normal tissue. 
153Samarium has a half-life of 46 hours, but that portion of the drug not complexed to bone is 
completely eliminated through the kidneys within 6 hours of administration.   
 
4.2 ANIMAL STUDIES 
 
The efficacy of 153Sm-EDTMP has been demonstrated in both murine and canine models 
of osteogenic sarcoma.  Winderen et al. reported that 153Sm-EDTMP could effectively treat 
orthotopic human osteosarcoma implanted in immunodeficient mice (5).  Early studies with 
canine osteogenic sarcoma showed that 153Sm-EDTMP caused a period of reversible 
pancytopenia. Subsequently, forty dogs with spontaneous osteogenic sarcomas were treated with 
one or two doses of 1 mCi/kg 153Sm-EDTMP.  Small lesions, metastatic lesions, and lesions of 
the axial skeleton responded well, while large lesions with minimal tumor bone formation 
responded poorly (6). The major toxicity was hematopoietic. In another study of canine 
osteosarcoma, there was a complete remission in 1 of 9 dogs treated with 1 mCi/kg (7). A 
dosimetry study in this animal model system showed that approximately 20 Gy were delivered to 
bone tumors by administration of 1-1.5 mCi/kg 153Sm-EDTMP (8). 


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4.3 HUMAN STUDIES 
 
153Sm-EDTMP is licensed by the Food and Drug Administration for the treatment of 
disseminated skeletal metastases from prostate and breast cancer.  In a Phase I trial of adult 
patients treated with doses anticipated to deliver up to 280 cGy to sites of disease, pain relief was 
noted in 22 of 34 patients with skeletal metastases, and stabilization or regression of the 
metastatic lesions occurred in 15 of 34.  The only side effect was myelosuppression (9).  In a 
Phase II study, also of adults, pain relief was noted in 14 of 23 patients, with toxicity limited to 
myelosuppression (10). Similar results were achieved in a Phase I/II trial of 52 patients with 
prostate cancer who received doses of 0.5 – 3.0 mCi/kg (11). 
The first report of a patient treated for osteogenic sarcoma with 153Sm-EDTMP was 
published in 1996. A 35-year-old man with a primary osteogenic sarcoma of the first lumbar 
vertebra had a local relapse with significant pain and neurologic dysfunction related to spinal 
cord compression.  He was treated with 2 doses of 153Sm-EDTMP, 8 weeks apart, at 
approximately 1 mCi/kg per dose.  He had significant, though transient (6 months), improvement 
in neurologic function and resolution of his pain (12).  Additionally, a group from Munich 
reported their results treating 6 patients who had unresectable localized or metastatic osteogenic 
sarcoma with a combination of multi-agent chemotherapy, 153Sm-EDTMP, and external beam 
radiation. The 3 patients treated with all of these agents (chemotherapy, 153Sm-EDTMP, and 
external beam radiation) had responses, including one 3-plus year survivor (13).  
A report from the Mayo Clinic described the results of a Phase I trial of high dose 153Sm-
EDTMP in patients with metastatic osteogenic sarcoma using stem cell support to bypass dose 
limitations imposed by myelosuppression, which was the sole toxicity reported. Thirty patients 
were treated, and all of them had either a reduction in opiate requirement or complete resolution 
of their pain. The maximally tolerated dose on that study was 30 mCi/kg. This group measured 
the dose of radiation delivered to the tumor, and found that dose delivered correlated with the 
dosage of 153Sm-EDTMP administered (14).   
Our group has recently completed a two-phase study of eleven heavily pre-treated 
patients with osteosarcoma, who received tandem dosing of 153Sm-EDTMP (15-16).  With 
regards to patient outcome, though the study was terminated early based on protocol definition of 
clinical response, six patients showed radiographic stabilization. Toxicity was limited to 
hematologic suppression, manageable with stem cell transfusion support.  We demonstrated that 
the total dose delivered to the tumor site with the initial “tracer” administered activity, and the 
subsequent higher, “treatment” administered activity displayed a strictly proportionate, linear 
relationship within each patient.  Using this relationship, we plan to calculate the “treatment” 
administered activity necessary to achieve a planned total dose to tumor based on dosimetry 
mapping of the initial “tracer” activity.  This allows a more accurate calculation and prediction of 
tumor exposure from a given infusion of 153Sm-EDTMP.   
These studies suggest that a significant quantity of 153Sm-EDTMP can be given with 
manageable toxicity, and that treatment infusion needed to reach a planned total dose delivered 
to the tumor site can be predicted based on an individual patient’s dosimetry results after the 
initial tracer dose.  Depending on the individual patient’s total dose exposure, we could then 
combine 153Sm-EDTMP treatment with supplemental external beam radiation therapy.  A recent 
paper reported that reasonable response times >3-5 years resulted with mean radiation dosing of 
68.4 Gy (17).  With tumoricidal dosing estimated to be 70-75 Gy, a proportion of this could be 


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given infusionally as 153Sm-EDTMP, potentially decreasing the intensity of external beam 
radiation therapy needed to reach these target doses and minimizing local tissue damage.   
The primary goal of this study will be to examine tumor response after radiation 
treatment via a combination of 153Sm-EDTMP and external beam radiotherapy.  A well-
described characteristic of calcified osteogenic sarcoma lesions, as well as many bony 
metastases, is that despite necrosis or lack of viable tumor being detectable on histologic 
analysis, the tumor frequently does not shrink by radiographic imaging.  Therefore the major 
clinical endpoint in evaluating clinical response will be lack of progression (stable disease or 
better by RECIST criteria).  The favorable, manageable toxicity profile of 153Sm-EDTMP would 
meet the needs of our study population of poor-risk, heavily pre-treated patients who might not 
otherwise be candidates for additional toxic therapy.  This novel strategy of combined infusional 
and external-beam radiotherapy might prove to be an effective means for local control and offer 
significant clinical benefit.     
 
4.4 HYPOXIA AND [18F] FLUOROMISONIDAZOLE (18F-MISO) PET  
 
Hypoxia has been demonstrated in solid tumors and has been shown to be associated with 
resistance to chemotherapy, as well as potentially contributing to a more aggressive and invasive 
phenotype.  One of the key players thought to orchestrate these changes is hypoxia inducible 
factor 1-alpha (HIF1-α), which acts as a transcription factor inducing production of numerous 
proteins that alter microenvironment and promote growth, neoangiogenesis, and invasion.  Yang 
et al investigated HIF1-α expression in osteogenic sarcoma, and noted that 80% of tumors 
expressed HIF1-α, with increased microvessel density, a marker for hypoxia and likely resultant 
angiogenesis within tumor tissue (18).  [18F]-MISO PET scanning has been described in the 
literature as a tool to measure hypoxic areas in tumors (19).  [18F]-MISO accumulates in viable 
tissues preferentially when pO2<10 mmHg and is dependent on nitroreductase activity within the 
cell.  It is not dependent on blood flow, and is not retained in necrotic tissue.  Studies have 
demonstrated changing hypoxia status in irradiated non-small cell lung cancer using this 
modality, as well as several papers in soft tissue sarcoma and head and neck cancers (20-24).   
In our previous work, we demonstrated that changes in SUVmax measured by traditional 
FDG-PET scanning did not correlate with response to therapy.  This suggests that FDG-PET 
may underestimate treatment response, possibly due to post-therapy inflammatory changes.  Our 
interest in using [18F]-MISO PET is two-fold.  Our main question is whether tumors with higher 
[18F]-MISO PET indices prior to treatment (increased hypoxia) might display less response to 
our proposed radiation therapy, which might ultimately allow us to predict patients likely to 
benefit.  We also will investigate whether an improvement in oxygenation status (decrease in 
[18F]-MISO indices) following treatment might correlate with histologic response to therapy 
given the lack of uptake demonstrated in necrotic tissue.  In an effort to improve sensitivity of 
the [18F]-MISO assessment of hypoxia and ensure attention to tumor volumes, we will combine 
the imaging with traditional [18F]-FDG PET.   
 
5.0 ELIGIBILITY CRITERIA 
5.1 INCLUSION CRITERIA 
 
5.1.1 Subjects will be between 10 and 65 years of age, inclusive.   
 


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5.1.2 Patient must have unresectable primary tumor or metastases (including tumors with an 
intralesional resection.) 
 
 
 
5.1.2.1 For Stratum 1, patients must have a confirmed histologic diagnosis of 
osteosarcoma.    
 
 
5.2.1.2 For Stratum 2, any histologically confirmed solid tumor diagnosis is eligible. 
 
5.1.3 Patients must have measurable disease that is avid for phosphonate compounds as 
demonstrated by a positive Tc-99m bone scan. Not all lesions must be 
positive on bone scan. 
 
5.1.4 Adequate organ function: 
 
5.1.4.1 Adequate renal function, defined as a measured creatinine clearance >70 
ml/min/1.73 m2 or normal radioisotope GFR. 
5.1.4.2 Adequate hematologic function, defined as a platelet count >50,000/mm3 and an 
absolute neutrophil count > 500/mm3 
 
5.1.5 Life expectancy of > 8 weeks 
 
5.1.6 Karnofsky performance status > 50% 
 
 5.1.7 Patients must have recovered from the effects of any prior chemotherapy, as determined by 
the treating physician and studyteam, based in part on organ function defined 
above.   
 
5.1.8 A stem cell product collected prior to the infusion of 153Sm-EDTMP must be available, 
either by peripheral stem cell mobilization or bone marrow harvest prior to trial 
entry.  A minimum of 2 x 106 CD34+ cells/kg ideal body weight is required.   
 
5.1.9  The patient and/or the patient’s legally authorized guardian must acknowledge in writing 
that consent to become a study subject has been obtained, in accordance with institutional 
policies approved by the U.S. Department of Health and Human Services. 
 
5.2 EXCLUSION CRITERIA 
 
5.2.1 Patients must not be pregnant or breastfeeding. Sexually active patients are strongly advised 
to use accepted, effective forms of contraception. 
 
5.2.2 Patients who have received prior radiotherapy to all areas of current active disease are 
ineligible. 
 
5.3 INFORMED CONSENT  
 
Informed consent will be obtained from the parents or legal guardian of minor children. 
Patients over the age of 18 years will provide their own informed consent.  Either assent or 


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consent will also be obtained at a developmentally appropriate level from subjects that are 
minor children. 
 
5.4 REGISTRATION 
 
To register a patient, the following documents should be completed by the Research Nurse or 
Study Coordinator and faxed (410-502-9933) or emailed (crocc@jhmi.edu) to the 
Coordinating Center: 
 Fax cover sheet 
 Registration form 
 Signed patient consent form 
 HIPAA authorization form 
 Eligibility screening checklist 
Copy of required screening tests and scansThe Coordinating Center will then verify eligibility and 
complete the registration process, by: 
 Assigning a patient study number 
 Registering the patient on the treatment portion of the study with the Sidney Kimmel 
Comprehensive Cancer Center’s Clinical Research Office 
 Faxing or e-mailing the patient study number to the participating site 
 Calling or e-mailing the research nurse or data manager at the participating site, verbally 
confirming registration and the last eligible start date for treatment. 
 
6.0 TREATMENT PLAN 
 
6.1 PRETREATMENT EVALUATION 
 
6.1.1 History and physical examination, including symptoms, height, weight, and body surface 
area 
 
6.1.2 Laboratory evaluation, including CBC with differential and platelet count, comprehensive 
metabolic panel, urinalysis, 24-hour urine for creatinine clearance, phosphorus, 
magnesium, LDH, serum C-telopeptides (JHH Pathology test code 6315) and parathyroid 
hormone. Alkaline phosphatase and LDH will be fractionated if elevated to determine the 
contribution of bone isoforms (Quest referral tests).  
 
6.1.3 Radiographic evaluation: chest X-ray, Tc-99m bone scan, and other imaging that may 
include CT, MRI, and/or PET/CT scans of primary tumor and any large metastases.   
 
6.1.4 Cardiac evaluation:  baseline EKG to be obtained prior to treatment.   
 
6.1.5 As part of the study protocol, subjects will undergo a pre-treatment [18F]-MISO/[18F]-FDG  
whole body PET scanning as delineated in section 6.2.4.  6.2 OVERALL TREATMENT 
PLAN 
 


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This is a treatment protocol to establish the safety and efficacy of radiation therapy 
consisting of high-dose 153Sm-EDTMP and external beam radiotherapy for the treatment of 
high-risk osteogenic sarcoma and solid tumors with bony metastases. The primary endpoint 
will be clinical response of tumor lesions, defined as either stable disease or decrease in the 
size of the tumor by radiographic imaging (which may include CT or MRI) using RECIST 
1.1 criteria.  Progression will be defined as appearance of new lesions or expansion of 
current lesions by 20% as per RECIST 1.1 criteria.  In some patients, additional information 
on clinical response may be obtained from histology (percent tumor necrosis) in cases where 
patients proceed to resection or biopsy following radiation therapy. Other treatment 
endpoints include progression-free and overall survival.  We will obtain post-treatment 
[18F]-MISO and [18F] FDG PET scans to be analyzed but these images will not be used to 
define clinical response. 
The first administered activity of 153Sm-EDTMP will be a low “tracer” infusion 
administered at 1 mCi/kg on Day 1.  Using the 3-dimensional dosimetry package 3D-RD, we 
will perform three-dimensional dosimetry using SPECT images after administration of the 
“tracer” activity to determine the distribution of dose delivered to the tumor and the 
surrounding normal tissues.  As quickly as feasible (goal is within seven days), using the 
dosimetric results from the tracer administration, a combined treatment plan will be 
designed aimed at delivering the target dose to the entire tumor.  This plan will be designed 
using methodology uniquely available at Hopkins (3D-RD software); we will import the 3-
dimensional absorbed dose map resulting from 153Sm-EDTMP therapy, adjusted to 
correspond to the fractionation schedule used in external beam radiotherapy, into the 
external beam planning system (Pinnacle), by fusing (registering) the SPECT/CT and 
absorbed dose map with the external beam planning CT, allowing a treatment plan to be 
generated from the combination of (1) scaling of the tracer absorbed dose map to the 
requisite 153Sm therapeutic activity and (2) external beam fields designed to optimally 
complement the radiopharmaceutical absorbed dose map to deliver a target of 75 Gy to each 
and every tumor voxel while respecting normal organ constraints (25).     
The first portion of the combined plan, that is, the second, “treatment” 153Sm-EDTMP 
infusion, will then be implemented on Day 8. Maximum activity administered will be 30 
mCi/kg, which is the maximally tolerated dose permitting recovery of myelosuppression 
with auto-stem cell infusion (14).  After the “treatment” infusion, SPECT scans will again 
be performed to confirm total dose delivered and subsequently adjust the external beam 
portion of the treatment plan, as necessary.  External beam radiotherapy will begin as early 
as possible between Days 15 and 22.  The total dose to be used will be modified based on 
surrounding tissue tolerances.  On Day 24, previously harvested autologous peripheral blood 
or bone marrow stem cells will be infused in order to ameliorate the expected 
myelosuppression.  External beam radiation therapy will not be administered on Day 24 
(anticipated to be a Friday), nor on Days 25 or 26, in order to provide time for infused 
hematopoietic stem cells to home to the bone marrow and leave the circulation.  
 
 Patients will be reimaged one month following completion of external beam radiation by 
CT/MRI for evidence of clinical response (defined as stable disease or better by RECIST 
1.1 criteria) or disease progression.  In the event of progression of a single lesion, local 
therapy such as radiofrequency ablation or cryoablation may be provided so that the 
response of stabilized lesions can continue to be monitored.  If suspicious lesions remain on 


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thoracic CT scan or on MRI of the primary site after the completion of therapy, further 
evaluation by biopsy may be clinically indicated, and potentially surgical intervention 
pursued if persistent disease is found. Percent necrosis of any resected tumor will be 
evaluated pathologically.  
 
6.2.1 Stem cell collection  
 
Although ifosfamide mobilization is preferred, any method for obtaining autologous 
hematopoietic stem cells (HSC) is acceptable.  The timing of stem cell collection is at the 
discretion of the treating physician, as long as stem cells are collected prior to 
administration of 153Sm-EDTMP. 
 
Recommended, but not required, approach if prior collection not available and no evidence 
of Ifosfamide resistance:  Peripheral blood stem cells will be collected as per standard 
protocols after a cycle of Ifosfamide given as a single agent, at a dose of 3 g/m2/day for 5 
days with MESNA. The MESNA will be administered according to institutional standards.   
 
G-CSF will be administered daily upon completion of the chemotherapy at a dose of 10 
μg/kg/day subcutaneously.   Peripheral blood CD34+ cell count will be monitored daily 
beginning on Day 7 after chemotherapy is completed, or when ANC begins to rise, and 
pheresis will be performed when indicated.  
 
Collection of 5 x 106 CD34+ cells/kg will be the goal, with the product split into 2 aliquots 
and stored frozen until needed. If more than 6 x 106 CD34+ cells/kg are collected, three 
aliquots will be stored. Pheresis on consecutive days will be performed if necessary to meet 
this target.  A minimum collection of 2 x 106 CD34+ cells/kg will be required for treatment 
with 153Sm-EDTMP.   
 
If peripheral stem cell collection is not feasible or cell mobilization is inadequate, bone 
marrow harvest in the operating room under general anesthesia will be an alternative source 
and may be performed as per standard protocols.   
  
6.2.2 Radiation Dosimetry 
 
153Sm SPECT/CT imaging with the CT acquisition in high resolution mode will be 
collected at approximately 4 hours after infusion of the “tracer” dose; SPECT/CT imaging 
with CT acquisition in attenuation correction (low-res.) mode will be performed at 24 and 
48 hours post-infusion to determine the absorbed dose for a given administered activity of 
153Sm-EDTMP.  The 24 and 48 hour post-infusion SPECT/CT scans can be obtained any 
time one and two days after treatment, as long as the specific number of hours post-
infusion is recorded.  We will use the in-house developed software package, 3D-RD, to 
calculate lesion absorbed dose maps that will be transferred to the external radiotherapy 
software so that a combined radiotherapy treatment plan is generated.   The combined 
treatment plan will be used to determine the administered activity and external beam 
radiation needed to deliver a total combined, absorbed dose 75 Gy to the lesion while 
respecting toxicity constraints to adjacent dose-limiting tissues.  This approach is based on 


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previous studies showing that lesion absorbed scales with administered activity (16).  We 
have also demonstrated the ability to adjust for dose rates by using the biologic effective 
dose (BED) formalism and thereby incorporate radiopharmaceutical therapy into an 
external radiotherapy treatment plan (25-26).  153Sm planar imaging of the abdomen will be 
performed at 1 and 2 hours after the “treatment” infusion to allow an assessment of 
radiation delivered to kidneys.  SPECT/CT imaging will also be collected at three later 
time-points after the “treatment” administration: approximately 4 hours, 24 hours, and 48 
hours.  The 24 and 48 hour post-infusion scans can again be obtained at any time on the 
first and second day after treatment, as long as the specific number of hours post-infusion is 
recorded.  If lesion dosimetry from the therapy study is inconsistent with the low dose 
projection, the combined treatment plan will be revised accordingly.  This treatment dose 
will not exceed 30 mCi/kg, the dose previously delineated by Anderson, et al as the 
maximally tolerated dose for reversible hematologic toxicity (14).   
 
Based on experience and patient tolerability, the number and frequency of SPECT/CT 
scans may be modified over the course of the trial.   
 
6.2.3 Autologous Peripheral Blood Stem Cell or Bone Marrow Infusion 
 
Sixteen days after administration of the treatment dose of 153Sm-EDTMP, autologous 
peripheral blood stem cells or bone marrow will be reinfused according to standard 
institutional protocols.    
 
6.2.4. Acquisition of [18F]-MISO/ [18F]-FDG PET imaging 
 
We plan to obtain investigational imaging of tumor hypoxia using [18F]-MISO in 
combination with traditional [18F]-FDG PET imaging.   Following treatment, we will 
analyze the [18F]-MISO PET data to determine any correlation to clinical response defined 
by traditional RECIST criteria with CT/MRI imaging, and percent necrosis as determined 
by histology as detailed in section 10.1.     
 
Protocol:  Patients will undergo FDG-PET/CT according to standard protocols, and [18F]-
MISO PET scanning as per the described protocol (21).  Images will be compared side-by-
side to ensure accurate inclusion of tumor fields, as described by Rajendran (23).  Four 
venous blood samples will be collected five minutes apart to normalize Tumor/Blood 
ratios as described in reference 23.  Additionally, ratios between tumor and contralateral 
soft tissue, as well as tumor/adjacent muscle will be obtained.  Ratios of greater than 1.2 
will be considered hypoxic. Ratios will be converted to milliliter volume to measure 
hypoxic tumor volume.  We will discount any lesions occurring in the liver or bladder 
from study due to inaccurate readings previously reported.     
 
6.2.5 Planning and administration of external beam radiation therapy 
 
Initial planning CTs for radiation therapy will be performed just prior to initiation of 
therapy.  After each samarium infusion, if tolerable, the patient will be placed in a 
reproducible treatment position using an appropriate immobilization device based on 
treatment site while data from SPECT/CT is obtained.  Alternatively, the two CT 


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components will be co-registered and combined fields generated.  Subsequent radiation 
therapy will be planned to reach a total minimum dose to tumor of 75 Gy as described (25).  
The dose of supplemental EBRT will be decided after determination of the EBRT dose 
equivalent delivered by the 153Sm in order to reach a total minimum dose to the gross tumor 
volume (GTV) of 75 Gy. GTV will be defined as gross tumor on the two planning CT 
scans. A margin of 1.5 cm will be added to the GTV to create a clinical target volume 
(CTV) which will be modified to exclude adjacent normal tissues that are not involved by 
tumor. An additional margin of 5 mm-1 cm will be placed around the CTV to create a 
planning target volume (PTV) and will be dependent on treatment site and immobilization 
technique.  
 
Conformal techniques such as intensity-modulated radiotherapy (IMRT) or tomotherapy 
will be used to plan the supplemental EBRT. The goal will be to achieve a target 
supplemental EBRT dose coverage of D95>95% to the PTV. Normal tissue dose 
constraints based on QUANTEC will be applied and respected.   Standard protocols apply 
for supportive care based on site irradiated, and toxicity will be closely documented.    
 
6.3 ON-STUDY EVALUATION 
 
6.3.1 Dosimetric studies by 153Sm SPECT/CT to be assessed at approximately 4, 24, and 48 
hours after injection of tracer dose of 153Sm-EDTMP; SPECT/CT will also be collected at 
approximately 4, 24, and 48 hours following the therapeutic administration of 153Sm-
EDTMP.  Scans can be obtained at any time on the first and second day after infusion of 
153Sm-EDTMP, as long as the specific number of hours post-infusion is recorded. 
 
6.3.2 Complete evaluation, including history and physical exam, vital signs, weights, and 
laboratory evaluation including complete blood counts and a complete metabolic panel, Mg 
and Phosphorous to be performed weekly until hematopoietic recovery and until recovery 
from therapy-related toxicities. 
 
6.3.3 Because of the risk of renal and bladder toxicity from the excretion of 153Sm-EDTMP that 
is not adsorbed to tumor, care will be taken to monitor patients closely for urinary tract 
toxicity. Prior to treatment, patients will have a complete urinalysis, measurement of BUN 
and creatinine, and 24- hour urine collection for creatinine clearance. These tests will be 
repeated as clinically indicated based on urinary symptoms and at the completion of 
therapy.   
 
6.3.4 Restaging evaluation to include radiologic imaging by CT or MRI of the primary tumor 
and metastases, follow up [18F]-MISO/[18F]-FDG PET, plain radiographs of primary lesion, 
and Tc-99m bone scan.  These studies will occur approximately one month after 
completion of external beam radiotherapy.  Based on our prior experience with [18F]-FDG 
PET and the lack of correlation between clinical response and SUV levels, we will not use 
[18F]-MISO/[18F]-FDG PET SUVmax measurements to determine clinical response while 
the patient is receiving treatment.   
 


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6.3.5 CT scan of chest and Tc-99m bone scan every 4 months after completion of therapy for one 
year, then every 6 months for 1 year, and then yearly for 3 years. Thereafter scans will be 
repeated only as clinically indicated. 
 
6.3.6 Evaluation for long-term skeletal toxicity will be performed every 6 months for the first 4 
years after completion of therapy, and will include alkaline phosphatase and LDH (bone 
fractions), serum C-telopeptide and parathyroid hormone levels, and bone density scans. 
 
6.3.7 If any lesions are resected after patient has completed radiation therapy, percent necrosis 
will be determined by the pathologist and recorded. 
 
 
 


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6.4 Schedule of Assessments 
Table 1.  Schedule for On-Study Patient Evaluations.   
(Note this does not include additional clinically appropriate testing in the setting of stem cell 
rescue and routine monitoring while on external beam radiation therapy.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation 
PreTx1
1st Sm 
2nd Sm 
External Beam Radiati
Week 
‐3‐ 0 
1 
2 
3 
4 
5 
> 5
1st Day of Week 
‐21 ‐ 0 
1 
8 
15 
22 
24 
29 
H&P, Vital signs and Wt   
x 
x 
x 
X3 
x 
 
x 
Ht and BSA (baseline only) 
x 
 
 
 
 
 
 
CBC 
x 
 
x 
x3 
x 
 
x 
CMP  
x 
 
x 
x3 
x 
 
x 
Ca/Phosphorus/Mg 
x 
 
x 
x 
x 
 
x 
Alk Phos4, LDH4 
x 
 
 
 
    
 
 
C‐telopeptides (JHH Path test code 6315) + PTH 
x 
 
 
 
 
 
 
Ionized Ca level5 
 
x 
x 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
Creatinine Clearance6 
x 
 
 
 
 
 
 
Hematopoietic stem cell (HSC) collection7 
x 
 
 
 
 
 
 
EKG8 
x 
x 
x 
 
 
 
 
Chest X‐ray 
x 
 
 
 
 
 
 
CaCO3 (oral) 
 
X9 
X9 
 
 
 
 
Mycotic disease prophylaxis10(oral) 
 
x 
x 
x 
x 
x 
x 
Pneumocystis carinii pneumonia prophylaxis11(oral) 
 
x 
x 
x 
x 
x 
x 
Stem Cell Infusion 
 
 
 
 
 
x 
 
Rad Onc Planning CT 
x12 
 
 
 
 
 
 
153Sm planar imaging  of abdomen  
 
 
x13 
 
 
 
 
SPECT/CT 
 
X14 
x14 
 
 
 
 
CT/MRI15 
x 
 
 
 
 
 
 
CT chest 
 
 
 
 
 
 
 
99mTc‐Bone Scan 
x 
 
 
 
 
 
 
Plain radiographs of primary lesion
no 
 
 
 
 
 
 
18F‐FDG PET/CT 
x 
 
 
 
 
 
 
18F‐MISO PET 
x 
 
 
 
 
 
 


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Table 1 Footnotes: 1 Pre-treatment radiographic evaluation must be obtained within 3 weeks of study entry.  Pre-
treatment laboratory studies must be obtained within 2 weeks of study entry.  Blood tests need not be repeated prior 
to first 153Sm-EDTMP treatment. 
2 Start between D15 and D22 
3 Weekly H&P, labs til CBC and AE recovery 
4 Alk phosphatase and LDH will be fractionated if elevated. (Quest lab referral tests) 
5 Check prior to administration of 153Sm-EDTMP 
6 Measured creatinine clearance or nuclear medicine GFR. Do not use calculated creatinine clearance.  
7 Ifos + Mesna x 5 days recommended. Peripheral CD-34 cell count done daily starting at chemo D7 until high 
enough for pheresis.  
8 Obtain at screening, pre and at completion of 153Sm-EDTMP infusions on Days 1 and 8. 
9 CaCO3 to be administered prior to 153Sm-EDTMP; 1000 mg calcium carbonate the morning of each samarium 
infusion  
10 Days 1-75 
11 From Day 1 until 6 months after completion of therapy 
12 Timing of Rad Onc Planning CT relative to study entry at discretion of treating physician, and coordinated by 
Radiation Oncology. 
13 153Sm planar imaging of the abdomen will be performed at 1 and 2 hours after the “treatment” infusion. 
14 SPECT/CT scans to be obtained after 153Sm-EDTMP infusions at approximately 4, 24, and 48 hrs post each 
injection of 153Sm-EDTMP. The 24 and 48 hour post- infusion SPECT/CT scans can be obtained any time one and 
two days after treatment, as long as the specific number of hours post-infusion is recorded.        
15 Choice of imaging modality and location as clinically indicated.  To include primary tumor and any large 
metastases.   
16 Four tubes of venous blood drawn 5 minutes apart; drawn only in conjunction with FMISO PET scans, and are to 
be processed by nuclear medicine as a part of that scan protocol.   
 
 


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T
a
b
l
e
 
2
 
F
o
o
t
n
o
t
e
s
:
  
1
 
W
e
e
k
ly H&P, labs til CBC and AE recovery 
2 Alk phosphatase and LDH will be fractionated if elevated. (Quest lab referral tests) 
3 Measured or nuclear medicine GFR  
4 Days 1-75 
5 From Day 1 until 6 months after completion of therapy.  
6 Choice of imaging modality and location as clinically indicated.  To include primary tumor and any large 
metastases.   
 
 
 
Table 2.  Schedule for Post Treatment and Follow Up Patient Evaluations 
Evaluation 
Post Tx Assessment 
(30 days after final tx) 
Months post End
4 
6 
8 
12 
18 
H&P, Vital signs and Wt    
x 
x 
x 
x 
x 
x 
CBC1 
x 
x 
x 
x 
x 
x 
CMP1  
x 
x 
x 
x 
x 
x 
Phosphorus, Mg 
x 
x 
x 
x 
x 
x 
Alk Phos2,  LDH2 
x 
 
x 
 
x 
x 
C‐telopeptides (JHH Path test code 6315) 
x 
 
x 
 
x 
x 
PTH 
x 
 
x 
 
x 
x 
Bone density scan  
 
 
x 
 
x 
x 
Urinalysis 
x 
 
 
 
 
 
Creatinine Clearance 3 
x 
 
x 
 
x 
x 
Chest X‐ray 
 
x 
 
x 
x 
x 
Mycotic disease prophylaxis4 
     x (thru D75) 
 
 
 
 
Prophylaxis for Pneumocystis carinii pneumonia (PCP)5 
x 
x
x
 
 
 
CT/MRI6 
x 
x 
 
x 
x 
x 
CT chest 
 
x 
 
x 
x 
x 
99mTc‐Bone Scan 
x 
x 
 
x 
x 
x 
Plain radiographs of primary lesion
x 
 
 
 
 
 
18F‐FDG PET/CT 
x 
 
 
x 
x 
 
18F‐MISO PET 
x 
 
 
x 
x 
 
Blood samples with F‐MISO PET7
x 
 
 
x 
x 
 


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6.5 SUPPORTIVE CARE GUIDELINES 
 
6.5.1 153Sm-EDTMP infusions 
 
6.5.1.1 Stable central venous access is required, preferably through the placement of a 
double-lumen central venous catheter.  Intravenous fluids will be administered to 
assure line patency pre 153Sm-EDTMP administration and to thoroughly flush line 
post 153Sm-EDTMP administration.   
 
6.5.1.2 Administration of 153Sm-EDTMP will be performed under the direction of the 
institution’s Radiation Oncology Department/Division, according to standard 
procedures for the delivery of radioactive isotopes. Medical Physics personnel 
will be present for the entire procedure.  The appropriate dose will be removed 
from the supplier’s vial with a protected syringe and will be administered over 1-2 
minutes followed by flushing of IV line to ensure line is cleared of samarium.  
Isolating patient and shielding from radioactivity is not necessary for153Sm-
EDTMP administration.    
 
6.5.1.3 Patients will take 1000 mg calcium carbonate the morning of samarium infusion 
to decrease the risk of transient samarium-related hypocalcemia. Ionized calcium 
level will be checked prior to administration of the 153Sm-EDTMP.  Additional 
calcium gluconate may be given as needed for ionized calcium less than 1.2 
mmol/L.  Calcium gluconate will be available for treatment of symptomatic 
hypocalcemia. 
  
6.5.1.4 A 12-lead EKG will be checked prior to administration of 153Sm-EDTMP.  A 
second 12-lead EKG will be checked at the completion of the infusion. If any 
EKG changes are noted or patients develop symptoms attributable to 
hypocalcemia, patients may be discharged with additional calcium carbonate and 
arrangements made for recheck of calcium levels the following day.   
 
6.5.2 Auto-stem cell infusion and recovery 
 
Pediatric and adult guidelines for preventing and managing complications of autologous 
HSC transplant patients in effect at the time of treatment should be followed and may 
supersede the following recommendations. 
 
6.5.2.1 Blood component support. All blood products will be irradiated to prevent graft-
versus-host disease. Transfusions with leukocyte-poor packed red blood cells will 
be given as needed to maintain the hematocrit greater than 25%. Platelets will be 
given as needed to maintain the platelet count above 10,000, or higher as 
clinically indicated. 
 
6.5.2.2 Infectious prophylaxis. Patients should be given prophylaxis against mycotic 
disease from Day 1 through Day 75. Suspected or documented fungal infections 
should be promptly treated according to standards for transplant recipients. Patients 


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should receive effective prophylaxis for Pneumocystis carinii pneumonia, from Day 
1 until 6 months after treatment is completed. 
 
6.5.2.3 Management of fever. Management of fever in neutropenic patients will be 
according to practice guidelines for the bone marrow transplant service. Broad 
spectrum antibiotics will be initiated, after appropriate cultures are obtained, for any 
fever >38.5°C. Persistent unexplained fever will be treated as a presumptive 
invasive fungal infection. 
 
6.5.2.4 Immunizations. Patients will not receive any immunizations for at least 6 months 
after completion of therapy. They will not receive any live viral vaccines until 
appropriate T lymphocyte counts and responses to diphtheria and tetanus vaccines 
have been demonstrated. Immunization of household members for influenza in the 
first two years after treatment will be recommended as for households of autologous 
BMT recipients. 
 
6.5.3 Concomitant medications 
   
While on study care should be taken to avoid medications that potentially will worsen 
pancytopenias or hypocalcemia.  Additionally, patients may not receive bisphosphonate 
therapy while on trial.   
 
6.5.4 Radiation therapy.   
 
Complete consent and counseling will be specific to the radiation site and plan, and will be 
administered by treating radiation oncologist.   
 
7.0 TOXICITY AND COMPLICATIONS 
 
 7.1 IFOSFAMIDE: Nausea, vomiting, anorexia, anemia, leucopenia, thrombocytopenia, hair 
loss, arrhythmia (rare), sleepiness, confusion (rare), seizures (rare), electrolyte imbalance, 
hemorrhagic cystitis, renal failure or insufficiency, myocardial necrosis (rare), scarring of the 
bladder or lungs, infertility, and second malignancy (very rare). 
 
7.2 MESNA: Nausea, vomiting, stomach pains, headache, diarrhea, allergic reactions, and pains 
in the arms, legs, and joints (all very rare). 
 
7.3 153Sm-EDTMP: Pain at the tumor site, slow bone growth (rare) or bone deformity (rare). 
The EDTMP component may cause hypocalcemia and may very rarely cause reactions such 
as wheezing, low blood pressure, hives, or trouble breathing. 
 
7.4 STEM CELL INFUSION: Hypertension, nausea, bradycardia, garlic-like odor to the breath 
(all 
due to residual DMSO used as a cryopreservative). 
 


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7.5 G-CSF: headache, fever, chills, decreased appetite, pains in bones, chest, belly or joints, and 
rash. 
 
7.6 EXTERNAL BEAM RADIOTHERAPY: The specific risks associated with external beam 
radiotherapy depend on the sites to be treated and the techniques that are used. These will be 
discussed in detail at the time of treatment by the radiation oncologist. 
 
8.0 AGENT INFORMATION 
 
8.1 153SM-EDTMP  
 
 
153Samarium is a beta- and gamma-emitting lanthanide element. It has 3 principal beta 
emissions of 640 keV, 710 keV, and 810 keV maxima. These medium energy beta particles 
are tumoricidal. It also emits a gamma photon of 103 keV that allows for scintigraphic 
imaging. 153Samarium is chelated with EDTMP (also known as lexidronam), a bone seeking 
tetraphosphonate compound. The chelated complex, 153Sm-EDTMP, is supplied sterile and 
pyrogen-free from the manufacturer (EUSA Pharma) under the trade name Quadramet. It is 
dissolved in a saline solution (typically 10 ml total volume) that is infused intravenously over 
a 1-2 minute period. 
 
8.2 IFOSFAMIDE (IFEX) 
 
NSC-109724. Commercially available.  
Formulation:  Lyophilized powder, 1 g and 3 g per vial. 
Storage:  Room temperature. Reconstitution: Reconstitute 1 gm vial with 20 ml sterile water 
and 3 g vial with 60 ml sterile water, to a final concentration of 50 mg/ml. Further dilution 
with NS, D5W, or Lactated Ringer’s is acceptable. Stability: Discard reconstituted drug after 
one week at 30° or 3 weeks at 5°C.  
Toxicities:  Myelosuppression. Alopecia. Nausea and vomiting. Hemorrhagic cystitis, and 
acute tubular necrosis. Lethargy, confusion, somnolence, excitement, disorientation, and 
hallucination. Transient liver function abnormalities. 
  
8.3 MESNA (SODIUM 2-MERCAPTOETHANESULFONATE) 
 
NSC-113891. Commercially available.  
Formulation: 1,000 mg/10 mL multidose vials which contain 10.4 mg/mL of benzyl alcohol 
as a preservative.  
Storage: Room Temperature. Reconstitution: Dilution of Mesna with NS, D5W, or Lactated 
Ringer’s is acceptable. Stability: MESNA is not light-sensitive, but is oxidized to diMESNA 
when exposed to oxygen. Non-preserved ampules should be used immediately after opening, 
while benzyl alcohol-preserved vials may be stored and used for 8 days. After further 
dilution for administration, either product is chemically stable for at least 24 hours. Lack of 
an antimicrobial preservative suggests that the non-preserved product should be used within 
6-8 hours after diluted for administration. Toxicities: Bad taste in the mouth, nausea and 
vomiting, diarrhea. Young children receiving high doses of benzyl alcohol (> 99 mg/kg/day) 
may develop the gasping syndrome manifested by gasping, metabolic acidosis and multiple 


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organ system failure. Benzyl alcohol is the preservative in multidose vials of MESNA. It 
results from inability to adequately conjugate benzoic acid with glycine, a metabolic pathway 
poorly developed under 8 weeks of age. 
 
9.0 TREATMENT EVALUATION 
 
9.1 DEFINITIONS 
 
9.1.1 Radiologic Response 
 
9.1.1.1 Complete response: Complete resolution of all disease by radiologic imaging (CT 
or MRI). 
 
9.1.1.2 Partial response: > 50% reduction in the sum of the products of perpendicular tumor 
diameters. 
 
9.1.1.3 Minor response: A 25-50% reduction in the sum of the products of the tumor 
diameter without the emergence of new lesions. No individual lesion progressing 
more than 25% in a single dimension 
9.1.1.4 Stable disease: No progressive disease. 
 
9.1.1.5 Progressive disease: Emergence of new lesions or progression of any lesion by 
more than 20% in a single dimension. 
 
9.1.2 Histologic Response 
 
9.1.2.1 Complete response: 100% necrosis. 
 
9.1.2.2 Good response: ≥ 90%, but < 100%, necrosis. 
 
9.1.2.3 Poor response: < 90% necrosis. 
 
9.1.3 Clinical Response 
 
Patients will be considered a clinical response if they have stable disease or any radiologic 
response by RECIST 1.1 criteria.  Dates of progression or death will also be recorded in 
order to calculate progression-free and overall survival.  Toxicities will be graded 
according to the Bearman criteria for bone marrow transplant studies and according to the 
NCI Common Terminology Criteria for Adverse Events version 4.0. 
 
9.2 CRITERIA FOR REMOVAL FROM STUDY  
 
Patients will be removed from the study for patient or parent choice, or for excessive 
toxicity at the discretion of the principal investigators. 
 
10.0 SERIAL MEASUREMENTS (see Table 1 in Section 6.3) 


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10.1 Time of entry into the study:  99mTc bone scan, X-rays and/or CT or MRI evaluation of the 
primary and metastatic lesions  (specific modality at clinician’s discretion).  A pre-treatment 
[18F]-MISO/ [18F]-FDG PET scan will be obtained for baseline readings as part of study. 
 
10.2 One month after completion of external beam radiotherapy:  repeat initial imaging modality 
and territories, as well as any other imaging clinically indicated.  [18F]-MISO/ [18F]-FDG 
PET will be obtained at that time as well. 
 
10.3 Subsequent follow up as per Table 1. Scans will be repeated every 4 months for the first 
year after completion of therapy, every 6 months during the second year after therapy, and 
yearly thereafter for a total of 5 years. 
 
10.4 At progression, patient will undergo repeat [18F]-MISO/[18F]-FDG PET.  
 
11.0 STATISTICAL CONSIDERATIONS 
11.1 OVERVIEW 
 
This protocol will assess the proportion of clinical tumor responses, defined as progression-
free survival at 6 months, and the toxicities associated with high-dose 153Sm-EDTMP 
(MTD at 30 mCi/kg) after an initial lower dose of the agent along with external beam 
radiation therapy in patients with high-risk osteogenic sarcoma.   
 
Primary objective:  The primary objective of this study is to determine if the addition of 
external beam radiation therapy to infusional 153Sm-EDTMP can delay the progression of 
target lesions.  The primary endpoint is 6-month progression free survival (PFS).  It is a 
combined effect of the entire treatment.  To be evaluable, patients must meet all eligibility 
criteria, including signing a consent form, and have completed treatment according to 
protocol without major deviations. Patients who are enrolled but unevaluable will be 
replaced on the study.  Only patients enrolled on Stratum 1 (i.e., with a diagnosis of 
osteosarcoma) will be evaluated for the Primary Objective. 
 
Secondary objectives:   
1. Describe the short and long-term toxicity profile of combined treatment with 153Sm-
EDTMP and external beam radiation therapy. 
2. Estimate the local control rate. (Stratum 1 only) 
3. Determine the overall survival (OS). (Stratum 1 only) 
4. Describe the distribution of absorbed doses delivered to each targeted lesion and the 
distribution of equivalent uniform doses delivered to each patient.  
5. Model the relationship between absorbed doses and time to progression. 
6. Determine the correlation of hypoxic volume and maximum tumor/blood ratio obtained 
by [18F]-MISO PET scanning with patient outcomes. 
 
11.2 STUDY DESIGN 
 


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This is a single-arm study with 2 strata:  Stratum 1 for patients with osteosarcoma, and 
Stratum 2 for patients with other high risk solid tumors.  Stratum 2 is exploratory in nature, 
and the goal of including these patients is to facilitate accomplishing secondary objectives 
related to toxicity and the feasibility of administering this treatment regimen to solid tumor 
patients.  If possible, we will, however, use patients on Stratum 2 to estimate response rates 
of tumors other than osteosarcoma.  For Stratum 1, 6-month PFS as the primary endpoint.  
The study will pre-specify target lesions for each patient in Stratum 1 that will be used to 
assess PFS, with the intention that every lesion radiographically evident at the time of 
enrollment will be a target lesion.  Events will be the first disease progression at any of the 
target lesions or death from any cause. All patients treated on Stratum 1 will be included in 
the determination of PFS, regardless of treatment modification or discontinuation.  The 
design will include interim analyses for futility if it seems unlikely that the treatment has 
sufficient activity.  The historical PFS in 11 patients treated with 153Sm-EDTMP similar to 
how we are proposing, but without the external beam component, was 15.8%.  For this 
study of 153Sm-EDTMP plus external beam radiation therapy, a 6-month PFS of 35% 
would be the lowest that would be considered acceptable, and PFS that is convincingly 
worse than this would be considered grounds for discontinuing further study.  The non-
parametric Kaplan-Meier estimate will be used to monitor the PFS function.  After 8 
patients have been enrolled, the design will include an interim analysis for futility that 
could halt the trial if it seems likely that this regimen does not have sufficient clinical 
activity.  The study is designed to stop if we are 80% certain that the 6-month PFS is below 
15%.         
 
11.3 STATISTICAL ANALYSIS PLAN 
 
11.3.1 Estimate the PFS for subjects treated on Stratum 1. 
 
Sample size: The primary measure of efficacy will be PFS at 6-months for Stratum 1 
patients.  In specific, the 6-month PFS for this treatment will be compared to a reference of 
15.8% (hazard rate = 0.308/person-month i.e. median of 2.25 months).  In patients with 
metastatic osteosarcoma a 6-month PFS of 35% would be considered promising, and is the 
benchmark for this study.  Assuming exponential survival, 4 patients per year will be 
accrued for 5 years (20 total), one year of additional follow-up, and a one-sided 0.05 alpha 
level test, the sample size of 20 will have 82% power to detect a hazard ratio of 1.76.   
  
Early stopping guideline for safety:  The study will be monitored after every patient for 
non-hematologic grade 4 toxicities following initiation of external beam radiation therapy.  
This stopping rule for toxicity will hold enrollment if the posterior probability of risk being 
larger than 0.2 is 75% or higher.  The prior for this toxicity monitoring rule is beta (1, 5).  
This distribution means that our prior guess at this type of grade 4 toxicity is 16.7%, and 
there is 95% probability that it is between 0.51% and 52.2%.   The operating characteristics 
of the stopping rule are shown below and are based on 5000 simulations: 
Toxicity stopping rule: 
Study termination if:  
2 AEs 
3 AEs 
4 AEs 
5 AEs 
6 AEs 
And number of patients between: 
2 - 3  
4 – 7 
8 – 12 
13 – 16 
17 - 20 


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Operating characteristics of stopping rule based on 5000 simulations: 
True Toxicity Risk 
Prob. Declare 
Treatment Too 
Toxic 
Avg. Sample Size 
0.05 
1.0% 
19.8 
0.10 
6.4% 
19.2 
0.15 
17.1% 
17.9 
0.20 
33.7% 
16.2 
0.25 
54.0% 
13.8 
0.30 
69.1% 
12.0 
0.35 
82.9% 
9.7 
0.40 
92.6% 
7.9 
 
 
Early stopping guideline for futility and simulations:  Simulation is used to demonstrate 
the operating characteristics of the study for a sample size of 20.  The study will be 
monitored for futility with a primary endpoint of 6-month PFS.  The non-parametric 
Kaplan-Meier estimate will be used to estimate the PFS function at 6-months.  After 8 
patients have been enrolled, the design will include an interim analysis for futility that 
could halt the trial if it seems likely that the treatment does not have sufficient clinical 
activity.      
The sample size of 20 and the study design operating characteristics assume a 5 year 
accrual period with an additional follow-up of one year.  The null 6-month PFS is 15.8%.  
We have designed the study to stop early only if the posterior probability of 6-month PFS 
being less than 0.15 is 80% or higher.  Simulations were carried out with exponential 
survival and staggered patient entry.  We assume on average 1 patient will enter the study 
every three months.  Interim analyses begin once 8 patients have been entered on the study 
and occur after groups of 4 patients thereafter up to a maximum of 20 patients.  The interim 
analysis estimates of 6-month PFS are based on analyses with an underlying Dirichlet 
process prior.  We approximate the posterior distribution, which is actually a mixture of 
Beta distributions, the mixture depending on the amount of censoring, with a single Beta 
distribution.  The parameters of this posterior Beta distribution are based on the number of 
failures and the effective sample size at 6-months, combined with the parameters of the 
prior.   
The following table summarizes the operating characteristics of the futility stopping rule 
under various scenarios for the underlying exponential PFS, based on 5000 simulations.  
For futility monitoring we characterize the uncertainty of the 6-month PFS estimate with 
the prior: beta (1, 4).  This implies that our prior guess at the 6-month PFS in this study is 
20% and there is 90% certainty that the 6-month PFS is between 1.3% and 52.7%.   
Table 2.  Interim monitoring rule operating characteristics 
6-month 
PFS 
Prob Stop 
for Futility 
Avg N 
Estimated 
6-mo PFS 
lo 90% Post Int'l 
hi 90% Post Int'l 
0.10 
0.60 
14.2 
0.07 
0.0 
0.20 
0.15 
0.39 
16.2 
0.12 
0.0 
0.30 


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0.20 
0.23 
17.7 
0.18 
0.0 
0.35 
0.25 
0.12 
18.7 
0.23 
0.0 
0.40 
0.30 
0.07 
19.2 
0.29 
0.0 
0.45 
0.35 
0.04 
19.6 
0.34 
0.15 
0.50 
0.40 
0.02 
19.8 
0.40 
0.20 
0.60 
 
Analysis for primary objective:  Overall hazard rate estimates and 95% confidence 
intervals as well as Kaplan-Meier (KM) estimates will be used to summarize PFS over 
time.  The 6-month PFS with 95% confidence interval will be reported.   
11.3.2 Describe the toxicity profile of this regimen in the short and long-term.   
 
Toxicities will be graded according to CTCAE v4.0 and the RTOG Cooperative Group 
Common Toxicity Criteria, and attributable toxicities grade 3 or higher will be recorded.  
For purposes of evaluation, we will consider toxicities resulting from the administration of 
153Sm-EDTMP separately from toxicities resulting after initiation of external beam 
radiation therapy.  [However, we will hold accrual after enrollment of five patients to 
evaluate cumulative toxicity from the combined regimen.] Adjustments to external beam 
therapy in response to toxicity would be made in accordance with standard Radiation 
Oncology treatment protocols and clinical judgment.    
 
11.3.3 Describe the distribution of absorbed doses delivered to each targeted lesion and the 
distribution of equivalent uniform doses delivered to each patient. 
 
The total absorbed dose delivered to each targeted lesion will be limited by the tolerance 
of surrounding normal tissue.  We will produce histograms showing the distribution of 
radiation absorbed doses by lesion, and summarize the results by patient for the lesion 
receiving the lowest absorbed dose in each patient.  With a sample size of 20 patients, we 
will be able to estimate the proportion of patients whose lesions are all treated to an 
absorbed dose of ≥ 80 Gy with a precision of ±23%. 
 
11.3.4 Model the relationship between absorbed dose and time to progression for patients 
enrolled in Stratum 1.   
 
We expect a total dose of 80 to 100 Gy to produce a local control rate of 80%, while a 
total absorbed dose of 60 to 70 Gy may produce a local control rate of 50 – 70%, and the 
local control rate would decline steeply at lower absorbed doses.  We will use a 
generalized mixed effects model treating dose and time as fixed effects and the random 
effect of individual patients for the outcome of progression of each targeted lesion.  If at 
least 10 patients have at least one lesion that receives a radiation dose with similar 
effectiveness to our historical control experience, and at least one lesion receiving the 
targeted dose, this analysis would have 80% power to demonstrate a significant dose-
response with alpha 0.05. 
11.3.5 Determine overall and progression-free survival for patients enrolled in Stratum 1. 


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Survival curves will be estimated by using the Kaplan-Meier method.  Progression-free 
survival is defined as time from registration to the first observation (documentation) of 
disease progression or death.  Patients who are lost to follow-up will be censored for 
determination of PFS on the date of their last evaluations. Overall survival is defined as 
time from registration to death due to any cause. 
 
11.3.6 Determine correlation of hypoxic volume and maximum tumor/blood ratio obtained by 
[18F]-MISO PET scanning with patient outcomes.   
 
Cox regression analysis will be performed to measure association between hypoxia based 
on HV and max T/B ratio with Kaplan-Meier survival and time-to-progression curves.  
Additional regression analysis will be performed to evaluate the link between hypoxic 
indices and uptake of 153Sm-EDTMP and clinical response based on radiologic response 
and presence of necrosis on histology.   
 
11.4 STUDY ACCRUAL  
Based on prior accrual data, we anticipate enrolling five patients per year, with an expected 
study duration of five years.   
 
12.0 DATA RECORDING, MANAGEMENT, AND MONITORING 
 
12. 01To register eligible patients on study, the investigator will fax the completed registration 
form to the Johns Hopkins Oncology center Clinical Research Office at 410-614-1328. 
 
12.02 Informed consent must be signed by the patient or in the case of a minor, the parent or legal 
guardian. 
 
12.03 If a patient does not receive protocol therapy, the patient is removed from protocol. 
Reasons for cancellation must be submitted in writing to the Principal Investigator. Once a 
patient has been given protocol treatment, all forms must be submitted. 
 
12.04 Case report forms, including dosimetry, toxicity and response evaluation will be completed 
in a timely manner. 
12. 05 This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan 
(12/6/2012).  The Clinical Research Office QA Group will perform an audit after 
the first subject has been treated and then periodically depending on the rate of 
accrual and prior audit results.  All trial monitoring and reporting will be reviewed 
annually by the SKCCC Safety Monitoring Committee. 
The PI is responsible for monitoring the study.  Data must be reviewed to assure the 
validity of data, as well as, the safety of the subjects.  The PI will also monitor the 
progress of the trial, review safety reports, and clinical trial efficacy endpoints and 
to confirm that the safety outcomes favor continuation of the study. 
The PI will be responsible for maintaining the clinical protocol, reporting adverse 
events, assuring that consent is obtained and documented, reporting of unexpected 
outcomes, and reporting the status of the trial in the continuing renewal report 


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submitted to the IRB and to the trial monitoring review group. Content of the 
continuing renewal report at a minimum should include year-to-date and full trial 
data on: accrual and eligibility, protocol compliance, treatment administration, 
toxicity and ADR reports, response, survival, regulatory compliance, compliance 
with prearranged statistical goals.  The report should be submitted in a timely 
manner according to the schedule defined by Johns Hopkins Medicine Institutional 
Review Board. 
 
12.1 REPORTING OF ADVERSE REACTIONS 
 
12.1.1 Definitions 
 
12.1.11An adverse event is any new, undesirable medical occurrence or change of an 
existing condition in a subject that occurs during treatment (which may include a 
specified post treatment period), whether or not considered to be product related. 
Abnormal laboratory findings considered by the reporting physician to be 
clinically significant, e.g. those that are unusual or unusually severe for the 
population being studied, should be recorded as adverse events. 
 
12.1.12 A serious adverse event is defined by regulatory/clinical criteria. It is one that 
suggests a significant hazard or side effect, regardless of the investigator’s or 
sponsor’s opinion on the relationship to study material. This includes, but may not 
be limited to, any event that (at any dose): 
• is fatal; 
• is life threatening (places the subject at immediate risk of death); 
• requires in-patient hospitalization or prolongation of existing hospitalization; or 
• is persistent and results in significant disability/incapacity. 
 
12.1.2 Investigator’s Reporting Obligations 
 
12.1.2.1 Grade 4 (life-threatening) or grade 5 (fatal) adverse events that are unexpected 
(no listed on the package label) with an attribution of possible, probable, or 
definite must be reported to the FDA within 10 business days.  
 
12.1.2.2 Reports to the FDA should be submitted in writing (FDA Form 3500 
MEDWATCH) to: 
 
 
 
 
10903 New Hampshire Avenue  
             
 
Silver Spring, MD 20993  
                
 
Ph. 1‐888‐4636‐3332 
Fax 1‐888‐463‐6332 
www.fda.gov/medwatch 
with a copy simultaneously submitted to the Johns Hopkins Institutional 
Review Board. 
 
12.1.2.3  Johns Hopkins Institutional Review Board reporting requirements:  The 
Organization has the responsibility to report unanticipated problems involving 


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risk to subjects or others under Policy 103.6(b), serious or continuing non-
compliance under Policy 103.7, and suspension or termination of approved 
research under Policy 113.1, to the appropriate agencies.  The Institutional 
Official (IO) is authorized as the individual who will submit reports when an 
IRB has made a determination under the three cited policies.  In cases where the 
IRB and IO determine that additional information is required before submitting 
a final report, a preliminary report may be made to the appropriate officials, 
supporting federal agency (as applicable), OHRP, and FDA (as applicable), 
within one month of the IRB’s determination. 
 
  
 
12.1.2.4 A draft preliminary or final report will be prepared for review by the IO and 
General Counsels (GCs).  The draft report will contain the following 
information: 
 The nature of the event 
 The findings of the organization 
 The actions taken by the organization and IRB, including plans to protect the 
rights and welfare of the participants 
 The reasons for the organization’s and IRB’s actions 
 The plans for continued oversight or investigation or action. 
 
The draft report will be finalized by the IO and the GCs.  The IO will sign the 
report within 20 days of the agreed upon final revision of the report. The final 
report will be submitted to the OHRP if the research is conducted, funded, or 
overseen by DHHS; to FDA, if the research is regulated by FDA; and to other 
agencies that are signatories to the Common Rule [1], if the research is 
conducted, funded or overseen by that agency. A copy of the report will be sent 
to the reviewing IRB, ORA if the project is funded by an outside sponsor, Risk 
Management (if applicable), and the PI.  The IO may determine the report 
should be provided to the Director of the department in which the PI is 
appointed as faculty and the Dean of the School of Medicine.  If the event 
involves unauthorized use, loss, or disclosure of PHI, a copy will be sent to the 
HIPAA Privacy Officer.  12.7.2.3 All toxicities should be recorded on the flow 
sheet. 
 
12.1.2.5 Notify the P. I. immediately of any fatal toxicity. 
 
12.2 EARLY STOPPING RULE 
 
Data will be reviewed on an ongoing basis. An early stopping rule for safety is described 
above (Section 11.3.1).   For the stopping rule, the requirement for hospitalization in the 
first five weeks after samarium for temporary hematopoietic, infectious, or GI toxicities 
will not per se be considered a defining criterion of seriousness of an adverse event. 
 
This is a Level 1 study under the SKCCC CRO Data and Safety Monitoring Plan. Data 
monitoring of this protocol will occur on a regular basis with the frequency dependent on 


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the rate of subject accrual and the progress of the study. Trial monitoring and reporting will 
be done through the Clinical Research Review and Monitoring Committee (CRC). 
 
13.0 MULTICENTER GUIDELINES 
 
Protocol Chair 
 
 
The Protocol Chair is responsible for performing the following tasks: 
 Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments 
 Assuring that all participating institutions are using the correct version of the 
protocol. 
 Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
 Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
 Reviewing data from all sites 
 
 
Coordinating Center 
 
 
The Coordinating Center is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site. 
 Managing central patient registration. 
 Collecting and compiling data from each site. 
 Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
 
Participating Sites 
 
 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
 Submitting data to the Coordinating Center. 
 Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 
 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
 Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
 Collecting and submitting data according to the schedule specified by the protocol. 
 
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