F18 NaF PET/CT and Whole Body and Axial MRI for the Detection of Metastases in Patients With Biochemical Recurrence of Prostate Cancer
Phase: NA
Conditions: Recurrent Prostate Cancer
Sponsor: City of Hope Medical Center

IRB#: 13365 
 
Version Date:  10/27/2017 
Version:  04 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
 
TITLE: F18 NaF PET/CT and Whole Body and axial MRI for the Detection of Metastases in Patients 
with Biochemical Recurrence of Prostate Cancer 
CITY OF HOPE PROTOCOL NUMBER:  13365 
VERSION:  04 
 
DATE(S) OF AMENDMENT AND REVISION: 
COH Initial Submission  
Protocol dated 08/29/13 
Version 00 
COH Amendment 01  
Title Page dated 09/30/14 
 
 
Version 01 
COH Amendment 02 
Protocol dated 12/16/14  
 
 
Version 02 
COH Amendment 03 
Protocol dated 04/08/16  
 
 
Version 03 
COH Amendment 04 
Title Page dated 10/27/17 
 
 
Version 04 
 
DISEASE SITE: 
PROSTATE CANCER 
 
STAGE (if applicable): 
IV, (M0 – biochemically recurrent prostate cancer) 
 
MODALITY: 
Imaging: F18 NaF PET/CT and Whole Body/axial (WB/axial) MRI 
 
PHASE/TYPE: 
Phase II Imaging /non-therapeutic 
PRINCIPAL INVESTIGATOR: 
Cy Stein M.D. 
CO-PRINCIPAL INVESTIGATOR: 
Jinha Park  M.D. 
COLLABORATING INVESTIGATORS: 
 
Helen Chen, M.D., Sam Chung, M.D., 
Steve Koehler, M.D., Paul Frankel, 
Ph.D. (Statistics), Daphne Stewart, 
M.D., Jeffrey Wong M.D., Christina 
Yeon, M.D.  
PARTICIPATING CLINICIANS: 
 
Sumanta Pal M.D. 
Alexander Jung M.D  
 
 
 
PARTICIPATING INSTITUTION: 
City of Hope National Medical Center, 
Duarte, CA 
 
City of Hope, South Pasadena, CA 
 
 

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                                               Experimental Design Schema 
 
                                                                              Consent/Registration 
 
                                                          CT chest, abdomen, pelvis, BS (TXR as needed) 
                                                                                 Possible outcomes 
 
 
                          Consistent with visible recurrence.   Indeterminate              Negative 
 
                                                     
                                                                            
                            Biopsy if appropriate,  
                            additional imaging as clinically indicated,  
                            follow treatment patterns and PSA 
                            until disease progression or 1yr  
                         whichever is first. 
 
                                                                       WB/axial MRI  F-18 NaF PET/CT   
                                                                               Possible outcomes  
 
 
  Consistent with visible recurrence.   Indeterminate           Negative 
 
 
 
Biopsy, when feasible recommended in all patients with MRI or NaF PET/CT consistent with recurrence or indeterminate   
Record PSA response to Salvage Therapy (if given), perform 4-6 month follow up scans if clinically indicated and follow for 
1yr or until progression                                                                 
 
 
 
 

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Protocol Synopsis 
Protocol Title: 
F18 NaF PET/CT and WB/axial MRI for the Detection of  Metastases in Patients with  Biochemical 
Recurrence of Prostate Cancer (PC) 
 
Brief Protocol Title for the Lay Public (if applicable): 
Using newer scan techniques to screen for recurrence in prostate cancer patients who have rising PSA 
after prostatectomy 
Study Phase: 
Phase II 
Participating Sites: 
City of Hope Cancer Center 
Rationale for this Study: 
Current imaging modalities have low sensitivity to detect recurrence in patients who have rising PSA 
after prostatectomy as evidenced by a high percentage of patients who fail to respond to salvage local 
therapy. While not routinely used, MRI is part of the NCCN guidelines for evaluating disease in this 
patient population, and F-18 NaF PET/CT is FDA approved for the detection of bone metastasis, the 
most common site of distant recurrence. As a result, we will implement the routine use of these new 
imaging modalities in addition to the historically used imaging tests in a prospective cohort to 
document the added benefit.  We hypothesize that combination of WB/axial MRI and F-18 NaF 
PET/CT will   localize the site of recurrence in significant proportion of these patients.  
 
Objectives: 
Primary Objective : To determine the proportion of patients with biochemically-recurrent PC in 
whom imaging with WB/axial MRI and F-18 NaF PET/CT results in detection of metastatic disease 
not visualized on CT scan and bone scan.  
Secondary Objectives: 
To estimate the percent of eligible patients with negative, indeterminate and positive CT 
scan/bone scan and targeted X-rays if done. 
To determine the proportion of patients with biochemically recurrent PC in whom recurrence in 
the prostate bed can be visualized using WB/axial  MRI in the absence of detection using CT scan. 
To correlate the presence of metastatic disease detected using WB/axial MRI and/or F-18 NaF 
PET/CT with the predicted 6-year probability of progression-free survival based on the Memorial 
Sloan Kettering Cancer Center salvage RT PC nomogram, and with PSA levels at baseline.  
To compare the role of axial MRI of the spine to WB/axial MRI with respect to their ability to 
identify sites of disease. Similarly, to evaluate the relative contribution of F-18 NaF PET and 
MRI.   
 
 
 
 

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Patients with two PSA values  ≥0.2 ng/mL at least 4 weeks after prostatectomy will undergo imaging 
studies including CT of the chest, abdomen and pelvis and bone scan. Targeted X Rays will be 
obtained in case of equivocal findings if suggested by the radiologist.  The results of the scans will be 
classified as: 1) consistent with visible recurrence, 2) indeterminate 3) negative. 
Patients who were classified as having negative bone scan and CT scan (estimated ≥90% of patients) 
will undergo MRI (axial MRI and WB MRI) and F-18 NaF PET/CT. The outcome of these studies 
will be reported as 1) consistent with visible recurrence, 2) indeterminate 3) negative.  In cases of 
findings consistent with visible recurrence or indeterminate a biopsy of the lesion of interest will be 
recommended if feasible. Any enrolled patient without a positive biopsy will be followed and their 
treatment (at discretion of treating physician), PSA values and outcome will be recorded to evaluate 
the scan result specificity and sensitivity in relation to additional information provided with follow-
up  (e.g. if patients undergo Salvage Radiation Therapy, PSA response will be recorded which will 
have significant implication in the interpretation of radiologic findings (see 10).Subsequently all 
patients without biopsy proven metastasis will undergo follow up imaging studies  (the type of 
imaging to be recommended by radiologist))  within 4-6 months to reassess any abnormalities in the 
context of time, ongoing therapy or no therapy.   
Sample Size: 
Total Sample size is 56.  Anticipated accrual is 2-3 patients a month.  
 
Estimated Duration of the Study 
24 months 
Summary of Subject Eligibility Criteria: 
Patients with 2 PSA values ≥0.2 ng/mL at least 4 weeks after surgery will be evaluated. Patients who 
were started on androgen deprivation therapy will not be allowed on this protocol Patients who have 
started radiographic evaluation and underwent CT scan and/ or BS prior to registration to the study 
will be able to participate under a late registration provision, provided that WB/axial MRI and F-18 
NaF PET/CT can be completed within 4 weeks of the CT scan and BS. 
Investigational Product Dosage and Administration: 
Not Applicable.  
 
Clinical Observations and Tests to be Performed: 
CT of the chest, abdomen and pelvis and bone scan. Targeted X Rays if suggested by the radiologist. 
If negative, WB/axial MRI and F-18 Sodium Fluoride PET /CT. Biopsy of suspected lesions will be 
performed if feasible, and repeat scans will be performed for patients with suspicious lesions.   
Statistical Considerations: 
  
Sponsor/Licensee: 
City of Hope  
 
Case Report Forms 
 
 

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Table of Contents 
 
SECTION .............................................................................................................................. PAGE 
1.0 
Objectives ........................................................................................................................... 8 
2.0 
Background ......................................................................................................................... 9 
2.1 
Introduction/Rationale for Development ............................................................... 9 
2.2 
Overview of Proposed Study ............................................................................... 11 
3.0 
Patient Eligibility .............................................................................................................. 12 
3.1 
Inclusion Criteria ................................................................................................. 12 
3.2 
Exclusion Criteria ................................................................................................ 12 
3.3       Inclusion of Women and Minorities ..................................................................... 12 
4.0 
Screening and Registration Procedures............................................................................. 13 
4.1 
Screening Procedures ........................................................................................... 13 
4.2 
Informed Consent ................................................................................................ 13 
4.3 
Registration Requirements/Process ..................................................................... 13 
5.0 
Intervention ....................................................................................................................... 13 
5.1       Methods ................................................................................................................ 14 
5.2       Planned Duration of the Study .............................................................................. 15 
5.3       Subject Follow-Up ................................................................................................ 15 
6.0 
Delays / Modifications to Imaging Studies Schedule ....................................................... 15 
7.0 
Data and Safety Monitoring .............................................................................................. 15 
7.1       Definition of Risk Level ....................................................................................... 15 
7.2 
Monitoring and Personnel Responsible for Monitoring ...................................... 15 
7.3 
Definitions ........................................................................................................... 16 
7.4 
Reporting of Unanticipated Problems and Adverse Events ................................. 16 
8.0    Risks ...................................................................................................................................... 18 
8.1       CT scan ................................................................................................................. 18 
8.2       Bone scan .............................................................................................................. 18 
8.3 
PET/CT ................................................................................................................ 19 
8.4       MRI ....................................................................................................................... 19 
8.5       Biopsy ................................................................................................................... 19 
9.0  Study Calendar ........................................................................................................................ 20 
10. Endpoint Evaluation Criteria/Measurement of Effect .............................................................. 21 
10.1     Verification of Scan Results ................................................................................. 22 

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10.2    Follow-up scans ..................................................................................................... 23 
11.0  Data Reporting/Protocol Deviations ..................................................................................... 25 
11.1   Confidentiality and Storage of Records .................................................................. 25 
11.2   Subject Consent Form ............................................................................................. 25 
11.3   Data Collection Forms and Submission Schedule .................................................. 25 
11.4   Protocol Deviations ................................................................................................. 25 
12.0   Statistical Considerations ..................................................................................................... 26 
13.0 Human Subject Issues ............................................................................................................ 27 
13.1  Institutional Review Board ...................................................................................... 27 
13.2  Recruitment of Subjects ........................................................................................... 27 
13.3  Advertisements ........................................................................................................ 27 
13.4  Study location and Performance Sites ..................................................................... 27 
13.5  Confidentiality ......................................................................................................... 27 
13.6  Financial Obligations and Compensation ................................................................ 28 
13.7   Informed Consent Processes ................................................................................... 28 
14.0 References .............................................................................................................................. 28 
 

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Abbreviations 
Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
SAE 
Serious Adverse Event 
 
 
 
1.0 
Objectives  
Primary Objective:  
To determine the proportion of patients with biochemically-recurrent PC in whom imaging with WB/axial 
MRI and F-18 NaF PET/CT results in  detection of metastatic disease not visualized on CT scan and bone 
scan. 
 
Secondary Objectives: 
1. To estimate the percent of eligible patients with negative, indeterminate and positive CT 
scan/bone scan and targeted X-rays if done. 
2. To determine the proportion of patients with biochemically recurrent PC in whom 
recurrence in the prostate bed can be visualized using MRI in the absence of detection 
using CT scan. 

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3. To correlate the presence of metastatic disease detected using WB/axial MRI and/or F-18 
NaF PET/CT with the predicted 6-year probability of progression-free survival based on 
the Memorial Sloan Kettering Cancer Center salvage RT PC nomogram, and with PSA 
level at baseline. 
4. To compare the role of axial MRI of the spine to WB/axial MRI with respect to their 
ability to identify sites of disease. Similarly, to evaluate the relative contribution of F-18 
NaF PET and WB/axial MRI.   
 
 
 
2.0 
Background 
2.1 
Introduction/Rationale for Development 
Background 
Each year, approximately 32,000 men in the United States will have a recurrence of prostate cancer (PC) 
after radical prostatectomy.1  For most of these patients the only manifestation of recurrent disease is an 
increasing level of serum prostate specific antigen (PSA) in the blood detected through routine monitoring 
after surgery. A PSA level of ≥0.2 ng/mL is considered the threshold for biochemical recurrence.2 For 
those patients who have a recurrence, some will have disease that is initially confined to the prostate bed 
and pelvis. Patients who have not previously received adjuvant radiation therapy (RT) can potentially be 
cured by local salvage RT. However, this treatment approach is complicated by the inability to distinguish 
between those patients with an isolated local recurrence and those patients with occult distant metastases 
who will not benefit from salvage RT.3, 4 Therefore accurate localization of recurrent disease has 
significant therapeutic implications.  
Currently, there is no consensus regarding the use of specific imaging techniques in patients with 
biochemically recurrent prostate cancer. National Comprehensive Cancer Center (NCCCN) guidelines 
suggest obtaining “+/- CT scan, +/- bone scan, +/- Ultrasound, +/- MRI” indicating lack of any 
meaningful guidelines.  In addition, in 2011, the FDA approved F-18 NaF PET/CT for the detection of 
bone metastases for Medicare beneficiaries through the Coverage with Evidence Development/National 
oncologic PET Registry program (NOPR) adding to the available options with limited guidelines. 
Currently at City of Hope, patients who present with a PSA level of ≥0.2 ng/mL after radical 
prostatectomy typically undergo computed tomography scan (CT) of the abdomen and pelvis, bone scan 
(BS), targeted X-rays (TXR), and occasionally Prostascint scanning, with the primary goal of excluding 
the presence of metastatic disease. However, these imaging modalities often fail to detect metastatic 
disease, especially early in the course of PC recurrence when the cancer burden is low.5 The value of 
abdominal and pelvic CT in the detection of metastases in patients with biochemically-recurrent PC is 
low, especially when PSA levels are <10 ng/mL.6The detection of metastatic bone cancer with BS is low 
because it detects bone deposits from osteoblasts, not directly from cancer cells;7 BS is positive in <1% of 
patients who present with biochemically-recurrent PC and a PSA level of <10 ng/mL.5 Prostascint 
scanning has significant limitations because it only recognizes the intracellular domain of prostate 
specific membrane antigen (PSMA) and, likely due to the low detection rate, Prostascint scans do not 
correlate with the efficacy of salvage RT in PC.8  As a result, the reported long-term success rate of 
salvage RT ( in patients with negative CT scan and bone scan) ranges from 10-50%. This suggests that 
the majority of patients (50-90%) with biochemically-recurrent PC have occult metastases that are not 
visualized by standard imaging approaches,9, 10,11. It is therefore clinically very important to improve the 
accuracy of radiologic assessment of patients with biochemically recurrent PC. This may have significant 
importance in the appropriate selection of patients for local salvage therapy or systemic treatments. Our 

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strategy involves the application of the two more recent imaging techniques (each either part of the 
NCCN guidelines or FDA approved) that have demonstrated the potential to better detect distant 
metastatic disease in patients with high risk prostate cancer.  As the previous studies did not restrict the 
population to biochemically recurrent prostate cancer only, additional studies in this specific and more 
uniform patient population are needed to help refine and provide more meaningful imaging guidelines, 
motivating this prospective imaging study.  Specifically, these imaging tests are often not routinely 
covered by insurance in this setting despite the NCCN and FDA guidelines/approval, and we hope that 
this study will help convince the community that these newer tests are justified in this specific patient 
population. 
MRI 
MRI can detect bone metastases in cancer patients. It’s superiority over bone scan has been repeatedly 
demonstrated 12, 13, 14, 15.  As a result, some have called MRI a “gold standard” for detection and 
confirmation of bone metastases (14, 15, 16), although due to availability, inconvenience and cost, many 
centers have not adopted its routine use.    
Classically, the terms sensitivity and specificity are used in evaluating diagnostic tests.  However, it is 
infeasible to know if microscopic metastatic disease was missed when the scans are negative, and as a 
result the human studies comparing  MRI to bone scan and targeted X-rays use a measure of “sensitivity” 
(based on “best valuable comparator (BVC)”) that only conveys that the MRI is superior to bone scan and 
targeted X-rays.  In a study by Lecouvet et al. (17)  66 patients with high-risk prostate cancer were 
evaluated with standard bone scan and X-rays and MRI of the axial skeleton.  BVC was a panel of 
reference consisting of the CT correlation of equivocal MRI findings, prospective systematic follow-up 
bone scan and MRI studies at 6 months, and clinical and biologic follow-up obtained during 6 months of 
follow-up. MRI did not incorrectly declare any patient to have metastatic disease out of the 25 without 
evidence of metastasis at initial staging based on final BVC attribution.l. In addition, of the 41 patients 
determined to have metastatic disease by BVC, all 41were positive on MRI, suggesting that MRI did not 
miss any lesions identified by other scans.  More importantly, 7 of the 23 (30%) of patients who would 
have been considered negative with bone scan and targeted X-rays were determined to have metastatic 
disease on MRI, and considered positive by BVC.  Combined, this demonstrates that MRI has high 
specificity (no false positive calls), did not miss any positive findings on bone scan and X-ray, and was 
able to visualize evidence of metastatic disease in 30% of the patients deemed negative on bone scan and 
X-ray.  As a result, there is a general consensus about the superiority of MRI techniques over bone scan in 
the detection of bone metastases, although the high sensitivity quoted in the literature is known to not 
relate to the more classic definition of sensitivity (e.g. sensitivity to detect a known lesion of a certain 
size) and the quoted specificities also need further evaluation  
Whole-body MRI (WB MRI) has a number of distinct advantages over other imaging techniques, 
including the ability to simultaneously assess bone and soft tissue, high soft tissue contrast, no ionizing 
RT, and a versatile ability to measure both anatomic and functional tissue properties based on different 
tissue contrast modes. WB MRI has been shown to be feasible for detecting metastasis in cancer 
patients.18, 19 WB MRI has also demonstrated superiority in detecting bone metastases in high-risk PC 
patients compared with standard imaging techniques.17 Diffusion Weighted Imaging MRI (DWI-MRI) is 
another specialized MRI imaging technique that has been applied as a WB scan to detect abnormal tissue 
cellularity in cancer patients.20 WB DWI-MRI outperformed BS in detecting bone metastases in a study 
of 100 patients with high-risk PC (56 of these patients had biochemical recurrence following local 
therapy). Specifically, WB DWI-MRI detected bone metastases in 5 of 44 (11%) of patients in whom BS 
was negative.21 By conducting both axial MRI and WB MRI the performance of the MRI imaging should 
be better than one alone, and the differences between these two MRI imaging approaches can also be 
explored.  
F-18 sodium fluoride imaging with positron emission tomography CT (F-18 NaF PET/CT) 

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F-18 NaF PET/CT is a molecular imaging technique FDA approved for detection of bone metastasis in 
PC patients. Fluoride tracer uptake is a biomarker for bone metabolism. PET/CT has higher resolution, 
contrast, and sensitivity than traditional bone single-photon emission computed tomography (SPECT) 
imaging and greater specificity than BS.22 CT alone may be unable to identify small metastatic lesions 
<3mm. The functional contrast provided by the PET tracer may be able to partially overcome this 
shortcoming.  
In the series of 44 high-risk prostate cancer patients Even-Sapir et al. 23 reported that 21patients were 
negative on the F-18 NaF PET/CT, and all of these patients had no clinical or imaging evidence of 
metastatic spread for at least the 6-month follow-up period.  In addition, 23 patients were determined to 
have metastatic disease based on definitive PET/CT, biopsy, imaging and follow-up.  20 of the 23 were 
determined to be positive based on PET/CT and 3 were equivocal.  By comparison, BS was negative in 
10, and BS plus SPECT were negative in 5.  In another study positive detection rate by F-18 NaF of bone 
metastases not seen on CT and bone scan was 16.2%.24  
The complementary strengths of MRI and PET/CT imaging suggest an advantage to combining these 
scans for staging patients. Previous research has explored the suitability of combining WB/axial MRI 
with PET/CT in cancer patients,25 and the advantage of a multiparametric approach towards detecting 
metastatic spread in PC patients has been suggested.26  
 
However, no group has evaluated F-18 NaF PET/CT plus WB/axial MRI in patients with biochemically 
recurrent prostate cancer (or prostate cancer in general), nor have they evaluated it in the context of 
patients with negative CT scan, BS and targeted X-rays.  In view of the poor performance of currently 
utilized imaging techniques coupled with data supporting both F-18 PET/CT and MRI, along with NCCN 
guidelines for the use of MRI and FDA approval of F-18 NaF PET/CT for evaluating bone lesions, we 
propose a novel  diagnostic  approach: adding WB/axial MRI and F-18 NaF PET/CT to standard imaging 
(CT scan and BS) for patients negative on CT scan and BS to better detect and characterize metastatic and 
recurrent disease in biochemically-recurrent PC patients. If successful, our study has the potential to 
change the paradigm of disease management for patients with biochemically recurrent PC by: 1) 
identifying a clinically significant proportion of patients with distant metastasis and excluding them from 
salvage RT, thus sparing them the morbidity and cost of an unnecessary treatment; and 2) enriching for 
patients who have the highest likelihood of benefitting from salvage RT, thus better justifying RT-
associated morbidity and the substantial cost of treatment. 
Hypothesis 
We hypothesize that combination of WB/axial MRI and F-18 NaF PET/CT will detect metastatic disease 
in a significant proportion of patients (>5%) with biochemically recurrent prostate cancer who have a 
negative bone scan, CT scan and targeted X-rays.   
 
2.2 Overview of Proposed Study 
After informed consent is obtained, patients will be screened for eligibility. Eligible patients will be 
registered for a study. The 6-year probability of progression-free survival based on the Memorial Sloan 
Kettering Cancer Center salvage RT PC nomogram will be recorded. Patients will then undergo imaging 
studies including CT of the chest, abdomen and pelvis. Targeted X-rays (TXR) will be obtained in case of 
equivocal findings if suggested by the radiologist. Patients who have CT scan and or bone scan that are 
interpreted as positive or indeterminate will be managed in a standard way at the discretion of the treating 
physician. That will frequently include additional imaging modalities and therapy as appropriate , Patients 
with CT scan and bone scan that are interpreted as negative (estimated ≥ 90 %) will undergo WB/axial 

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MRI scan and 18-F NaF PET/CT scan. All imaging studies should be ideally completed within a 4-week 
period, although up to 8 weeks will be allowed. 
One of the possible outcomes will be assigned to WB/axial MRI scan, and F18 NaF PET/CT scan: 1) 
consistent with visible recurrence   2) indeterminate 3) negative. In cases when the combination of  
WB/axial MRI  and 18-F NaF PET/CT scan are interpreted as consistent with recurrence or indeterminate   
biopsy of the lesion of interest will be recommended if feasible (The presence of histologically proven 
metastasis will be considered the “gold standard” for the confirmation of metastasis, while recognizing 
that such confirmation will be rarely achieved.).Fifty six patients will be evaluated over 24 months.  
 
 
3.0 
Patient Eligibility 
Prior to the initiation of screening procedures, the purpose and procedures of the study will be explained 
to each subject, and each subject will then sign an Institutional Review Board (IRB) approved consent 
form. The subject will subsequently undergo screening assessments to determine if he meets the 
eligibility criteria for the study. 
3.1 Inclusion Criteria  
3.1.1 
History of prior radical prostatectomy for prostate cancer    
3.1.2 
Two PSA values ≥0.2 ng/mL at least 4 weeks after prostatectomy. 
3.1.3 
Patients who have started radiographic evaluation and underwent CT scan and/ or bone 
scan prior to registration to the study will be able to participate under a late registration 
provision, provided that the more modern scans (WB/axial MRI and F-18 NaF PET/CT) 
can be completed within 8 weeks after CT scan and bone scan. 
3.1.4 
Patients must be ≥ 18 years old. 
 
3.2 Exclusion Criteria 
 
3.2.1 
Patients with known metastatic disease 
3.2.2 
PSA recurrence not verified by elevated PSA as discussed in the eligibility section. 
 
3.2.3  
Patients who initiated androgen deprivation therapy or other systemic therapy 
(chemotherapy, immunotherapy, targeted therapy) for PSA recurrence. Nutritional 
supplements used for treatment of PSA recurrence will be allowed  
3.3   Inclusion of Women and Minorities 
Prostate cancer is exclusively disease of men. The study is open anyone regardless of race and ethnicity.  
Efforts will be made to extend the accrual to a representative population, but in a trial which will accrue 
approximately 55 subjects, a balance must be struck between subject safety considerations and limitations 
on the number of individuals exposed to potentially toxic or ineffective treatments on the one hand and 
the need to explore racial, and ethnic aspects of clinical research on the other.  If differences in outcome 
that correlate to racial or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 

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4.0 
Screening and Registration Procedures 
4.1 Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values, even if the studies were 
done before informed consent was obtained.  Reference is made to Section 9.0 – Study Calendar. 
4.2 Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
subject and a signed informed consent will be obtained.  Documentation of informed consent for 
screening will be maintained in the subject’s research chart and medical record.   
4.3 Registration Requirements/Process 
Once the signed informed consent has been obtained, all pretreatment evaluations have been performed, 
and patient’s eligibility has been confirmed by the study coordinator a patient will be entered on study.   
To register a patient, the research nurse or data manager must complete the eligibility/registration form 
and fax a copy of the completed eligibility checklist, required pre-study tests (laboratory and pathology 
report), signed Informed Consent, signed Patients' Bill of Rights and HIPAA authorization form. (FAX 
Number: 626-256-8654).   
The nurse or data manager must log into the Electronic Data Capture (EDC) system and enter the 
eligibility/registration data for their reserved patient. To complete the registration process, the study 
coordinator will: 
 
Verify eligibility 
 
Register the patient on study 
 
Assign a patient accession number 
 
Confirm the patient study number in the EDC system 
 
Call the research nurse or data manager and verbally confirm that the patient information is 
available to view in the EDC system.   
5.0 
Intervention 
 
After informed consent is obtained, patients will be screened for eligibility. Eligible patients will be 
registered for a study. The 6-year probability of progression-free survival based on the Memorial Sloan 
Kettering Cancer Center salvage RT PC nomogram11 will be recorded. Patients will then undergo 
including CT of the chest, abdomen and pelvis and BS. TXR will be obtained in case of equivocal 
findings if suggested by the radiologist. Patients who had positive or indeterminate bone scan or CT scan 
will be taken off the study. Patients with negative bone scan and CT scan will undergo WB/axial MRI 
scan, and 18-F NaF PET/CT scan.  All imaging studies will be completed within an 8 -week period. If the 
patients underwent standard CT scan and bone scan prior to enrollment to the study, they will be able to 
participate under a late registration provision, provided that the more modern scans (WB/axial MRI and 
F-18 NaF PET/CT) can be completed within 8 weeks of  CT scan and bone scan. 
 . 

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5.1   Methods 
CT scan 
A protocol routinely used at City of Hope for a CT scan of the chest/ abdomen/ pelvis will be used for this 
study. A non-contrast scan will be initially acquired over the liver and the kidneys. 125 mL Isovue 370 
iodinated contrast agent (Bracco, Princeton, NJ) adjusted for weight will be injected intravenously. After 
a 40-second delay, a chest scan will be acquired. Following a cumulative 75-second delay, an abdominal 
scan will be acquired from the diaphragm to the pelvic crest. 180 seconds will be allowed to elapse to 
permit contrast to reach the bladder before a final pelvic scan is acquired. Each scan will be acquired in a 
single breath hold with the following parameters: 120 kV, pitch = 1.375, mA selected based on patient 
weight, and reconstruction using filtered back projection (FBP) with matrix size = 512 x 512 with two 
different resolutions 2.5mm x 2 mm and 5 mm x 5 mm, and slice overlap of 0.5 mm and 0 mm, 
respectively. 
 
Bone Scan (BS)  
A protocol routinely used at City of Hope for a BS will be used in this study based on a dual-head GE 
Infinia Imaging System (GE Medical Systems, Waukesha, WI). 18 m Ci Tc-99 m methylene 
diphosphonate (MDP) will be injected intravenously. The patient will be asked to void all fluids prior to 
image acquisition. 2.5 hours post-injection, the patient will be scanned in the anterior to posterior 
direction with a single WB pass. Spot images will be taken of the lateral skull, anterior/ posterior chest 
and pelvis, and any other areas requested by the referring physician. Total imaging time will be 40-60 
minutes. Data will be acquired for a total of 1000 k counts for the torso and 500 k for the extremities and 
will be reconstructed on a 256 x 256 matrix. 
WB/axial MRI 
All MR images will be acquired on a 3T MRI System (Magnetom Verio Model, Siemens Healthcare, 
Erlangan, Germany). The MR exam will consist of three types of images; T2-weighted, T1-weighted, and 
DWI. The sequence parameters for each of these scans are shown below (Table 2). DWI-MRI will consist 
of an echo planar imaging sequence with diffusion-sensitizing gradients in x, y, and z planes that will be 
applied before and after 180  pulses. Diffusion will be measured in orthogonal planes and averaged in 
order to avoid directional bias since it is expected that tumors will show anisotropic movement of water. 
Images will be acquired for two b-values (50, 800) reflecting a range of sensitivity for the pulse sequence 
to changes in diffusion. 
 
Table 2: Sequence parameters for anatomic MRI acquisitions 
 
T2 Whole Body 
Coronal – breath hold 
T1 Whole Body 
Coronal –breath hold 
DWI Whole Body 
Axial 
 
Head 
Thorax 
Head 
Thorax 
Head 
Thorax 
Sequence 
STIR 
Same 
SE 
TSE 
EP 2D Diff 
Same 
TR (ms) 
5000 
3000 
500 
750 
9000 
Same 
TE (ms) 
105 
93 
8.7 
8.7 
70 
Same 
TI (ms) 
200 
Same 
- 
- 
- 
- 
FOV (mm) 
480 x 480 
450x450 
480x480 
same 
400 x 400 
Same 

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Slice (mm) 
5.0 
Same 
5.0 
same 
5.0 
Same 
Matrix Size 
384 x 384 
Same 
384 x 384 
same 
160 x 160 
Same 
 
F-18 Na-F PET/CT 
F-18 Na-F PET/CT scan will be performed using a standard clinical protocol commonly used at City of 
Hope. All images will be acquired on a helical 16 Slice Discovery ST (GE Medical Systems, Waukesha, 
WI). Approximately 10 mCi in 1-1.5 mL of NaF will be injected intravenously based on patient weight. A 
period of 45 minutes will be allowed to permit tracer circulation, uptake, and clearance prior to the scan. 
Image acquisition will consist of as many bed positions as required to cover the entire patient from head-
to-toe for approximately 2 minutes per bed position. PET data will be reconstructed using an iterative 
algorithm with matrix size = 128 x 128, FOV = 70 cm, slice thickness of 5.5 mm, attenuation, random, 
scatter, decay, and dead time corrections. The CT part of the scan will be acquired without contrast and 
120kV and mA adjusted based on the patient, pitch=1. CT images will be reconstructed using FBP with 
matrix size=512 x 512, 0.25 mm slice overlap, 0.98 mm isotropic in plane resolution, and 3.27 mm slice-
thickness. 
 
5.2   Planned Duration of the Study 
5.2.1  The initial imaging studies will be performed within 8 weeks of registration o the 
protocol, Subsequent follow up imaging will be performed within 4-6 months after registration to 
the study.    
5.3   Subject Follow-Up 
Patients will be followed clinically and will undergo periodic laboratory and radiographic tests until week 
52 or until disease progression requiring therapy (see Study calendar 9.0). 
6.0 
Delays / Modifications to Imaging Studies Schedule 
In case the patient is not able to complete all the required imaging procedures within 8 weeks, patient will 
be replaced. However patients who completed all the standard imaging studies (CT scan and bone scan) 
and at least one newer imaging study (WB/axial MRI, F-18 NaF PET/CT) will be considered for analysis. 
Patients who decline recommended biopsy will not be excluded from analysis.   
7.0 
Data and Safety Monitoring 
7.1   Definition of Risk Level 
      This is a Risk Level 2 study, as defined in the “City of Hope Data and Safety 
Monitoring Plan”, http://www.coh.org/dsmc/Pages/forms-and-
procedures.aspx because it involves imaging studies and biopsies where the 
risk of harm is low. 
 
 
7.2        Monitoring and Personnel Responsible for Monitoring 
The PI is responsible for monitoring protocol conduct.  The PI will report   to the COH DSMC any 
deviations, adverse events and/or serious adverse events related to study procedures and report 
unanticipated problems to the DSMC and IRB.  

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7.3 
Definitions 
Adverse Event - An adverse event (AE) is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected adverse event that results in any of the following outcomes: 
 Death 
 Life-threatening experience (places the subject at immediate risk of death from 
the event as it occurred); 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect 
 Secondary Malignancy, or 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
 
 
7.4      Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems: Unanticipated problems must be reported to the COH DSMC and IRB within 
5 calendar days according to definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-
policies.aspx.  Any unanticipated problem that occurs during the study conduct will be reported to the 
DSMC and IRB by submitting electronically in iRIS (http://iris.coh.org). 

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Serious Adverse Events - All SAEs occurring during this study, whether observed by 
the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and 
Table 1 below.  Those SAEs that require expedited reporting will be submitted 
electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the protocol continuation reports (see Table 1 below). 
Table 1:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
Required Reporting Timeframe to DSMC  
Attribution 
UNEXPECTED 
EXPECTED 
 
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar  days 
No reporting required* 
Unlikely, Unrelated 
No reporting required* 
No reporting required* 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, 
Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
5 calendar days 
5 calendar days 
 
Grade 1 and 2 AND resulting in hospitalization# 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
*Such events are not required to be reported to the DSMC.  These events should be included with 
the SAE/AE summary provided in the IRB Annual Continuation reports. 
 
# Hospitalization = Unplanned admission equal to or greater than 24 hours 

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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
8.0    Risks          
8.1 CT scan  
There is a slight risk of developing an allergic reaction to the iodine contrast material. This reaction can 
be mild (itching, rash) or severe (difficulty breathing or sudden shock).  Death resulting from an allergic 
reaction is rare.  Most reactions can be controlled by the use of additional drugs to prevent the allergic 
type reaction.  Participants should inform their doctor if they have allergies of any kind (such as hay 
fever, iodine allergy, eczema, hives, or food allergies).  The contrast material used during a CT scan can 
also cause water loss or damage to the kidneys that may lead to kidney failure.  This is of particular 
concern if there is underlying poor kidney function, dehydration, or diabetes.  Participants will be exposed 
to a limited and medically acceptable dose of radiation during the procedure.  There is always a slight risk 
from being exposed to any radiation, including low levels of X-rays used for a CT scan.  Participants may 
also experience discomfort related to lying still in an enclosed space for a prolonged period of time. 
8.2 Bone scan 
There is a slight risk of developing an allergic reaction to the contrast material..  This reaction can be mild 
(itching, rash) or severe (difficulty breathing or sudden shock).  Death resulting from an allergic reaction 
is rare.  Most reactions can be controlled by the use of additional drugs to prevent the allergic type 
reaction.  Participants should inform their doctor if they have allergies of any kind (such as hay fever, 
iodine allergy, eczema, hives, or food allergies).  There is always a slight risk from being exposed to any 
radiation, including low levels used for a bone scan.  Participants may also experience discomfort related 
to lying still in an enclosed space for a prolonged period of time. 
 

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8.3 PET/CT 
The tracer used in the PET/CT scan is radioactive but short lived and poses little to no risk.  Participants 
may experience claustrophobia from being inside the PET/CT scan or experience mild discomfort from 
lying on the PET scanner table.  A sedative such as Diazepam or lorazepam may be prescribed if 
participant is unable to relax, lie still, or for those who experience claustrophobia.  There can be side 
effects from diazepam or lorazepam. The more common side effects are: 
 
Drowsiness which is temporary and may require additional medication 
 
Dizziness which is temporary and may require additional medication 
 
Dry mouth which is temporary and may require additional medication 
 
Diarrhea which is temporary and may require additional medication 
 
Upset stomach which is temporary and may require additional medication 
 
Blurred vision which is temporary and may require additional medication 
 
Participants may experience pain and tenderness, bruising or a skin reaction at the injection site when 
given the study drug injection that will be administered through an intravenous (IV) catheter.  As with any 
IV placement, there is a risk of infection at the site but the careful and clean procedure used for placing 
the IV almost completely removes this risk.   
8.4 MRI 
Risks include possible anxiety and claustrophobia related to being placed in the large body scanner; 
temporary discomfort related to having to lie still during the procedure; and possible pain, infection and 
bleeding related to venipuncture if contrast dye is used.  Because MRI works through a powerful 
magnetic field, it cannot be done if participants have a pacemaker, intracranial aneurysm clips or other 
metal implants (for example, types of implants used in eye surgery or orthopedic [bone] surgery), 
artificial limbs and other medical devices that contain iron.  Also, there is a risk that metal objects coming 
near the magnet may become dangerous as they are pulled toward the magnet.  The magnetic field will 
stop a watch that is within several yards of the magnet.  Severe injury or death can occur when subjects 
with implanted neurological stimulators undergo MRI scans.  Participants should discuss any metal 
devices in their body with the study staff.  In addition, when having an MRI scan, iron pigments in 
tattooed eyeliner or in eye makeup can potentially cause temporary skin irritation and/or swelling around 
the eye. For subjects that need an MRI scan and have reduced kidney function there is a chance of 
developing "nephrogenic systemic fibrosis," a condition characterized by thickening and itchiness of the 
skin, stiffening of the joints and possible reduction in the ability to move around. This condition is 
associated with the MRI contrast agent gadolinium and occurs mostly in subjects with severe kidney 
disease.  The risk to subjects with mild kidney problems is anticipated to be small. Participants will be 
questioned and examined, if necessary, to confirm that they may undergo MRI scanning without 
additional risk.  An x-ray may be performed to rule out the presence of a suspected foreign body before 
the MRI. 
8.5   Biopsy 
Biopsy will be recommended in selected patients (Table1)  
Risks of biopsy will depend on the site of biopsy and patient’s underlying medical conditions like 
potential coagulopathy. Risks include: Pain and discomfort, bleeding at the biopsy site, tenderness at the 
biopsy site, scarring at the biopsy site, rarely, an infection at the biopsy site. 

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9.0 
Study Calendar          
Table 1 Schedule of Events (time scale in weeks)                                                                                                               
 
                                                                                           
 
Week  
 
Pre-Study * 
1-8 
1-8 
1-12 
16-24 
   28-36 
40-52 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
X 
X 
X 
Performance Status 
X 
 
 
 
X 
X 
X 
CBC w/diff, plts 
X 
 
 
 
X 
X 
X 
Serum chemistry a 
X 
 
 
 
X 
X 
X 
PSA 
X 
 
 
 
X 
X 
X 
Testosterone 
X 
 
 
 
X 
X 
X 
Radiologic 
evaluation (bone 
scan, CT chest abd 
/ pelvis b  
 
X 
 
 
Xf 
 
 
Targeted (Xrays) c 
 
X 
 
 
Xf 
 
 
WB/axial MRI, F-
18 NaF PET/CT d 
 
 
X 
 
Xf 
 
 
Biopsy of 
suspected 
abnormality e 
 
 
 
X 
 
 
 
  
*     Prestudy tests should be performed within 8 weeks of registration. 
a) 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  
potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
b) 
If  bone scan and/or CT scan and/or targeted X-rays were  already performed before study registration 
they can be utilized for the study purposes under late registration provision, provided that patients can be 
registered and complete WB/axial MRI and F-18 NaF PET/CT within 8 weeks of the oldest standard 
study.      
c) 
If recommended by radiologist due to inconclusive findings on bone scan and CT scans.      
d) 
 WB/axial MRI  F-18 NaF PET/CT will be performed AFTER bone scan, CT scan and (if needed) 
targeted  X-rays have been completed. All the imaging studies should be completed within 8 weeks of 
registration (except under late registration provision – see b). 
e) 
In patients in whom the results of WB/axial MRI and /or F-18 NaF PET/CT are consistent with 
recurrence or indeterminate.   
f) 
In patients in whom the results of all the imaging studies and biopsy (if performed) were not conclusive 
for metastasis. The specifics of which imaging study (or studies) to be performed at week 16- 24 will be 
determined based on the recommendation of radiologist. 

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10.    Endpoint Evaluation Criteria/Measurement of Effect 
 
All scans will be interpreted by two board-certified radiologists with CT, MRI and nuclear medicine 
expertise who will be dedicated members of the research team. In cases of differences in interpretation 
between the two radiologists, the final reading will be determined by consensus conference involving a 
third radiologist, also a dedicated member of the research team. One of the three possible outcomes will 
be assigned to the combination of CT scan and BS (and TXR) if obtained:  1) consistent with visible 
recurrence 2) indeterminate or 3) negative.  
Figure 1.  
CT scan chest/abdomen /pelvis BS (TXR as needed) 
Possible outcomes 
 
 
                           Consistent with visible recurrence.  Indeterminate            Negative 
 
 
                                                     
                             Biopsy if appropriate,  
                             additional imaging as clinically indicated,  
                             follow treatment patterns and PSA 
                             until disease progression or 1yr  
                           whichever is first. 
                                          
            
WB/axial MRI, F-18 NaF PET/CT 
Possible outcomes  
 
 
  Consistent with visible recurrence.    Indeterminate            Negative 
 
 
    
                                                        
Biopsy, when feasible recommended in all patients with MRI or NaF PET/CT consistent with recurrence or indeterminate   
Record PSA response to Salvage Therapy (if given), perform 4-6 month follow up scans if clinically indicated and follow for 
1yr or until progression                                                                 

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Patients who have CT scan and /or bone scan that are consistent with or indeterminate for metastases will 
be managed in a standard fashion at the discretion of treated physician. It may include additional imaging 
studies, biopsies and subsequent therapy. Patients with CT scan and bone scan interpreted as negative 
(estimated ≥ 90%) will undergo additional imaging. including WB/axial  MRI and F-18 NaF PET/CT. 
Possible outcomes :1) consistent with recurrence 2) indeterminate 3) negative will be assigned to  
WB/axial MRI and F-18 NaF PET/CT. In cases of WB/axial MRI interpreted as consistent with visible 
recurrence or indeterminate a biopsy of the lesion of interest will be recommended if feasible.   
 
10.1   Verification of Scan Results 
10.1.1 Biopsy of Suspected Metastases 
Biopsy of metastatic sites of prostate cancer patients is feasible.27 Bone biopsies of patients with 
known, advanced metastatic prostate cancer are performed with increasing frequency with yield 
exceeding 50 % (personal communications, Dr. Maha Hussein , University of Michigan)   We 
estimate that in our population of patients  biopsies will  be accomplished in approximately 25% 
of  cases of suspicious lesions because  of their likely  small size or difficult location and 
targeting . Based on our personal experience and personal communications we anticipate 
extremely high willingness of patients to undergo biopsy of suspected lesions.  
The presence of histologically proven metastasis will be considered the “gold standard” for the 
confirmation of metastasis.   However since majority of patients will not be able to undergo 
biopsies we will utilize two additional strategies to confirm the interpretation of imaging studies. 
10.2.PSA Response To Salvage Radiation Therapy 
The majority of our population of patients (unless biopsy proven metastases are discovered) will 
be offered salvage radiation therapy to the prostate bed. The concept of this therapy is that all the 
recurrent cancer cells may be located in the radiation field around prostate bed. Therefore the 
expected result of salvage RT is PSA level becoming undetectable (<0.04 ng/dL) within 6-8 
weeks following completion of therapy.  
 
Possible scenarios: 
a) The undetectable PSA level following salvage RT would be a very strong indicator that any 
visible abnormalities outside of the radiation field are false positives. If those lesions were “real” 
metastases (even extremely small) they would be expected to produce detectable amounts of 
PSA.  
 
b) If PSA does not become undetectable (< 0.04 ng/dL) in patients with completely normal scans 
that would be considered false negative. 
 
c) In patients who have abnormalities visible on the scans and inwhom salvage RT to prostate bed 
does not result in undetectable PSA level, then it is highly likely that the visible lesions are indeed 
true positives (likely sources of persistent PSA elevation).  This scenario is the most difficult to 
interpret, because it is possible (but in my opinion much less likely) that the source of PSA is 
related to invisible metastases and identified lesions are benign. 

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10.2   Follow-up scans 
Evolution of lesions over the period of time provides invaluable help in the verification of original 
interpretation of the scans even in the absence of biopsy. Therefore all the patients will undergo follow up 
scans (the type advised by radiologist) 4-6 months after registration to the protocol. These scans will be 
interpreted in the context of ongoing therapy (i.e. hormonal therapy) or observation. Several possible 
scenarios will allow us to interpret and verify the findings on the original scans.  
a) The persistence, growth, increase in numbers and intensity of enhancement of lesions in patients on 
observation would strongly favor the interpretation of a true positive finding.  
b) Complete stability over time or resolution of lesions without ongoing therapy would strongly favor 
false positive interpretation.  
c) Evolution of lesions (regression, radiologic signs of healing in the context of ongoing hormonal 
therapy (and lack of any history of trauma) would strongly support the interpretation of true positive scans 
d) Complete stability of lesions despite ongoing hormonal therapy would favor false positive 
interpretation  
                   
By combining these three elements of verification of original interpretation of WB/axial MRI and F-18 
NaF PET/CT we will be able to provide the most robust assessment of sensitivity and specificity of these 
imaging modalities in the literature that may prove to be quite useful in the management of patients with 
biochemically recurrent prostate cancer.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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                Table 1  
Interpretation of Imaging with WB/axial MRI and F-18 NaF PET/CT based on subsequent biopsy, therapy and follow up 
imaging  (not all patients will be classified as below  depending on additional systemic therapy given) 
Original MRI/PET 
Interpretation 
Biopsy 
PSA response to salvage  
RT 
Follow up scans 
FINAL Interpretation of 
Baseline MRI/PET 
Mets 
 
+ 
NA 
Regardless 
TP 
  _ 
 or      
NA 
<0.04 
Mets 
Indeterminate 
Indeterminate 
FP 
No mets  
FP 
≥0.04 
Mets 
TP 
Indeterminate 
TP 
No mets 
Indeterminate 
NA 
Mets  
TP 
Indeterminate 
TP 
No mets 
FP 
Indeterminate 
+ 
NA 
Regardless 
TP 
-  
or NA 
<0.04 
Mets 
Indeterminate 
Indeterminate 
FP 
No mets 
FP 
≥0.04 
Mets 
TP 
Indeterminate 
TP 
No mets 
Indeterminate 
NA 
Mets 
TP 
Indeterminate 
Indeterminate 
No mets 
FP 
Negative  
N/A 
<0.04 
Mets  
Indeterminate 
Indeterminate 
TN 
No mets 
TN 
 ≥0.04 
Mets  
FN 
Indeterminate 
FN 
No mets 
Indeterminate 
NA 
Mets 
Indeterminate 
Indeterminate 
TN 
No mets 
TN 
 
TN – True negative 
FN – False negative 
TP – True positive 
FP – False positive 
 

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11.0   Data Reporting/Protocol Deviations 
11.1   Confidentiality and Storage of Records 
The original data collection forms will be stored at the originating institution in a secure location. Study 
data will be entered into an electronic case report form (eCRF) using an encrypted, password protected, 
secure electronic data capture (EDC) application that meets all HIPAA requirements.  When results of 
this study are reported in medical journals or at meetings, identification of those taking part will not be 
disclosed.  Medical records of subjects will be securely maintained in the strictest confidence, according 
to current legal requirements.  They will be made available for review, as required by the FDA, HHS, or 
other authorized users such as the NCI, under the guidelines established by the Federal Privacy Act and 
rules for the protection of human subjects. 
11.2  Subject Consent Form 
The original signed and dated Informed Consent form, HIPAA research authorization form, and the 
California Experimental Subject’s Bill of Rights will be stored in the research record. At the time of 
registration, a copy of the original signed and dated consent documents will be available to the patient and 
another copy will be stored in the medical record.  All Institutional, NCI, Federal, and State of California 
requirements will be fulfilled. 
11.3  Data Collection Forms and Submission Schedule  
All data will be collected using Medidata EDC electronic case report forms.  Data will be sent to the City 
of Hope Department of Biostatistics and stored in a secure location. 
11.3.1   Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research associate and 
signed by an authorized investigator prior to registering the subject.  See Section 4.3 for the 
registration procedure. 
11.3.2   Prior Therapy Forms and On-Study Forms 
Within two weeks of registration, the clinical research associate will submit Prior Therapy Forms 
and On-Study Forms. 
11.4   Protocol Deviations 
             11.4.1 Deviation Policy 
This protocol will be conducted in accordance with COH’s “Clinical Research Protocol Deviation 
Policy” located at 
http://www.coh.org/dsmc/Documents/Institutional%20Deviation%20Policy.pdf. 
Deviations from the written protocol that could increase patient risk or alter protocol integrity 
require prior IRB approval of a single subject exception (SSE) request.  In addition, if 
contractually obligated, the sponsor must also approve the deviation.  IRB pre-approved SSE 
protocol modifications are considered an amendment to the protocol and not a deviation.  The 
submission of a deviation report is not required. 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 
inclement weather, family responsibilities, security alerts, government holidays, etc.  This can 
also extend to complications of disease or unrelated medical illnesses not related to disease 
progression.  The PI has the discretion to deviate from the protocol when necessary so long as 
such deviation does not threaten patient safety or protocol scientific integrity.  Examples include, 
but are not limited to:  a) dose adjustments based on excessive patient weight; b) alteration in 

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treatment schedule due to non-availability of the research participant for treatment; c) laboratory 
test results which are slightly outside the protocol requirements but at levels that do not affect 
participant safety.  These instances are considered to be deviations from the protocol.  A 
deviation report will be submitted to the DSMC/IRB within five days. 
11.4.2 Reporting of Deviations 
All deviations will be reported to the COH DSMC within five days.  The DSMC will forward to 
report to the IRB following review. 
             11.4.3   Resolving Disputes 
The COH Investigational Drug Service (IDS) cannot release a research agent that would cause a 
protocol deviation without approval by the PI.  Whenever the protocol is ambiguous on a key 
point, the IDS should rely on the PI to clarify the issue. 
In situations where there is misperception or dispute regarding a protocol deviation among the 
persons involved in implementing the protocol, it is the responsibility of the PI to resolve the 
dispute and the PI may consult with the DSMC chair (or designee) to arrive at resolution. 
 
12.0   Statistical Considerations  
We expect more than 90% of the patients enrolling in this study will be negative for metastatic disease 
based on CT, bone scan and targeted X-rays if ordered.   
Primary Endpoint/Sample size justification: 
With 56 patients enrolled, we expect more than 45 patients or more to be negative for metastatic disease 
based on CT, bone scan and X-rays.  Historically, more than half of these patients are expected to have 
undocumented metastatic disease.  The use of WB/axial MRI and 18-F NaF PET will be considered 
worthwhile if more than 8% of these patients (8% rate) are determined to be positive for metastatic 
disease based on the newer scan technologies.    Assuming 45 patients, this requires at least 4 patients to 
be determined to have metastatic disease on the newer scans that were considered to be without metastatic 
disease on the standard scans.  With 45 patients, and requiring at least 4 patients, there is less than a 5% 
chance of declaring a discouraging 3% rate to be promising (type I error), and greater than 86% power for 
declaring a true 15%  rate to be a success.  The actual power should be higher as it is expected number of 
patients negative on standard scans is approximately 49 patients. The percent of patients with negative 
standard scans and positive on the newer scans can be estimated with a 95% CI half-width of less than 
15%. Final determination of success will include an evaluation of the follow-up scans and treatment 
results (when applicable) to fully evaluate the role of the newer scans. 
Accrual: 
56patients will be accrued over 24 months for an accrual rate between 2-3 patients a month. 
Secondary Endpoints: 
The secondary endpoints in the context of this study are exploratory: 
1. To estimate the percent of eligible patients with negative, indeterminate and positive CT 
scan/bone scan and targeted X-rays if done. With 56 patients, the percent positive for 
metastatic disease can be estimated with a 95% CI half-width of less than 13%. 
 
 

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2. To determine the proportion of patients with biochemically recurrent PC in whom 
recurrence in the prostate bed can be visualized using MRI in the absence of detection 
using CT scan. This is exploratory, since detection in the prostate bed on CT does not 
preclude patients from RT salvage therapy, the denominator for this rate will not be 
known or estimated a priori. 
 
3. To correlate the presence of metastatic disease detected using WB/axial MRI and/or F-18 
NaF PET/CT with the predicted 6-year probability of progression-free survival based on 
the Memorial Sloan Kettering Cancer Center salvage RT PC nomogram, and with PSA 
level at baseline. 
 
4. To compare the role of axial MRI of the spine to WB MRI with respect to their ability to 
identify sites of disease. Similarly, to evalue the relative contribution of F-18 NaF PET 
and MRI.  This is an exploratory aim as the number of patients with sites of disease 
visualized on the MRI technology will not be known a priori.   
 
13.0   Human Subject Issues 
 
13.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17,  must review and approve this protocol and the informed consent form prior to initiation of the study.  
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
13.2   Recruitment of Subjects 
Patients for the study with will be recruited from patients undergoing therapy for metastatic castration 
resistant prostate cancer at the City of Hope Cancer Center    
13.3   Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to 
be posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and 
approved by the IRB prior to their use to recruit potential study subjects. 
13.4   Study location and Performance Sites 
This study will be performed at City of Hope 
13.5   Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating 
to protected health information (PHI).  The study will record individual results of imaging studies and this 
will be linked to the subject’s identity using a coded study number.  The principal investigator, co-
investigators, and radiology technicians will have access to this information, but all information will be 
treated confidentially.  No identifiers will be used in any subsequent publication of these results.   

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13.6 Financial Obligations and Compensation 
Therapy on the protocol utilizes standard of care and newer imaging. The standard of care scans 
(CT scan, bone scan and if needed targeted X-Rays) and if needed biopsy of suspected lesions will 
be the responsibility of the research participant and/or the insurance carrier.  The research 
participant will be responsible for all copayments, deductibles, and other costs of treatment and 
diagnostic procedures as set forth by the insurance carrier.  The research participant and/or the 
insurance carrier will be billed for the costs of treatment and diagnostic procedures in the same 
way as if the research participant were not in a research study.  Newer imaging studies (WB/axial  
MRI, F-18 NaF PET/CT ) will be covered by a study budget.  Neither the research participant nor the 
insurance carrier will be responsible for these procedures related to this study. 
 
In the event of physical injury to a research participant, resulting from the newer scan procedures, 
appropriate medical treatment will be available at the City of Hope to the injured research 
participant, however, financial compensation will not be available.  The research participant will not 
be paid for taking part in this study. 
 
13.7   Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without prejudice, including as applicable, their current or future 
care or employment at City of Hope or any relationship they have with City of Hope.  Research subjects 
will be afforded sufficient time to consider whether or not to participate in the research. 
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those subjects who 
do comprehend the fundamental aspects of the study, consent will be obtained and documented, followed 
by eligibility testing.  The research team will review the results of eligibility testing and determine if the 
subject is a candidate for study enrollment.  
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