Clinical trial NCT03822845
Conditions: Prostatic Neoplasms Prostatic Neoplasms, Castration-Resistant
Keywords: Nuclear scans PET imaging prostate cancer
Sponsor: Michael Graham PhD, MD
Start date: 2019-03-01; Completion date: 2021-03-30
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study investigates if a new drug (PSMA) makes prostate cancer easier to identify in positron-emission tomography (PET) imaging. If this works, prostate cancer treatments can be prescribed that match the location of the disease. PSMA is radiolabeled with Gallium-68 (Ga-68). This means a participant receives a small dose of radiation from the drug - less than the annual radiation limit for a medical worker.

To test this new drug, participants will receive an injection of Ga-68 PSMA and then have a PET scan. This PET scan, and the reported results, will be entered into the medical record and shared with the treating oncologists.

Detailed description:
This study evaluates PSMA-HBED-CC labelled with Gallium-68, abbreviated 68Ga PSMA. This is a radiotracer that attaches to receptors in the membrane of prostate cancer cells. The 68Ga PSMA is identified using a positron emission tomography (PET) scanner. It is believed that 68Ga PSMA will identify prostate cancer more precisely than normal imaging methods (MRI, CT, or ultrasound). Imaging is key to successful treatment - disease must be identified to be treated.

The 68Ga PSMA will be tested in men who have biochemical recurrence of prostate cancer after surgery or radiation treatment. Participants undergo the 68Ga PSMA PET scan before further treatment. Clinical information, including any MRI, CT, or ultrasound imaging and biopsy/surgery information, will be used to determine if the 68Ga PSMA PET imaging was better than the standard imaging. The study team will collect this information for about 1 year after the PSMA scan.

Depending on findings, participants may be invited back for a second 68Ga PSMA scan. This is done if the first scan showed positive lymph nodes or soft tissue metastases but a surgery or biopsy result does not.

The results from these scans will be shared with the participant. Results will also be entered into the participant's medical record and shared with the treating oncologists.

Arms: arm 1: Ga-68 PSMA-HBED-CC PET/CT scan
Interventions: intervention 1: Ga-68 PSMA-HBED-CC PET
Intervention descriptions: intervention 1: Ga-68 PSMA-HBED-CC is an investigational PET drug (radionuclide), that binds to the prostate specific receptors. The dose will be about 5mCi (range 3-7 mCi) and administered intravenously.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Accuracy Assessment of 68Ga PSMA-HBED-CC PET in Patients with  
Biochemical Recurrence 
Sponsor Investigator: 
Michael M. Graham, PhD, MD 
University of Iowa Department of Radiology 
Iowa City, IA 52242 
(319) 356-1616 
michael-graham@uiowa.edu  
Sub-Investigators: 
Yusuf Menda, MD 
Janet Pollard, MD 
Parren McNeely, MD 
Yousef Zakharia, MD 
Chad Tracy, MD 
Mark Smith, MD 
Kenneth Nepple, MD 
John Sunderland, PhD 
James Brown, MD 
Paul Gellhaus, MD 
Rohan Garje, MD 
Biostatistician: 
Timothy Ginader, MS 
Biostatistician 
Holden Comprehensive Cancer Center 
University of Iowa Hospitals and Clinics 
timothy-ginader@uiowa.edu  
Protocol Number: 
TBD 
IND Number: 
135,727 
Protocol version /Date: 
Initial submission – 21 September 2018  
 
 


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SUMMARY OF CHANGES 
Section 
 
Change 
 
 
 
 
 
 
September 21, 2018 
 
 
Receipt 
 
Initial submission to FDA, 1571 0007 
 
 
 


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SCHEMA  
 


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TABLE OF CONTENTS 
1. 
Objectives ............................................................................................................................................ 6 
1.1. 
Primary objective ................................................................................................................... 6 
1.2. 
Secondary objective ............................................................................................................... 6 
1.3. 
Exploratory objective ............................................................................................................. 6 
2. 
Background and Rationale .................................................................................................................. 6 
2.1. 
Current imaging of prostate cancer ........................................................................................ 6 
2.2. 
Prostate Cancer, Biochemical Recurrence ............................................................................. 6 
2.3. 
68Ga-HBED-CC PSMA (68Ga PSMA-HBED-CC) ................................................................ 7 
2.4. 
Prior human subjects experience ............................................................................................ 7 
2.5. 
Rationale .............................................................................................................................. 10 
3. 
Subject Selection ............................................................................................................................... 11 
3.1. 
Eligibility Criteria ................................................................................................................ 11 
3.2. 
Exclusion Criteria ................................................................................................................ 11 
4. 
Registration Procedures .................................................................................................................... 12 
5. 
Procedures ......................................................................................................................................... 12 
5.1. 
Imaging preparation ............................................................................................................. 12 
5.2. 
68Ga PSMA-HBED-CC administration ................................................................................ 12 
5.3. 
Prohibited Medications ........................................................................................................ 12 
5.4. 
PET/CT scan ........................................................................................................................ 12 
5.5. 
Visual Interpretation of PET data ........................................................................................ 12 
5.6. 
Follow-up imaging ............................................................................................................... 13 
5.7. 
General Concomitant Medication and Supportive Care Guidelines .................................... 13 
5.8. 
Follow-Up ............................................................................................................................ 13 
5.9. 
Criteria for removal from study ........................................................................................... 13 
6. 
Patient Assessments .......................................................................................................................... 14 
6.1. 
Post-consent Baseline Data Collection ................................................................................ 14 
6.2. 
Pre-Imaging Assessments (Baselines) ................................................................................. 14 
6.3. 
Post-Imaging Assessments ................................................................................................... 14 
6.4. 
Follow-up ............................................................................................................................. 15 
7. 
Drug Information .............................................................................................................................. 15 
7.1. 
68Ga PSMA-HBED-CC IND 135,727 (M. Graham, sponsor) ............................................. 15 
8. 
Dose Modifications & Delays ........................................................................................................... 16 
9. 
Adverse Events: Reporting Requirements ........................................................................................ 16 
9.1. 
Determination of Reporting Requirements .......................................................................... 16 
9.2. 
Institutional Review Board reporting requirements ............................................................. 16 


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9.3. 
FDA reporting requirements [M. Graham, sponsor] ............................................................ 16 
9.4. 
Routine Adverse Event Reporting Requirements to DSMC ................................................ 17 
9.5. 
Serious Adverse Event Reporting to DSMC ........................................................................ 17 
10. 
Clinical Trial Monitoring .................................................................................................................. 17 
10.1. 
University of Iowa’s Human Subjects Office ...................................................................... 17 
10.2. 
The Holden Comprehensive Cancer Center ......................................................................... 17 
11. 
Study Calendar .................................................................................................................................. 19 
12. 
Efficacy Assessments ........................................................................................................................ 20 
12.1. 
68Ga-PSMA-HBED-CC PET Results Definition ................................................................. 21 
12.2. 
Reference standard definition: ............................................................................................. 22 
13. 
Statistical Considerations .................................................................................................................. 27 
13.1. 
Statistical Justification ......................................................................................................... 27 
13.2. 
Primary and Secondary Endpoints using histopathology/biopsy and  
conventional imaging follow-up .......................................................................................... 28 
13.3. 
Definitions of 68Ga PSMA-HBED-CC accuracy ................................................................. 28 
13.4. 
Other statistical considerations ............................................................................................ 30 
15. 
Data sharing ...................................................................................................................................... 31 
15.1. 
Remote 68Ga PSMA-HBED-CC PT/CT Analysis ................................................................ 31 
15.2. 
Relevant clinical metadata ................................................................................................... 31 
16. 
References ......................................................................................................................................... 32 
 
 
 


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1. OBJECTIVES 
1.1. 
Primary objective 
1.1.1. 
Determine sensitivity on a per-subject and per-region basis of 68Ga PSMA-
HBED-CC PET/CT for detecting tumor location, confirming with 
conventional imaging, clinical follow-up, and histopathology/biopsy where 
available. 
1.2. 
Secondary objective 
1.2.1. 
Determine positive predictive value on a per-subject and per-region basis 
of 68Ga PSMA-HBED-CC PET/CT for detecting tumor location, confirming 
with histopathology and conventional imaging. 
1.2.2. 
Determine sensitivity on per-subject and per-region basis of 68Ga PSMA-
HBED-CC PET/CT for detecting tumor location, confirming with 
histopathology. 
1.2.3. 
Determine detection rates on a per-subject basis of 68Ga PSMA-HBED-CC 
PET/CT stratified by PSA value (0.2 - <0.5, 0.5 - <1.0, 1.0 <2.0, 2.0 - <5.0, 
5.0 or greater.   
1.2.4. 
Continue to evaluate safety of 68Ga PSMA-HBED-CC injection as 
categorized by CTCAE 4.03. 
1.3. 
Exploratory objective 
1.3.1. 
Determine the impact of 68Ga PSMA-HBED-CC PET/CT on clinical 
management in patients who have prostate cancer with biochemical 
recurrence. 
2. BACKGROUND AND RATIONALE 
2.1. 
Current imaging of prostate cancer 
Per NCCN guidelines,1 at the time of biochemical recurrence, imaging for prostate 
cancer is performed to detect and characterize the disease to determine treatment or 
guide change in management. Imaging can evaluate anatomic or functional 
parameters. The following imaging is recommended as standard techniques at this 
time-point: 
• 
Imaging is performed for the detection and characterization of disease to 
select treatment or guide change in management. 
• 
Anatomic imaging techniques include plain film radiographs, ultrasound, 
CT, and MRI. 
• 
Functional imaging techniques include radionuclide bone scan, PET, and 
advanced MRI techniques such as spectroscopy and diffusion-weighted 
imaging (DWI). 
2.2. 
Prostate Cancer, Biochemical Recurrence 
Biochemical recurrence will be defined using the AUA and ASTRO-Phoenix 
definitions. Specifically: 
2.2.1. 
Post radical prostatectomy (RP) – AUA recommendation2 is PSA greater 
than 0.2 ng/mL measured 6–13 weeks after RP and Confirmatory persistent 


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PSA greater than 0.2 ng/mL. 
2.2.2. 
Post-radiation therapy – ASTRO-Phoenix consensus definition3 nadir + 
greater than or equal to 2 ng/mL rise in PSA 
 
2.3. 
68Ga-HBED-CC PSMA (68Ga PSMA-HBED-CC) 
Current evidence regarding detection rate of biochemical recurrence (BCR) 
with 68Ga-HBED-CC PSMA (68Ga PSMA-HBED-CC) PET/CT from two recent 
papers: 
• 
Morigi, 2015: Detection rate was 50% when PSA was below 0.5 ng/mL, 
69% for PSA 0.5–2.0 ng/mL, and 86% when PSA was above 2.0 4. 
• 
Eiber, 2015: Detection rate was 57.9% for PSA 0.2 to <0.5 ng/mL, 72.7% 
for PSA 0.5 to <1, 93.0% for 1 to <2.0, and 96.8% for ≥ 2.0 5.  
2.4. 
Prior human subjects experience 
Safety. No adverse drug reactions have been reported in the literature for 68Ga 
PSMA-HBED-CC. As a PET tracer, the drug should remain pharmacologically inert 
and not perturb the biological system. Afshar-Oromieh and colleagues6,7 as well as 
Green et al.8 have clearly stated that no adverse events or pharmacologic events were 
observed during their studies. Adverse events were not discussed in other reviewed 
studies9-16 or case reports.17,18 In total, these papers provide data regarding more than 
1200 subjects without any noted adverse reactions.  
Efficacy. To date, there have been 14 studies6,7,10-12,14,15,19-25 describing use of 68Ga 
PSMA-HBED-CC and 4 clinical trials.8,13,16 
Maurer et al. (2014) [Germany].11 The purpose of this retrospective study was 
to investigate the diagnostic efficacy of 68Ga PSMA-HBED-CC PET imaging 
when compared against radical prostatectomy and templated lymph node 
dissection as well as conventional imaging (CT, MRI). The primary inclusion 
criterion was intermediate-to-high risk prostate cancer scheduled to undergo 
radical prostatectomy. The only exclusion criterion was presence, or history, 
of a secondary malignancy. A total of 130 patients were reviewed. A contrast 
enhanced diagnostic CT was performed at the same imaging session as the 
PET scan. A double-trained board certified radiologist-nuclear medicine 
physician blinded to post-operative histopathological results analyzed all the 
imaging data sets (68Ga PSMA-PET/CT and PET/MR). Conventional imaging 
was read prior to the 68Ga PSMA-PET data. Results yielded a patient-based 
ROC AUC of 0.835 (95% CI 0.763 – 0.908) for 68Ga PSMA-PET and an 
AUC of 0.691 (95% CI 0.592-0.789) for conventional imaging. For 68Ga 
PSMA-PET, patient-based sensitivity was 65.9 %, specificity was 98.9%, and 
an overall accuracy of 88.5%. In contrast, conventional imaging had a patient-
based sensitivity of 43.9%, specificity of 85.4%, and an overall accuracy of 
72.3%. On a template-based analysis driven by lymph node dissection, 
the 68Ga PSMA-PET sensitivity was calculated as 78.2%, specificity as 
99.1%, and accuracy as 95.7%. Conventional imaging resulted in a sensitivity 
of 29.1%, specificity of 97.2%, and accuracy of 86.1%. 


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Van Leeuwen et al. (2017) [Australia].13 The purpose of this prospective trial 
was to assess accuracy of 68Ga PSMA-HBED-CC PET/CT for lymph node 
staging in intermediate- and high-risk prostate cancer. Criteria for selection 
included planned radical prostatectomy, treatment naïve, negative bone scan, 
no concurrent (or history of) a secondary malignancy, and at >5% risk of 
metastatic lymph nodes. Patients with suspected extra-nodal disease on prior 
contrast-enhanced CT were excluded. 68Ga PSMA-HBED-CC PET/CT was 
performed <4 weeks before the radical prostatectomy and lymph node 
dissection. A total of 30 men were enrolled and evaluated. A non-contrast 
enhanced CT was performed at the same imaging session of the 68Ga PSMA-
HBED-CC PET. Images were analyzed by two nuclear medicine physicians; 
it is not stated if the physicians were blinded to the pathologic results or if the 
scan interpretations were completed prior to surgery. Results yielded a 
patient-based specificity of 95%, sensitivity of 64%, positive predictive value 
of 88%, and negative predictive value of 82%. Lymph node analysis yielded 
specificity of 100%, sensitivity of 58%, PPV of 94% and NPV of 98%. The 
mean size of true-positive metastatic lymph nodes was 4.7 mm (± 1.4mm) 
and false-negative size was 2.7mm (± 1.3mm). 
Eiber et al. (2015) [Germany].10 The purpose of this retrospective study was 
to investigate the detection rate of 68Ga PSMA-HBED-CC PET/CT in men 
with biochemical recurrence (PSA ≥ 0.2 ng/mL). Only men who had 
undergone a radical prostatectomy, had not received chemotherapy, and had a 
diagnostic CT done with the PSMA imaging study were included. Men 
undergoing antiandrogen therapy (n=70) were included. A total of 248 
subjects were included in the analysis. The active comparator was the 
diagnostic CT done simultaneously with the PET imaging. Scans were 
interpreted by a board certified radiologist and a board certified nuclear 
medicine physician. The reviewers were not blinded. No significant detection 
effect was observed with anti-androgen use (p=0.0783). PSMA was able to 
identify additional areas of disease involvement in 61 subjects (24.6%) 
whereas CT showed additional regions in 17 subjects (6.9%). A significant 
limitation of the study was a lack of histopathology for outcome comparisons. 
Sensitivity, specificity, positive and negative predictive values were not 
provided. 
Afshar-Oromieh et al. (2015) [Germany].7 The purpose of this retrospective 
study was to analyze the diagnostic value of 68Ga PSMA-HBED-CC PET/CT 
in a large cohort with multiple variables. The cohort was designed to align 
with a generalized population; men were included if they had suspected 
progressive disease following conventional therapy (radiation therapy and/or 
radical prostatectomy, n=292) or to determine metastatic disease burden prior 
to initial therapy (n=27). Of those with suspected recurrence, 86 were on 
antiandrogen therapy. A non-contrast enhanced diagnostic CT scan was 
performed at the same imaging session as the PET scan; additionally, a low-
dose attenuation scan was performed for the 68Ga PSMA-HBED-CC PET. 
Scans were interpreted by two board-certified nuclear medicine physicians. 


page 9 of 34 
No adverse events or clinically detectable pharmacological effects were noted 
in any of the subjects following injection of the PSMA-HBED-CC 
radiotracer. A total of 901 tumor lesions were observed in 319 subjects. 
Lesion-based analysis yielded sensitivity of 76.6%, specificity of 100%, 
negative predictive value of 91.4%, and positive predictive value of 100%. 
Because all patients were assumed to have tumor and therefore could not be 
considered ‘true negative,’ the authors did not provide a per-patient 
calculation. 
Green et al. (2017) [Indiana University School of Medicine]8. The purpose of 
this small study was to estimate human radiation dosimetry for 68Ga PSMA-
HBED-CC under approval of an RDRC research protocol. Both 
biodistribution and pharmacokinetics were evaluated in subjects (n = 9). 
Administered dose of 68Ga PSMA-HBED-CC was 3.04 mCi and images were 
acquired at 15 minutes post-injection, 60 minutes post-injection, and 90 
minutes post-injection. Subjects reported no symptoms or adverse reactions 
following radiopharmaceutical administration. Organ dose estimates were 
provided for 22 organs and for whole body. 
Afshar-Oromieh et al. (2017) [Germany].23 The purpose of this retrospective 
study was to quantitate detection of recurrent prostate cancer disease in 1007 
consecutive subjects scanned with 68Ga PSMA-11 relative to PSA level, 
doubling time, PSA velocity, Gleason score (GSc), ADT, and patient age. In 
79.5% of patients, at least one lesion with characteristics suggestive of 
recurrent PCa was detected. A pathological (positive) PET/CT scan was 
associated with PSA level and ADT. GSc, amount of injected activity, patient 
age, PSA doubling time and PSA Velocity were not associated with a 
positive 68Ga PSMA-11 PET/CT scan in multivariate analysis. PSA>2.0 
resulted in sensitivity >85%. See Figure 1 below. 
 
 
Figure 1: Probabilities of a 
pathological 
68Ga-PSMA-11 
PET/CT scan and plot of the 
rates of pathological PET/CT 
scans with confidence intervals 
  
 
 
 
 
Emmett et al (2017) [Australia].24 This study examined the value of 
PSMA-informed Salvage Radiation Treatment (SRT) in improving 
treatment outcomes in the context of biochemical failure after RP in 164 


page 10 of 34 
men with relatively low serum PSA (0.05-1.0 ng/mL). Detection rate for 
these PSA ranges were in good agreement with Afshar-Oromieh et al.23 The 
study concluded PSMA PET is independently predictive of a treatment 
response to SRT and stratifies men into a high treatment response to SRT 
(negative or fossa-confined PSMA PET) versus men with a poor response to 
SRT (nodes or distant disease on PSMA PET). A negative PSMA PET 
predicted a high response to salvage fossa radiotherapy. 
   
 
Figure 
2. 
PSMA 
PET 
Positivity at incremental PSA 
levels in men with rising PSA 
after radical prostatectomy. 
 
 
 
It should be noted that radiolabeled PSMA ligands have been shown to be taken up 
by rectal carcinoma,26 gastrointestinal stromal tumors,27 renal cell carcinoma,28 
pancreatic serous cystadenoma,29 stromal hyperplasia of the breast,30 B-cell follicular 
non-Hodgkin’s lymphoma,31 and Paget disease.32 
Summary. To date, a prospective, well-controlled clinical trial evaluating the 
efficacy of 68Ga PSMA-HBED-CC PET/CT has not been performed for prostate 
cancer. Robust trials for both initial diagnosis and men with suspected prostate cancer 
recurrence needs to be designed and performed. Current retrospective review of 68Ga 
PSMA-HBED-CC PET/CT done in foreign nations suggests strong efficacy of 
the 68Ga PSMA-HBED-CC radiotracer. Currently, three clinical trials are underway – 
two foreign, one domestic.33-35 Additional pivotal phase 3 trials should be completed 
in the U.S. to determine effectiveness in the generalized population and determine 
requirements for implementation if found effective. 
2.5. 
Rationale 
Imaging and staging of prostate cancer is critical for surgical and treatment planning. 
We aim to image patients with suspected metastatic prostate cancer using Gallium-68 
labeled HBED-CC PSMA (68Ga PSMA-HBED-CC) in order to demonstrate its 
utility. We plan to contribute this data towards a multi-center initiative targeting drug 
registration of the 68Ga PSMA-HBED-CC compound, so that this agent will become 
widely available for clinical imaging of prostate cancer patients.  
68Ga PSMA-HBED-CC has become of particular interest due to 2 recent publications. 
The first article demonstrated that 68Ga PSMA-HBED-CC PET/CT had a higher 
sensitivity for the detection of disease than F-18 choline in a head-to-head intra-
patient comparison that included 37 patients7. The second paper looked at the 
sensitivity of 68Ga PSMA-HBED-CC in the detection of metastatic lesions in patients 


page 11 of 34 
with recurrent prostate cancer8. Their results showed a detection rate of 50% for 
patients with a PSA less than 1 ng/ml, and detection rate above 85% for patients with 
a PSA greater than 2 ng/ml. These detection rates are significantly higher than that 
reported by groups using F-18 choline9. However, 68Ga PSMA-HBED-CC was not 
patented and therefore no company or private entity will make the investment 
required to bring 68Ga PSMA-HBED-CC to market. In the vacuum of availability, 
academic groups must take the lead in order to collect the necessary data for future 
FDA approval.  
We aim to study the ability of 68Ga PSMA-HBED-CC to detect disease at 
biochemical recurrence in post-prostatectomy or post-radiation patients. 
3. SUBJECT SELECTION 
3.1. 
Eligibility Criteria 
3.1.1. 
Pathologically proven prostate adenocarcinoma. 
3.1.2. 
Rising PSA after definitive therapy with prostatectomy or radiation therapy 
(external beam or brachytherapy). 
• If post-radical prostatectomy, PSA > 0.2 ng/mL measured > 6 weeks 
post-operatively and confirmatory persistent PSA greater than 0.2 ng/mL 
(AUA recommendation for biochemical recurrence). 
• If post-radiation therapy, PSA that is equal to, or greater than, a 2 
mg/mL rise above PSA nadir (ASTRO recommendation for biochemical 
recurrence). 
3.1.3. 
A PSA level result within the last 2 months meeting criteria in 3.1.2.  
3.1.4. 
Not receiving any other investigational agents (i.e., unlabeled drugs or drugs 
under an IND for initial efficacy investigations). 
3.1.5. 
No other malignancy within the past 2 years (skin basal cell or cutaneous 
superficial squamous cell carcinoma or superficial bladder cancer are 
exempt from this criterion). 
3.1.6. 
Karnofsky performance status (KPS) of ≥ 50 (ECOG/WHO 0, 1, or 2) 
within the last 3 months. 
3.1.7. 
Ability to understand and willingness to provide informed consent. 
3.2. 
Exclusion Criteria 
3.2.1. 
Cannot receive furosemide. 
3.2.2. 
History of Stevens-Johnson syndrome. 
3.2.3. 
History or diagnosis of Paget’s disease. 
3.2.4. 
Malignancy other than current disease under study. 
3.2.5. 
Allergy to sulfa or sulfa-containing medications. 
3.2.6. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 


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4. REGISTRATION PROCEDURES 
Once informed consent is signed:  
• 
Attach scanned copy of completed eligibility checklist in OnCore for review by the 
CRSO/designated safety monitor at the time of quarterly audits. 
• 
Enter subject into the OnCore database of the Holden Comprehensive Cancer Center. 
5. PROCEDURES 
Protocol should not supersede standard of care procedures for patient safety. 
5.1. 
Imaging preparation 
5.1.1. 
Oral hydration. Participants will be encouraged to maximize hydration the 
day before and day of 68Ga PSMA-HBED-CC imaging. 
5.1.2. 
Furosemide. 20 mg furosemide (IV push) will be administered concurrently 
or immediately after radiotracer administration to minimize PET scatter 
artifacts from excreted radiotracer accumulation in the kidney and urinary 
bladder. 
5.1.3. 
Contrast. Imaging contrast will not be ordered as part of this study.  
5.2. 
68Ga PSMA-HBED-CC administration 
5.2.1. 
Dose. 3-7 mCi (111 – 259 MBq). Target 5 mCi. 
5.2.2. 
Route of administration. Intravenous. 
5.2.3. 
Frequency. Once per PET scan. 
5.2.4. 
Uptake time. 75 minutes ± 25 minutes. Target 75 minutes 
5.3. 
Prohibited Medications 
None. 
5.4. 
PET/CT scan 
5.4.1. 
Scan coverage. Scan coverage will extend from mid-thigh to the base of the 
skull, starting from the mid-thighs to minimize urinary bladder radiotracer 
accumulation at the start of PET imaging. Subject to void immediately prior 
to imaging. 
5.4.2. 
Bed position. Scan time will be dependent on scanner capabilities. At a 
minimum, 3 minutes per bed position will be used. 
5.4.3. 
Discharge. Subject must be monitored for adverse events for a minimum of  
2 hours post-injection. 
5.4.4. 
Clinical Interpretation. A board-certified nuclear medicine physician on-
site will interpret the images within 3 business days of the imaging study.  
5.4.5. 
Results dissemination. The clinical interpretation will be shared with the 
subject’s clinician and will be included in the subject’s medical record.  
5.5. 
Visual Interpretation of PET data  
Regions of suspected disease will be graded on a two-point scale by a trained reader 
(0=Negative or 1=Positive). A region will be judged as positive if at least one lesion 


page 13 of 34 
in this region is visually positive. Regions are defined in Table 12-1 in Section 12. 
Criteria for visual interpretation positive for disease are detailed in Section 12.1.1.  
5.6. 
Follow-up imaging 
All subjects should be followed as per standard of care consistent with the 
institution/physician. Reports and copies of any conventional imaging obtained 
during the 12 month window following the PSMA-HBED-CC PET/CT scan will be 
obtained. Clinical notes will also be reviewed to identify metastatic lesions. 
Interpretation of follow-up imaging is performed by local institution following 
standard procedures. Preferable comparison imaging would be the same imaging 
device as the initial re-staging work-up as per RECIST guidelines.  
68Ga PSMA-HBED-CC PET positive findings will be validated as true positive or 
false positive as outlined in more detail below. False negative 68Ga PSMA-HBED-CC 
PET findings will only be determined when positive biopsies of 68Ga PSMA-HBED-
CC PET negative lesions that are present on conventional imaging are performed as 
part of standard clinical care. This scenario is uncommon. 
68Ga PSMA-HBED-CC PET validation based on follow-up imaging (CT, MRI, bone 
scan): 
5.6.1. 
Lymph nodes 68Ga PSMA-HBED-CC positive nodes will be assessed for 
change in size using standard of care follow-up imaging. 
5.6.2. 
PSMA-positive osseous or metastatic lesions. 68Ga PSMA-HBED-CC 
positive osseous or distant metastatic lesions will be followed by other 
imaging (bone scan, NaF PET, CT or MRI) at the treating physician’s 
discretion and local standard of care.  
5.6.3. 
Biopsy. Biopsies to determine metastases or provide information for re-
staging should be performed at treating physician’s discretion and per local 
standard of care. 
5.7. 
General Concomitant Medication and Supportive Care Guidelines 
In general, subjects may receive full concomitant and supportive care throughout this 
trial.   
5.8. 
Follow-Up  
5.8.1. 
Active follow-up. Subjects will be actively followed for acute adverse 
events for 10 radioactive half-lives rounded up to the calendar day (as per 
the established standard). With a half-life of 67.71 minute for 68gallium, the 
active follow-up will be a minimum of 1 calendar day.  
5.8.2. 
Long term follow-up. After the active follow-up period, the subject will 
return to standard follow-up with their physician. Subject’s outcome will be 
followed through passive chart review. Contact with subject and/or subject’s 
treating physicians may occur to better define treatment outcomes. 
5.9. 
Criteria for removal from study 
• 
Consent. Subjects must be able to continue to provide consent for this 
study. If a treating physician or study team member believes a subject can 
no longer provide prospective consent, the investigator will be contacted to 


page 14 of 34 
determine if the subject can provide consent and is able to continue on 
study. 
• 
Refusal to continue in the study. In this event, the reasons for withdrawal 
will be documented. 
6. PATIENT ASSESSMENTS 
6.1. 
Post-consent Baseline Data Collection 
Post-consent, the following data should be collected 
6.1.1. 
Serial PSA. Most recent serial PSA values defining biochemical recurrence 
(i.e., two PSA values meeting AUA or ASTRO recurrence criteria). 
6.1.2. 
PSA. Baseline PSA levels reported in the 3 months prior to the 68Ga PSMA-
HBED-CC PET/CT should be obtained.  
6.1.3. 
Pathology. Copy of original pathology report documenting Gleason score 
and date sample obtained. Also, obtain a copy of any pathology reports 3 
months prior to the 68Ga PSMA-HBED-CC PET/CT. 
6.1.4. 
Bone scan. If a bone scan was performed within 3 months of 68Ga PSMA-
HBED-CC PET/CT, obtain a copy of the images and the report. 
6.1.5. 
MRI. If an MRI was performed within 3 months of 68Ga PSMA-HBED-CC 
PET/CT, obtain a copy of the images and the report. 
6.1.6. 
CT scan. If a CT was performed within 3 months of 68Ga PSMA-HBED-CC 
PET/CT, obtain a copy of the images and the report. 
6.1.7. 
AC/CT. If no conventional imaging has been done in the prior 3 months, the 
low dose AC/CT from the PSMA PET can be used for baseline imaging.   
6.2. 
Pre-Imaging Assessments (Baselines) 
6.2.1. 
Change in management. A pre-imaging survey of planned clinical 
management will be performed ≤ 10 days prior to 68Ga PSMA-HBED-CC 
PET/CT imaging. Subject must be deemed eligible prior to completion of 
this form. This can be completed before or after the subject is consented.  
6.2.2. 
Constitutional adverse events. A baseline evaluation will be obtained prior 
to injection and will be graded against CTCAE. 
6.2.3. 
Vital signs. Heart rate, blood pressure, and temperature will be obtained 
immediately before and after injection of 68Ga PSMA-HBED-CC, in a 
supine position. 
6.3. 
Post-Imaging Assessments 
6.3.1. 
Vital signs. Heart rate, blood pressure, and temperature will be obtained 
when subject is supine immediately after the imaging. 
6.3.2. 
Constitutional adverse events. Prior to discharge from the PET Imaging 
Center, the subject will be assessed for untoward medical event(s) that have 
occurred since injection of 68Ga PSMA-HBED-CC.  These will be graded 
with CTCAE. 
6.3.3. 
Symptom review. Subject will be contacted by telephone or in person 
between 1 to 3 business days after PSMA-HBED-CC imaging to screen for 


page 15 of 34 
adverse events. Subject must be contacted at least once after 24h post-
injection. 
6.4. 
Follow-up 
6.4.1. 
Change in management. A post-imaging survey of clinical management 
using PSMA-HBED-CC PET/CT information will be performed ≤ 30 days 
of PSMA-HBED-CC PET/CT imaging for assessment of change in clinical 
management. 
6.4.2. 
Change in management 6 months post imaging. A survey of clinical 
management will be performed approximately 6 month after the PSMA-
HBED-CC PET/CT imaging for assessment of change in clinical 
management. 
6.4.3. 
Follow-up imaging. Conventional imaging ordered per standard of care up 
to 12 months post 68Ga PSMA-HBED-CC PET/CT, will be obtained for 
study analysis.  Readers will be unblinded to all results and will be 
specifically informed of the location of the 68Ga PSMA-HBED-CC PET 
positive lesions so follow-up measurements may be performed on the same 
lesions. 
6.4.4. 
Treatment. Information regarding treatments and changes in treatments 
ordered per standard of care up to 12 months post 68Ga PSMA-HBED-CC 
PET/CT, will be obtained for study analysis. 
6.4.5. 
Pathology. Results from pathology ordered per standard of care up to 12 
months post 68Ga PSMA-HBED-CC PET/CT, will be obtained for study 
analysis. 
6.4.6. 
Laboratory. Results from laboratory reports related to prostate cancer 
monitoring (e.g. PSA levels) ordered per standard of care up to 12 months 
post 68Ga PSMA-HBED-CC PET/CT, will be obtained for study analysis. 
6.4.7. 
Second 68Ga PSMA-HBED-CC PET/CT (if medically indicated). If the 
1st 68Ga PSMA-HBED-CC PET/CT scan shows lymph nodes or visceral 
(soft tissue) lesions positive for prostate cancer disease, but surgery or 
biopsy results in negative pathology; the subject may be asked to return to 
complete a 2nd Ga-68 PSMA-HBED-CC PET/CT imaging visit. 
7. DRUG INFORMATION 
7.1. 
68Ga PSMA-HBED-CC IND 135,727 (M. Graham, sponsor) 
7.1.1. 
Availability. Drug is available from the P E T Drug Manufacturing Unit at 
the University of Iowa Hospitals & Clinics. 
7.1.2. 
Compatibility. No known compatibility issues. 
7.1.3. 
Storage and stability. Store drug in shielded container as per local 
institutional guidelines. Drug has a 3 hour stability. Expiration is provided 
on label. 
7.1.4. 
Toxicities. No known toxicities.  


page 16 of 34 
8. DOSE MODIFICATIONS & DELAYS 
Not applicable. 
9. ADVERSE EVENTS: REPORTING REQUIREMENTS 
This study will be monitored by internal oversight specialists at the University of Iowa. The 
Data and Safety Monitoring Plan of the Holden Comprehensive Cancer Center provides 
standard operating procedures to monitor all clinical cancer trials at the UIHC. All 
investigator-initiated trials are automatically monitored by the Data and Safety Monitoring 
Committee (DSMC). A detailed data and safety monitoring plan for this study is on file with 
the DSMC. This study has been assigned as a risk level 4 as an IND phase 2b/3 study 
9.1. 
Determination of Reporting Requirements 
The clinical research team is responsible for collecting and recording the research 
data. As these results are collected, all toxicities and adverse events will be identified 
and reported to the principal investigator (PI). The PI will determine final relationship 
of the event to the investigational products (68Ga PSMA-HBED-CC): 
• 
Grade 1 and 2 events do not require attributions assigned. 
• 
Grade 3 and higher adverse events require attribution determination. 
• 
All serious adverse events (SAEs) require attribution determination.  
Toxicity will be graded according to NCI’s Common Toxicity Criteria (CTCAE v4). 
The principal investigator will have final responsibility for determining the attribution 
of toxicity as it is related to the investigational product. 
9.2. 
Institutional Review Board reporting requirements 
Adverse events that meet criteria of both serious and attributed (possible, probable, or 
definite) to the study agent. Thus: 
• 
Serious adverse events and 
• 
Attributable to 68Ga PSMA-HBED-CC  
Report to the IRB via HawkIRB within 10 business days of event 
9.3. 
FDA reporting requirements [M. Graham, sponsor] 
Adverse events that meet criteria of serious, unexpected, and attributed (possible, 
probable, or definite) to 68Ga PSMA-HBED-CC must be reported to the sponsor or 
the sponsor’s appointed designee: 
• 
Only serious adverse events are reported to FDA[21 CFR 312.32] 
• 
Attributable to 68Ga PSMA-HBED-CC with a causal relationship as 
described [21 CFR 312.32 (c)(1)(i)] 
• 
Unexpected, as defined by the FDA: “…not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; 
or, if an investigator or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended.” 


page 17 of 34 
9.4. 
Routine Adverse Event Reporting Requirements to DSMC 
For non-serious adverse events, documentation must begin at radiotracer injection 
and continue through 24 hours post injection.  
Routine adverse events will be reported by submission of an adverse events log to the 
DSMC at the time of DSMC review.  
9.5. 
Serious Adverse Event Reporting to DSMC 
Serious adverse events occurring after 68Ga PSMA-HBED-CC injection will require a 
notification to the DSMC within 1 business day of learning of the event. The SAE 
capture window will be from the administration of 68Ga PSMA-HBED-CC through 
24 hours after administration. Serious adverse events that occur after this window are 
reportable if they are deemed reasonably attributed to the investigational drug, 68Ga 
PSMA-HBED-CC. 
10. CLINICAL TRIAL MONITORING 
Clinical trial monitoring will be conducted to ensure the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol and/or 
amendment, with good clinical practice (GCP), and with applicable regulatory 
requirement(s). 
10.1. University of Iowa’s Human Subjects Office 
The University of Iowa’s Human Subjects Office (HSO) provides five different types 
of monitoring visits (post-approval responsibilities review, post-approval monitoring 
and education visit, directed monitoring, department of defense sponsored research 
monitoring, student principal investigator review). The HSO also provides an IND 
educational visit combined with a post-approval responsibilities review. 
• 
Monitoring is performed by the HSO from their roster of qualified 
individuals. 
• 
Monitoring is on-site. 
• 
An educational IND visit will be requested by the PI. This will be done after 
IRB approval. The IRB indicate if accrual can begin prior to this visit. 
• 
For the educational IND visit, if subjects have been consented, all signed 
consent documents will be reviewed. 
• 
For the educational IND visit, the principal investigator will be provided a 
copy of the report documenting the visit within 1 month. 
• 
Monitoring plans are not study specific. The plans are maintained by the 
HSO and are available for public review on-line. 
10.2. The Holden Comprehensive Cancer Center 
The Holden Comprehensive Cancer Center (HCCC) will provide monitoring for this 
investigator-initiated trial in compliance with their overarching monitoring plan on 
file with the National Cancer Institute (NCI) as well as with the individual clinical 
monitoring plan on file for this trial. Specifically: 


page 18 of 34 
• 
Monitoring is performed by the HCCC from their roster of qualified 
individuals. 
• 
Eligibility review is ongoing, through remote review from OnCore, the 
clinical trials software. 
• 
Monitoring is on-site and begins with the accrual of the first subject and will 
be performed at least twice per year. Frequency is adjusted based on risk, 
reported SAEs, compliance, patient population, and accrual rate. 
• 
A minimum of 25% of subjects will be monitored for the entire study. 
• 
Items reviewed include: eligibility, consent document, compliance to 
protocol, SAE reporting per institutional and federal requirements, accuracy 
of data against primary source, and investigational drug documentation. 
• 
The sponsor-investigator will be provided draft copies of the report within 
one month of the visit. 
• 
Independent audits will be conducted by the HCCC to verify monitoring is 
being performed per the filed clinical monitoring plan. The audit procedures 
are documented in their Quality Assurance Management Plan on file with 
the NCI. 
 
 


page 19 of 34 
11. STUDY CALENDAR 
 
Screening 
Baseline 
V1 - PSMA-HBED-CC 
PET/CT b,c 
Follow-up 
Injection 
Scan  
Immediate 
Long-term 
Karnofsky PSa 
X 
 
 
 
 
 
PSA 
 
≤3 mo V1 
 
 
 
Xd 
imaging pull 
 
≤3 mo V1 
 
 
 
Xd 
pathology pull 
X 
≤3 mo V1 
 
 
 
Xd 
serial PSA pull 
Xe 
 
 
 
 
 
change in managementf 
 
≤10d V1 
 
 
≤30d V1 
6 months V1 
68Ga PSMA-HBED-CC 
 
 
5 mCi 
 
 
 
20 mg IV furosemide 
 
 
X 
 
 
 
HR, BP, Temp 
 
 
supineg 
supineg 
 
 
voiding 
 
 
 
Xh 
 
 
Adverse event queryi 
 
X 
X 
Xi 
 
 
 
 
 
 
 
 
 
a within 3 months of date eligibility is assessed. 
b Scan will be clinically interpreted and entered into the medical record.  
c A 2nd 68Ga PSMA-HBED-CC PET/CT imaging visit may occur, if medically indicated. The 2nd scan will be 
obtained identical to 1st scan.  
d data from follow-up imaging, laboratory PSA levels, and pathology as ordered for standard of care or study 
purposes will be analyzed and mined for outcomes 
e serial PSA documenting biochemical recurrence as defined by AUA and/or ASTRO (as appropriate) 
f change in management forms completed by referring/treating physician at three timepoints:  within 10 days prior to 
imaging, within 30 days post-imaging, and then approximately 6 months post-imaging 
g HR, BP, temp performed with subject supine immediately before and after injection and post-imaging of the scan 
h subject should void immediately prior to the scan.  
i final adverse event assessment is done 1 to 3 days post-injection but no earlier than 24 hours post-injection 
 
 
 
 
 


page 20 of 34 
12. EFFICACY ASSESSMENTS 
Determination of efficacy requires two primary assessments.  
The first assessment is the clinical read of the 68Ga-PSMA-HBED-CC PET/CT scan. A 
trained reader will identify lesions positive for prostate cancer disease, and based on these 
results, will categorize specifically defined anatomical regions of the subject (Table 12-2) as 
positive for disease by 68Ga-PSMA-HBED-CC PET/CT. Criteria are described in Section 
12.1 below. 
The second assessment is the reference standard determination of disease positivity or 
negativity also performed on the same specifically defined anatomical regions (Table 12-2).  
The reference standard definitions are described below, and consist of a combination of 
pathological confirmation, conventional imaging follow-up evidence, and serial PSA 
measurements. Criteria are described in Section 12.2 below. 
For purposes of endpoints, four major regions are identified for final analysis as defined in 
Table 12-1. Each region is divided into subregions as defined in Table 12-2. All primary data 
from 68Ga-PSMA-HBED-CC PET interpretations, pathology results, and conventional 
imaging results, will be collected per the subregions defined below. The final region 
assignments and results will be derived from the subregion data as applicable. 
Region 
Description 
1 
Prostate Bed 
2 
Pelvis outside of prostate bed including lymph nodes 
3 
Extrapelvic soft tissue, lymph nodes and organ metastases (non-bone) 
4 
Bone metastases 
    Table 12-1. Major Analysis Regions 
Region 2: Pelvis outside of 
prostate bed 
Region 3: Extrapelvic soft 
tissue 
Region 4: Bone metastases 
Right obturator 
Lung 
Spine 
Left obturator 
Liver 
Ribs 
Right external iliac 
Pancreas 
Pelvis 
Left external iliac 
Spleen 
Extremities 
Right internal iliac 
Intestine 
Skull 
Left internal iliac 
Mesentary 
Sternum 
Other pelvic regions 
Brain 
Clavicle 
 
Other soft tissue 
Other bone 
 
Abdominal nodes 
 
 
Thoracic nodes 
 
 
Other nodes 
 
   Table 12-2. Subregion Classification 


page 21 of 34 
12.1. 
68Ga-PSMA-HBED-CC PET Results Definition 
Imaging interpretation 68Ga-PSMA-HBED-CC PET: 
Clinical Interpretations:  PET images will be interpreted by a board certified 
nuclear medicine physician or a board-certified radiologist experienced in reading 
PET at the time of the imaging study is acquired.  
Reader Positivity and Negativity Definition: Sub-regions defined in Table 12-2 will 
be graded for the presence of suspected disease on a two-point scale by each reader 
(0=Negative or 1=Positive). A region will be judged as positive if at least one lesion 
in this region is visually positive. 
12.1.1. Criteria for visual interpretation:  
Sub-regions of suspected disease will be graded on a two-point scale by each 
central reader (0=Negative or 1=Positive). A region will be judged as positive 
if at least one lesion in this region is visually positive. 
12.1.1.1. Lymph nodes will be considered positive if the 68Ga-PSMA-
HBED-CC uptake is focal and greater than blood pool (adjacent 
or mediastinal blood pool).  
- 
Lymph nodes will be classified further by region: pelvic, 
retroperitoneal, thoracic and other.  Additionally, pelvic lymph 
nodes will be sub-classified according to their localization as 
follows: R/L obturator, R/L external iliac, R/L internal iliac 
and other (total of 7 subgroups).  These pelvic sub-regions will 
be correlated with reference standard results in these sub-
regions, however this sub-region data will not be directly used 
for evaluation of the primary or secondary endpoints, but for 
exploratory analysis. 
12.1.1.2. Visceral lesions will be considered positive if the 68Ga-PSMA-
HBED-CC uptake is focal and greater than physiologic 
background activity of the involvement organ or anatomic site. 
- 
Visceral lesions will be classified further by major organ: lung, 
liver, pancreas... as defined in Table 12-2.  These sub-regions 
will be correlated with reference standard results in these sub-
regions, however this sub-region data will not be directly used 
for evaluation of the primary or secondary endpoints, but for 
exploratory analysis. 
12.1.1.3. Bone lesions will be considered positive if the 68Ga-PSMA-
HBED-CC uptake is focal and greater than physiologic bone 
marrow. 
- 
Bone lesions will be classified further by region: spine, ribs, 
pelvis, extremities, skull, sternum, and clavicle, as defined in 
Table 12-2.  These sub-regions will be correlated with 
reference standard results in these sub-regions, however this 
sub-region data will not be directly used for evaluation of the 


page 22 of 34 
primary or secondary endpoints, but for exploratory analysis.  
12.1.1.4. Prostate bed and prostate lesions will be considered positive if 
the 68Ga-PSMA-HBED-CC uptake is focal and greater than 
physiologic background activity of the involved organ or 
anatomic site. 
12.2. Reference standard definition: 
12.2.1. Histopathology/Biopsy will be the primary determinate of tissue positivity 
and negativity for prostate cancer disease. Pathology date, organ, and 
location as well as any notes related to the pathology will be obtained from 
the subject chart.  The anatomical region/sub-region the pathology occurred 
in will be assigned by the investigator team: 
68Ga-PSMA-HBED-CC positive findings are aimed to be confirmed by 
histopathology/biopsy if clinically feasible.  Pathology performed 60 days 
before or after the 68Ga-PSMA-HBED-CC PET will be available for 
correlation. 
Histopathological procedures and biopsies will be performed as clinically 
indicated and as per institutional protocol. 
12.2.1.1. Lymph Nodes, Visceral Lesions, and Bone Lesions positive for 
disease by pathology. 
− Lesions with positive pathologic confirmation will be regarded as 
positive for disease. The regionality of the resected tissue will be 
assigned into respective regions and sub-regions as described above in 
Table 12-2. 
12.2.1.2. Lymph Nodes and Visceral Lesions negative for disease by 
pathology. 
− Tissue removed and negative for pathology are considered negative for 
prostate cancer disease, unless subsequent conventional imaging 
or 68Ga-PSMA-HBED-CC PET imaging demonstrates that targeted 
tissue were not resected. In this case: 
i. Subjects can be rescanned with dedicated CT, MRI, or 68Ga-
PSMA-HBED-CC PET/CT to determine if the suspicious 68Ga-
PSMA-HBED-CC tissue was removed. If the tissue is 
confirmed as removed, this is considered negative for disease. 
ii. If 68Ga-PSMA-HBED-CC PET/CT positive tissue is still 
present, a needle biopsy can be pursued at the discretion of the 
treating physician. Images of the procedure will be reviewed to 
determine if the correct tissue was biopsied. 
- 
If the 68Ga-PSMA-HBED-CC PET/CT positive tissue was 
biopsied, a negative pathologic finding of the biopsied 
tissue is considered negative for disease. 


page 23 of 34 
- 
If the 68Ga-PSMA-HBED-CC PET/CT positive tissue was 
biopsied, a positive pathologic finding of the biopsied 
tissue is considered positive for disease. 
- 
If biopsy or re-biopsy is not performed, or the wrong tissue 
was biopsied, change in node size as measured by 
conventional imaging and as defined below will be the 
criteria by which disease status will be defined. 
12.2.1.3. Bone lesions:  Given the high rate of false negative biopsies for 
osseous metastases in subjects with prostate cancer, subjects with 
negative bone biopsies of 68Ga-PSMA-HBED-CC PET positive 
lesions will be further evaluated: 
- 
If pathology demonstrates an alternative diagnosis that is 
known to be 68Ga-PSMA-HBED-CC positive (e.g. renal cell 
carcinoma metastases, Paget’s disease), then this will be 
considered negative for disease. 
- 
If pathology is indeterminate, then follow-up imaging as 
described below will be performed as per clinical standards at 
the site. 
12.2.1.4. Although not routinely performed during standard practice, 
immunohistochemical staining for PSMA of tumor specimens 
(primary and lymph node metastases) may be performed, 
although not required. 
12.2.1.5. All regions not sampled for biopsy/histopathology will be 
designated 
as 
indeterminate 
for 
disease 
by 
pathology. 
Conventional imaging follow-up may be used in these cases to 
determine tissue status. 
12.2.2. Follow-up imaging will be used as a secondary assessment for prostate 
cancer in the event pathology information is not available: 
All subjects will be tracked for follow-up conventional imaging between 3-12 
months post 68Ga-PSMA-HBED-CC (dedicated CT, MRI and/or bone scan) 
as per site standard of care.  Follow up imaging analysis will only be 
performed on subjects that have positive 68Ga-PSMA-HBED-CC findings 
because conventional imaging assessment for disease is primarily targeting 
suspicious 
lesions 
identified 
by 
68Ga-PSMA-HBED-CC 
PET/CT. 
Interpretation and measurements will be performed by a board certified 
radiologist experienced in reading the modality in question (CT, MRI…). 
Preferably, the follow-up conventional imaging should be the same 
modality/modalities as the initial staging work-up to allow for reproducible 
and accurate comparisons.  The attenuation correction CT acquired during 
the 68Ga PSMA-HBED-CC PET may be used as a comparison conventional 
imaging scan, if no other imaging is available.  Conventional imaging 


page 24 of 34 
standards as described below will be used to determine tissue positive for 
prostate cancer disease. Conventional imaging will not be used to determine 
negative prostate cancer disease regions due to its inherently low negative 
predictive value. 
Tissue positive for prostate cancer disease based on follow-up imaging: 
12.2.2.1. Lymph nodes will be assessed by change in size.  
i. 
Positive for disease:  
a. For subjects undergoing systemic treatment (alone or in 
combination with targeted treatment): If on post-treatment 
follow-up imaging within 3-12 months, visually suspicious 
lymph nodes seen on CT or MRI decrease by more than 30% in 
short axis diameter and PSA declines by more than 50%. 
- 
If PSA increases by more than 25% (PCWG3 definition of 
recurrence) on systemic therapy, then an increase in the 
size of lesion by more than 20% in the short axis diameter 
will be considered a positive for disease. 
b. In subjects with localized suspected lymph node(s) receiving 
targeted treatment without concomitant systemic treatment 
there are two ways to achieve positive for disease designation: 
- 
If the subject shows a decrease of PSA by greater than 50% 
after targeted treatment and the lymph node does not 
enlarge (change in size less than 20% in the short axis 
diameter or less than 3 mm increase in short axis diameter) 
[OR] 
- 
If on post-treatment follow-up imaging within 3-12 months, 
lymph nodes seen on CT or MRI decrease by more than 
30% in short axis diameter (with a minimum of 3 mm in 
change in size) 
c. For untreated subjects: If on follow-up imaging within 3-12 
months, lymph nodes seen on CT or MRI increase by more 
than 20% in short axis diameter (with a minimum of 3 mm in 
change in size). 
ii. 
Negative for disease: 
- 
Conventional imaging follow-up will not be used for 
assessment of negativity for disease. 
iii. 
Indeterminate for disease 


page 25 of 34 
- 
Regions with no lymph nodes determined to be positive by the 
conventional imaging criteria described above and without 
pathology will be designated regions indeterminate for prostate 
cancer disease. 
- 
Subjects that have had neither pathology sampling, nor 
conventional imaging follow up will have all regions 
designated as indeterminate for disease by reference standard. 
12.2.2.2. Visceral lesions (non-lymph node soft tissue or organ) and 
prostate bed and prostate lesions will be assessed by change in 
size.  
i. 
Positive for disease:  
a. For subjects undergoing systemic treatment (alone or in 
combination with targeted treatment): If on post-treatment 
follow-up imaging within 3-12 months, visually conspicuous 
lesions seen on CT or MRI decrease by more than 30% in long 
axis diameter and PSA declines by more than 50%. 
- 
If PSA increases by more than 25% (PCWG3 definition of 
recurrence) on systemic therapy, then an increase in the 
size of lesion by more than 20% in the long axis diameter 
will be considered positive for disease. 
b. In subjects with localized suspected lesions(s) receiving 
targeted treatment without concomitant systemic treatment 
there are two ways to meet positive disease criteria: 
- 
If the subject demonstrates a decrease of PSA by greater 
than 50% after targeted treatment [OR] 
- 
If on post-treatment follow-up imaging within 3-12 months, 
lesions seen on CT or MRI decrease by more than 30% in 
long axis diameter (with a minimum of 3 mm in change in 
size) 
c. For untreated subjects: If on follow-up imaging within 3-12 
months, lesions seen on CT or MRI increase by more than 20% 
in long axis diameter (with a minimum of 3 mm in change in 
size). 
ii. 
Negative for disease:  
- 
Conventional imaging follow up will not be used for 
assessment of negativity for disease 


page 26 of 34 
iii. 
Indeterminate for disease 
- 
Regions with no visceral lesions determined to be positive by 
the conventional imaging criteria described above and without 
pathology will be designated as visceral regions indeterminate 
for prostate cancer disease. 
- 
Prostate bed and prostate regions not determined to be positive 
by the conventional imaging criteria described above and 
without pathology will be designated as prostate regions 
indeterminate for prostate cancer disease. 
- 
Subjects that have had neither pathology sampling, nor 
conventional imaging follow up will have all prostate and 
visceral regions designated as indeterminate for disease by 
reference standard. 
12.2.2.3. Bone lesions will be considered: 
i. 
Positive for disease on baseline assessment: 
- 
Any positive sclerotic lesion on the CT portion of the 68Ga-
PSMA-HBED-CC PET or on a separate CT obtained within 
three months of the PET/CT. 
- 
Focal uptake on the baseline bone scan performed within three 
months of 68Ga-PSMA-HBED-CC PET. 
- 
Any MRI lesion in bone read as positive on the initial MRI 
performed within three months of 68Ga-PSMA-HBED-CC 
PET. 
ii. 
Positive for disease on follow up: 
- 
Any new positive sclerotic lesion on CT within 12 months 
of 68Ga-PSMA-HBED-CC PET scan 
- 
Any new MRI bone lesion within 12 months of 68Ga-PSMA-
HBED-CC PET scan  
- 
Any new focal uptake in bone within 12 months of 68Ga-
PSMA-HBED-CC PET scan 
- 
In subjects with localized suspected bone lesion(s) receiving 
targeted treatment without concomitant systemic treatment: 
- 
If the subject demonstrates a decrease of PSA by greater than 
50% after targeted treatment. 


page 27 of 34 
iii. 
Negative for disease: 
- 
Conventional imaging follow up will not be used for 
assessment of negativity for disease 
iv. 
Indeterminate for disease: 
- 
Regions with no bone lesions determined to be positive by the 
conventional imaging criteria described above and without 
pathology will be designated bone regions indeterminate for 
prostate cancer disease. 
13. STATISTICAL CONSIDERATIONS  
13.1. Statistical Justification 
The primary objective of this study is to evaluate the sensitivity of Ga PSMA-HBED-
CC PET/CT for detection of metastatic prostate cancer in the biochemical recurrent 
population. Current standard of care techniques, such as [[C-11]choline, and [F-
18]Axumin, yield approximately 70% per patient sensitivity36-39 with actual 
sensitivities related to plasma PSA levels. Preliminary estimates from our pilot study, 
along with relevant literature, suggest Ga PSMA-HBED-CC PET/CT may have a 
sensitivity > 80%, which would be considered a clinically significant improvement 
relative to existing techniques.  To evaluate sensitivity, patients must undergo both 
Ga PSMA-HBED-CC imaging, as well as evaluation for biochemical recurrence by 
pathology and/or follow-up conventional imaging.  Sensitivity is defined as: 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆=
𝑛𝑛𝑛𝑛𝑛𝑛𝑏𝑏𝑒𝑒𝑒𝑒 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (𝑇𝑇𝑇𝑇)
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (𝑇𝑇𝑇𝑇) + 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 (𝐹𝐹𝐹𝐹) 
 
True positive results are patients that had metastatic prostate cancer detected by Ga 
PSMA-HBED-CC PET/CT that was confirmed by the reference standard.  False 
negative results are patients that did not have metastatic prostate cancer detected by 
Ga PSMA-HBED-CC PET/CT; however, the reference standard indicated cancer.  
See section 12.2 for definition of the reference standard. 
Based on our University of Iowa experience and that of peer institutions, we estimate 
15% of patients in this population will have pathologic confirmation and an additional 
15% patients will have confirmatory conventional imaging, resulting in 
approximately 30% of the patient population being eligible for this study.  We 
anticipate the ability to accrue 240 total patients, resulting in approximately 70 
evaluable patients in our study’s timeframe.  A sample size of 70 evaluable patients 
achieves 80% power to detect a difference of 13% to 83% sensitivity, using a one-
sided binomial test at a 5% significance level.   
 
 


page 28 of 34 
13.2. Primary and Secondary Endpoints using histopathology/biopsy and 
conventional imaging follow-up 
Primary: Sensitivity on a per-subject basis of 68Ga PSMA-HBED-CC PET/CT for 
detection of tumor location confirmed by histopathology/biopsy and conventional 
imaging follow-up will be calculated and reported along with the corresponding two-
sided 95% confidence intervals. The confidence intervals will be constructed using 
the Wilson score method.   
Secondary: PPVs on a per-subject and per-region-basis of 68Ga PSMA-HBED-CC 
for detection of tumor location confirmed by histopathology/biopsy and conventional 
imaging follow-up will be calculated and reported along with the corresponding two-
sided 95% confidence intervals. The confidence intervals will be constructed using 
the Wilson score method. 
The following definitions will define accuracy of 68Ga PSMA-HBED-CC for 
detection of tumor location confirmed by histopathology/biopsy and conventional 
imaging follow-up. 
13.3. Definitions of 68Ga PSMA-HBED-CC accuracy 
13.3.1. True positive definitions 
13.3.1.1. 
68Ga 
PSMA-HBED-CC 
PET/CT 
positive 
for 
nodal 
metastases – and pathology (if available) positive for that node, 
or node positive for disease by imaging as defined in Section 
12.2.2.1 If these criteria are met, the subject is defined as true 
positive for nodal disease. 
13.3.1.2. 
68Ga PSMA-HBED-CC PET/CT positive for visceral 
metastases – and pathology (if available) positive for that 
visceral lesion, or, visceral lesion positive for disease by imaging 
as defined in Section 12.2.2.2. If these criteria are met, the 
subject is defined as true positive for visceral disease. 
13.3.1.3. 
68Ga PSMA-HBED-CC PET/CT positive for osseous 
metastases - and pathology (if available) positive for that 
osseous lesion, or, osseous lesion positive for disease by imaging 
as defined in Section 12.2.2.3. If these criteria are met, the 
subject is defined as true positive for osseous disease. 
13.3.1.4. A single nodal, visceral, or osseous region determined as true 
positive as defined above is sufficient to define the subject as 
true positive by 68Ga PSMA-HBED-CC PET/CT. 
13.3.2.  True negative definitions 
13.3.2.1. 
68Ga 
PSMA-HBED-CC 
PET/CT 
negative 
for 
nodal 
metastases – and pathology (if available) negative for disease, 
and, extra-pelvic node not positive for disease by imaging. If 
these criteria are met, the subject is defined as true negative for 
nodal disease. 
 


page 29 of 34 
13.3.2.2. 
68Ga PSMA-HBED-CC PET/CT negative for visceral 
metastases – and pathology (if available) negative for disease, 
and, visceral lesion not positive for disease by imaging. If these 
criteria are met, the subject is defined as true negative for 
visceral disease. 
13.3.2.3. 
68Ga PSMA-HBED-CC PET/CT negative for osseous 
metastases - and pathology (if available) negative for disease, 
and, osseous lesion not positive for disease by imaging. If these 
criteria are met, the subject is defined as true negative for 
osseous disease. 
13.3.3. False positive definitions: 
13.3.3.1. 
68Ga 
PSMA-HBED-CC 
PET/CT 
positive 
for 
nodal 
metastases, pathology (if available) is negative, and imaging 
demonstrates that node is not positive for disease. If these criteria 
are met, the subject is defined as false positive for nodal disease. 
13.3.3.2. 
68Ga 
PSMA-HBED-CC 
PET/CT 
positive 
for 
nodal 
metastases, but pathology (if available) is positive for node but 
in a different nodal region than the node seen on PSMA PET. If 
these criteria are met, the subject is defined as false positive for 
nodal disease. 
13.3.3.3. 
68Ga PSMA-HBED-CC PET/CT positive for visceral lesion, 
pathology (if available) is negative, and imaging demonstrates 
that the visceral lesion is not positive for disease. If these criteria 
are met, the subject is defined as false positive for visceral 
disease. 
13.3.3.4. 
68Ga PSMA-HBED-CC PET/CT positive for visceral lesion, 
but pathology (if available) is positive for visceral lesion but in a 
different region than the visceral region seen on PSMA PET. If 
these criteria are met, the subject is defined as false positive for 
visceral disease. 
13.3.3.5. 
68Ga PSMA-HBED-CC PET/CT positive for osseous lesion, 
pathology (if available) is negative, and imaging demonstrates 
that the osseous lesion is not positive for disease. If these criteria 
are met, the subject is defined as false positive for osseous 
disease. 
13.3.3.6. 
68Ga PSMA-HBED-CC PET/CT positive for osseous lesion, 
but pathology (if available) is positive for osseous lesion but in a 
different region than the osseous region seen on PSMA PET. If 
these criteria are met, the subject is defined as false positive for 
osseous disease. 
13.3.3.7. A subject is defined as false positive for disease by 68Ga PSMA-
HBED-CC PET/CT if one or more regions as defined above are 
defined as false positive regions and the subject is not defined as 


page 30 of 34 
true positive as defined in Section 13.3.1 
13.3.4. False negative definitions: 
13.3.4.1. 
68Ga 
PSMA-HBED-CC 
PET/CT 
negative 
for 
nodal 
metastases, and pathology (if available) positive for any node or 
positive for disease by imaging as defined in Section 12.2.2.1. If 
these criteria are met, the subject is defined as false negative for 
nodal disease. 
13.3.4.2. 
68Ga PSMA-HBED-CC PET/CT negative for visceral lesion, 
and pathology (if available) positive for any visceral lesion, or, 
visceral lesion positive for disease by imaging as defined in 
Section 12.2.2.2. If these criteria are met, the subject is defined 
as false negative for visceral disease 
13.3.4.3. 
68Ga PSMA-HBED-CC PET/CT negative for osseous lesion, 
and pathology (if available) positive for any osseous lesion, or, 
osseous lesion positive for disease by imaging as defined in 
Section 12.2.2.3. If these criteria are met, the subject is defined 
as false negative for osseous disease. 
13.3.4.4. A subject is defined as false negative for disease by 68Ga PSMA-
HBED-CC PET/CT if the subject is negative for disease in all 
regions by 68Ga PSMA-HBED-CC PET/CT, but positive for 
disease by pathology or follow-up imaging in any region. 
13.3.5. Non-evaluable definitions:  
13.3.5.1. Any region that does not have sufficient data to meet the criteria 
for definition of true positive region, true negative region, false 
positive region, or false negative region will be classified as non-
evaluable. 
13.3.5.2. Any region that does not have sufficient data to meet the criteria 
for definition of true positive subject, true negative subject, false 
positive subject, or false negative subject will be classified as 
non-evaluable. 
13.4. Other statistical considerations 
13.4.1. Detection rates on a per-patient basis of 68Ga PSMA-HBED-CC PET/CT 
stratified by PSA value (0.2 - <0.5, 0.5 - <1.0, 1.0 - <2.0, 2.0 - <5.0, 5.0) 
will be summarized in tabular format and compared between PSA strata 
using chi-square analysis.  
13.4.2. The impact of 68Ga PSMA-HBED-CC PET/CT on clinical management in 
BCR patients will be evaluated using descriptive statistics.  
13.4.3. Safety will be reported descriptively as rates of patient reported adverse 
events. 


page 31 of 34 
15. DATA SHARING 
It is intended that data collected in this study be combined with data collected at other 
academic sites in the US conducting similar trials (harmonized protocols are being 
independently used by these sites) for the purpose of FDA approval of 68Ga PSMA-HBED-
CC for prostate cancer imaging.   
15.1. Remote 68Ga PSMA-HBED-CC PT/CT Analysis  
Imaging data will be codified and sent to a remote site for centralized blinded 
interpretation. Imaging data will be interpreted by three different readers in a random 
order at separate reading sessions. Cross sectional imaging from the CT will be 
available for anatomic correlate. Final reads for each subject will be interpreted as 
positive or negative for the presence of pelvic nodal disease, and positive or negative 
for the presence of osseous metastatic disease and soft tissue metastases outside of the 
pelvis. All centralized review readers will have undergone 68Ga PSMA-HBED-CC 
PET/CT training. 
15.2. Relevant clinical metadata  
Relevant clinical data necessary to determine prostate cancer disease status (e.g. PSA 
levels, de-identified conventional imaging DICOM data, histopathology data, and 
other data as described in this protocol as necessary to determine disease status) will 
be made available for support of regulatory submission.  
 
 


page 32 of 34 
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