A Single Arm Phase II Study of Bone-Targeted Sn-117m-DTPA in Symptomatic Castration Resistant Prostate Cancer With Skeletal Metastases
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Prostate Adenocarcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:  10437 
Version Date:  January 10, 2022 
 
i 
To:  
Cancer Therapy Evaluation Program  
From:  
Zin Myint, M.D. 
Date:  
January 10, 2022 
Re: 
Amendment for Protocol 10437: “A Single Arm Phase II Study of Bone-targeted Sn-
117m-DTPA in Symptomatic Castration Resistant Prostate Cancer with Skeletal 
Metastases” 
 
SUMMARY OF CHANGES – Protocol 
 
# 
Section 
Amendments 
1.  
Cover 
letter 
Co-investigator name is added on page 1.  
2.  
Cover 
letter 
Local IRB number is added on page 1.  
3.  
 
3.1 
PSMA PET scan is added to be used as a baseline scan.  
PSA value has modified from 5 ng/ml to 1 ng/ml.  
Duration of EBRT for bone pain prior to starting study treatment has modified 
from 12 weeks to 4 weeks.   
4.  
 
5.1 
 
 
5.5 
 
The total amount of whole blood in citrate CPT tubes requirement has changed 
from 20 mL to 24 mL. (as EET Biobank can only provide three 8mL CPT citrate 
tubes).  
Changed three 8 mL of CPT citrate tubes.  
5.  
 
 
11 
 
 
PSMA PET scan is added as acceptable baseline scan.  
Urinalysis collection time has changed to only two collection time-points (baseline 
and prior to C2) 
Foot note (f) – urinalysis will be collected as indicated time-points or as clinically 
indicated.  
Foot note (g) –PSMA PET CT scan is added as acceptable baseline scan. 
 
 
 

1 
NCI Protocol #: 
10437 
 
Local Protocol #: 
75028 
 
ClinicalTrials.gov Identifier:  NCT04616547  
 
TITLE:  A Single Arm Phase II Study of Bone-targeted Sn-117m-DTPA in Symptomatic 
Castration Resistant Prostate Cancer with Skeletal Metastases 
 
Corresponding Organization: LAO-OH007 / Ohio State University Comprehensive Cancer 
Center 
 
Principal Investigator: 
Zin Myint, M.D. 
 
Medical Oncologist 
University of Kentucky, Markey Cancer Center 
Ben F. Roach Building, Cc453 
800 Rose Street 
Lexington, KY 40536 
Phone:  410-236-8095 
Fax:  859-257-7715 
Zin.myint@uky.edu 
 
 
Co-Investigator:                          Charles Kunos, M.D., Ph.D. 
                                                      Radiation Oncologist 
                                                      University of Kentucky, Markey Cancer Center 
                                                      HSRB Office, Room 111 
                                                      800 Rose Street 
                                                      Lexington, KY 40536 
                                                      Email: Charles.Kunos@uky.edu 
 
Translational PI: 
William H. St. Clair, M.D., Ph.D. 
 
Radiation Oncologist 
University of Kentucky, Markey Cancer Center 
HSRB Office, Room 306 
800 Rose Street 
Lexington, KY 40536 
Phone:  859-323-6486 
Fax:  859-257-5187 
stclair@email.uky.edu 
 
Translational Co-PI: 
Xiaoqi Liu, Ph.D. 
                                                      Basic Scientist 
                                                      Department of Toxicology and Cancer Biology 
University of Kentucky, Markey Cancer Center 
HSRB Office, Room 306 

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Version Date:  January 10, 2022 
2 
800 Rose Street 
Lexington, KY 40536 
Phone:  859-562-2006 
Fax:  859-257-5187 
Xiaoqi.Liu@uky.edu 
 
Imaging PI 
Riham El Khouli, M.D., Ph.D. 
 
Nuclear Medicine Physician 
University of Kentucky, Markey Cancer Center 
800 Rose Street, Hx302 
Lexington, KY 40536 
Phone:  859-323-2454 
Fax: 859-257-4457 
Email: Rhel222@uky.edu 
 
Participating Organizations 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
 
Statistician: 
                                                                          Donglin Yan, Ph.D. 
 
                                                                    University of Kentucky, Markey Cancer Center 
 
                                                                    800 Rose Street 
 
                                                                    Lexington, KY 40536 
 
                                                                    Phone:  859-323-0577 
 
                                                                    Email:  Donglin.yan@uky.edu 
 
 
 
 
Study Coordinator:  
 
Responsible Research Nurse: 
Jeri Z. Reynolds, RN, BSN, CCRC 
      Heather Heath, RN, CCRP 
 
789 South Limestone Street                                 800 Rose Street Room 420 
Markey Cancer Center                                          Markey Cancer Center 
Lexington, KY 40536                                           Lexington, KY 40536 
Phone: 859-218-0131                                           Phone: 859-323-6720 
Fax: 859-257-0100                                                Fax: 859-257-7715 
Email: jzreyn0@uky.edu                                       Email: heather.flynn@uky.edu 

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3 
 
 
Responsible Data Manager: 
 
Jeri Z. Reynolds, RN, BSN, CCRC 
789 South Limestone Street 
Markey Cancer Center 
Lexington, KY 40536 
Phone: 859-218-0131 
Fax: 859-257-0100 
Email: jzreyn0@uky.edu 
 
Responsible Radiation Safety Officer 
Bryan Lemieux, MS, CHP, DABMP 
800 Rose Street, H28 
Lexington, KY 40536 
Phone: 859-257-7128 
Email: bryan.lemieux@uky.edu 
 
NCI-Supplied Agent:  Sn-117m-DTPA (NSC 824376) 
 
IND #:  
 
IND Sponsor:  DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
Original / August 5, 2020 
 
 
 
 
Revision 1 / September 24, 2020 
 
 
 
 
Revision 2 / October 8, 2020 
 
 
 
 
Revision 3a / November 30, 2020 
 
 
 
 
Revision 4 / December 21, 2020 
 
 
 
 
Revision 5 / February 26, 2021 
 
 
 
 
Revision 6a / September 30, 2021 
 
 
 
 
      Revision 6b / October 5, 2021 
 
Revision 6 / October 20, 2021 
 
Revision 7/ January 10, 2022 
 
 

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SCHEMA 
 

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TABLE OF CONTENTS 
SCHEMA 
......................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease ...........................................................................................................9 
2.2 
CTEP IND Agent ...................................................................................................10 
2.3 
Rationale ................................................................................................................15 
2.4 
Correlative Studies Background ............................................................................16 
3. 
PATIENT SELECTION ....................................................................................................20 
3.1 
Eligibility Criteria ..................................................................................................21 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Minorities ...........................................................................................23 
4. 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
Investigator and Research Associate Registration with CTEP ..............................24 
4.2 
Site Registration .....................................................................................................25 
4.3 
Patient Registration ................................................................................................29 
4.4 
General Guidelines .................................................................................................32 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................33 
5.1 
Summary Table for Specimen Collection ..............................................................33 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies .............34 
5.3 
Specimen Procurement Kits and Scheduling .........................................................34 
5.4 
Specimen Tracking System Instructions ................................................................34 
5.5 
Specimen Collection ..............................................................................................38 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank ................................40 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories .........................42 
5.8 
Biomarker Plan ......................................................................................................43 
5.9 
Exploratory/Ancillary Correlative Studies ............................................................45 
5.10 
Special Studies .......................................................................................................47 
6. 
TREATMENT PLAN ........................................................................................................51 
6.1 
Agent Administration .............................................................................................51 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................53 
6.3 
General Concomitant Medication and Supportive Care Guidelines ......................53 
6.4 
Duration of Therapy ...............................................................................................54 
6.5 
Duration of Follow-Up ..........................................................................................55 
7. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................55 
7.1 
PRO-CTCAE .........................................................................................................55 

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8. 
PHARMACEUTICAL AGENT INFORMATION ...........................................................56 
8.1 
CTEP IND Agent ...................................................................................................56 
9. 
STATISTICAL CONSIDERATIONS...............................................................................59 
9.1 
Study Design/Endpoints.........................................................................................59 
9.2 
Sample Size/Accrual Rate ......................................................................................61 
9.3 
Stratification Factors ..............................................................................................61 
9.4 
Analysis of Secondary Endpoints ..........................................................................61 
9.5 
Analysis of Exploratory Endpoints ........................................................................64 
9.6 
Reporting and Exclusions ......................................................................................65 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................65 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................65 
10.2 
Adverse Event Characteristics ...............................................................................66 
10.3 
Expedited Adverse Event Reporting ......................................................................67 
10.4 
Routine Adverse Event Reporting .........................................................................70 
10.5 
Pregnancy ...............................................................................................................71 
10.6 
Secondary Malignancy ...........................................................................................71 
10.7 
Second Malignancy ................................................................................................72 
11. 
STUDY CALENDAR .......................................................................................................73 
12. 
MEASUREMENT OF EFFECT AND DISEASE PROGRESSION ................................76 
12.1 
Antitumor Effect – Bone and PSA Response Parameters .....................................76 
12.2 
Disease Progression in Soft Tissue Lesions...........................................................77 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................82 
13.1 
Study Oversight .....................................................................................................82 
13.2 
Data Reporting .......................................................................................................82 
13.3 
Data Quality Portal ................................................................................................85 
13.4 
CTEP Multicenter Guidelines ................................................................................85 
13.5 
Collaborative Agreements Language .....................................................................85 
13.6 
Genomic Data Sharing Plan ...................................................................................87 
13.7 
Incidental/Secondary Findings Disclosure Procedure ...........................................87 
14. 
REFERENCES ..................................................................................................................89 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................94 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE .....................................................................................................95 
APPENDIX C 
PATIENT CLINCAL TRIAL WALLET CARD ......................................96 
APPENDIX D 
BRIEF PAIN INVENTORY (SHORT FORM) ........................................97 
APPENDIX E 
PATIENT PAIN INVENTORY AND ANALGESIC USE 

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FORMS, PAPER FORMAT (IF DIGITAL IS NOT USED..............................................96 
APPENDIX F 
PATIENT’S PAIN MEDICATION LIST .................................................97 
APPENDIX G 
TABLE OF PRO-CTCAE AND CTCAE ITEMS FOR 
COLLECTION ..................................................................................................................98 
APPENDIX H 
MEDIDATA PATIENT CLOUD REGISTRATION ................................99 
APPENDIX I 
HYGIENE/SAFETY INSTRUCTIONS FOR 
TREATMENT WITH SN-117M-DTPA .........................................................................105 
APPENDIX J 
QUANTITATIVE IMAGING AND DOSIMETRY OF 
SN-117M-DTPA ..............................................................................................................107 
APPENDIX K 
Sn-117m-DTPA SITE ON-BOARDING FORM ....................................110 
APPENDIX L 
Sn-117m-DTA ORDER FORM ..............................................................113 
 
 
 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To evaluate the efficacy of Sn-117m-DTPA on sustained pain response in patients with 
castration-resistant prostate cancer (CRPC) metastatic to at least two bone sites with at 
least one clinically meaningful pain at baseline (≥4 on an 11-point pain intensity scale).  
Sustained pain response is defined as:  1) achieving pain index ≤3 within a 12-week 
period and 2) maintaining pain index ≤3 over a 16-week period. 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess the safety and tolerability of Sn-117m-DTPA per CTCAE v5.0. 
 
1.2.2 To measure Sn-117m-DTPA activity by gamma-camera dosimetry scans (serial full body 
planar images) obtained at 1 hour, 4 hours (or within 4-6 hours), 24 hours (or within 16-
24 hours), 48 hours (or within 36-48 hours), 72 hours (or within 60-72 hours), 1 week (±2 
days), and 4 weeks (±2 days) after the first Sn-117m-DTPA administration. 
 
1.2.3 To evaluate the therapeutic efficacy of Sn-117m-DTPA at 24 weeks as measured by 
Prostate Cancer Working Group 3 (PCWG3) criteria. 
 
1.2.4 To evaluate time to the first symptomatic skeletal event defined as i) the first use of 
external-beam radiation therapy to relieve skeletal symptoms; ii) new symptomatic 
pathologic vertebral or nonvertebral bone fractures; iii) spinal cord compression; or iv) 
tumor-related orthopedic surgical intervention. 
 
1.2.5 To evaluate the overall pain response rate at 24 weeks. 
 
1.2.6 To evaluate the duration of pain response defined as from the time of improvement in 
pain response (pain index ≤3) until the pain recurs. 
 
1.2.7 To measure changes and time to progression in serum prostate-specific antigen (PSA) 
and serum alkaline phosphatase (ALP) levels. 
 
1.2.8 To measure patient-reported outcomes (PROs) and adverse events (AEs) (PRO-CTCAE) 
captured by digital instruments. 
 
1.2.9 To evaluate progression-free survival (PFS) and overall survival (OS) 
 
1.3 
Exploratory Objectives 
 
1.3.1 To examine any tumor genomic alterations that may be associated with response or 
resistance to Sn-117m-DTPA, a radiopharmaceutical agent. 
 
1.3.2 To examine the changes in systemic inflammatory markers (such as interferon [IFN]-

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gamma, tumor necrosis factor [TNF]-alpha, interleukins [IL]-8, IL-10, and IL-17) by 
flow cytometry, and changes in markers of immune function by measuring the percentage 
and absolute number of CD4+ T helper cells, CD8+ T cytotoxic cells, T regulatory cells, 
polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSCs), and mononuclear 
MDSCs (M-MDSCs) prior to treatment vs. end of cycle 1, end of cycle 2, and at week 24 
and correlate values and/or changes with treatment outcomes. 
 
1.3.3 To evaluate the feasibility of measuring polo-like kinase 1 (Plk1) expression via 
immunohistochemistry (IHC) staining on archival tissues. 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
2.1.1 Castration-Resistant Prostate Cancer (CRPC) 
 
Metastatic CRPC (mCRPC) remains incurable with a poor prognosis despite improvements in 
treatment that include novel hormonal agents (Kirby et al., 2011).  This disease is the second 
leading cause of cancer deaths in the United States (Siegel et al., 2018).  mCRPC is largely 
driven by inactivation of the androgen receptor (AR) signaling pathway (Yamaoka et al., 2010).  
The current therapeutic armamentarium for mCRPC is limited to chemotherapy and novel 
androgen blockers, such as enzalutamide or abiraterone, which provide only moderate survival 
benefit (Ryan et al., 2013; Scher et al., 2012).  To date, radium-223 is the first and only approved 
targeted alpha therapy for mCRPC, with a median OS benefit of approximately 3 months.  
Studies also showed that radium-223 significantly prolonged the time to the first symptomatic 
skeletal event with a median benefit of 5.8 months (Parker, et al., 2013).  mCRPC remains an 
area of significant unmet medical need for the development of new novel therapeutic agents. 
 
2.1.2 Bone Metastases in Prostate Cancer 
 
Bone metastases are a major cause of morbidity from prostate cancer.  Prostate cancer 
preferentially spreads to the bones.  More than 80% of men who die from prostate cancer have 
bone metastases, the vertebral column, pelvis, ribs, and proximal long bones being the most 
common sites of bone metastases (Harada et al., 1992).  Metastases to vertebrae may cause 
spinal cord compression, nerve root compression, or cauda equina syndrome.  Metastases to the 
base of the skull can impinge on cranial nerves.  Clinical fractures are common, with most 
fractures involving the vertebral bodies.  Most prostate bone metastases appear osteoblastic by 
radiographic imaging, characterized by excess bone formation and excess bone resorption 
(Chirgwin and Guise, 2007).  This pathological acceleration of bone remodeling results in 
disorganized bone with impaired biomechanical properties.  
 
Most patients with mCRPC develop bone metastases with debilitating pain that is itself 
associated with shorter survival (Armstrong et al., 2007).  For many, pain symptoms are rarely 
fully eliminated despite optimal management with narcotic analgesics, which confer numerous 
other side effects.  Given the rising rate of prostate cancer secondary to the U.S. aging 
demographic imperative, novel treatments are needed that effectively control pain and enable 

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reduction of narcotics.  Thus, non-pharmacological modalities of treatment are being revisited, 
such as palliative targeted radiation therapy.  
 
2.1.3 Bone-seeking Radionuclide Therapy 
 
Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain 
(Joshi et al., 1965; Lawrence and Tobias, 1956; Firusian et al., 1976).  Among these, 
phosphorus-32 (Joshi et al., 1965), strontium-89 (Blake et al., 1986; Porter et al., 1993), 
samarium-153 (Collins et al., 1993; Resche et al., 1997), and rhenium-186 (De Klerk et al., 
1997; Maxon et al., 1991) are all beta-emitters, and radium-223 dichloride is an alpha particle-
emitter (Parker, et al., 2013); the major dose limitation is bone marrow toxicity.  Unlike 
conventional external beam radiotherapy (EBRT), targeted bone-seeking radionuclide therapy 
allows targeted drug delivery with reduction of collateral damage to normal tissues (Sfakianakis 
and DeLand, 1982).  To date, these agents have demonstrated modest pain palliation.  However, 
trials have not consistently evaluated pain and other associated PROs (such as physical function, 
fatigue, etc.) in concordance with Food and Drug Administration (FDA) guidance and 
contemporary methodology (Basch et al., 2012; Basch et al., 2014; Farrar et al., 2010). 
 
2.2 
CTEP IND Agent 
 
Sn-117m-diethylenetriaminepentaacetic acid (DPTA; stannic pentetate injection) is a 
radiopharmaceutical being developed for treatment of malignant bone metastases, starting in the 
1980s by Srivastava and colleagues at Brookhaven National Laboratory (Srivastava et al., 1985; 
Sn-117m-DPTA Investigator’s Brochure, 2020).  It has undergone both nonclinical and clinical 
study; as of February 24, 2020, 107 patients have been enrolled in Sn-117m-DPTA 
interventional clinical trials, including patients with bone-metastatic cancers of the prostate, 
breast, kidney, lung, and pancreas (Sn-117m-DPTA Investigator’s Brochure, 2020).   
 
2.2.1 Mechanism of Action 
 
Sn-117m is a radioactive isotope of tin that is a low-energy conversion electron emitter (127 
keV, 129 keV, 152 keV, and 140 keV) and also yields a gamma emission of 159 keV (Ponsard et 
al., 2009).  These low-energy conversion electron and gamma emissions can be used for therapy 
and imaging, respectively.  The penetration depth of the conversion electrons produced by Sn-
117m is 300 mcm, resulting in irradiation of tissues only to that distance, sparing bone marrow 
and other tissues adjacent to the bone-tumor interface (Srivastava et al., 1985).  The gamma 
radiation also produced by the isotope enables imaging similar to Tc-99m (Oster et al., 1985).  
Tin binds to bone and especially to hypermetabolic areas in bone, such as bone adjacent to tumor 
metastases, similarly to calcium (Sn-117m-DPTA Investigator’s Brochure, 2020). 
 
2.2.2 Nonclinical Studies 
 
Systematic study of the distribution and excretion of inorganic tin in its various chemical forms 
began in the mid-1980s.  Radioactive isotopes of tin were used to assess the biological behavior 
of the metal in each of its oxidation states in salts and coordination complexes upon intravenous 
(IV) injection in mice (Srivastava et al., 1985).  Sn-117m-DTPA demonstrated the best 

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11 
characteristics in terms of specificity toward bone.  Its uptake in bone equaled that of stannous 
chloride (20% injected dose [ID]/g at 30 minutes after injection), but with much less nontarget 
organ uptake.  Bone retained about 50% ID at one day, while blood pool, liver, and kidney 
retained much less than 1% ID each at that time.  Nonosseous tin appeared to have undergone 
rapid excretion via the urinary system after Sn-117m-DTPA administration:  nearly half of the 
ID disappeared from the animal in the span of 30 minutes after injection.  Concentration of tin in 
bone declined only slightly throughout the 168-hour post-injection observation period (to 17% 
ID/g), while concentration in other tissues declined rapidly in concert with the tracer's 
appearance in urine. 
 
Biodistribution of Sn-117m-DTPA in various animal models of human bone diseases showed 
preferential skeletal uptake with rapid disappearance from soft tissue after IV injection (Oster et 
al., 1985).  In mice, most of the radioactivity was found by whole-body autoradiography to 
reside in cortical bone three hours after IV injection of Sn-117m-DTPA.  Autoradiographs did 
not show any radioactivity in the adjacent bone marrow cavity.  Sn-117m-DTPA behaved like 
technetium diphosphonate and technetium pyrophosphate bone-scanning radiopharmaceuticals in 
other ways, as well.  For example, Sn-117m-DTPA localized in areas of ischemic muscle 
damage in rabbits, a phenomenon observed with the technetium-based bone-seeking tracers and 
attributed to calcification in the infarcted muscle.  Also in rabbits, it demonstrated uptake in 
areas of osteomyelitis and in areas of induced osteogenesis (healing after surgical bone lesion).  
In rats, experimentally induced hypervitaminosis A reduced bone:soft tissue values of Sn-117m-
DTPA, in correspondence to the vitamin's actions on bone metabolism.  Sn-117m-DTPA also 
displayed uptake autoradiographically in human osteosarcoma xenografts in nude (athymic) 
mice.  Bone levels of radioactivity after IV injection of Sn-117m-DTPA were as high as or 
higher than those measured after other bone-seeking radiopharmaceuticals, including the 
diagnostic tracer technetium (Tc-99m-etidronate), as well as the other investigational therapeutic 
radiopharmaceuticals, rhenium (Re-186-etidronate) and samarium (Sm-153-EDTMP) 
(Srivastava et al., 1994). 
 
Lam et al. reported that bisphosphonate does not influence samarium bone uptake when 
combined bisphosphonate and samarium (153Sm-EDTMP) is used to treat hormone-refractory 
prostate cancer patients (Lam et al., 2008).  The post hoc analyses from the ASLYMPCA 
(radium-223) study indicated that bisphosphonates have a beneficial additive effect on bone 
health when given in combination with radium-223 (Sartor et al., 2014).  As these combinations 
have been shown to be safe and feasible, we propose the combination of bisphosphonate and Sn-
117m-DTPA will be safe and effective as well. 
 
Acute IV toxicity of Sn-117m-DTPA was evaluated in groups of three mice at each of three dose 
levels:  5.1, 25.5, and 51 mg/kg, expressed in terms of tin (Sn-117m-DTPA Investigator’s 
Brochure, 2020).  Mice given the lowest dose displayed no observable toxic response, one of the 
three mice at the middle dose level died, and all animals at the highest dose level succumbed.  
The median lethal dose, estimated from these data at about 30 mg tin/kg, agrees reasonably well 
with values in rodents for the soluble tin salt, stannous tartrate (about 20 mg tin/kg, IV in rats).  
In another group of mice, an intraperitoneal injection of Sn-117m-DTPA at a dose of 51 mg 
tin/kg (uniformly lethal when given IV), resulted in only one of three mice dying.  Thus, it 
appears that the rate at which the animal becomes exposed to the drug affects toxic response, 

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implying that a slower rate of administration will benefit tolerability.  In later studies of Sn-
117m-DTPA at doses of 4.7 to 5.1 mg tin/kg IV, some mice displayed mild reactions upon 
injection, and displayed occasional dyspnea and hemorrhagic areas of the lungs a day later. 
 
A single-dose acute IV toxicology study of 2, 4, or 18 mcmol Sn-117m-DTPA/kg in mice found 
no clinical observations indicative of toxicity during the in-life phase of the study (Sn-117m-
DTPA Investigator’s Brochure, 2020).  No animals died, nor were any animals sacrificed 
moribund, during the in-life phase of the study.  There were no significant body weight changes 
between control and test group animals at both the 2-day and 14-day time points post-dosing.  
Gross necropsy did not reveal any signs of toxicity.  No differences in spleen or liver weights at 
gross necropsy were reported.  Hematologic findings were limited to a minor yet statistically 
significant elevation in neutrophils and a depression of lymphocyte levels in the males relative to 
the control (low and high-dose groups) at 48 hours post-dose.  Red blood cells were decreased at 
48 hours in the mid-dose group males.  These changes were not considered biologically 
meaningful.  There was a decrease in blood urea nitrogen at 48 hours in the low-dose male mice 
relative to the control group that was not considered biologically meaningful.  Histopathologic 
examination revealed an increase in hepatocyte mitotic figures in only the high-dose males at 48 
hours post-dose.  This finding was resolved at 14 days post-dose.  Other lesions were considered 
incidental and/or unrelated to treatment. 
 
2.2.3 Clinical Pharmacology 
 
2.2.3.1 
Phase 1 Biodistribution and Dosimetry Study 
 
Sn-117m-DTPA was administered at doses ranging from 0.1 to 1.7 mCi IV to 10 cancer patients 
with bone metastases (Atkins et al., 1993).  Radiation dose estimates were calculated for seven 
of the patients.  Imaging revealed bone uptake and distribution into metastases similar to that 
seen on·Tc-99m-MDP images in the same patients.  No other specific organ uptake was seen, 
other than very faint renal activity following radionuclide administration.  The ratios of levels in 
lesion to normal bone varied from 1 to 15, with a typical value of about 4.  Approximately 10-
fold more radioactivity was absorbed by bone surface than by bone marrow; the ratio of bone to 
kidney radiation absorbed dose was >300-fold.  Over half of the administered radioactivity 
localized in bone.  Radioactivity concentration in bone was nearly constant over the duration of 
the study.  Blood activity disappeared rapidly with a biexponential curve.  Urinary excretion was 
limited.  Image quality was good, despite the low level of radioactivity administered.  Median 
bone uptake at 24 and 48 hours was 64.6% (range:  37.7%-83.8%) and 61.0% (range:  35.4%-
81.5%), respectively.  Eight of 10 patients had bone uptake >50% of administered dose. 
 
2.2.3.2 
Phase 1/2 Dose-ranging Study 
 
Sn-117m-DTPA has a monoenergetic gamma photon of 159 keV in 86% abundance.  Sn-117m-
DTPA was administered at doses ranging from 71 to 286 mcCi/dose to 47 cancer patients with 
painful bone metastases (Krishnamurthy et al., 1997; Srivastava et al., 1998).  In the initial 17 
patients, total body clearance of Sn-117m-DTPA showed two compartments:  soft tissue and 
bone (Krishnamurthy et al., 1997).  The soft tissue component accounted for 22.4% of the dose 
and consisted of four subcomponents with an average biologic clearance half-life of 1.45 days.  

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Initial clearance was very rapid; 15 minutes after injection, the mean and standard deviation of 
the activity remaining in the vasculature was 14.8%±4.8% of the amount injected.  The bone 
component accounted for 77.6% of the total dose and showed no biologic clearance.  Peak 
uptake in normal bone was observed within 24 hours and within metastatic lesions within 3-7 
days.  The ratio of uptake in tumor/normal bone ranged from 2 to 9.  Mean urinary excretion was 
22.4% within 14 days; half of that was excreted in the first 24 hours.  The distribution of activity 
on the bone scans was observed to be similar to that observed for a Tc-99m labeled 
diphosphonate bone scan.  In the expanded series, including a total of 43 patients for whom 
biodistribution data were obtained, overall bone uptake was 69.7±14.7% (Srivastava et al., 
1998).  Uptake was higher in prostate cancer (n=29, mean 75.8%±12.0%) as compared to breast 
cancer patients (n=7, mean 54.8%±15.7%). 
 
2.2.4 Clinical Safety 
 
2.2.4.1 
Phase 1/2 Dose-ranging Study 
 
The phase 1/2 dose-ranging study found decrease in total white blood cell count to be the only 
significant toxicity (Srivastava et al., 1998).  While the incidence of leukopenia was highest in the 
highest dose group (5/12 evaluable patients, 42%), severe toxicity was uncommon.  Three patients 
(two at 10 mCi/70 kg and one at 16 mCi/70 kg) developed grade 3 neutropenia.  One patient, treated 
with 5 mCi/70 kg, developed grade 4 neutropenia.  The investigators attributed all these instances of 
neutropenia to chemotherapy administered following Sn-117m-DTPA administration.  No patient 
exhibited significant thrombocytopenia.  One patient reported pruritus the day after dosing; this was 
controlled by antihistamines.  Mean decrease in total white cell count was 1,870±1,450 cells/mcL; 
mean decrease in platelet count was 66,000±64,600/mcL.  No dose-response trend was noted for 
either white cells or platelets.  Nadirs were at 34±16 days (n=35) for total white blood cells and 
41±26 days (n=34) for platelets. 
 
2.2.4.2 
Randomized, Active-Control Study (Diatide, Inc. study 117-30) 
 
Single doses of Sn-117m-DTPA at 5, 12.5, or 30 mCi/70 kg were administered to prostate cancer 
patients with painful bone metastases, compared to a standard dose (1.0-5.5 mCi, median 4 mCi) 
of Metastron (Sr-89-chloride) as the control (Sn-117m-DTPA Investigator’s Brochure, 2020).  
The average number of AEs per patient was slightly higher in the 30 mCi Sn-117m-DTPA 
group:  approximately 11 events versus 8 events for each of the other groups.  There was no 
trend towards increasing overall incidence of severe AEs with dose of Sn-117m-DTPA.  The 
SOC category “Investigations” was the most common category of AEs and consisted mainly of 
clinically significant changes in clinical laboratory measurements and vital signs.  The 30 
mCi/70 kg Sn-117m-DTPA group exhibited the highest incidence with 86% of patients 
experiencing adverse events compared to 68% and 69% of patients in the 5 mCi/70 kg and 
12.5m Ci/70 kg Sn-117m-DTPA groups, respectively, and 53% in the Sr-89-chloride group.  The 
30 mCi/70 kg Sn-117m-DTPA group also had the highest incidence of gastrointestinal disorders, 
and GI events in this group were more likely to be considered study treatment-related.  The 
incidence of respiratory, thoracic, and mediastinal disorders appeared to be dose-related among 
the Sn-117m-DTPA patients, though no such trend was noted in severe AEs in that category.  
Considering all Sn-117m-DTPA treatment patients together, the incidence of respiratory, 
thoracic, and mediastinal disorder events was comparable to the incidence in Sr-89-chloride 

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patients:  29% versus 37% respectively. 
 
Regardless of treatment group, most events were mild or moderate in severity (Sn-117m-DTPA 
Investigator’s Brochure, 2020).  The lowest overall incidence of severe events occurred in the 30 
mCi/70 kg Sn-117m-DTPA treatment group:  6 patients in that group (43%) versus 10 (53%) in 
the 5 mCi/70 kg group, 10 (63%) in the 12.5 mCi/70 kg group, and 9 (47%) in the Sr-89-chloride 
group experienced severe AEs.  The percentage of events that were considered by investigators 
related to study drug (including possibly or probably related) were similar in the four treatment 
groups (21% to 24% of events).  The MedDRA SOC with the highest incidence of related events 
was investigations (42%, 38%, and 43% of patients in the 5 mCi, 12.5m Ci, and 30 mCi Sn-
117m-DTPA groups respectively, and 26% of patients in the Sr-89-chloride group). 
 
Twenty of 68 patients (29%) across all treatment groups experienced SAEs (Sn-117m-DTPA 
Investigator’s Brochure, 2020).  However, only two patients had serious adverse events (SAEs) 
that were considered possibly related to study drug.  Disorientation and spinal cord compression 
experienced by one patient who received 5 mCi/70 kg of Sn-117m-DTPA, and an increased 
white blood cell count observed in a patient treated with Sr-89-chloride, were considered 
possibly drug related.  The latter increased WBC count was in association with chills and rigor, 
vomiting and diarrhea, and increased bone pain.  The WBC count returned to normal following 
antibiotic treatment.  All other SAEs were considered unrelated to study drug.  Eight patients had 
SAEs with an outcome of death:  three each in the 5 and 12.5 mCi Sn-117m-DTPA groups and 
two in the 30 mCi Sn-117m-DTPA group.  The 12.5 mCi Sn-117m-DTPA group had the highest 
number and percentage of patients experiencing SAEs:  44% compared to 26%, 21%, and 26% 
in the 5 and 30 mCi Sn-117m-DTPA groups and the Sr-89-chloride group, respectively.  Three 
patients exhibited clinically significant changes in vital signs following injection of study drug.  
One Sr-89-chloride patient experienced decreased heart rate; one 5 mCi/70 kg Sn-117m-DTPA 
patient experienced decreased systolic blood pressure, and one 12.5 mCi/70 kg Sn-117m-DTPA 
patient displayed an increase in blood pressure.  These events were all considered possibly 
related to study drug, but they did not require treatment; all resolved without sequelae and were 
not considered SAEs. 
 
2.2.5 Clinical Efficacy – Pain Palliation 
 
The phase 1/2 dose-ranging study evaluated the effects of Sn-117m-DTPA administration on 
pain relief using daily 5-point numeric pain rating scales (Krishnamurthy et al., 1997; Srivastava 
et al., 1998).  About one quarter of all patients entered had complete and an additional one third 
>50% relief of pain.  There appeared to be a threshold in complete pain relief, though the numbers in 
each dose group were small.  More striking was a decrease in the time to onset of pain relief, with a 
mean time to onset of pain relief of 22 days at the lowest dose, plateauing at 5 days for doses of 12.5 
mCi/70 kg and above.  Mean duration of response was 3.3 months, with a maximum of 13.4 months; 
complete responses generally lasted longer than partial responses.  Three patients with prostate 
cancer received second doses upon worsening of pain.  Two had complete responses and one had a 
partial response to the second dose.  Neither radiologic time to progression nor OS was assessed in 
this study. 
 
2.2.6 Additional Safety Considerations 
 

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Sn-117m-DTPA contains pentetic acid (pentetate), a chelating agent used for heavy metal 
detoxification (Klaassen, 1990).  A related chelating agent, edetate, chelates serum calcium upon 
injection in the absence of calcium in the formulation (Sn-117m-DTPA Investigator’s Brochure, 
2020).  Rapid injection of edetate has caused hypocalcemic tetany, although slow infusion does 
not, due to replenishment of serum calcium from tissue stores.  As a member of the same drug 
class, pentetate also has the potential to cause hypocalcemic tetany if injected too rapidly.  
Calcium chloride is added to the Sn-117m-DTPA formulation.  Some pentetate does remain free 
in solution, but no evidence of hypocalcemic tetany has appeared in clinical studies of Sn-117m-
DTPA. 
 
Edetate administration in large repeated-daily doses for lead detoxification has been associated 
with nephrotoxicity, which reverses upon cessation of the repeated administrations (Sn-117m-
DTPA Investigator’s Brochure, 2020).  Edetate administration has also been associated with 
decreases in serum ALP activity due to chelation and excretion of zinc, a trace mineral 
component of the enzyme, though edetate is not known to interfere with clinical laboratory tests.  
As Sn-117m-DTPA is a member of the same family of chelating agents, it should be noted that it 
has the potential to cause similar events. 
 
The medical literature contains a case report of a fatal outcome in a patient who suffered 
disseminated intravascular coagulation (DIC) and who received Sr-89-chloride for treatment of 
bone pain due to metastatic bone disease (Leong et al., 1994; Sn-117m-DTPA Investigator’s 
Brochure, 2020).  Although not chemically related to Sr-89-chloride, Sn-117m-DTPA belongs to 
the same drug class as the former, so may have the potential to cause similar events. 
 
Results of previous clinical studies of Sn-117m-DTPA do not suggest that patients will risk 
developing severe myelotoxic responses as a consequence of exposure to anticipated doses (Sn-
117m-DTPA Investigator’s Brochure, 2020).  However, patients who have previously received 
cytotoxic chemotherapy may experience more marrow suppression than patients who have not 
previously received cytotoxic chemotherapy.  Eligibility criteria for bone marrow competency 
must be observed when screening patients, and complete blood counts and serum chemistry will 
be performed regularly for enrolled patients to monitor for myelosuppression and institute any 
necessary treatment delays (see Sections 7 and 11). 
 
2.3 
Rationale 
 
Sn-117m-DPTA localizes selectively in bone, a unique physical characteristic.  In addition, a 
major advantage of Sn-117m-DTPA is the low energy conversion electrons emitted (0.2-0.3 
mm), which minimizes the radiation dose to the bone marrow and results in deeper tissue 
penetration (~300 mcm).  Thus, this radiopharmaceutical has low bone marrow toxicity 
compared to the beta and alpha emitters.  Sn-117m-DTPA has a gamma photon of 158.6 keV, 
and its half-life is 13.6 days.  Atkins et al. (1993) studied the whole-body distribution of Sn-
117m-DTPA and showed that more than 50% of the administered activity was absorbed in the 
bones of patients with metastatic cancer.  The red marrow absorbed dose was low compared with 
the bone surface dose.  All other tissues received less than 1/10 of the dose received by red 
marrow. 
 

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A pilot study of 15 patients with painful skeletal metastases from myriad solid tumors evaluated 
treatment with Sn-117m-DTPA at 71-143 mcCi/kg (Atkins et al., 1995).  Results demonstrated 
pain relief without inducing bone marrow toxicity.  Krishnamurthy et al. (1997) studied the 
biokinetics and imaging characteristics of Sn-117m-DTPA radioactivity in 17 patients with 
metastatic bone pain.  Three dose levels were administered IV:  180 mcCi/kg, 229 mcCi/kg, and 
285 mcCi/kg of patient body weight.  Pain palliation was observed with all three doses, with 
responses in 60-83% of cases.  The duration of pain palliation ranged from 3 to 14 months from 
a single administration of Sn-117m-DTPA.  The majority (59%) of the administered Sn-117m-
DTPA was taken up in bony metastatic lesions and peaked in three to seven days, whereas peak 
uptake in normal bones occurred by 24 hours.  The remaining radioactivity was excreted by the 
urinary tract (37%). 
 
In a phase 1/2 study, 47 patients with painful bone metastases from a variety of malignancies 
(including 30 patients with prostate cancer) were treated with five different levels of Sn-117m-
DTPA radioactivity (Srivastava et al., 1998).  The dose levels, based on kg of body weight, were 
as follows:  2.64 MBq (71 mcCi), 5.29 MBq (143 mcCi), 6.61 MBq (179 mcCi), 8.46 MBq (229 
mcCi), and 10.58 MBq (286 mcCi).  Approximately 45% of patients obtained reduction of pain 
by at least 50%, and 30% experienced complete relief of pain for more than two weeks.  There 
was no correlation between response rate and the dose levels.  However, the time to onset of pain 
relief was shorter (5 ± 3 days) with doses ≥12.5 mCi/70 kg than with doses ≤10 mCi/70 kg (19 ± 
15 days). 
 
In a randomized phase 2 study of three dose levels of Sn-117m-DTPA compared to Sr-89-
chloride, a dose of 30 mCi Sn-117m-DTPA was well tolerated (Data on file, Serene LLC).  The 
study was stopped early due to commercial considerations, and only safety results were 
analyzed.  The results of this study demonstrate, however, that a dose of at least 30 mCi/70 kg 
(approximately 1.73 m2) could be administered safely. 
 
Collectively, there is mounting evidence that Sn-117m-DTPA has promising palliative efficacy 
with minimal toxicity.  Thus, additional evaluation of this agent in patients with bony metastases 
is urgently required. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Whole Exome Sequencing (WES) 
 
Biologic Rationale:  Gene expression profiling is an important tool to elucidate the novel 
biomarkers of radio-sensitivity in order to predict treatment response.  Radiation induces DNA 
damage and thus causes cell death.  Upregulation of DNA damage response pathways was 
associated with radiation sensitivity (Kamran and Mouw, 2018).  Extent of somatic copy number 
alterations and increased expression of PI3K and JAK/STAT pathway components were 
associated with radiation resistance. 
 
Hypothesis:  We propose to test for DNA damage repair (DDR) gene alterations (BRCA1/2 
loss/mutation, ATM, ATR, CHEK1/2 loss/mutation, RAD50, PALB2, CDK12, FANCA, POLE 
mutation), somatic mutations in MMR genes (MLH1, MSH2, MSH6, PMS2), replication stress 

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(CCNC1, CCNE1, MYCN amplification) and TP53, PIK3CA, FBXW7, and KEAP1 mutations and 
will correlate with treatment outcomes.  Additionally, we propose to test for germline variants 
such as MLH1, MSH2, MSH6, PMS2 (for Lynch syndrome), and homologous recombination 
genes such as BRCA1, BRCA2, ATM, PALB2, and CHEK2.  Archival tissue will be employed as 
available (no new baseline biopsies will be performed). 
 
2.4.2 RNA Sequencing (RNAseq) 
 
Biologic Rationale:  Radiation-induced gene expression changes mainly involve p53 signaling, 
cell cycle regulation, DNA repair, and inflammatory response (Bosma et al., 2020).  The ability 
to predict tumor response to radiation therapy is a necessary avenue to improve treatment 
outcomes.  RNAseq allows for a much broader dynamic detection of both protein-coding and 
non-coding RNAs that play significant roles in prostate cancer progression. 
 
Hypothesis:  We will explore the differences in RNA expression between radiosensitive and 
radioresistant treatment outcomes in prostate cancer patients who undergo treatment with Sn-
117m-DTPA. 
 
Relevant Preclinical Data:  Young et al. (2014) studied novel predictive biomarkers in vitro by 
analyzing the expression of genes involved in DNA repair pathways by RNAseq in radioresistant 
(PC-3) and radiosensitive (LNCaP) prostate cancer cell lines.  The study demonstrated that 
radiosensitive LNCaP cells down-regulated BRCA1, FANCG, RAD51, MCM7, CDC6, and 
ORC1, whereas the radioresistant PC-3 cell line up-regulated these genes. 
 
2.4.3 Polo-like Kinase (PLK1) 
 
Biologic Rationale:  PLK1, a critical cell cycle regulator, is overexpressed in prostate cancer, and 
its level of expression is associated with tumorigenicity in prostate cancer (Zhang et al., 2015) 
(Figure 1).  PLK1-associated phosphorylation of Mre11 leads to premature DNA damage 
checkpoint termination and reduced DNA repair (Weichert et al., 2004).  Thus, cancer cells with 
higher levels of PLK1 tend to continue to enter mitosis with damaged DNA, resulting in a higher 
level of cell death. 
 
Hypothesis:  We propose to evaluate the feasibility of measuring the expression level of PLK1, a 
critical cell cycle regulator, to be used as a biomarker to predict the efficacy of radiotherapy.  
Tissues will be subjected to immunohistochemistry to measure the levels of PLK1 prior to 
radiotherapy.  These studies will interrogate whether it is feasible to do this exploratory study, 
and this will help guide future biomarker studies. 
 
Relevant Preclinical Data:  Our preliminary data showed that mice with Plk1 overexpression are 
much more sensitive to radiotherapy than Plk1-negative mice (Figure 2) (Li et al., 2017).   
 

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2.4.4 Systemic Inflammatory Markers 
 
Biologic Rationale and Relevant Preclinical Data:  Our preclinical animal data studied the 
changes of IL-8 (pro-inflammatory cytokine) and PSA levels in tumor-bearing mice after 
treatment with radiotherapy (Xu et al., 2012).  It showed that an inverse relationship between IL-
8 and PSA levels is associated with the response of PCa cells to radiation (Figure 3). 
 
Hypothesis:  We predict that patients with low IL-8/PSA ratios have a potential to respond to 
radiotherapy much better than those with high IL-8/PSA ratios.  We propose to examine the 
irradiation-induced changes in systemic inflammatory markers such as IFN-gamma, TNF-alpha, 
IL-8, IL-10, and IL-17 prior to treatment vs. after one and two cycles of treatment, and 8 weeks 
after completing treatment, and correlate values/changes with treatment outcomes. 
 
Figure 1.  PLK1 level is correlated with 
tumorigenicity in different prostate cell 
lines.  Immunoblot of PLK1 in RWPE-1, 
LNCaP, C4-2, and PC3 cells. 
Figure 2.  Plk1-KI mice are hypersensitive to irradiation (IR). 
(A)  Mouse embryonic fibroblasts (MEFs) from control and CMV-
Cre/Plk1-KI mice were plated at clonal density and subjected to 
increasing doses of IR.  The number of colonies appearing after 10 
days on the irradiated plates indicate the reduced viability of Plk1-
overexpressing MEFs upon IR exposure.  To quantify the number of 
cells remaining on the plates after IR, samples were stained with MTT 
and lysed, and absorbance was measured with a standard plate reader.  
The values reported are means ± S.D. of three independent experiments 
(bottom panel).  **p <0.01.  (B)  Mice at the age of 10 weeks were 
subjected to 5 Gy whole-body IR and imaged after 4 months. 

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2.4.5 Immune Cells 
 
Biologic Rationale:  The effects of ionizing radiation are seen not only in tumor cells but also in 
the tumor microenvironment.  In general, lymphocytes (T cells, B cells, and natural killer [NK] 
cells) are among the most radiosensitive cells, followed by monocytes, macrophages, and 
antigen-presenting cells (APCs), specifically dendritic cells (DCs), which have a higher radio-
resistance (Bauer et al., 2011; Manda et al., 2012).  Additionally, radiation therapy can cause 
overproduction of inflammatory chemokines and cytokines including granulocyte colony-
stimulating factor (G-CSF), macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-
CSF), IL-6, IL-10, vascular endothelial growth factor (VEGF), transforming growth factor 
(TGF)-beta, tumor necrosis factor (TNF)-alpha, chemokine ligand (CCL) 2, CCL5, and 
prostaglandin E2.  The overproduction of these chemo-cytokines results in altering myelopoiesis 
and causing release of MDSCs.  MDSCs suppress antitumor responses of T and NK cells and 
expand regulatory T cells, promoting cancer progression (Umansky et al., 2016).  IL-6 is 
critically important for MDSC generation and survival.  There is a correlation between increased 
IL-6 concentrations and MDSC frequencies and their suppressive functions (Chi et al., 2014).  
MDSCs are increasingly recognized as important contributors to immunosuppression in the 
Figure 3.  The effects of PSA and IL-8 on radioresistance of PCa cells.  To determine the roles of PSA 
and IL-8 in radiosensitivity of PCa cells, LNCaP cells were treated with IL-8 protein or stably transfected 
with IL-8 cDNA (A) and stably transduced with PSA shRNA lentivirus (B).  PC3 cells were stably 
transduced with PSA cDNA and IL-8 shRNA lentivirus (C).  The levels of PSA were quantified by western 
blots, and the levels of IL-8 were quantified by either western blots or an ELISA kit. 

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tumor micro-environment and are also closely associated with resistance to RT (Kang et al., 
2020). 
 
Hypothesis:  We propose to evaluate the correlation between frequencies of MDSCs, immune 
function markers, and treatment outcomes.  The markers of immune function will be evaluated 
by measuring the percentage and absolute number of CD4+ T helper cells, CD8 T+ cytotoxic 
cells, NK cells, T regulatory cells, PMN-MDSCs, and M-MDSCs by flow cytometry prior to 
treatment vs. after one and two cycles of treatment, and 8 weeks after completing treatment, and 
correlate changes with treatment outcomes.  PMN-MDSCs are defined as CD15+ HLA-DRlow 
CD14+/- and M-MDSCs are defined as CD15- HLA-DRlow CD14+ CD11b+ CD33+ by flow 
cytometry. 
 
2.4.6 Patient-Reported Outcomes by Common Terminology Criteria for Adverse Events (PRO-
CTCAE) 
 
The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (CTCAE) was designed for patients to report their symptomatic AEs in a complementary 
manner to clinician graded CTCAE AE items (https://healthcaredelivery.cancer.gov/pro-ctcae).  
While the measurement system has been validated, the current use of PRO-CTCAE in clinical 
trials remains exploratory.  Clinician reported AE items remains the safety standard.  There is no 
real-time review of the patients’ responses.  Patients are encouraged to report their concerning 
symptoms to their physicians and/or nurses. 
 
In this study, the symptomatic AEs to be collected are nausea, vomiting, constipation, diarrhea, 
numbness and tingling, dizziness, general pain, joint pain, fatigue, painful urination, urinary 
urgency, urinary frequency, and change in usual urine color. 
 
For any one of these items, patient may be asked 1-3 questions for the presence, frequency, 
severity, and level of interference.  For these 5 PRO-CTCAE items, patients will be asked a total 
of 11 questions.  These PRO-CTCAE items correspond to nausea, vomiting, constipation, 
diarrhea, numbness and tingling, joint pain, fatigue, painful urination, urinary urgency, urinary 
frequency, change in usual urine color, CTCAE items that clinicians are reporting.  Patients will 
report every 2 weeks from the beginning of treatment until Week 28, and then every 3 months 
for a total of 12 months after the first Sn-117m-DTPA administration. 
 
Studies have demonstrated that clinicians under-report symptomatic AEs compared to patient 
reporting of symptoms in Health-Related Quality of Life instruments.  Patient reporting may 
provide more complete information, particularly for lower grade chronic toxicities that may 
impair tolerability over time.  The PRO-CTCAE data will be evaluated for data quality, to 
characterize baseline symptom status of patients on study, to explore the development of 
symptomatic AEs and their change over time, and to explore the patient scores with clinician 
graded AEs. 
 
3. 
PATIENT SELECTION 
 

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3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed adenocarcinoma of the 
prostate that is castration-resistant, defined as: 
o A castrate serum testosterone level ≤50 ng/dL or 1.7 nmol/L 
o Bilateral orchiectomy or maintenance on androgen ablation therapy with 
luteinizing hormone-releasing hormone (LHRH) or antiandrogen such as 
bicalutamide.  Androgen deprivation therapy needs to be maintained throughout 
the study unless a patient has had orchiectomy by surgery.  
o Serum PSA progression defined as two consecutive increases in PSA over a 
previous reference value, each measurement at least 1 week apart. 
 
3.1.2 Progression after androgen receptor blockers (enzalutamide, apalutamide, or 
darolutamide) or androgen synthesis blockers (abiraterone acetate) or chemotherapy 
(docetaxel or cabazitaxel).  There are no maximum number of prior therapies. 
 
3.1.3 Progressive castration-resistant prostate cancer with two or more skeletal metastases 
identified by Tc-99m bone scintigraphy or prostate specific membrane antigen (PSMA) 
PET scan .  
 
3.1.4 Patients must have self-reported moderate to severe pain at trial entry (baseline weekly 
average “worst pain in the past 24-hours” scores of ≥4 on an 11-point numeric rating 
scale [NRS], the Brief Pain Inventory – Short Form [BPI-SF] item #3 for worst pain). 
 
3.1.5 Patients must either currently employ regular (not occasional) analgesic medication use 
for cancer-related bone pain or have undergone treatment with EBRT for bone pain 
within 4 weeks before starting study treatment. 
 
3.1.6 Age ≥18 years.  Children <18 years of age are excluded from the study as the prevalence 
of prostate cancer is extremely rare in this age group. 
 
3.1.7 Patients must have a life expectancy ≥3 months. 
 
3.1.8 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.9 Patients must have a serum PSA value ≥1 ng/mL. 
 
3.1.10 Patients must have adequate organ and marrow function as defined below to be eligible 
for the first treatment administration: 
 
− 
absolute neutrophil count 
 
≥1,000/mcL 
− 
platelets  
 
≥100,000/mcL 
− 
hemoglobin 
 
>10.0 g/dL 
− 
total bilirubin 
 
≤2.5 × institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
 
≤5 × institutional ULN 
− 
creatinine  
 
≤1.7 mg/dL 

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OR 
− 
glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 (see Appendix B) 
 
3.1.11 Patients receiving bisphosphonates or denosumab prior to enrollment can maintain 
therapy throughout all or part of the study.  The bisphosphonate may be stopped or 
started at the discretion of the investigator throughout the study (i.e., both treatment phase 
and follow-up).  Injection of bisphosphonates should be done at least 2 hours before or 
after study drug administration. 
 
3.1.12 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.13 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.14 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible 
if they have an undetectable HCV viral load. 
 
3.1.15 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.16 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be eligible 
for this trial, patients should be class 2B or better. 
 
3.1.17 The effects of Sn-117m-DTPA on the developing human fetus are unknown.  For this 
reason and because radionuclides are known to be teratogenic, male participants and their 
female partners must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while her male partner is 
participating in this study, she should inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 6 months after completion of Sn-
117m-DTPA administration. 
 
3.1.18 Patients must be willing and able to comply with the protocol and agree to return to the 
hospital for follow-up visits and examinations. 
 
3.1.19 Ability to understand and the willingness to sign a written informed consent document.   
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients must not have visceral metastases (such as liver and lung) as assessed by 

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abdominal/pelvic CT or chest X-ray within 12 weeks before starting study treatment. 
 
3.2.2 Patients must not have malignant lymphadenopathy exceeding 3 cm in short-axis 
diameter. 
 
3.2.3 Patients must not have imminent or established spinal cord compression based on clinical 
findings and/or MRI. 
 
3.2.4 Patients who have had chemotherapy, immunotherapy, or external radiotherapy within 4 
weeks prior to entering the study. 
 
3.2.5 Patients must not have received systemic radiotherapy with radium-223, strontium-89, 
samarium-153, rhenium-186, or rhenium-188 for the treatment of bony metastases within 
24 weeks before starting study treatment. 
 
3.2.6 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1) with the exception of alopecia. 
 
3.2.7 Patients must not have received any investigational agents within 4 weeks before starting 
study treatment, nor be scheduled to receive one during the planned treatment period. 
 
3.2.8 Patients must not have unmanageable urinary incontinence. 
 
3.2.9 Patients must not have had known non-pathological bone fractures within 2 months 
before starting study treatment. 
 
3.2.10 Patients must not have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to Sn-117m-DTPA. 
 
3.2.11 Patients must not have uncontrolled intercurrent illness, including: 
o Any uncontrolled infection 
o Grade 2 or greater motor or sensory neuropathy 
 
3.2.12 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.3 
Inclusion of Minorities 
 
NIH policy requires that members of minority groups and their subpopulations be included in all 
NIH-supported biomedical and behavioral research projects involving NIH-defined clinical 
research unless a clear and compelling rationale and justification establishes to the satisfaction of 
the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the 
health of the subjects or the purpose of the research.  Exclusion under other circumstances must 
be designated by the Director, NIH, upon the recommendation of an IC Director based on a 
compelling rationale and justification.  Cost is not an acceptable reason for exclusion except 
when the study would duplicate data from other sources.  Please see 

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• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (Investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the Clinical 
Investigator (CI) on the DTL must be rostered at the enrolling site with a participating 
organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO), and 
• Compliance with all protocol-specific requirements (PSRs). 

NCI Protocol #:  10437 
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26 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a PO on the protocol.  One 
way to search for a protocol is listed below. 
 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-OH007, and 
protocol number 10437, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB, IRB data will load automatically to the 
CTSU.)  
 
4.2.2 Protocol Specific Requirements for Protocol 10437 Site Registration 
 
• Specimen Tracking System Training Requirement: 
o The Study PI will conduct the site initiation training (SIV) for each site.  Study 
investigators and staff must review initial site initiation slides and/or attend site 
initiation webinar, as well as reviewing all amendments. 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 
 
• The following three documents must be submitted to NCIPMBTRFDOCS@mail.nih.gov 
(Note: please submit all documents simultaneously in a single e-mail with the subject line “NCI 
Protocol 10437:” 
o Upon CTEP receipt of these documents it will take at least one week to set-up the site 
and personnel. 

NCI Protocol #:  10437 
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1. 
A valid facility Radiation Material License (RML) approved for medical use of Sn-
117m with a valid expiration date. 
o Updates to the license must be submitted throughout the course of the trial in the 
same fashion. Sites will not be able to enroll study subjects or submit requests for 
Sn-117m-DTPA without a valid facility license on file. 
2. 
A fully completed “Sn-117m-DTPA Site On-Boarding Form” (see Appendix K). 
o Updates to the provided information on this form must be submitted throughout the 
course of the trial in the same fashion. 
o The form must: 
o Identify the targeted radiopharmaceutical treatment facility (TRF) and 
address to where the Sn-117m-DTPA will be shipped. 
o Document the availability of a Sn-117m calibrated dose calibrator and the 
date of last calibration. 
o Identify the CTEP registered physician investigator Authorized Users of 
Sn-117m-DTPA for medical use responsible for prescribing Sn-117m-
DTPA at the Targeted Radiopharmaceutical Facility (TRF) treating site and 
overseeing subject therapy with this agent. One CTEP registered physician 
investigator Authorized User of Sn-117m-DTPA for medical use is required 
to be identified, but at least two are preferred for sites with adequate 
personnel. 
o Identify the qualified site shipping contact personnel responsible for 
receiving, storing, and dispensing Sn-117m-DTPA. Two CTEP registered 
study site personnel registered at the Associate Plus, Non-Physician 
Investigator or Investigator registration type are required to be identified 
that have been identified by the site RSO as Sn-117m-DTPA trained 
personnel.  
o The identified study site personnel are not mutually exclusive. CTEP 
registered study site personnel may be identified to serve in multiple contact 
roles on the On-Boarding Form. 
3. 
A Radiation Safety Officer (RSO) provided list of individuals at the site that are 
Authorized Users of Sn-117m for medical use (if not included on the RML) and an 
RSO provided list of personnel trained and credentialed by your RSO to handle, 
receive, store, dispense and manage Sn-117m-DTPA waste. 
o Any updates to the provided Authorized User list or list of trained personnel must 
be submitted throughout the course of the trial in the same fashion.  
• Each enrolling site must be aligned to a credentialed TRF provider for the protocol on the 
CTSU website. Sites will manage TRF provider associations via the Provider Association page 
from 
the 
Regulatory 
section 
on 
the 
CTSU 
members’ 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be associated to a credentialed 
TRF for the protocol to participate on this trial. Enrolling sites are responsible for ensuring 
appropriate agreements and IRB approvals are in place if the provider is not directly aligned 

NCI Protocol #:  10437 
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28 
with the enrolling site. An individual with a primary role on any roster is required to update 
provider associations, though all individuals at a site may view provider associations. To find 
who holds primary roles at your site, view the Person Roster Browser under the RUMS section 
on the CTSU website. 
• Sites must be a qualified user of Sn-117m-DTPA for medical use prior to site activation and 
must attest to having a valid calibrated dose calibrator for measuring Sn-117m radioactivity 
upon submission of the On-Boarding Form. Sn-117m-DTPA must be added to a site’s 
radioactive material license and document training for administration and handling of the 
agent. To request training (provided at the expense of Serene LLC), contact Dr. Chad Smith, 
F.X. Masse Associates, Inc., P.O. Box 1636, Gloucester, MA 01931; Phone 978-283-4888; 
Email: info@fxmasse.com. 
If necessary, a calibration reference standard may be requested from IsoTherapeutics by 
contacting Kim Miller; Phone: (979) 848-0800; Email: orders@isotherapeutics.com. Upon 
receipt of the reference standard and completion of calibration of the dose calibrator, a copy of 
the site’s calibration document with calibration date must be submitted to CTEP at the following 
e-mail address: NCIPMBTRFDOCS@nih.gov. Use the Subject: “NCI Protocol 10437 
Calibration Documentation.” 
 
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to the 
Regulatory section, and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section on the CTSU members’ website.  The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site receiving 
an approved site registration status and enrolling patients to the study.  To maintain an approved 
site registration status the CI must re-sign the DTL at least annually and when a new version of 
the DTL is released; and activate new task assignments requiring CI sign-off.  Any individual at 
the enrolling site on a participating roster may initiate the site DTL.  Once the DTL is submitted 
for CI approval, only the designated DTL Administrators or the CI may update the DTL.  
Instructions on completing the DTL are available in the Help Topics button in the DTL 
application and include a Master Task List, which describes DTL task assignments, CI signature, 
and CTEP registration requirements. 
CTEP will use the identified Authorized Users of Sn-117m-DTPA for medical use and identified 
RSO trained personnel list (along with the submitted site Radiation Material License) to create a 

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credentialed TRF in RSS for the trial site and an associated Sn-117m-DTPA credentialed person 
roster for the TRF.  This roster will be used to identify Authorized Users on the Delegation of 
Tasks Log. 
• Authorized User physician investigators of Sn-117m-DTPA for medical use must be 
registered with CTEP at the Investigator level and be listed on the site DTL with the task 
of Authorized User Prescriber.  A minimum of one Authorized User Prescriber 
investigator is required.  A minimum of two is preferred.  
• Sn-117m-DTPA Study Shipping Contact sub-investigators must be listed on the site DTL 
with the task Authorized User Drug Mailing.  A minimum of two Authorized User Drug 
Mailing sub-investigators are required and must be registered with the NCI as an 
Associate Plus, Non-Physician Investigator or Investigator.  
Other site-level Authorized Users of Sn-117m-DTPA for medical use may be identified on the 
DTL with the task Authorized User Medical Use.  There are no minimum requirements for 
identifying these individuals, but if identified, must be registered with the NCI as an Associate 
Plus, Non-Physician Investigator or Investigator.  All individuals assigned to the Authorized 
User tasks must be identified as such by the site Radiation Material License indicating their 
authority as an Authorized User of Sn-117m-DTPA for medical use or site Radiation Safety 
Officer authorized list indicating their authority as an Authorized User of Sn-117m-DTPA for 
medical use or site trained personnel for Sn-117m-DTPA. 
 
 
4.2.4 Checking Site Registration Status 
 
A site’s registration status may be verified on the CTSU website.  
 
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB type. 
 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol.  It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with the NCI or 
their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment.  OPEN or IWRS will populate the 
patient enrollment data in NCI’s clinical data management system, Medidata Rave. 

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30 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
• If a DTL is required for the study, the registrar must hold the OPEN Registrar task on the 
DTL for the site. 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  The IWRS system also sends an email confirmation of the registration.  
You may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System or the IWRS Slot 
Reservation System to ensure that a slot on the protocol is available to the patient.  Once a slot 
reservation confirmation is obtained, site staff may then proceed to enroll the patient to this 
study.  
 
Sites must reserve a slot in IWRS.  The multi-institution program coordinator will verify slot 
availabilities prior to consenting patients.  The required forms, including the eligibility criteria 
checklist and registration form, should be provided to the study team.  The study team will 
review the request and, once a slot is allocated, will communicate with the sub-site regarding the 
decision. 
 

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4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through Rave user roles:  “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the Early-Phase 
and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly known as 
the ETCTN Biorepository).   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions on use of the STS can be found in Section 5.4. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN link of the CTSU website 
at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
855-828-6113 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.3.4 Patient Registration for Medidata Patient Cloud 
 
a. Medidata Patient Cloud  
 
This study includes the use of Medidata Patient Cloud electronic patient-reported outcomes.  
Patients will be allowed the paper format option if they are not comfortable using the digital app 
format or if it is not available.  All sites will participate in the collection.  After the patient is 
registered to the trial via OPEN, and if the patient is willing to participate in electronic data 
collection (or paper, which will be converted to electronic by site staff), the site staff will then 
complete a registration for the patient to the Patient Cloud through iMedidata.  Note:  Site staff 
must have already completed required eLearning for the Patient Cloud application to register a 
patient and information about the training is in the Medidata Patient Cloud Registration 
Appendix (Appendix H).  The registration to the Patient Cloud will create a unique patient 
registration code that the site staff will provide to the patient.  The patient (with assistance from 

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32 
the site staff) should be instructed to download the Patient Cloud app onto his/her own device 
(IOS, Android, phone, or tablet) and use the unique patient registration code to create an account.  
Once the patient's account is set up, the patient will be able to complete the submission of patient 
reported outcomes electronically for the trial.  
 
For sites providing a shared institutional device for use by multiple patients on site:  
 
• The site staff should assist the patient with access and registration to the Patient Cloud 
app, and the patient can then complete the electronic data submission independently.  Site 
staff may need to assist patients with logging on to the device at each visit.  
 
b. CRA Patient Registration Instructions for Medidata Patient Cloud 
 
Please visit the Medidata Learning Tool (https://learn.mdsol.com/patient-cloud/en/video-library-
for-providers-102101952.html) for reference information on Patient Cloud for CRAs.  
 
i. 
The subject registration process starts in iMedidata.  Begin by selecting the Patient Cloud 
Registration link for your study 
ii. 
The patient management app will display, select your STUDY and SITE from the drop 
downs and click Launch. 
iii. 
Now you can register your first patient.  Create a subject ID and select a Country / 
Language from the drop down, (these are the only required data fields). The subject 
initials are optional, but are helpful in identifying which subject ID maps with which 
activation code.  When finished, click Add. 
iv. 
The subject added and will include the date the patient was added, the subject ID, subject 
initials, (if included) and a unique auto-generated activation code.  The activation code is 
unique for each patient and linked to the subject ID, it is not interchangeable.  In addition, 
there is a status section, which indicates if the patient has registered.  When the patient 
has registered the status will change from "invited" to "registered". 
 
Reminder- site staff must have already completed the Medidata Patient Cloud training in order to 
register study participants.  Please visit the Medidata Learning Tool for reference information on 
Patient Cloud for CRAs (https://learn.mdsol.com/patient-cloud/en/video-library-for-providers-
102101952.html). 
 
There are multiple versions of the app available.  Ensure that the correct version of the app is 
downloaded by the patient by verifying the correct version per the study build requirements.  
Note: only 1 version of the app is active per protocol and this protocol is using Patient Cloud. 
 
 Patient Cloud 
 
 
 
 
4.4 
General Guidelines 
 

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34 
slides must be processed in order, and numbered sequentially. 
 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies 
 
N/A 
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits  
 
Kits for the collection and shipment of blood in CPT tubes to the EET Biobank can be ordered 
online via the Kit Management system: https://kits.bpc-apps.nchri.org.  
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit.  Please note that protocol may include more than 
one type of kit.  Each user may order two kits per kit type per day (daily max = 6 kits).  Kits are 
shipped ground, so please allow 5-7 days for receipt.  A complete list of kit contents for each kit 
type is located on the Kit Management system website. 
 
Note:  Kits or supplies are only provided for specimens shipped to the Biobank. Institutional 
supplies must be used for all other specimen collection and processing.  
 
5.3.2 Scheduling of Specimen Collections 
 
Please adhere to the following guidelines when scheduling procedures to collect specimens:  
 
• Fresh blood in EDTA may be collected and shipped Monday through Friday.  
• Blood in CPT processed for plasma and mononuclear cells can be collected any day and 
shipped on Monday through Thursday.  
 
5.4 
Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 

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patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies, the radiology and operative 
report(s) must also be uploaded into Rave.  Important:  Remove any personally identifying 
information, including, but not limited to, the patient’s name, date of birth, initials, medical 
record number, and patient contact information from the institutional pathology report 
prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List Report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like plasma and PBMCs): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, plasma, PBMC) 
• Collection date (to be added by hand) 
 
5.4.2.2 Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, Formalin 
Fixed Tissue, etc.) 

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• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number 
• Block number from the corresponding pathology report 
• Collection date (to be added by hand)  
• Slide section number (only if archival tissue is submitted as slides) (to be added by 
hand) 
 
5.4.2.3 Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder.  A generated PDF is emailed to the user as a result of saving that form. 
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line.   
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page.  Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers:  https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/ 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time.  
The last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 

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5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be set up 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal Patient 
ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates unique 
Specimen ID.  
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
• Label specimen containers and write collection date on each label.  After collection, store 
labeled specimens as described in Section 5.5. 
• Apply an extra specimen label to each report before scanning.  Return to the Histology 
and Disease form to upload any initial Pathology, Radiology, Molecular Reports (up to 
4), Surgical (or Operative) reports and Tissue Biopsy Verification form (when 
applicable).  Return to Specimen Tracking Enrollment CRF to upload any molecular 
report (one per specimen) and/or specimen specific pathology or related report (one per 
specimen).  Uploaded reports should have protected health information (PHI) data, like 
name, date of birth, mailing address, medical record number or social security number 
(SSN), redacted.  Do not redact SPID, block number, diagnosis, or relevant dates 
(such as collection date), and include the UPID and patient study ID on each 
document (either by adding a label or hand writing).  
 

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Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  In the specimen folders for additional specimens (if any) that will 
be shipped with the initial specimen, please use the Copy Shipping form to derive 
common data into additional Shipping Status forms. A few unique fields will still need 
to be entered in Shipping Status. 
 
Step 5:  Print shipping list report and prepare to ship.  
• The Shipping List Report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed copy 
includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on the 
Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
Step 8:  Monitor the Receiving Status form located in each specimen folder for acknowledgment 
of receipt and adequacy. 
 
5.5 
Specimen Collection  
 
5.5.1 Archival Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen  
 
If previously-collected FFPE tissue will be submitted, then the following criteria must be met: 
• Tissue is preferred from radical prostatectomy specimens, however, a core or excisional 
biopsy of a tumor lesion is acceptable. 
• Tissue is preferred to be collected within 3 years prior to registration for whole genome 
sequencing/RNA sequencing and PLK1 immunohistochemistry staining.  Archival 
tissues must be collected within 3 years to perform RNA squencing study.  However, two 
decade old tissues are acceptable to use for DNA sequencing and PLK1 
immunohistochemistry studies.  
• Submission of either FFPE tumor tissue block(s) or unstained slides is acceptable; FFPE 
tumor blocks are preferred.  The optimal block is at least 70% tumor.  Specimen size 
requirement is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success of 

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DNA extraction decreases at suboptimal tissue volume. 
 
If an existing block cannot be submitted, the following are requested, if available.  If submitting 
unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 72 
hours from the date the slides are cut, otherwise a new sample will be requested.  
• Four (4) unstained charged slides (4-5 µm) 
• 15-20 (10-micron) unstained uncharged slides 
• 1 H&E stained slide (3-5 µm) 
 
Process and number slides sequentially (e.g., unstained charged slides should be created first and 
labeled with 1 – 4, and additional unstained slides should be processed next and be labeled 5 – 
n). 
 
See Section 5.4.2 for labeling instructions. 
 
5.5.2 Blood Collection  
 
5.5.2.1 Collection of Blood in EDTA Tubes for Shipping Whole Blood (WES baseline sample) 
 
1. Label EDTA tubes according to the instructions in Section 5.4.2. 
2. Collect 10 mL blood in EDTA tube(s) and gently invert tube to mix. 
3. Ship on day of collection (whenever possible) according to instructions in Section 
5.6. 
4. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment.  
 
5.5.2.2 Collection of Blood in CPT Sodium Citrate Tubes for Plasma and PBMC Processing 
(Immune Cells and Inflammatory Markers samples) 
 
1. Label CPT sodium citrate tubes according to the instructions in Section 5.4.2. 
2. Collect three (3) 8-mL samples and gently invert to mix. 
3. The samples can be stored on ice up to 2 hours before processing.  
4. Centrifuge the vacutainers at 3,000 rpm (approx. 1,700 x g) at 21 C for 12 minutes so 
as to produce plasma.  The resulting plasma should be stored in 1 ml aliquots at -80 C 
or below. 
5. The PBMC layer should be transferred to a fresh tube with sterile PBS and 
centrifuged at 300 x g for 15 minutes.  Repeat the washing step, then cryopreserve in 
10% DMSO/FBS, preferably in 0.5 mL aliquots with 2,000,000 cells per aliquot.  The 
samples should be frozen in a “Mr. Frosty”, or similar below-freezing apparatus and 
stored in liquid nitrogen the next day for long term storage. 
6. Ship on day of collection (whenever possible) according to instructions in Section 
5.6. 
7. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment.  Ship frozen plasma and mononuclear cells according 
to instructions in Section 5.6. 
 

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5.6 
Shipping Specimens from Clinical Site to the EET Biobank 
 
5.6.1 General Shipping Information 
 
When kits are provided, the shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank.  In winter months, please include extra insulation, such as bubble 
wrap, inside the shipping container. 
 
For all archival tissue, the corresponding anatomical clinical pathology report is required both in 
the package and uploaded in the ETCTN specimen tracking system.  If this is not available at the 
time of shipment, then it must be sent to the EET Biobank as soon as possible and uploaded to 
the ETCTN specimen tracking system, or the specimen will not be processed.  The pathology 
report must state the disease diagnosis made by the reviewing pathologist. 
 
5.6.1.1 
Required Forms for Specimen Submissions: 
 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID.  
 
Tissue  
Required Forms 
Archival Tissue 
1. Shipping List 
2. Corresponding Pathology Report 
 
Other (blood, blood product, urine, 
stool, etc.)  
1. Shipping List 
 
5.6.2 Specimen Shipping Instructions 
 
Archival (FFPE) tissue may be shipped on Monday through Thursday.  
 
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday.  
 
5.6.2.1 
Shipping of FFPE Blocks and Glass Slides  
 
1. Before packaging blocks or slides, verify that each specimen is labeled according to 
Section 5.4.2.2. 
2. Blocks should be placed in a hard-sided container, preferably a special block holder, to 
protect the specimen.  Glass slides are to be placed in plastic slide holders.  Place tissue 
paper on top of the separated slides prior to closing the slide holder to reduce slide 
movement during shipment. 
3. Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 

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4. Include a copy of the corresponding pathology report, labeled with the Patient Study ID 
and Universal Patient ID and a shipping manifest from the Specimen Tracking System 
with each shipment. 
5. Please include a cold pack when shipping on hot days and extra insulation on cold days. 
6. Ship specimens to the address listed below.  FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt.  
 
5.6.2.2 
Shipping Blood in an Ambient Shipper 
 
1. Before packaging specimens, verify that the collection tube is labeled according to 
instructions in section 5.4.2.1 
2. Place the blood collection tube into a zip-lock bag.   
3. Place zip-lock bag into a biohazard envelope with absorbent material.  Expel as much air 
as possible and seal the envelope securely.  
4. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 
5. Place the specimen(s) and a copy of the shipping manifest into a sturdy shipping 
container. In winter months please use an insulated container and include extra insulation, 
such as bubble wrap, inside the shipping container to prevent specimens from freezing.  
6. Close the container and tape shut. 
7. Attach a shipping label to the top of the shipping container.  
8. Attach an Exempt Human Specimen sticker to the side of the container. 
Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.2.3 
Shipping Frozen Specimens in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions in section 5.4.2.1 and that lids of all primary receptacles containing liquid are 
tightly sealed.  
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 
and time point.  
3. Place the zip-lock bags in the biohazard envelope containing absorbent material.  Expel 
as much air as possible and seal securely.  
4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.  
5. Place frozen specimens in the kit compartment with dry ice.  Layer the bottom of the 
compartment with dry ice until it is approximately one-third full.  Place the frozen 
specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
compartment is almost completely full.  When packaging specimens, ensure that you 
leave enough room to include at least 5 pounds of dry ice in the shipment.  
6. Insert a copy of the shipping list(s) into a plastic bag and place in the kit chamber. 
7. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
8. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable sealing 
tape.  Do not completely seal the container. 

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9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 
11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.6.3 Shipping Address 
 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions.  
There is no central Courier account for this study.  Sites are responsible for the cost of shipments 
to the EET Biobank.  
 
5.6.4 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank 
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
5.7 
Shipping of Specimens from Clinical Site to Other Laboratories  
N/A 

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43 
5.8 
Biomarker Plan  
 
List of Biomarker Assays in Order of Priority 
Note for participating sites: Please see Section 5.1 for details on specimens to collect.  The specimens tested are not always the 
same specimens that are submitted by the site, as processing of blood and tissue will occur at the Biobank prior to testing.  
 
Priority Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial (Integral, 
Integrated, or 
Exploratory) AND 
Purpose 
Specimens 
Tested 
Collection Time Points 
Mandatory or 
Optional 
Assay Laboratory and Lab PI 
Tissue-based Biomarkers 
1 
Whole 
Exome 
Sequencing 
NGS 
CLIA: N  
Exploratory 
Molecular 
characterization of the 
tumor 
DNA from 
FFPE tumor 
Archival 
O 
NCLN Genomics Laboratory 
Mickey Williams 
mickey.williams@nih.gov 
2 
RNAseq 
NGS 
CLIA: N 
Exploratory 
Molecular 
characterization of the 
tumor 
RNA from 
FFPE tumor 
Archival  
O 
NCLN Genomics Laboratory 
Mickey Williams 
mickey.williams@nih.gov 
3 
Polo-like 
Kinase (PLK) 
IHC 
CLIA: N 
Exploratory 
To evaluate efficacy in 
predicting response to 
therapy 
Unstained 
slides from 
FFPE tumor 
Archival  
O 
Liu Laboratory, University of 
Kentucky 
Xiaoqi Liu 
Xoaoqi.Liu@uky.edu 
Blood-based Biomarkers 

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Priority Biomarker 
Name 
Assay 
(CLIA: Y/N) 
Use in the Trial (Integral, 
Integrated, or 
Exploratory) AND 
Purpose 
Specimens 
Tested 
Collection Time Points 
Mandatory or 
Optional 
Assay Laboratory and Lab PI 
1 
Systemic 
inflammatory 
markers 
(IFN-gamma, 
IL-6, IL-8, IL-
10, IL-17, 
TNF-alpha) 
Flow 
Cytometry 
CLIA: N 
Exploratory 
To examine the 
irradiation induced 
changes in inflammatory 
markers of immune 
function 
Plasma and 
PBMCs from 
CPT sodium 
citrate tube  
Pre-treatment 
Cycle 1 Week 8 
Cycle 2 Week 8 
Week 24 
O 
St. Clair Laboratory, University 
of Kentucky 
William H. St. Clair 
stclair@email.uky.edu 
2 
Immune cells 
(CD4+ T 
helper cells, 
CD8+ T 
cytotoxic 
cells, T 
regulatory 
cells, MDSCs) 
Flow 
Cytometry 
CLIA: N 
Exploratory 
To examine the 
irradiation induced 
changes in inflammatory 
markers of immune 
function 
Plasma and 
PBMCs from 
CPT sodium 
citrate tube 
Pre-treatment 
Cycle 1 Week 8 
Cycle 2 Week 8 
Week 24 
O 
St. Clair Laboratory, University 
of Kentucky 
William H. St. Clair 
stclair@email.uky.edu 
3 
Whole 
Exome 
Sequencing 
NGS 
CLIA: N 
Exploratory 
Germline Control 
DNA from 
blood in 
EDTA tube 
Pre-treatment 
M when 
archival tissue 
or slides are 
submitted. 
NCLN Genomics Laboratory 
Mickey Williams 
mickey.williams@nih.gov 
 
 

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45 
 
5.9 
Exploratory/Ancillary Correlative Studies 
 
5.9.1 Whole Exome Sequencing / RNA Sequencing 
 
5.9.1.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
FFPE tissue blocks will be sectioned to generate an initial hematoxylin and eosin (H&E)-stained 
slide.  All H&E stained slides will undergo a pathology QA review and annotation for 
macrodissection.  Following macrodissection, tumor tissue from unstained slides will be scraped 
for co-extraction of DNA and RNA.  The nucleic acids will be analyzed to determine 
concentration and quality.  Aliquots of DNA and RNA will be shipped to the central sequencing 
laboratory for analysis. 
 
DNA will be extracted from blood collected in the EDTA tube at pre-treatment.  Blood DNA 
will be quantitated, and then stored in a -80°C freezer until shipping to the NCLN Genomics 
Laboratory for analysis. 
 
5.9.1.2 
Site(s) Performing Correlative Study 
 
WES and RNAseq will be conducted in the NCLN Genomics Laboratory under the leadership of 
Mickey Williams, Ph.D. 
 
5.9.1.3 Shipment of specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
NCLN Genomics Laboratory at The University of Texas MD Anderson Cancer 
Center 
Attn: Jincy Veliyathu or Khushali Rajendra Patel 
Zayed Building 
CTLU Z3.4020 
6565 MD Anderson Blvd 
Houston, TX 77030 
 
5.9.1.4 
Contact information for notification of specimen shipment 
 
Thomas Forbes 
NCLNGenomicsReceiving@nih.gov 
 
5.9.2 Polo-like Kinase 
 
5.9.2.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
Unstained slides will be shipped for this assay.  Archival tumor tissue slides will be stored at 
room temperature until shipment.  If archival blocks are received, then slides will be sectioned 
for distribution.   
 

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46 
 
 
5.9.2.2 
Site Performing Correlative Study 
 
Immunohistochemistry for PLK1 will be performed in the laboratory of Xiaoqi Liu, Ph.D., at the 
University of Kentucky. 
 
5.9.2.3 
Shipment of specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
Markey Biospecimen SRF  
Dana Napier  
744 Rose Street, Combs 107 
Lexington, KY 40506 
Phone: 859-323-7374 
 
5.9.2.4 
Contact information for notification of specimen shipment 
 
Please send an email notification of shipment, including protocol ID, patient study ID, study 
visit, and tracking number to Dana Napier at the Markey Biospecimen SRF 
(markey.bstp@uky.edu) 
 
5.9.3 Systemic Inflammatory Markers 
 
5.9.3.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
Frozen plasma and PBMC samples will be accessioned and stored at -80°C until shipment to the 
laboratory for analysis once all timepoints for a patient are collected.   
 
5.9.3.2 
Site Performing Correlative Study 
 
Systemic inflammatory marker changes will be analyzed in the laboratory of William H. St. 
Clair, M.D., Ph.D., at the University of Kentucky. 
 
5.9.3.3 Shipment of specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
Markey Biospecimen SRF  
Dana Napier  
744 Rose Street, Combs 107 
Lexington, KY 40506 
Phone: 859-323-7374 
 
5.9.3.4 
Contact information for notification of specimen shipment 
 
Please send an email notification of shipment, including protocol ID, patient study ID, study 
visit, and tracking number to: Dana Napier at the Markey Biospecimen SRF 

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47 
 
(markey.bstp@uky.edu) 
 
5.9.4 Immune Cells 
 
5.9.4.1 
Specimen(s) Receipt and Processing at the EET Biobank 
 
Frozen plasma and PBMC samples will be accessioned and stored at -80°C until shipment to the 
laboratory for analysis once all timepoints for a patient are collected.   
 
5.9.4.2 
Site Performing Correlative Study 
 
Immune cell population changes will be analyzed in the laboratory of William H. St. Clair, M.D., 
Ph.D., at the University of Kentucky. 
 
5.9.4.3 Shipment of specimens from the EET Biobank to Site Performing Correlative Study  
 
Specimens will be shipped from the EET Biobank to: 
Markey Biospecimen SRF  
Dana Napier  
744 Rose Street, Combs 107 
Lexington, KY 40506 
Phone: 859-323-7374 
 
5.9.4.4 
Contact information for notification of specimen shipment 
 
Please send an email notification of shipment, including protocol ID, patient study ID, study 
visit, and tracking number to: Dana Napier at the Markey Biospecimen SRF 
(markey.bstp@uky.edu) 
 
5.10 
Special Studies 
 
5.10.1 Sn-117m-DTPA Dosimetry 
 
5.10.1.1 
Outcome Measure 
 
Sn-117m-DTPA activity will be evaluated as a primary correlative of radioactivity distribution.  
Tin is an avid bone seeker, and its biodistribution is nearly identical to that of Tc-99m-MDP 
(Swailem et al., 1998).  The highest tin distribution is seen in bone surfaces (82%) with 
increased uptake in bone metastases.  Other normal physiological tissue retention can be seen in 
liver, lungs, spleen, heart, and kidneys, and their uptake varies with the rates of clearance. 
 
5.10.1.2 
Assessment 
 
5.10.1.2.1 
Method of Assessment 
 
Sn-117m-DTPA activity will be assessed by gamma camera dosimetry outlined here and in 

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48 
 
Appendix J.  A positive Sn-117m-DTPA scan is defined as tumor uptake ≥ normal liver uptake 
observed on planar imaging.  Focal and heterogeneous Sn-117m-DTPA bone uptake will be 
correlated with the baseline Tc-99m-MDP dosimetry results. 
 
5.10.1.2.2 
Timing of Assessment 
 
Serial whole-body (head to mid-thigh) planar images in the anterior and posterior projections 
will be acquired during the first cycle only, 1 hour, 4 hours (or within 4-6 hours), 24 hours (or 
within 16-24 hours), 48 hours (or within 40-48 hours), 72 hours (or within 60-72 hours), 1 week 
(±2 days), and 4 weeks (±2 days) after the first Sn-117m-DTPA dose (see the table below).  If 
one or more images are not performed at the correct time, make-up whole-body scans are not 
needed, especially for patients that live in the vicinity of the clinic.  
 
Table:  Dosimetry image acquisition timelines 
 
Timing (Target range) 
Imaging 
1 hr 
Whole body scan * 
4 hrs (4-6 hrs) 
Whole body scan 
24 hrs (16-24 hrs) 
Whole body scan + SPECT/CT 
48 hrs (40-48 hrs) 
Whole body scan + SPECT/CT 
72 hr (60-72 hrs) 
Whole body scan 
1 week (+/- 2 days) 
Whole body scan 
4 weeks (+/- 2 days) 
Whole body scan 
*No voiding between radiopharmaceutical infusion and 1st imaging.  
SPECT/CT: single-photon emission computed tomography/computed tomography 
 
Dosimetry reference standard preparation and utilization 
 
After each therapeutic session, the residual activity in the vial will be measured in a dose 
calibrator, labelled as a reference standard, and kept for further imaging.  The reference standard 
will be placed at the inferior part within the field of view of whole-body scans at all time points.  
Caution will be taken for the standard reference not to touch the patient during imaging.  
Optional 3D SPECT scans will be performed at 24 hours and 48 hours in the upper abdomen to 
include kidneys, liver, and spleen.  Extending coverage can be done to include regions 
determined by the planar imaging.  
 
5.10.1.3 
Data Recording 
 
5.10.1.3.1 
Method of Recording 
 
We will compare radiopharmaceutical whole-body retention rates of our patients to the 
previously reported values.  Image based dosimetry analysis will be performed.  
1) Equipment:  Large-field-of-view dual-head gamma camera will be used.  
2) Energy window:  20% window centered at 159 KeV 
3) Collimator:  Low-energy high-resolution parallel-hole (LHRP) collimator  
 

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49 
 
Image Analysis:  
 
Geometric mean will be calculated from anterior and posterior images for both whole-body.  
Counts in whole-body images will be normalized at the first image, scanning the patient with 
100% of the injected activity at 1 hour before patient void or by subtracting the percent of 
injected activity eliminated in the urine before the first image acquisition.  
 
Patient-specific organ mass (liver, spleen, and kidneys) will be obtained by measuring organ 
volume using CT scan and assuming liver, spleen, and kidney density as 1.03 g/cc.  Regions of 
interest (ROIs) will be placed over whole body, liver, spleen, and kidneys, as well as the 
dosimetry reference standard on both anterior and posterior planar whole body images.  Both 
total counts and number of pixels will be recorded for each ROI.  Target organ radiation 
absorbed dose will be calculated using the MIRD schema or related methodology. 
 
5.10.1.3.2 
Timing of Recording 
 
Dosimetry scans will be assessed within one week of Sn-117m-DTPA administration. 
 
5.10.2 Sn-117m-DTPA Palliative Pain Effect 
 
5.10.2.1 
Outcome Measure 
 
The effect of Sn-117m-DTPA treatment on cancer-related bone pain will be assessed via patient 
reports of pain intensity and changes in analgesic use to manage pain.  Patients will be asked to 
complete the BPI-SF questionnaire, which rates several aspects of pain and the effects of pain on 
common activities, on an 11-point scale; a “0” represents “no pain/no pain relief/does not 
interfere”, and an “11” represents “pain as bad as you can imagine/complete relief/completely 
interferes”.  Patients will also be asked to complete a simple analgesic use log by choosing 
among the options of “decreased”, “stable”, or “increased” use of any pain medication. 
 
5.10.2.2 
Assessment 
 
5.10.2.2.1 
Method of Assessment 
 
The Sn-117m-DTPA palliative pain effect will be measured by using a pain index as described in 
the table below (Nilsson et al., 2012). 
 
Classification of pain index based on diary pain intensity rating and analgesic intake 
Pain response 
Pain index 
Diary pain rating change from 
baseline 
Analgesic intake 
compared with 
baseline 
Complete 
1 
Decrease ≥90% 
Stable or reduced 
Marked  
2 
Decrease ≥50% to <90% 
Stable or reduced 
Moderate 
3 
Decrease >33% to <50% 
Stable or reduced 
Minimal 
4 
Decrease ≥20% or increase <33% 
Stable 
None 
5 
Decrease <20% or increase <20% 
Stable  

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50 
 
Pain progression 
6 
Increase ≥20% 
Stable or increased 
Decrease <20% or increase <20% 
Increased 
Decrease ≥20% 
Increased 
 
 
 
This pain index is derived from a combination of the following 11-point pain intensity scale and 
analgesic consumption categorized according to the World Health Organization (WHO) 
analgesic ladder. 
 
Pain intensity scale (Item #3 on the BPI-SF, worst pain)  
 
Analgesic Use/Consumption 
PATIENT-REPORTED ANALGESIC LOG 
Decrease 
Stable 
Increase 
 
Both narcotic and non-narcotic analgesic use and pain intensity scales will be captured using the 
Medidata Patient Cloud where patients will be able to complete the submission of their worst 
pain score and analgesic log electronically.  A paper format option is allowable in case a digital 
collection format is not available or the patient is not comfortable using the app (Appendix E).  
Clinical research coordinators will verify the medication and fill out the pain medication list 
(Appendix F) with every clinic visit.    
 
5.10.2.2.2 
Timing of Assessment 
 
Pain at baseline and analgesic use (pre-treatment, Week 0) will be measured via serial (daily) 
assessments in a 7-day run-in period.  Patients will be considered evaluable if they complete 
assessments on ≥4 days within the 7-day run-in period.  During treatment, pain and analgesic use 
will be measured every 2 weeks through Week 28, followed by routine clinic follow-up until 1 
year or when patients experience new pain.  Complete pain assessments via the full BPI-SF 
(Appendix D) will be collected at baseline, after Cycle 1, after Cycle 2, and at Week 28.  Pain 
assessments will be halted at the patient’s request or if the patient discontinues study treatment 
for reasons other than disease progression. 
 
5.10.2.3 
Data Recording 
 
5.10.2.3.1 
Method of Recording 
 
• Pain assessments and analgesic logs will be post-processed using Medidata Rave EDC 
(electronic data capture).  Data collection for this study will be done through Medidata 

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51 
 
Rave. 
 
5.10.2.3.2 
Timing of Recording 
 
• The pain score and analgesic data will be assessed for inclusion determination during the 
pre-screening period within 2 weeks of a patient’s enrollment.  
 
 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described in Sections 6.1 and 
6.3 may be administered with the intent to treat the patient's malignancy. 
 
Study Regimen Description 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
Sn-117m-DTPA 
20 mCi/70 kg  
(0.28 mCi/kg) 
Slow IV injection 
over 10 min 
Day 1 
8 weeks* 
 
*Treatment continues for 2 cycles.   
 
Retreatment after 2 cycles is allowed after an evaluation of AEs if: 
• pain (≥4 on 11-point intensity scale) recurs within 6 months after a 16-week pain 
observation period  
AND 
• no disease progression on bone scans (≤2 new bone lesions), or evidence of clinical 
progression (such as development of cancer-related symptoms)  
 
Patients will be administered two additional cycles (8 weeks apart) if they meet the retreatment 
criteria.  The maximum treatment dose per patient is four injections in this study. 
 
Patients will be instructed to maintain a high fluid intake (drink at least two to three quarts of 
fluid every 24 hours) for 2 weeks after each Sn-117m-DTPA treatment to minimize a 
concentrated radioactive excretion.  In general, drinking alcoholic beverages should be kept to a 
minimum or avoided completely.  Patients will be educated on hygiene instruction/precautions 
on post-therapy treatment (see Appendix I).  
 
Required Criteria for Each Re-Treatment: 
 
Patients must have adequate organ and marrow function as defined below to be eligible 
for subsequent treatments after the first treatment administration: 
 

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52 
 
− 
leukocytes  
 
≥2,000/mcL 
− 
absolute neutrophil count 
 
≥1,000/mcL 
− 
platelets  
 
≥75,000/mcL 
− 
hemoglobin 
 
≥8.0 g/dL 
− 
total bilirubin 
 
≤ 2.5 × institutional ULN 
− 
AST(SGOT)/ALT(SGPT) 
 
≤5 × institutional ULN 
− 
creatinine* 
 
≤1.7 mg/dL 
OR 
− 
glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 (see Appendix B) 
*Should a 40% increase over the baseline serum creatinine value occur during the course of 
treatment, with a concomitant decrease of over 40% in creatinine clearance as calculated 
from serum creatinine concentrations according to Cockroft’s method (see Appendix B), 
patients must also have a measured creatinine clearance (or GFR) performed, unless 
resolved within 16 weeks.  
 
6.1.1 CTEP IND Agent 
 
6.1.1.1 
Sn-117m-DTPA 
 
Visually inspect solution for particulate matter or discoloration prior to administration.  Sn-117m-
DTPA solution is not to be diluted or mixed with any other solutions.  Sn-117m-DTPA doses are 
administered by slow intravenous injection over 10 minutes into a free-flowing IV line containing 
0.9% sodium chloride.  The intravenous access line is to be flushed with 0.9% sodium chloride after 
injection of Sn-117m-DTPA.  Doses must be administered by Authorized Users in a designated 
clinical setting licensed accordingly for medical use of Sn-117m-DTPA. 
Vials are to be assayed immediately prior to and after withdrawal of the subject dose.  Record 
radioactive activity administered according to institutional protocol and on the NCI Drug 
Accountability Record Form.  The actual radioactivity administered must be within the tolerance 
limits of ± 10% of the calculated radioactivity. 
 
Administration is associated with potential risks to other persons from radiation or contamination 
from spills of bodily fluids such as urine, feces, or vomit.  Therefore, radiation protection 
precautions must be taken in accordance with national and local regulations. 
 
Sn-117m-DTPA should be handled by the user in a manner which satisfies both radiation safety 
and pharmaceutical quality requirements.  Appropriate aseptic precautions should be taken.  
Follow normal working procedures for the handling of radiopharmaceuticals and use universal 
precautions for handling and administration such as gloves and barrier gowns and when handling 
blood and bodily fluids to avoid contamination. 
 
In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of 
radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize 
the distance to radiation sources, and to use adequate shielding.  Any unused product or materials 

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used in connection with the preparation or administration are to be treated as radioactive waste 
and should be disposed of in accordance with local regulations.  
 
Sn-117m-DTPA must be added to a site’s radioactive material license and document training for 
administration and handling of the agent.  To request training (provided at the expense of Serene 
LLC), contact Dr. Chad Smith:  
 
Chad A. Smith, Ph.D., CHP 
F.X. Massé Associates, Inc. 
Health and Medical Physics Consultants 
PO Box 1636 
Gloucester, MA 01931 
Phone: 978-283-4888 
Fax: 978-281-6702 
Email: info@fxmasse.com 
 
6.2 
Definition of Dose-Limiting Toxicity 
 
Toxicity will be assessed using the NCI’s CTCAE version 5.0.  A DLT is defined as an AE or 
abnormal laboratory value assessed as being at least possibly related to the study medication, 
which occurs within 60 days after the second cycle of Sn-117m-DTPA. 
 
A DLT is defined as: 
 
Hematologic DLT  
- 
Grade ≥3 neutropenia or thrombocytopenia lasting ≥14 days 
- 
Grade ≥3 thrombocytopenia with bleeding lasting ≥14 days 
 
Non-hematologic DLT 
- 
Grade 3 or 4 toxicity at least possibly related to study treatment and not reversible to 
grade ≤1 within 24 hours, spontaneously or with standard supportive measures (e.g., 
antiemetics, electrolyte replacement), EXCEPT: 
o Grade 3 nausea/vomiting or diarrhea that lasts <72 hours 
o Grade 3 fatigue that lasts <7 days 
o Grade ≥3 electrolyte abnormality that lasts <72 hours, unless the patient has 
clinical symptoms, in which case all grade 3 electrolyte abnormalities count as 
DLT.  
o Grade 3 amylase or lipase elevation without associated symptoms or clinical 
manifestations of pancreatitis 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
6.3.1 Concomitant Prostate Cancer Therapy 
 
• Patients receiving bisphosphonates or denosumab prior to enrollment can maintain 
therapy throughout all or part of the study.  The bisphosphonate may be stopped or 

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started at the discretion of the investigator throughout the study (i.e., both treatment phase 
and follow-up).  Injection of bisphosphonates should be done at least 2 hours before or 
after study drug administration.  
• Patients who have not undergone bilateral orchiectomy are allowed and should receive 
LHRH agonists or antiandrogen such as bicalutamide throughout the study (i.e., both 
treatment phase and follow-up).  
• Cytotoxic chemotherapy, androgen receptor blockers, androgen biosynthesis inhibitors, 
other systemic radioisotopes, hemi-body external radiotherapy, and other investigational 
drugs should not be used during the treatment period.  These treatments can be given if at 
least 8 weeks after the last injection. 
• Colony stimulating factors (e.g., erythropoietin and granulocyte colony stimulating 
factors) and transfusions products (e.g., red blood cell transfusion, and/or platelet 
transfusion) as dictated by standard practice are acceptable while the subject is enrolled 
in the study. 
 
6.3.2 Analgesic Use 
 
Use of all analgesic medications is allowed throughout the study, including all opioid types. 
 
6.3.3 Drug-Drug Interactions 
 
Because there is a potential for interaction of Sn-117m-DTPA with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.   
 
6.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 2 cycles 
or until one of the following criteria applies.  Re-treatment is allowed upon AE evaluation if pain 
re-occurs within 6 months after a 16-week pain observation period. 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s), defined as DLT in Section 6.2 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 

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• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
If a patient is withdrawn from the study during the treatment period (and will not return for any 
more visits), he will be encouraged to come to safety follow-up visits at 4 weeks and 12 weeks 
after his last Sn-117m-DTPA administration. 
 
6.5 
Duration of Follow-Up 
 
Patients will be followed every 2 weeks during treatment (16 weeks), then every 4 weeks until 
Week 28, and then every 3 months or as clinically indicated for 12 months after the first Sn-
117m-DTPA dose or until death, whichever occurs first.  After the 1-year follow-up period, dates 
of death will be collected for all patients until the final patient completes his 1-year follow-up.  
Patients removed from study for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event. 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
No Sn-117m-DTPA dose modification is allowed.  Patients will be monitored continuously for 
AEs throughout the study. Patients must be instructed to notify their physician immediately for 
any and all side effects. Treatment interval is scheduled every 8 weeks or every 56 days with a 
window period of +/- 7 days for all time points.  If the treatment needs to be delayed due to an 
adverse event, study drug administration can be delayed up to 8 weeks for recovery, with the 
following conditions: 
 
• Hematological toxicities must resolve to CTCAE grade 1 or less (or, if abnormal at 
baseline, not more than one grade above baseline) prior to administration of the next Sn-
117m-DTPA dose.  In the absence of recovery after 4 weeks, patients are to discontinue 
further study drug administrations. 
• Non-hematological toxicities must resolve to CTCAE grade 2 (gastrointestinal events) or 
grade 3 (other toxicities) prior to administration of the next dose. 
• If patients experience spinal cord compression during the treatment phase, Sn-117m-
DTPA administration can continue with up to a 4-week delay if the patient is adequately 
treated with steroids, local SBRT, or surgery. 
• If patients experience traumatic fracture in weight-bearing bones during the treatment 
phase, the study drug administration should be delayed 4 weeks from the fracture. 
 
As a general approach, it is suggested that all AEs be managed with supportive care when 
possible at the earliest signs of toxicity.  
 
7.1 
PRO-CTCAE 
 

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PRO-CTCAE data should not be used for determining dose delays or dose modifications or any 
other protocol-directed action. 
 
8. 
PHARMACEUTICAL AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agent 
 
8.1.1 Sn-117m-DTPA (NSC 824376) 
 
Stannic-117m Pentetate (Sn-117m-DTPA) 
(NSC 824376) 
 
Chemical Name:  Stannic-117m pentetate; Sn-117m-diethylenetriaminepentaacetic acid 
 
Other Names:  Sn-117m-DTPA 
 
Classification:  Conversion electron emitting radiopharmaceutical 
 
Molecular Formula: 117mSnHC14H18N3O10 M.W.: 
508.01 g/mole 
 
Mode of Action:  
Tin binds to bone and especially to hypermetabolic areas in bone, such as 
bone adjacent to tumor metastases, similarly to calcium. Stannic-117m pentetate produces 
conversion electrons with finite penetration, to 300 μm, resulting in irradiation of tissues only to 
that distance, sparing bone marrow and other tissues adjacent to the bone-tumor interface. The 
isotope also produces gamma radiation, enabling imaging. 
 
Description:  
Stannic-117m pentetate is a ligand metal chelate consisting of the 
radionuclide Sn-117m in the +4 oxidative state complexed to pentetate (DTPA), the chelating 
agent. The formulation is prepared using a 20:1 molar ratio of DTPA to Sn. Calcium chloride is 
added to the formulation as an excipient to combine with 80% of the excess (un-complexed) DTPA 
present in the formulation to minimize DTPA-related toxicity. Stannic-117m pentetate is a low 
energy conversion electron emitter with also energy emitted as gamma-radiation. Stannic-117m 
pentetate has a half-life of 14 days and decays to stable Sn-117. 
 
How Supplied:  Stannic-117m pentetate is supplied by Serene, LLC and distributed to clinical trial 
sites by IsoTherapeutics Group, Angleton, TX. under a DCTD, NCI-sponsored IND.  
 
Stannic-117m pentetate will be distributed by IsoTherapeutics Group in single-use vials prepared for 
the subject’s planned dose as a sterile, aqueous solution. The solution has a pH between 3 and 5 and 
contains the following excipients: calcium chloride and water for injection. The solution may contain 
sodium chloride for pH adjustment. Vials are shipped in a lead container and transported as a Type 
A radioactive package according to international transportation guidelines for radioactive 
materials. 

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Vials will only be shipped to Authorized Users at appropriately licensed facilities with a 
Radioactive Materials License approved for medical use of Stannic-117m pentetate. 
 
Preparation: Stannic-117m pentetate solution is not to be diluted or mixed with any other 
solutions. Vials are to be assayed in a Stannic-117m pentetate calibrated dose calibrator that has 
been calibrated with a NIST traceable Stannic-117m pentetate reference standard. Dose calibrators 
are to be calibrated at time of commissioning, after any maintenance procedures and at intervals of 
no greater than one year. Vials are to be assayed immediately prior to and after withdrawal of the 
subject dose. Record radioactive activity administered according to institutional protocol and on the 
NCI Drug Accountability Record Form. The actual radioactivity administered must be within the 
tolerance limits of ± 10% of the calculated radioactivity. 
A minimum of three (3) records of Stannic-117m pentetate radioactivity MUST be kept 
and submitted in RAVE for each individual patient administration: (1) radioactivity at 
initial dose shipment from IsoTherpaeutics, (2) radioactivity upon Site receipt, and 
(3) radioactivity at Site upon administration to the patient confirmed by radioactivity 
in the vial measured immediately prior to and after withdrawal of the subject dose. 
Storage: Store vials at room temperature (between 15-30°C). Store vials in the radiation shielding 
container until use. 
 
Stability: Vials will be labeled with an expiration date, which will be 14 days from the date of 
calibration prior to shipment. 
 
Route and Method of Administration: Visually inspect solution for particulate matter or 
discoloration prior to administration. Stannic-117m pentetate doses are administered by slow 
intravenous injection over 10 minutes into a free-flowing IV line containing 0.9% sodium chloride. 
The intravenous access line is to be flushed with 0.9% sodium chloride after injection of Stannic-
117m pentetate. Doses must be administered by Authorized Users in a designated clinical setting 
licensed accordingly for medical use of Stannic-117m pentetate. 
 
Special Handling and Precautions:  
 
Stannic-117m pentetate (a conversion electron emitting pharmaceutical) should be received, used 
and administered only by persons authorized to handle radiopharmaceuticals in designated 
clinical settings. The receipt, storage, use, transfer and disposal of Stannic-117m pentetate are 
subject to the regulations and/or appropriate licenses of the competent official organization 
(Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State). 
Administration may be associated with potential risks to other persons from radiation or 
contamination from spills of bodily fluids such as urine, feces, or vomit.  Therefore, radiation 
protection precautions must be taken in accordance with national and local regulations. 
 
Stannic-117m pentetate should be handled by the user in a manner which satisfies both radiation 

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safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. 
In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of 
radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize 
the distance to radiation sources, and to use adequate shielding.   
 
Any unused drug product or materials used in connection with the dispensing or administration 
are to be treated as radioactive waste and should be disposed of in accordance with local 
regulations. Unused doses and waste may be destroyed following applicable agreement state and 
federal regulations for decay in storage for Stannic-117m pentetate following 10 half-lives. 
Radiation protection precautions are to be followed in accordance with national and local regulations. 
Follow normal working procedures for the handling of radiopharmaceuticals and use universal 
precautions for handling and administration such as gloves and barrier gowns when handling blood 
and bodily fluids to avoid contamination. 
 
Patient Care Implications: Fertile men study participants and their partners must abstain or use 
effective contraception (including barrier method) while receiving study treatment and for at least 
6 months after the last dose of Stannic-117m pentetate. For at least 10-days after each dose, subjects 
should avoid close contact with others, should flush toilet several times after each use, and should 
avoid preparing food for others. Clothing soiled with patient fecal matter or urine should be washed 
promptly and separately from other clothing.  
 
Provide subject with instructions regarding hygiene precautions to abide by at time of therapy 
completion in accordance with local institutional policies and guidelines for radiation protection. 
 
Availability 
 
Sn-117m-DTPA is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Sn-117m-DTPA is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.5). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
Sn-117m-DTPA is supplied by Serene LLC and distributed by IsoTherapeutics under a 
DCTD, NCI-sponsored IND.  
• All requests for Sn-117m-DTPA must be submitted to IsoTherapeutics using the attached 
order request form attached in Appendix L.  Complete all requested fields on the order 
request form.  Obtain subject’s weight prior to each dose.  Requests must be submitted to 
IsoTherapeutics at least one week in advance of the planned administration date and must 
be shipped to the authorized facility address as identified on the Site On-Boarding Form 
and to a site shipping contact as identified on the Site On-Boarding Form.  A copy of the 
completed order request form must be retained as a study record.  

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59 
 
• Unused doses are to be accounted for on the NCI DARF.  Unused doses may be destroyed 
following applicable agreement state and federal regulations for decay in storage for Sn-
117m-DTPA.  
The Authorized User investigator prescribing Sn-117m-DTPA must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF), and be designated as 
such on the Site On-Boarding Form and the Delegation of Task Log. 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received using the NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator on this protocol. All Shipping 
Declaration Forms received with the Sn-117m-DTPA shipments are considered 
IND records and must be retained by the site along with the NCI Drug 
Accountability Records for the trial. 
 
8.1.3 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This is a single-arm, open-label phase 2 study to evaluate the efficacy of Sn-117m-DTPA on 

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60 
 
sustained pain response in patients with CRPC metastatic to at least two bone sites, with at least 
one clinically meaningful pain at baseline (≥4 on an 11-point pain intensity scale).  Sustained 
pain-response is defined as:  1) achieving pain index ≤3 within a 12-week period and 2) 
maintaining that pain index ≤3 over a 16-week time period (beginning when the pain index ≤3 is 
initially achieved).  The maximum duration of follow-up required to declare a patient a 
responder is 28 weeks, representing a patient who initially achieves pain index ≤3 toward the end 
of the 12-week period and is followed for an additional 16 weeks to confirm maintenance of pain 
index ≤3. 
 
Eligible patients will be assigned to receive Sn-117m-DTPA at 20 mCi/70 kg (0.28 mCi/kg) 
every 8 weeks for two cycles.  Treatment will last for 16 weeks with two treatment injections 
given at 8-week intervals.  The study utilizes a mini-max Simon two-stage design to assess anti-
tumor activity and pain benefit of Sn-117m-DTPA. 
 
Patients are not allowed to receive external radiation within 12 weeks from the start of treatment 
administration.  If their pain index does not reach ≤3 after 12 weeks, they are not meeting the 
primary endpoint, and they can then get external radiation for pain control. 
 
The sustained pain response rate under null hypothesis is p0=0.1 and the alternative hypothesis is 
p1=0.3.  The literature on sustained pain-relieving benefit with radiopharmaceutical drugs in 
prostate cancer with bone metastases is limited.  Nilsson et al. studied the dose-response 
relationship and pain-relieving effect of radium-223 (Nilsson et al., 2012).  Pain response at 
Week 8 was seen in 40% of patients.  The null hypothesis for sustained pain response in the 
absence of effective therapy and a strong literature support would assume 10%.  We propose that 
the sustained pain response with Sn-117mDTPA would achieve 30%.  Using the mini-max 
Simon’s two-stage design, the total sample size is 25 patients, with 10 patients for the first stage 
and 15 patients for the second stage.  If 1 or 0 patients achieve sustained pain response in the first 
stage, the study will be stopped early for futility; otherwise the trial continues to the second 
stage.  If 5 or fewer patients achieve sustained pain-response, then no further investigation of the 
study treatment is warranted.  This design has an estimated 5% type I error rate and 80% power.  
The planned sample size and interim analysis has a 3.28% actual type I error rate and 80.17% 
actual power.  The probability of stopping at the end of the first stage is about 55% under the null 
hypothesis.  Study enrollment will be interrupted for the interim efficacy analysis. 
 
The efficacy primary endpoint will also be summarized by the point estimation of the ORR with 
the corresponding 95% confidence intervals.  Patients who received any amount of study drug 
will be included in the denominator for the calculation of ORR. 
 
Summary statistics on safety endpoints will be calculated and reviewed at the interim analysis or 
anytime during the study at the investigator’s discretion.  If there is statistically significant 
evidence that the DLT probability exceeds 30%, the study should be suspended for further 
review.  A 95% exact binominal confidence interval will be calculated for the DLT rate.  If the 
observed lower bound of the confidence interval exceeds 30%, we consider it statistically 
significant evidence that the DLT probability exceeds 30%.  
 

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Events v 5.0 (CTCAE).  Safety and toxicity will also be assessed by patient-reported outcomes 
and adverse events (PRO-CTCAE) captured by digital instruments during treatment and 8 weeks 
after the last injection to monitor for acute toxicity and every 2-4 weeks for 6 months post-
therapy for monitoring of long-term toxicity.  CTCAE grades for the corresponding time period 
will be presented in conjunction with PRO-CTCAE scores.  PSA and ALP response rates will be 
calculated for each of the above defined categories with the corresponding confidence intervals.  
Post-hoc analysis on PSA and ALP levels may be conducted to explore possible trends in PSA 
and ALP levels.  Time to the first symptomatic skeletal event will be analyzed using the Kaplan-
Meier method.  Estimation and confidence intervals for the median time to first symptomatic 
skeletal event will be provided.  Patients who did not have a symptomatic skeletal event will be 
censored at the last study visit.  PFS will be analyzed in a similar manner as the time to first 
skeletal event.  Patients who did not have observed clinical progression will be censored at the 
last assessment.    
 
9.4.1 Sn-117m-DTPA Activity 
 
Gamma camera dosimetry will be used to evaluate whole-body distribution of Sn-117m-DTPA.  
Tin is an avid bone seeker, and its biodistribution is nearly identical to Tc-99m-MDP (Swailem 
et al., 1998).  The highest tin distribution is seen in bone surfaces (82%) with increased uptake in 
bone metastases.  Focal and heterogenous bone uptake in Sn-117m-DTPA will be correlated with 
baseline Tc-99m-MDP.  Other normal physiological tissue retention can be seen in liver, lungs, 
spleen, heart, and kidneys, and their uptake varies with the rates of clearance.  The tumor uptake 
observed using the Sn-117m-DTPA scan must be ≥ normal liver uptake observed on planar 
imaging.  
 
Statistical Plan:  
 
The Pearson’s correlation coefficient method will be used to assess the correlation between the 
baseline technetium-99 bone scintigraphy measurement and the Sn-117m-DTPA uptake.  If the 
observed data distribution is not appropriate to calculate the Pearson’s correlation, post hoc 
analysis will be conducted using non-parametric methods or other methods suitable to the 
observed data distribution. 
 
The gamma dosimetry scan measurements will be reported descriptively as the average and 
standard deviation of dosimetry scan measurements and plotted over time and grouped by organ 
systems. 
 
9.4.2 Overall Response Rate 
 
A Fisher’s exact 95% confidence interval will be calculated for the overall response rate.  The 
denominator will include all patients who received at least one dose of study treatment and do 
not have major protocol deviations.  Patients who do not have observed clinical response will be 
counted as negative responses. 
 
9.4.3 Time to First Symptomatic Skeletal Event 
 

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The time from study enrollment to 1) the first use of external-beam radiation therapy to relieve 
skeletal symptoms, 2) new symptomatic pathologic vertebral or non-vertebral bone fractures, 3) 
spinal cord compression, or 4) tumor-related orthopedic surgical intervention will be evaluated. 
 
9.4.4 Overall Pain Response Rate 
 
The rate of achievement of pain index ≤3 within 12 weeks from the first Sn-117m-DTPA will be 
evaluated. 
 
9.4.5 Duration of Pain Response 
 
The time from the achievement of pain response (pain index ≤3) to the recurrence of pain (pain 
index ≥4) will be evaluated. 
 
9.4.6 Serum Prostate-Specific Antigen and Alkaline Phosphatase Responses 
 
Levels of serum PSA and ALP will be measured at 4-week intervals and used to determine 
response rates for each molecular marker. 
 
PSA response rates will be determined for the following benchmarks: 
• ≥30% reduction of the blood level, compared to the baseline value 
• ≥50% reduction of the blood level, compared to the baseline value 
• Confirmed PSA response:  ≥50% reduction of the blood level, compared to the baseline 
value, and confirmed by a second PSA value approximately 4 or more weeks later 
 
ALP response rates will be determined for the following benchmarks: 
• ≥50% reduction of the blood level, compared to the baseline value 
• Confirmed ALP response:  ≥50% reduction of the blood level, compared to the baseline 
value, and confirmed by a second ALP value approximately 4 or more weeks later 
 
9.4.7 Patient-Reported Outcomes and Adverse Events 
 
Safety and toxicity will be assessed by PROs and AEs (PRO-CTCAE) captured by digital 
instruments every 2 weeks through Week 28 for acute and long-term toxicity. 
 
The PRO-CTCAE data will be evaluated for data quality, to evaluate the symptoms’ changes 
over time on study, to explore the development of symptomatic AEs and the change over time, 
and to explore the patient scores with clinician graded AEs.  PRO-CTCAE data will be 
summarized descriptively as the number (percent) of patients reporting each grade for individual 
items. 
 
9.4.8 Clinical Progression-Free Survival 
 
Clinical PFS will be calculated from the time of study enrollment until disease progression, 
which is defined as 1) symptomatic progression (increasing pain from a metastatic lesion); 2) 
progression of bone lesions assessed per PCWG3 criteria; or 3) progression of soft-tissue lesions 

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Changes from baseline vs. follow-up time points will be assessed using paired test 
methodologies.  WES data will be processed using the data processing and data analysis 
pipelines from the Biostatistics and Bioinformatics shared resource of Markey Cancer Center to 
identify candidate mutated genes with adjustment for false discovery rate.  
 
9.6 
Reporting and Exclusions 
 
9.6.1 Evaluation of Toxicity 
 
The Safety Population is defined as all patients who received at least one dose of study 
treatment.  Analyses of safety and toxicity will be based on the Safety Population. 
Safety and toxicity will be assessed through the frequency and percent of AEs, SAEs, DLT, and 
AEs of special interest (AESIs).  Toxicity will be assessed using Common Terminology Criteria 
for Adverse Events v 5.0 (CTCAE).  Safety and toxicity will also be assessed by patient-reported 
outcomes and adverse events (PRO-CTCAE) captured by digital instruments every 2 weeks until 
Week 28 for acute toxicity for monitoring of acute and long-term toxicity. 
 
9.6.2 Evaluation of Response 
 
The Per Protocol Population is defined as all patients who are in the Safety Population and have 
no major protocol violations that could influence the assessment of efficacy.  Efficacy analysis, 
including the analysis of primary and secondary endpoints (excluding safety and toxicity), will 
be based on the Per Protocol Population. 
 
Responses to treatment will be evaluated per PCWG3 criteria as described in Section 12.1 (for 
bone lesions). 
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
The prompt reporting of adverse events is the responsibility of each investigator engaged in 
clinical research, as required by Federal Regulations.  Adverse events must be described and 
graded using the terminology and grading categories defined in the NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE), Version 5.0.  The CTCAE is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  Attribution to 
protocol treatment for each adverse event must be determined by the investigator and reported on 
the required forms.  Please refer to the NCI Guidelines:  Adverse Event Reporting Requirements 
for further details on AE reporting procedures.  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 

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67 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that require expedited reporting are outlined in Section 
10.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 
CRA will enter AEs that occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration.  AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Event form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free. 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 

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report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
 
• Study specific documents:  Protocols > Documents > Education and Promotion, 
and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 

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• Renal failure (ranging from significantly reduced measured or estimated creatinine 
clearance to clinically overt renal failure other than that of obvious non-investigational 
agent-induced origin 
• Suspected radiation nephropathy of any type, such as radiation-induced thrombotic 
microangiopathy, manifesting as: 
o Proteinuria 
o Hypertension 
o Edema 
o Anemia 
o Decreased serum haptoglobin 
• General symptoms and signs of acute radiation toxicity, such as: 
o Increased frequency/urgency of urination 
o Nocturia 
o Dysuria 
o Bladder spasm 
o Bladder obstruction 
o Genitourinary ulceration of necrosis 
 
Grade 3 or higher bone marrow toxicities will also be reported as expedited AEs. 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.4.1 Clinician graded CTCAE is the AE (adverse event) safety standard.  PRO-CTCAE items 
are to complement CTCAE reporting.  Patients will respond to PRO-CTCAE items, but 
no protocol directed action will be taken.  Study specific PRO-CTCAE items for this 
protocol can be found in Appendix G.  
 
10.4.2 PRO-CTCAE is not intended for expedited reporting, real time review or safety 
reporting.  
 
10.4.3 Symptomatic Adverse Events reported by patients through PRO-CTCAE are not safety 
reporting and may be presented with other routine AE data. 
 
10.4.4 PRO-CTCAE Items 
 

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71 
 
Attribute acronyms: F=Frequency, S=Severity, I=Interference, P=Presence/Absence/Amount 
 
CTCAE Item version 5.0 
PRO-CTCAE Item (Attributes) version 1.0 
Constipation 
Constipation (S) 
Diarrhea 
Loose or watery stools (F) 
General Pain 
General Pain (FSI) 
Fatigue 
Fatigue (SI) 
Numbness and Tingling 
Numbness and Tingling (SI) 
Nausea 
Nausea (FS) 
Vomiting 
Vomiting (FS) 
Dizziness 
Dizziness (FS) 
Painful urination 
Painful urination (FS) 
Urinary urgency 
Urinary urgency (FS) 
Urinary frequency 
Urinary frequency (FS) 
Change in urine color 
Change in urine color (FS) 
Joint pain 
Joint pain (FS) 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient’s partner from the time of consent to 
90 days after the last dose of study drug must be reported and then followed for outcome.  
Newborn infants should be followed until 30 days old.  Please see the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more 
details on how to report pregnancy and its outcome to CTEP.  
 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  

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10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 

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11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans and x-rays must be done <8 weeks 
prior to the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. 
 
Visit dates and scans can be within ±7 days of planned dates.  Study treatment must start within 30 days of registration. 
 
 
Pre-
study 
Cycle 1 (8 weeks or 56 days) 
Cycle 2 (8 weeks or 56 days) 
Post-treatment 
Follow-upa 
Off-study 
visit 
W
1 
W2 
W4 
W6 
W8 
W1 
W2 
W4 
W6 
W8 
18 
weeks 
20 
weeks 
22 
weeks 
24 
weeks 
26 
weeks 
28 
weeks 
Sn-117m-DTPA 
 
A 
 
 
 
 
A 
 
 
 
 
 
 
 
 
 
 
A* 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain 
medication** 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X (every 3 
months) 
X 
Physical Exam 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Performance 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CBC/diff, 
platelets 
X 
X 
X 
X 
X 
Xi 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Serum 
chemistryb 
X 
X 
X 
X 
X 
Xi 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
PSA 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Adverse Events 
 
X--------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
 
Patient-reported 
pain intensity 
scale and 
analgesic usec 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-reported 
CTCAEd 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sn-117m-DTPA 
dosimetry 
(optional)e 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine collection 
for urinalysisf 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

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Pre-
study 
Cycle 1 (8 weeks or 56 days) 
Cycle 2 (8 weeks or 56 days) 
Post-treatment 
Follow-upa 
Off-study 
visit 
W
1 
W2 
W4 
W6 
W8 
W1 
W2 
W4 
W6 
W8 
18 
weeks 
20 
weeks 
22 
weeks 
24 
weeks 
26 
weeks 
28 
weeks 
Radiologic 
evaluation (CT 
of 
abdomen/pelvis 
and bone scan) 
and chest X-rayg 
or PSMA PET 
CT scan 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X (every 3 
months) 
 
Research blood 
for genomic 
whole exome 
sequencing 
(mandatory 
when archival 
tissue or slides 
are submitted) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research blood 
for exploratory 
studies 
(optional)h 
X 
 
 
 
 
Xh 
 
 
 
 
Xh 
 
 
 
X 
 
 
 
 
Archival tissue 
for genomic 
sequencing and 
exploratory 
PLK1 stain 
(optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A:  Sn-117m-DTPA: 
20 mCi/70 kg (0.28 mCi/kg) slow IV injection over 10 min on C1D1 and C2D1 
 
*Patients can be retreated if pain recurs within 6 months after 16-week pain observation period  
a:  Follow-up visit evaluation. Every 3 months or as clinically indicated up to one year from the first dose injection or disease progression 
b:  Albumin, ALP, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, sodium, potassium, total protein, SGOT [AST], SGPT [ALT]. 
c:  Pre-treatment daily baseline pain and analgesic use for 7 days (at least 4 out of 7 days) is required before treatment initiation. Patients will be asked to report their pain at its worst in the last 24 hours 
and analgesic use (stable/reduced/increased) by digital version every 2 weeks through Week 28, followed by routine clinic follow up or when they experience new pain during off-visit.  A full short 
version of brief pain inventory (BPI) will be asked at baseline, after Cycle 1, after Cycle 2, and at Week 24. 
d:  PRO-CTCAE survey items will be assessed by digital instruments.  Beginning at Week 28, surveys are requested every 3 months for 6 months after the last study treatment administration. 
e:  Serial DTPA dosimetry scans (optional) will be obtained at 1 hour, 4 hours (or within 4-6 hours), 24 hours (or within 16-24 hours), 48 hours (or within 36-48 hours), 72 hours ( or within 60-72 
hours), 1 week (+/2 days), and 4 weeks (+/2 days) post-infusion. The dosimetry scan will only be performed with first cycle of injection.  
f:  Urine collection for urinalysis will be collected at the indicated time points or as clinically indicated to monitor for microscopic or macroscopic hematuria as part of genitourinary toxicity monitoring.  
g: Imaging: Follow up tumor response will be evaluated by CT scan of abdomen and pelvis, bone scan and chest X-ray. If Chest X-ray shows abnormal or clinically symptomatic, then CT chest should 
be obtained. Follow-up scans at every 8 weeks will be performed as clinically indicated, per institutional standards. PSMA PET CT scan at baseline is also acceptable.  

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h:  Blood collections for research during Cycles 1 and 2 should be collected on the last day of each cycle. 
i:  CBC and serum chemistry should be performed 1 week before the start of Cycle 2. 
** Study coordinator/research nurse will require to ask pain medications list including names, dosage and frequency and also is required to fill out pain medication list form during every clinic visit. 

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12. MEASUREMENT OF EFFECT AND DISEASE PROGRESSION 
 
12.1 
Antitumor Effect – Bone and PSA Response Parameters 
 
12.1.1 Prostate Cancer Working Group 3 (PCWG3) Criteria 
 
The sections of the PCWG3 Criteria that apply to this trial are the criteria for PSA response and 
progression, and the criteria for bone lesion (non-target) “prevent/delay end points 
(progression),” described in the table below.  See Scher et al. (2016) for more details. 
 
Variable 
PCWG3 (2016) 
PSA 
o Recognize that a favorable effect on PSA may be delayed for 12 
weeks or more, even for a cytotoxic drug  
o Monitor PSA by cycle but plan to continue through early rises for a 
minimum for 12 weeks unless other evidence of progression 
o Ignore early rises (prior to 12 weeks) in determining PSA response  
 
Decline from baseline: 
o Record time from start of therapy to first PSA increase that is ≥25% 
and ≥2 ng/mL above the nadir, and which is confirmed by a second 
value 3 or more weeks later (i.e., a confirmed rising trend)  
 
No decline from baseline: 
o PSA progression ≥25% and ≥2 ng/mL after 12 weeks 
Bone 
For control/relieve eliminate end points: 
o Record changes as new lesions or no new lesions 
o Changes in intensity of uptake alone do not constitute progression or 
regression 
o First schedule reassessment:  
o No new lesions: continue therapy 
o New lesions: perform a confirmatory scan 6 or more weeks later 
o Confirmatory scan: 
o No new lesions: continue therapy 
o Additional ≥2 new lesions: progression 
o Subsequent scheduled reassessments: 
o No new lesions: continue 
o New lesions: progression 
 
o For delay/prevent end points (Progression)  
o Exclude pseudo-progression in the absence of symptoms or other 
signs of progression 
o At least two new lesions on first post-treatment scan, with at least two 
additional lesions on the next scan (2+2 rule)  
o If at least two additional new lesions are seen on the next 
(confirmatory) scan, the date of progression is the date of the first 
post-treatment scan, when the first two new lesions were documented.  

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77 
 
o For all scans after the first post-treatment scan, at least two new 
lesions  
o Date of progression is the date of the scan that first documents the 
second lesion  
Frequency of 
assessment of 
bone scan or 
other CT scans  
Every 8 to 9 weeks for the first 24 weeks, then every 12 weeks 
 
 
12.2 
Disease Progression in Soft Tissue Lesions 
 
Patients should be re-evaluated for response/disease progression every 8 weeks for the first 24 
weeks, and then every 12 weeks.  No confirmatory scan is required for soft tissue lesions 
following initial documentation of objective response.  
 
Response and progression in soft-tissue lesions will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
12.2.1 Definitions 
 
Evaluable for Toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with Sn-117m-DTPA. 
 
Evaluable for Objective Response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
12.2.2 Disease Parameters 
 
Measurable Disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 

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78 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-Measurable Disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target Lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-Target Lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 

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79 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest X-Ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor Markers.  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for PSA response (in recurrent prostate cancer) 

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have been published [J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
 
12.2.4 Response Criteria 
 
12.2.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.2.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
12.2.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 

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81 
 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.2.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.2.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.2.7 Response Review 
 
N/A 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
 

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Requirements to access Rave via iMedidata: 
 
• 
A valid account, and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 

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84 
 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits.  
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 619-7862 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 

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13.2.3 Data Submission for PRO-CTCAE Assessments 
 
Electronic collection of PRO-CTCAE through the Patient Cloud app is source documentation.  
The surveys are not stored on the devices.  Rather, each survey is available for the timeframe set 
by the protocol.  Once a patient submits the responses, the data goes directly from the device into 
the Rave database.  There are no documents to audit.  The electronic responses are the source 
documentation.  PRO-CTCAE is not intended for expedited reporting, real time review, or safety 
reporting.  PRO-CTCAE data are exploratory and not currently intended for use in data safety 
monitoring or adverse event stopping rules.  For paper collection of PRO-CTCAE items, the 
CRA will need to manually enter the data into Rave at the site. 
 
 
13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on 
the DQP.  A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP.  Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.  
13.4 
CTEP Multicenter Guidelines 
 
N/A 
 
13.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 

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86 
 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 

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87 
 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13.6 
Genomic Data Sharing Plan 
 
The investigators and statistician and/or bioinformaticians for the study will have access to all 
data on mutations and variants stored in the Theradex Data Base and GDC.  This information 
will be sequestered from access throughout the study until it is analyzed for purposes of 
reporting and publishing of the study results.  As specified in the CRADA for the agents used in 
the clinical study, the pharmaceutical collaborator will have at least 6 months, longer if needed 
for a regulatory filing, to review the data and or receive copies of the data once the study is 
completed and analyzed, or sooner, if specified for purposes of generating Intellectual Property.  
Once these timeframes have been exceeded, the data will be available through a Data Access 
Committee (DAC) in the GDC following NCI and Collaborator review of the proposals.  
 
 
13.7 
Incidental/Secondary Findings Disclosure Procedure 
 
Given the potential clinical implications conferred by detecting a germline and/or somatic 
mutation in one of the proven cancer susceptibility genes, this protocol will use the following 
disclosure procedure, consistent with the recommendations of the American College of Medical 
and Genomics (ACMG) (Green et al., 2013 and Kalia et al., 2016)  
 
The NCLN Genomics Laboratory will review the mutations/variants once at the time of initial 

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specimen evaluation according to the most recent version of the ACMG guidance on variants.  
The NCI Molecular Characterization Laboratory will not re-review all specimens received if a 
new version of the ACMG guidance is published after the initial review.  
 
For each participant with a pathogenic or likely pathogenic germline and/or somatic variant 
detected in the WES of blood (as defined in the ACMG guidance), the NCLN Genomics 
Laboratory will report to the Program Director or Scientific Officer the UPID and variant(s) 
identified.  The Program Director or Scientific Officer will contact Theradex to obtain the name 
of the protocol, investigator treating the patient, and the Principal Investigator of the grant.  The 
treating physician will be contacted by phone and in writing to ask the patient whether he or she 
is interested in learning more about the finding. 
 
If the patient wants to know more, the physician should contact the Program Director for more 
information about the mutation/variant.  The treating physician and a medical genetics counselor 
should meet with the patient to discuss the importance and meaning of the finding, but not the 
finding itself, and notify the patient that this research finding must be confirmed by Sanger 
sequencing at the patient’s/patient insurer’s expense in a Clinical laboratory Improvement 
Amendments (CLIA)-approved laboratory.  The treating physician and genetic counselor should 
inform the patient of the confirmed result and its meaning and significance to the patient.  If 
desired, the patient may elect to undergo genetic counseling and confirmatory CLIA-approved 
clinical testing on his or her own.  Neither the research laboratory nor the National Cancer 
Institute will be responsible for the costs incurred for any confirmatory genetic testing or 
counseling.  
 
 

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Siegel, R.L., K.D. Miller, and A. Jemal.  (2018).  Cancer statistics, 2018.  CA Cancer J Clin.  
68:7-30. 
 
Sn-177m-DTPA Investigator’s Brochure.  (2020).  Stannic (Sn-117m) Pentetate Injection.  
Serene, LLC.  Version 5 (February 24, 2020). 
 
Srivastava, S.C., G.E. Meinken, P. Richards, et al.  (1985).  The development and in vivo 
behavior of tin containing radiopharmaceuticals.  I.  Chemistry, preparation and biodistribution 
in small animals.  Int J Nucl Med.  12:167-74. 
 
Srivastava, S.C., G.E. Meinken, L.F. Mausner, et al.  (1994).  Nuclear, chemical, and 
mechanistic considerations in the use of 117Sn(4+)-DTPA relative to 186Re-HEDP and other 
agents for bone pain therapy.  In:  Technetium and Rhenium in Chemistry and Nuclear Medicine  
4.  Proceedings of the Fourth International Symposium on Technetium in Chemistry and Nuclear 
Medicine.  287-292.  Bressanone, Italy. 
 
Srivastava, S.C., H.L. Atkins, G.T. Krishnamurthy, et al.  (1998).  Treatment of metastatic bone 
pain with tin-117m Stannic diethylenetriaminepentaacetic acid: a phase I/II clinical study.  Clin 
Cancer Res.  4:61-68. 
 
Swailem, F.M., G.T. Krishnamurthy, S.C. Srivastava, et al.  (1998).  In-vivo tissue uptake and 
retention of Sn-117m(4+)DTPA in a human subject with metastatic bone pain and in normal 
mice.  Nucl Med Biol.  25:279-287. 
 
Umansky, V., C. Blattner, C. Gebhardt, and J. Utikal.  (2016).  The Role of Myeloid-Derived 
Suppressor Cells (MDSC) in Cancer Progression.  Vaccines (Basel).  4:36. 
 
Weichert, W., M. Schmidt, V. Gekeler, et al.  (2004).  Polo-like kinase 1 is overexpressed in 
prostate cancer and linked to higher tumor grades.  Prostate.  60:240-245. 
 
Xu, Y., F. Fang, D.K. St. Clair, and W.H. St. Clair.  (2012).  Inverse relationship between PSA 
and IL-8 in prostate cancer: an insight into a NF-kappaB-mediated mechanism.  PLoS One.  
7:e32905. 
 
Yamaoka, M., T. Hara, and M. Kusaka.  (2010).  Overcoming persistent dependency on 
androgen signaling after progression to castration-resistant prostate cancer.  Clin Cancer Res.  
16:4319-4324. 
 

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93 
 
Young, A., R. Berry, A.F. Holloway, et al.  (2014).  RNA-seq profiling of a radiation resistant 
and radiation sensitive prostate cancer cell line highlights opposing regulation of DNA repair and 
targets for radiosensitization.  BMC Cancer.  14:808. 
 
Zhang, Z., L. Chen, H. Wang, et al.  (2015).  Inhibition of Plk1 represses androgen signaling 
pathway in castration-resistant prostate cancer.  Cell Cycle.  14:2142-2148. 
 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX D 
BRIEF PAIN INVENTORY (SHORT FORM) 
 
The Brief Pain Inventory (Short Form) is provided beginning on the next page.

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APPENDIX E 
PATIENT PAIN INVENTORY AND ANALGESIC USE FORMS, 
PAPER FORMAT (IF DIGITAL IS NOT USED 
 
Pain intensity scale (Item #3 on the BPI-SF, worst pain)  
 
Date 
Pain scale 
09/19/20 
(for example) 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analgesic use/consumption 
 
                                 PATIENT-REPORTED ANALGESIC LOG 
Date 
Decrease 
Stable 
increase 
09/19/20 
(for example) 
 
    X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX F 
PATIENT’S PAIN MEDICATION LIST 
 
Date 
Medicine 
Dose 
How often taken in 
24 hours 
09/19/20  
(for example) 
Oxycodone  
Ibuprofen 
5 mg 
400 mg 
5 times  
3 times 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX G 
TABLE OF PRO-CTCAE AND CTCAE ITEMS FOR 
COLLECTION 
 
System Organ 
Class 
Sn-117m-DTPA 
- CAEPR 
Possible 
Related 
PRO-
CTCAE 
Items 
Attributes 
Gastrointestinal 
Disorders 
 
Constipation 
Severity 
 
Diarrhea 
Frequency 
Nausea 
Nausea 
Frequency 
& Severity 
 
Vomiting 
Frequency 
& Severity 
General 
Disorders and 
Administration 
Site Conditions 
 
Fatigue 
Severity & 
Interference 
Musculoskeletal 
and Connective 
Tissue 
Disorders 
 
General Pain 
Frequency, 
Severity, 
Interference 
 
Joint pain 
Frequency 
& Severity 
Nervous System 
Disorders 
 
Numbness 
and tingling 
Severity & 
Interference 
 
Dizziness 
Frequency 
& Severity 
Genitourinary 
System 
General  
 
Painful 
urination 
Frequency 
& Severity  
 
Urinary 
urgency 
Frequency 
& Severity  
 
Urinary 
frequency 
Frequency 
& Severity  
 
Change in 
usual urine 
color 
Frequency 
& Severity 
 
 
 
 

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APPENDIX H 
MEDIDATA PATIENT CLOUD REGISTRATION 
 
a. Introduction 
 
Electronic collection of patient-reported outcomes through Medidata Patient Cloud is 
preferred but not mandatory.  Patients who will be submitting PRO data via Patient Cloud 
must be registered to Patient Cloud by an authorized site staff after the patient has been 
registered to the study.  Patients may use their own device or one provisioned by the site.  
 
Sites can use a site-specific tablet for multiple study participants.  If a site-specific tablet is 
used, CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study 
participants log in to Patient Cloud with their passwords or their PIN codes on the same 
device.  
 
b. Patient Cloud Application Download 
 
Note that there are multiple versions of the Medidata Patient Cloud Application.  Patients 
should be instructed by the study team to download the Patient Cloud version.  The patient 
will receive an error if the wrong version is downloaded.  
 
Patient Cloud ePRO 
 
 
 
Patient Cloud 
 
 
 
 
c. CRA Site Users 
 
Site staff require access to the Patient Cloud application.  This access is granted through the 
iMedidata, and is similar to the process of obtaining access to Rave studies. Site staff will 
receive an invitation to the Patient Cloud application which they must accept in order to 
begin registering patients. Staff that have not previously activated their iMedidata/Rave 
account at the time of initial approval of site registration will also receive a separate 
invitation from iMedidata to activate their account. Medidata Account Activation and Study 
Invitation Acceptance instructions are located on the CTSU members’ website under Data 
Management > Rave Resource Materials. Site staff will not be able to access the study in the 
Patient Cloud application until all required Rave and study specific trainings (eLearnings 
assigned in iMedidata) are completed. 
 
Additional information on iMedidata/Rave is available on the CTSU members’ website under 
the Data Management tab and further under the Rave subtab or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
d. CRA Instructions for Setting the Patient Cloud App to Multi-User Mode 
 
Sites conducting studies entirely on-premises, where participants travel to the sites to fill out 
questionnaires, can use multi-user mode.  Multi-user mode lets multiple study participants 
log in to Patient Cloud with their passwords or their PIN codes on the same device.  If 

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patients will be using devices supplied by the institution, site staff will need to help the 
patient to access the device if the device is locked. 
 
The study provider will download the Patient Cloud app to the device and set the Patient 
Cloud App to multi-user mode if applicable.  **Verify the correct version is downloaded per 
the study build requirements.  Note only 1 version of the app is active per protocol. 
  
To switch from personal mode (default setting) to multi-user mode: 
1.     Tap About at the bottom of the log in screen. 
2.     Scroll to the bottom and tap Advanced User. 
3.     Tap Mode, then select Multi-User. 
4.     Tap Yes to confirm. 
5.     Tap the back arrows to return to the log in screen. 
Note: If enabling multi-user mode on a device, it is highly recommended that completion 
reminders are turned off on that device. 
For a video demonstration, see Show Me How to Switch to Multi-User Mode. 
 
e. Patient Users 
 
To use the Patient Cloud application, patients will need to use their own device (IOS, 
Android phone or tablet).  Short term data will only appear on the patient’s device until 
responses are completed and submitted.  The patient data will import directly into the 
database once the patient selects the “Submit” button and data will no longer be visible on the 
patient's device.  
 
Sites can provide a site-specific tablet for multiple study participant use on site.  If a site-
specific tablet is used, study staff need to setup the tablet for multiple users.  Multi-user mode 
lets multiple study participants log into the Patient Cloud application with their passwords or 
their PIN codes on the same device.  Refer to Appendix H Section d on Setting the Patient 
Cloud App to Multi-User Mode.   
 
f. Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
 
Downloading the Patient Cloud App 
 
If you are using your personal device, and you do not have the Patient Cloud app, use the 
following instructions.  When downloading the app, you must use the Apple ID or Google 
account associated with the device. If the Patient Cloud app is already on the device, or if you 
are using a provider's device, you can skip this section.  There are multiple versions of the 
app available.  Ensure that the correct version of the Patient Cloud app is downloaded by the 
patient. 
You will need an email address that you agree to use for this purpose.  The e-mail address is 
needed to uniquely identify you on the Patient Cloud Application, and to reset your password 
if needed.  Your e-mail address will only be used for this survey study, and will not be used 
for mail or marketing purposes. 
If you decide to use the electronic method to complete the questionnaires, and do not have an 
e-mail address, you may sign up for one at no charge at many different websites.  A few sites 
that are commonly used and will allow you to create an email address very easily are Yahoo, 
Gmail, and Outlook. 
 

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For iOS:  
 
1. An Apple ID is required for downloading the Patient Cloud app. 
2. Tap the App Store icon. 
3. Search for the appropriate Medidata Patient Cloud application and follow the 
installation instructions. 
 
Note: Patient Cloud is listed as an iPhone App in the App store. When using an iPad, please 
view the search results under iPhone apps. 
   
For Android: 
1. A Google account is required for downloading the Patient Cloud app 
2. Tap the Play Store icon. 
3. Search for the appropriate Medidata Patient Cloud application and follow the 
installation instructions. 
 
Registering 
 
You must register in order to complete and submit your study forms.  When you register, you 
will create a username, which is your email address, and a password that allows you to log in 
to the Patient Cloud application. 
 
Note: You must have an activation code to begin this process. If you do not have an 
activation code, please contact your provider.  
 
There are two possible ways to register.  Your provider may have sent you a link to a web 
address where you may register from any web browser, including the one on your device. 
The other way to register is on the Patient Cloud app. 
 
1. If registering from the Patient Cloud, tap Register on the bottom of the log in 
page.  If registering on the web, open the URL shield.imedidata.com on a web 
browser. 
2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 
4. Read the privacy notice and tap I agree.  Then tap OK to confirm. 
5. Enter and confirm your email address.  Tap Next. 
6. Enter and confirm your password.  Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to display 
the question of your choice. 
8. Enter your response to the security questions. 
9. Tap Create my account to complete your registration.  
If you registered on the Patient Cloud app, it automatically logs you out.  If you registered on 
the web, you are presented with the option to download the Patient Cloud app.  You can then 
proceed to log in with the credentials you created. 
 
Logging in to the App 
 
1. Enter your Email and Password that you created during the registration 
process.  (If you previously set a PIN code, just enter your four-digit PIN.) 
2. Tap Log in. 

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Note: If you do not remember your password, tap Forgot Password, and follow the 
instructions provided. 
 
Setting a PIN Code 
 
The first time you log in to the Patient Cloud app, you are given the option to create a PIN 
code.  A PIN code allows you to bypass the step of entering your email and password every 
time you need to log in to the Patient Cloud app.  Instead, you can enter a four-digit PIN. 
1. If you wish to set a PIN code the first time you log in, tap Yes when prompted. 
2. Note: You can also set your PIN at a later time by tapping the options menu 
on the top left of most pages and selecting Set PIN. 
3. Enter a four-digit PIN. 
4. Re-enter the four-digit PIN to confirm. 
 
If you forget your PIN code, tap Forgot PIN and you can access the app using your email 
and password. You may reset your PIN by tapping the options menu on the top left of most 
pages and selecting Set PIN. 
 
Resetting Your Password 
 
You can reset your password by using the options menu at the top left of most pages. 
1. Tap the options menu icon. 
2. Tap Reset Password. 
3. Follow the instructions to reset your password. 
 
Completing and Submitting Forms 
 
Once logged in, forms related to your study are displayed on the Tasks List page. Select a 
form, and complete and submit the form.  New forms can appear on the Tasks List page at 
any time, depending on how the study is designed. 
There are two types of forms displayed on the Task List page: 
• Scheduled Forms (with a 
 icon): These forms have a "Due Date" indicator in them 
so you are aware of the last day by which you will need to complete the form. If the 
form is due in less than one day, you will see the due time in hours. 
• Anytime Forms (with a 
 icon): These forms have "Last Completed Time" indicator 
on them which tells the most recent date or time when you completed the form.  If 
you start a form, but do not complete it, you will see an 'Incomplete" status beneath 
the form name, along with a half-moon icon.  
 
To complete and submit form(s): 
 
1. Select the appropriate form.  
2. Follow the on-screen instructions until you reach the end of the form where 
you may be given the opportunity to review and change your responses prior 
to submitting. 
3. If given the opportunity to review and update, review your responses by 
scrolling down the list; if you need to change an answer, tap the question to go 
back and change the answer. 
4. When you are ready to submit, tap Submit Your Data. 

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104 
 
 
1.Patient Cloud ePRO 
 
2. Patient Cloud 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX I 
HYGIENE/SAFETY INSTRUCTIONS FOR TREATMENT 
WITH SN-117M-DTPA 
 
Patient Name     
 
Date of Birth     
  
Medical Record Number   
 
 
You have received radioactive Tin DTPA to treat bone pain.  After treatment, please 
follow the instructions below for the time indicated.  These actions will keep you and 
your family safe. 
 
 
 
10 
Days 
Contact with people: 
❑ Try to stay at least 3 feet away from others. 
❑ Do not kiss anyone and do not have sex. 
Handling food and eating: 
❑ If you fix food for others, wash your hands well and wear gloves when doing so. 
❑ Use separate eating utensils. Wash separately with soap and water.  
❑ Drink at least two to three quarts of fluid every 24 hours for 14 days 
❑ In general, drinking alcoholic beverages should be kept to a minimum or avoided 
completely.  
 Washing and cleaning up: 
❑ Sit while you urinate. With the lid down, flush twice after each use. 
❑ Wipe the toilet seat after each use. 
❑ Cover your mouth and nose when you cough or sneeze. 
❑ Wash your hands often. Always wash them after you use the toilet, cough, or sneeze. 
❑ Wash your hands with soap and water.  Do not use hand sanitizers or such products. 
❑ Bathe or shower daily. Rinse out the sink, tub, and shower well after each use. 
❑ Use separate towels and bed linens. Wash them separately. Do not share them. 
❑ If you smoke, throw cigarettes into the toilet and flush away. Do not share cigarettes. 
30 
Days 
Contact with people: 
❑ Sleep in a separate bed. 
❑ Avoid prolonged contact with others - a brief hug is OK. 
❑ Do not nap with children or hold infants or children for extended periods of time. 
❑ Avoid long (more than 4 hours) trips where you have to sit near others. 
6 
Months 
❑ If you plan to travel by air within 6 months after radioactive therapy, please inform 
the Radiation Safety Officer during the interview or call 859-257-7128 thereafter. 
Comments (if any): 
If you have questions about these instructions, please call the Radiation Safety Officer 
at 859-257-7128. I understand and agree to follow these instructions. 
Patient/Guardian:                                                              Date/Time:   
 
 

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Radiation Safety Officer/Physician:  
                     Date/Time:  
 
 

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APPENDIX J 
QUANTITATIVE IMAGING AND DOSIMETRY OF SN-117M-
DTPA 
 
National Cancer Institute 
Division of Cancer Treatment and Diagnosis  
Cancer Therapy Evaluation Program (CTEP) 
Investigational Drug Branch 
 
Project Group: 
 
 
National Cancer Institute (NCI) 
Date Submitted: 
Cancer Therapy Evaluation Program (CTEP) 
Investigational Drug Branch (IDB) 
20 August 2020 
1. STANDARD OPERATING PROCEDURE: Quantitative Imaging and Dosimetry of Sn-117m-DTPA V1.0 
 
Protocol items to incorporate as an Imaging & Dosimetry Appendix to NCI protocol #10437: 
 
Characteristics of Sn-117m-DTPA 
Tin(Sn)-117m(4+)-DTPA is primarily a conversion electron emitter (13.9-day half-life) with a 
monoenergetic gamma photon of 159 keV in 86% abundance. The gamma component 
allows for the in vivo quantification of total-body uptake and retention imaging. 
Purpose of imaging procedure 
Secondary Objective:  To measure Sn-117m-DTPA activity by gamma-camera dosimetry 
scans (serial chest, abdomen & pelvis planar images) obtained at 1 hour, 4 hours (or within 
4-6 hours), 24 hours (or within 16-24 hours), 48 hours (or within 36-48 hours), 72 hours (or 
within 60-72 hours), 1 week (± days), and 4 weeks (±2 days) after the first agent injection. 
Dosage level 
20 mCi (first Sn-117m-DTPA injection) 
Radiation dose to main organs in 
men1 (Gy/MBq) 
Adrenals 
0.000164 
Brain 
0.000180 
Breasts 
0.000068 
Gallbladder wall 
0.000086 
Lower large intestine wall 
0.000124 
Small intestine wall 
0.000102 
Stomach wall 
0.000080 
Upper large intestine wall 
0.000094 
Heart wall 
0.000101 
Kidneys 
0.000159 
Liver 
0.000091 
Lungs 
0.000112 
Muscle 
0.000122 
Ovaries 
0.000000 
Pancreas 
0.000111 
Red marrow 
0.006108 
Osteogenic cells (bone surface) 
0.054864 
Skin 
0.000087 
Spleen 
0.000092 
Testes 
0.000079 
Thymus 
0.000091 
Thyroid 
0.000122 
Urinary bladder wall 
0.000170 
Uterus 
0.000000 
Whole body 
0.000535 
Patient preparation2 
Patient should be asked to void prior to Sn-117m-DTPA injection in order to avoid the need 
to void within two hours of the start of the procedure. 
 
Place an indwelling venous catheter in each arm, one for the Sn-117m-DTPA injection and 
the other for blood withdrawal. 
Field of views (FOVs) taken2 
Anterior and posterior Whole Body Sweep.  Chest, Abdomen & Pelvis—if there are relevant 
lesions, then additional views could be collected, as needed. After the first field is collected, 
the patient should remain on the couch without moving for subsequent imaging, if possible. 
 

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Version Date:  January 10, 2022 
 
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Reporting requirements 
Regions of interest will be drawn over normal bone and metastatic foci, and decay-
corrected counts of pixels will be drawn from all seven Sn-117m-DTPA scans. Counts per 
pixels will be plotted against time. Time to peak will be noted for both normal and metastatic 
bone lesions. The slope of the curve will be monitored for washout.  
Interpretation for dosimetry (or any 
other purpose) 
No action. Results will be analyzed and used for publication to evaluate patient to patient 
variability and impact of tumor burden.  Study will also provide accurate SPECT-imaging 
based dosimetry. 
Step by step imaging procedure 
Routine SPECT/CT imaging procedure in clinical practices should be used with the 
parameters specified above. 
Data to send 
Whole Body planar imaging, SPECT projections, attenuation map, and all CT slices (in 
DICOM format) 
Calculation 
The geometric mean counts from the planar anterior and posterior view counts (including 
the standard) in the first scan (1-hour post-injection prior to voiding) will be obtained as the 
square root of the anterior x posterior counts. The geometric mean counts of the standard 
will be subtracted from the total counts in the image, and, the net counts will be considered 
as 100% of the injected dosage. The net counts from subsequent scans will be corrected 
for physical decay. The geometric mean counts will be divided by the counts from the first 
study, and the results will be expressed as the percent injected dose retained. All results 
will be expressed as mean percent of injected dose ± standard deviation. The mean values 
will be analyzed by statistical t-tests using statistical software. Dosimetry software may be 
used. 
Reference 
1. 
Atkins HL, Mausner LF, Srivastava SC, Meinken GE, Straub RF, Cabahug CJ, Weber 
DA, Wong CTC, Sacker DF, Madajewicz S, Park TL, Meek AG. Biodistribution of Sn-
117m(4+)DTPA for palliative therapy of painful osseous metastases. Radiology 
1993;186:279-283. 
2. 
Krishnamurthy GT, Swailen FM, Srivastava SC, Atkins HL, Simpson LJ, Walsh TK, 
Ahman FR, Meinken GE, and Shah JH. Tin-117m(4+)DTPA: Pharmacokinetics and 
imaging characteristics in patients with metastatic bone pain. J Nuc Med 
1997;38(2):230-237. 
 

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Version Date:  January 10, 2022 
 
110 
 
APPENDIX K 
Sn-117m-DTPA SITE ON-BOARDING FORM 
(see next page) 

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Version Date:  January 10, 2022 
 
113 
 
APPENDIX L 
Sn-117m-DTA ORDER FORM 
(see next page) 

NCI Protocol #:  10437 
Version Date:  January 10, 2022 
 
114 
 
Sn-117m-DTPA Order form 
NCI Protocol 10437 
 
Send order to:  
 
Kim Miller at 
orders@isotherapeutics.com  
(979) 848-0800 
(receipt of order will be confirmed by Kim Miller) 
 
Patient study ID# (OPEN-assigned study ID): ______________________ 
 
Date of birth: ___________________ 
 
Date order placed: _______________ 
 
Weight of patient (kg): _____________ 
 
Planned injected dose (0.28 mCi/kg): ______________ mCi 
 
Date to be received: ________________ 
 
Date to be injected: _________________ 
 
Send dose to (shipping address of authorized location): 
 
_____________________________________________ 
_____________________________________________ 
_____________________________________________ 
_____________________________________________ 
 
 
Attn: ______________________________ 
Tel: _______________________________ 
Email: _____________________________ 
 
 
 
Submit order request at least one week prior to planned administration date.