Clinical trial NCT03388346
Conditions: Prostate Cancer Prostatic Neoplasm Prostatic Neoplasms, Castration-Resistant Prostatic Neoplasm of Uncertain Behavior
Keywords: 68Ga-PSMA-11 (68Ga)Glu-urea-Lys(Ahx)-HBED-CC 68Ga PSMA-HBED-CC
Sponsor: Michael Graham PhD, MD
Start date: 2018-02-16; Completion date: 2021-07-22
Enrollment: 22 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.

Men who are scheduled to undergo a prostatectomy are invited to test 68Ga PSMA. Participants undergo the 68Ga PSMA PET scan before the prostatectomy. Information from the prostatectomy, including any MRI, CT, or ultrasound imaging, will be used to determine if the 68Ga PSMA PET imaging was better than the standard imaging.

Depending on the prostatectomy 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 the surgery/biopsy results do 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
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: 
68Ga PSMA-HBED-CC in Intermediate to High-Risk Preprostatectomy Patients 
Sponsor Investigator: 
Michael M. Graham, PhD, MD 
University of Iowa Department of Radiology 
Iowa City, IA 52242 
(319) 356-1616 
michael-graham@uiowa.edu  
Co-Investigators: 
Yusuf Menda, MD 
Janet Pollard, MD 
Parren McNeely, MD 
Yousef Zakharia, MD 
Chad Tracy, MD 
Mark Smith, MD 
Kenneth Nepple, MD 
John Sunderland, Ph.D. 
 
Biostatistician: 
Timothy Ginader, MS 
Biostatistician 
Holden Comprehensive Cancer Center 
University of Iowa Hospitals and Clinics 
timothy-ginader@uiowa.edu  
Protocol Number: 
201708824 
IND Number: 
135,727 
Protocol version / Date: 
Amendment 5 – 18 September 2018 
Amendment 4 – 23 January 2018 
Amendment 3 – 28 November 2017 
Amendment 2 – 21 November 2017 
Amendment 1 – 31 October 2017 
FDA approved protocol - 20 April 2017 
 


page 2 of 35 
SUMMARY OF CHANGES 
Section 
 
Change 
 
 
 
September 18, 2018 
 
 
 
 
 
Cover Page 
 
Updated version and date 
 
 
 
TOC 
 
Updated TOC 
3.1 
 
- 
Added eligibility criteria of needing a PSA level result within 2 
months of assessing eligiblity.  
 
 
- 
Clarified the KPS should be within 3 months of assessing 
eligibility.  
11 
 
Updated study calendar to match updates to eligibility 
 
 
 
January 23, 2018 
 
 
Throughout protocol 
 
Formating 
Cover Page 
 
Updated version and date 
Schema 
 
Updated Schema 
TOC 
 
Updated TOC 
5 
 
Removed any mention of a 2nd research only scan during the 1st imaging 
PSMA imaging visit. The 2nd research only scan, detailed in Section 11- 
Correlative studies, is no longer part of the project. 
5.1.3 
 
Removed the option to obtain a diagnostic CT with the PSMA scan. 
5.5 
 
Updated references to tables and other sections since Correlative studies 
section was removed. 
5.6 
 
Continuing with surgery is at the discretion of the referring physican after 
reviewing the PSMA imaging results. 
5.7.1 
 
Added the option to repeat PSMA imaging. 
5.10 
 
Removed “Extraordinary medical circumstances”, not appropriate for this 
study. 
6.1 
 
Changed baseline data collection window from 30 day to 3 months prior to 
PSMA imaging.  
6.2 
 
Clarified pre-imaging assessments. 
6.3 
 
Clarified post-imaging assessments. 
6.4 
 
Added laboratory section 
11 
 
Removed Correlative studies section.  The research only scan will not be 
obtained. 
11 
 
Study Calendar updated to reflect changes in the protocol. 
12 
 
Updated all references to tables and other sections since Correlative 
studies section was removed. 
13 
 
Updated all references to sections since Correlative studies section was 
removed. 
 
 
 
November 28, 2017 
 
 
Cover Page 
 
Updated version and date, and added a biostatistician 
12 
 
Added optional 2nd PSMA PET/CT scan if medically indicated 
 
 
 
November 21, 2017 
 
 
Cover Page 
 
Corrected IND # 135,727, updated version and date 
7.1 
 
Corrected 68Ga PSMA-HBED-CC IND # 135,727 


page 3 of 35 
 
 
 
October 31, 2017 
 
 
Cover Page 
 
Added IRB #, IND #, and updated dated version and date 
Schema 
 
Updated Schema 
TOC 
 
Updated TOC 
1.1.1 
 
Specifide regional “pelvic” nodal metastases 
5.4.5 
 
Changed from central blind reader to internal blind readers. Also clarified 
reference to central blind reader to internal blind readers through 
remainder of study protocol. 
5.5 
 
Referenced Section 13 rather than having same information in multiple 
places in the protocol. 
6 
 
Clarified Patient Assessment section, added potencial research CT if 
clinical follow-up imaging is not obtained. 
7.1 
 
Added 68Ga PSMA-HBED-CC IND # 135,272 
12 
 
Clarified footnotes in study calendar 
13 
 
Updated Efficacy Assessment – This is the same information that was in 
the previous section 13, however, laid out in a way to more easily evaluate 
the PSMA scam, conventional imaging and pathology assessment.  
14.1 
 
Statistical Justification section added 
14.2 
 
Updated section references throughout, as information in Section 13 was 
moved around. 
14.3 
 
Updated section references throughout, as information in Section 13 was 
moved around. 
 
 
 
April 20, 2017 
 
v0.06 
Receipt 
 
Initial submission to FDA, 1571 0000 
 
 
 


page 4 of 35 
SCHEMA 
 


page 5 of 35 
 
TABLE OF CONTENTS 
 
Objectives ............................................................................................................................................ 7 
1.1. 
Primary objective.................................................................................................................. 7 
1.2. 
Secondary objective.............................................................................................................. 7 
1.3. 
Exploratory objectives .......................................................................................................... 7 
 
Background and Rationale .................................................................................................................. 7 
2.1. 
Current imaging of prostate cancer ...................................................................................... 7 
2.2. 
68Ga PSMA-HBED-CC (68Ga PSMA-11) ............................................................................ 8 
2.3. 
Prior human subjects experience .......................................................................................... 8 
2.4. 
Rationale ............................................................................................................................. 11 
 
Subject Selection ............................................................................................................................... 12 
3.1. 
Eligibility Criteria ............................................................................................................... 12 
3.2. 
Exclusion Criteria ............................................................................................................... 12 
 
Registration Procedures .................................................................................................................... 12 
 
Procedures ......................................................................................................................................... 12 
5.1. 
Imaging preparation............................................................................................................ 12 
5.2. 
68Ga PSMA-HBED-CC administration .............................................................................. 13 
5.3. 
Prohibited Medications ....................................................................................................... 13 
5.4. 
PET/CT Imaging Procedures .............................................................................................. 13 
5.5. 
Visual Interpretation of PET data (Internal blinded reads) ................................................ 13 
5.6. 
Post-Imaging Prostatectomy ............................................................................................... 14 
5.7. 
Post-Prostatectomy Procedures .......................................................................................... 14 
5.8. 
General Concomitant Medication and Supportive Care Guidelines ................................... 15 
5.9. 
Follow-Up .......................................................................................................................... 15 
5.10. 
Criteria for removal from study .......................................................................................... 15 
 
Patient Assessments .......................................................................................................................... 15 
6.1. 
Post-consent Baseline Data Collection ............................................................................... 15 
6.2. 
Pre-Imaging Assessments (Baselines) ................................................................................ 16 
6.3. 
Post-Imaging Assessments ................................................................................................. 16 
6.4. 
Follow-up ........................................................................................................................... 16 
 
Drug Information .............................................................................................................................. 17 
7.1. 
68Ga PSMA-HBED-CC IND 135,727 (M. Graham, sponsor) ............................................ 17 
 
Dose Modifications & Delays ........................................................................................................... 17 
 
Adverse Events: Reporting Requirements ........................................................................................ 17 


page 6 of 35 
9.1. 
Determination of Reporting Requirements ......................................................................... 17 
9.2. 
Institutional Review Board reporting requirements ........................................................... 17 
9.3. 
FDA reporting requirements [M. Graham, sponsor] .......................................................... 18 
9.4. 
Routine Adverse Event Reporting Requirements to DSMC .............................................. 18 
9.5. 
Serious Adverse Event Reporting to DSMC ...................................................................... 18 
 
Clinical Trial Monitoring .................................................................................................................. 18 
10.1. 
University of Iowa’s Human Subjects Office ..................................................................... 18 
10.2. 
The Holden Comprehensive Cancer Center ....................................................................... 19 
 
Study Calendar .................................................................................................................................. 20 
 
Efficacy Assessments ........................................................................................................................ 21 
12.1. 
68Ga-PSMA-HBED-CC PET Results Definition ................................................................ 22 
12.2. 
Reference standard definition: ............................................................................................ 23 
 
Statistical Considerations .................................................................................................................. 28 
13.1. 
Statistical Justification ........................................................................................................ 28 
13.2. 
Primary Endpoint: .............................................................................................................. 29 
13.3. 
Secondary Endpoints: ......................................................................................................... 30 
 
References ......................................................................................................................................... 32 
 
 
 


page 7 of 35 
 OBJECTIVES 
1.1. 
Primary objective 
1.1.1. 
Determine sensitivity, specificity, positive, and negative predictive value of 
68Ga PSMA-HBED-CC PET for detection of regional pelvic nodal 
metastases compared to pathology at radical prostatectomy (per patient, 
using nodal regional correlation). 
1.2. 
Secondary objective 
1.2.1. 
Determine sensitivity, specificity, positive, and negative predictive value of 
68Ga PSMA-HBED-CC PET for detection of extra-pelvic nodal metastases, 
visceral metastases, and osseous metastases compared to biopsy and 
imaging follow-up. 
1.3. 
Exploratory objectives 
1.3.1. 
Determine sensitivity, specificity, positive, and negative predictive value for 
detection of regional nodal metastases in comparison to cross-sectional 
imaging performed contemporaneously with 68Ga PSMA-HBED-CC PET. 
1.3.2. 
Compare progression free survival at one year (as measured by PSA) 
between patients with, and without, nodal metastases. 
1.3.3. 
Correlate SUVmax from 68Ga PSMA-HBED-CC PET and short-axis 
diameter (of nodal disease on cross-sectional imaging) to presence of true 
pathology. 
1.3.4. 
Quantify and describe the incidence of osseous and distant metastatic 
lesions. 
 BACKGROUND AND RATIONALE 
2.1. 
Current imaging of prostate cancer 
Prostate cancer is the most commonly diagnosed cancer and second leading cause of 
cancer death in American men.1 Existing conventional imaging (CT, MRI and bone 
scans) has a low sensitivity in detecting local recurrence or metastatic disease.2 The 
one exception is NaF PET/CT for the detection of osseous metastasis. Due to this 
limitation, numerous approaches to stage patients have been evaluated. 
C-11 and F-18 Choline PET imaging have been frequently used, as prostate cancer 
exhibits increased choline uptake that has been associated with increased cell 
membrane proliferation and increased levels of choline kinase.3 Choline uptake is 
increased in comparison to FDG in both androgen dependent and independent 
prostate cancer patients.4 Choline has also been shown to be sensitive for the 
detection of recurrent tumor, although sensitivity is somewhat lower in patients with 
PSA (prostate specific antigen) values of less than 1.0 ng/ml.5 There are two forms of 
choline that are used in imaging prostate cancer, C-11 and F-18 choline. C-11 choline 
has a short half-life of 20 minutes, which limits its detection for metastatic disease but 
results in improved local detection due to decreased urinary activity at the time of 
imaging. F-18 choline has significant urinary excretion that limits evaluation of the 
prostate but, but has been shown to have better detection rates for distant metastatic 
disease.6 C-11 choline has limited sensitivity for osseous metastasis, possibly due to 


page 8 of 35 
the decreased uptake time.7 Additionally, the sensitivity of C-11 choline is limited in 
patients with PSA values < 1.0 ng/ml.8-10 Although choline PET may be limited in 
sensitivity, it clearly shows more lesions than cross section imaging or bone scan in 
patients with known disease.11  In 2012, the Mayo Clinic obtained a new drug 
application approval from the FDA for the use of C-11 choline.  
A separate approach is to image prostate specific membrane antigen (PSMA). PSMA 
is expressed on the majority of prostate cancer cells, and so is an ideal target to 
image. The initial imaging approach to target PSMA was done using Indium-111-
capromab (Prostascint), a murine monoclonal antibody.12,13 Although there was early 
promise for the detection of nodal metastasis,14 the agent does not adequately 
visualize osseous metastasis15 and has limited sensitivity, although combination with 
SPECT/CT does improve lesion detection.16 One main limitation to In-111-capromab 
is that it takes a prolonged time to localize to the target tissue, which relates to both 
the size of the monoclonal antibody and its slow pharmacokinetics. Additionally, 
Prostascint also recognizes an intracellular epitope, so the antibody must cross the 
membrane to be effective. This likely only occurs in permeable dead or dying tumor 
cells.  
Because of the limitations of In-111 capromab, there have been continued efforts to 
develop agents that target the extracellular domain of the PSMA protein. The Ga-68 
labeled PSMA-HBED-CC compound has become of particular interest due to two 
important publications. The first study demonstrated that PSMA-HBED-CC has a 
higher sensitivity for the detection of disease than F-18 choline in a head-to-head 
intra-patient comparison that included 37 patients.17 The second paper looked at the 
sensitivity of PSMA-HBED-CC in detecting metastatic lesions in patients with 
recurrent prostate cancer.18 Their results demonstrated 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 choline.5 
2.2. 
68Ga PSMA-HBED-CC (68Ga PSMA-11) 
Current evidence regarding detection rate of biochemical recurrence (BCR) with 
68Ga-HBED-CC PSMA PET/CT from two recent papers: 
• 
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 2.0.19 
• 
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 ≥ 2.0.20 
2.3. 
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 colleagues17,18 as well as 
Green et al.21 have clearly stated that no adverse events or pharmacologic events were 
observed during their studies. Adverse events were not discussed in other reviewed 
studies20,22-28 or case reports.29,30 In total, these papers provide data regarding more 
than 1200 subjects without any noted adverse reactions.  


page 9 of 35 
Efficacy. To date, there have been 11 studies17,18,20,23,24,26,27,38-41 describing use of 
68Ga PSMA-HBED-CC and 4 clinical trials.21,25,28 Tables with key information of 
reviewed papers are provided (Tables 6-1, 6-2, and 6-3) in the body of the IND 
application. 
Maurer et al. (2014) [Germany].23 The purpose of this retrospective study was 
to investigate the diagnostic efficacy of 68Ga PSMA-HBED-CC -PET imaging 
when compared against radical prostatectomy, templated lymph node 
dissection, and 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 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%. 
Van Leeuwen et al. (2014) [Australia].25 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].20 The purpose of this retrospective study was to 
investigate the detection rate of 68Ga PSMA-HBED-CC PET/CT in men with 


page 10 of 35 
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 
antiandrogen 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 are not provided. 
Afshar-Oromieh et al. (2015) [Germany].18 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. 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, Indiana, US]. 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. 
It should be noted that radiolabeled PSMA ligands have been shown to be taken up 
by rectal carcinoma,31 gastrointestinal stromal tumors,32 renal cell carcinoma,33 
pancreatic serous cystadenoma,34 stromal hyperplasia of the breast,35 B-cell follicular 
non-Hodgkin’s lymphoma,36 and Paget disease.37 


page 11 of 35 
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 as well as those men with suspected 
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.42-44 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 to be effective. 
2.4. 
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 determine its utility. 
We plan to utilize this data to obtain further approvals of the 68Ga PSMA-HBED-CC 
compound, so that this agent will become widely available for clinical imaging in 
prostate cancer patients.  
68Ga PSMA-HBED-CC has been shown to be superior to choline based Carbon-11 
and Fluorine-18 PET imaging agents for the staging of prostate cancer. However, 
68Ga PSMA-HBED-CC was not patented and therefore no company or private entity 
will make the investment required to bring it to market. In the vacuum of availability, 
academic groups are taking the lead in order to collect the necessary data for future 
FDA approval.  
The rate of prostatectomy is increasing in high-risk prostate cancer patients (1), which 
means that there is an increasing unmet need to detect regional and distant metastases 
prior to surgery. Two published studies to date using 68Ga PSMA-HBED-CC PET in 
intermediate to high-risk patients prior to prostatectomy, demonstrated a per patient 
sensitivity for nodal metastases of 64-66% (2,3), much improved compared to 
conventional imaging modalities. We aim to study the ability of 68Ga PSMA-HBED-
CC to detect pelvic nodal disease in intermediate and high-risk preprostatectomy 
patients. 
 
 


page 12 of 35 
 SUBJECT SELECTION 
3.1. 
Eligibility Criteria 
3.1.1. 
Biopsy-proven prostate adenocarcinoma  
3.1.2. 
Intermediate to high-risk disease, defined as one of the following factors: 
PSA > 10, T2b or greater, or a Gleason score of 7 or greater. 
3.1.3. 
A PSA level result within the last 2 months. 
3.1.4. 
Planned prostatectomy with lymph node dissection 
3.1.5. 
Karnofsky performance status (KPS) of ≥ 50 (ECOG/WHO 0, 1, or 2) 
within the last 3 months. 
3.1.6. 
Must be treatment naïve (not have received neoadjuvant chemotherapy, 
radiation therapy, hormonal therapy, androgen deprivation therapy, or focal 
ablation techniques (e.g., HiFu) 
3.1.7. 
Not receiving any other investigational agents (i.e., unlabeled drugs or drugs 
under an IND for initial efficacy investigations 
3.1.8. 
Ability to understand and the willingness to provide informed consent. 
3.2. 
Exclusion Criteria 
3.2.1. 
Cannot receive furosemide. 
3.2.2. 
Allergy to sulfa or sulfa-containing medications. 
3.2.3. 
History of Stevens-Johnson syndrome 
3.2.4. 
Known Paget’s disease 
3.2.5. 
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. 
 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. 
• 
Scan the record of consent into the subject’s medical record. 
 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 


page 13 of 35 
bladder.  
5.1.3. 
Contrast. Imaging contrast will not be ordered as part of this study.  
5.1.4. 
Voiding. Participants will be asked to void their bladder immediately prior 
to radiotracer injection and before imaging. 
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 Imaging Procedures 
5.4.1. 
Scan coverage. Scan coverage will extend from mid-thigh to the base of the 
skull, starting from the mid-thighs to prevent 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. 
Local Analysis. A board-certified nuclear medicine physician on-site will 
interpret the images within 3 business days of the imaging study. These 
interpretations will not be used for final evaluation, however regional 
positivity results will be collected as study data.  
5.4.5. 
Internal Blinded Reads. Imaging data will be interpreted by two different 
readers in a random order at separate reading sessions. Cross sectional 
imaging from the PET will be available for anatomic correlation. 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 
readers will have undergone 68Ga PSMA PET training.  
5.4.6. 
Results dissemination. Results will be shared with the subject’s urologist 
and will be included in the subject’s medical record.  
5.5. 
Visual Interpretation of PET data (Internal blinded reads) 
Regions of suspected disease will be graded 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. Regions are defined in Table 12.1. in Section 12.  
Criteria for visual interpretation positive for disease are detailed in Section 12. 1.1. 
5.5.1. 
Lymph nodes. Considered positive if 68Ga PSMA-HBED-CC uptake is 
focal and greater than adjacent background. Pelvic lymph nodes will be 
subclassified according to their localization as follows: R/L obturator, R/L 


page 14 of 35 
external iliac, R/L internal iliac, and other pelvic nodes (total of 7 
subgroups). 
5.5.2. 
Visceral lesions. Considered positive if the 68Ga PSMA-HBED-CC uptake 
is focal and greater than physiologic background activity of the involvement 
organ or anatomic site. 
5.5.3. 
Bone lesions. Considered positive if the 68Ga PSMA-HBED-CC uptake is 
focal and greater than physiologic bone marrow. 
5.6. 
Post-Imaging Prostatectomy  
Prostatectomy and pelvic nodal dissection will be performed at the discretion of 
referring physican after reviewing imaging results. Nodal dissection should follow 
standard of care. 
5.6.1. 
Negative imaging. Subjects without evidence of positive nodal or 
metastatic disease on 68Ga PSMA-HBED-CC PET imaging will undergo 
radical prostatectomy and pelvic nodal dissection. The pelvic nodal 
dissection will be performed regardless of imaging results. 
5.6.2. 
Positive imaging. The urologist will be informed of the location of any 68Ga 
PSMA-HBED-CC PET positive (or suspicious) regional pelvic nodes prior 
to surgery. The surgeon should attempt to capture the suspicious node 
during the nodal dissection. 
5.6.3. 
Nodal dissection. Nodes will be marked by location using the standard 
procedures. For example, if the urologist removed left and right nodal 
regions separately, the subject will have two nodal regions (left/right). If the 
nodes are removed in six groups (bilateral internal/external/obturator nodes), 
the subject will have six nodal regions analyzed.  
5.6.4. 
Pathology: Specimens from prostatectomy will be evaluated for the 
presence of nodal metastasis. This will be reported on a per patient basis, 
and by region as positive or negative. The pathology report should list the 
number of nodes counted during the exam.  
5.6.5. 
Immunohistochemical staining (IHC) (optional). Although not routinely 
performed during standard practice, IHC staining for PSMA of tumor 
specimens (primary and lymph node metastases) is preferred. 
5.7. 
Post-Prostatectomy Procedures 
5.7.1. 
PSMA-positive with negative pathology. Subjects with 68Ga PSMA-
HBED-CC positive nodes without positive nodes on pathology, may be 
rescanned with CT (or MRI) to determine if the suspicious node was 
thought to be removed.  Additionally, clinicans will have the option to order 
a 2nd 68Ga PSMA-HBED-CC PET/CT as described in Section 6.4.4. 
5.7.2. 
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.  
5.7.3. 
Biopsy. Biopsies to determine metastases or provide information for re-
staging should be performed at treating physician’s discretion and per local 


page 15 of 35 
standard of care. 
5.7.4. 
CT or MRI. Subjects should undergo routine standard of care imaging. 
5.7.5. 
Positive disease identified by either 68Ga PSMA-HBED-CC PET/CT or 
follow-up conventional imaging will trigger locally performed anatomic 
measurement of lesion size(s) on both the baseline CT or MRI, and the 
follow-up CT or MRI of suspected site of disease. 
5.8. 
General Concomitant Medication and Supportive Care Guidelines 
In general, subjects may receive full concomitant and supportive care throughout this 
trial with the following considerations: 
• 
Subjects may not receive any other approved or investigational anti-neoplastic 
therapies for the treatment of prostate cancer from time of consent through 
prostatectomy.  
5.9. 
Follow-Up  
5.9.1. 
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). Since Gallium-68 has a half-life of 67.71 minutes 
the active follow-up will be a minimum of 1 calendar day.  
5.9.2. 
Long term follow-up. After the active follow-up period, the subject will 
return to standard follow-up with their physician. Subject’s outcome should 
be followed through passive chart review. Data collected must minimally 
include subsequent PSA measurements, and any evidence of disease 
progression. Contact with subject and/or subject’s treating physicians may 
occur to better define treatment outcomes. 
5.10. 
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 determine if the subject 
can provide consent and is able to continue on study. 
• 
Refusal to continue treatment. In this event, the reasons for withdrawal will be 
documented. 
 PATIENT ASSESSMENTS 
6.1. 
Post-consent Baseline Data Collection 
Post-consent, the following data should be collected 
6.1.1. 
Pathology. A copy of the pathology report documenting the Gleason score 
should be obtained.  Also, obtain a copy of any pathology reports 3 months 
prior to the 68Ga PSMA-HBED-CC PET/CT. 
6.1.2. 
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. 
6.1.3. 
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. 
6.1.4. 
CT scan. If a CT was performed within 3 months of 68Ga PSMA-HBED-CC 


page 16 of 35 
PET/CT, obtain a copy of the images and the report.  
6.1.5. 
PSA. Baseline PSA lab tests within 3 months of 68Ga PSMA-HBED-CC 
PET/CT should be obtained.  
6.2. 
Pre-Imaging Assessments (Baselines) 
6.2.1. 
Constitutional adverse events. A baseline evaluation will be obtained prior 
to injection and graded according to NCI’s Common Toxicity Criteria 
(CTCAE v4). 
6.2.2. 
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 session. 
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 
adverse events. Subject must be contacted at least once after 24 hours post-
injection. 
6.4. 
Follow-up 
6.4.1. 
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.   
6.4.2. 
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.  If the 1st Ga-68 PSMA-HBED-CC PET/CT scan shows 
lesions outside the pelvic region AND if imaging is NOT obtained per 
standard of care the research study will obtain a CT (abdomen and pelvis w/ 
contrast if contrast not contraindicated).  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. 
6.4.3. 
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. 
6.4.4. 
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. 


page 17 of 35 
 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.  
 DOSE MODIFICATIONS & DELAYS 
Not applicable. 
 ADVERSE EVENTS: REPORTING REQUIREMENTS 
This study will also 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 assigned to 68Ga PSMA-
HBED-CC. 
• 
All serious adverse events (SAEs) require attribution to 68Ga PSMA-HBED-CC.  
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 only 
• 
Attributable to 68Ga PSMA-HBED-CC 
Report to the IRB via HawkIRB within 10 business days of event 


page 18 of 35 
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: 
• 
Serious adverse events only [21 CFR 312.32] 
• 
Attributable to 68Ga PSMA-HBED-CCwith 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.” 
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 . 
 CLINICAL TRIAL MONITORING 
Clinical trial monitoring will be conducted to ensure that 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 
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. 


page 19 of 35 
• 
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: 
• 
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 20 of 35 
 STUDY CALENDAR 
 
Screening 
Baseline 
V1 - PSMA-HBED-CC 
PET/CT b,c 
Follow-up 
Injection 
Scan  
Immediate 
Long-term 
Karnofsky PSa 
X 
 
 
 
 
 
informed consent 
X 
 
 
 
 
 
PSA 
 
≤3 mo V1 
 
 
 
Xd 
imaging pull 
 
≤3mo V1 
 
 
 
Xd 
pathology pull 
X 
≤3 mo V1 
 
 
 
Xd 
68Ga PSMA-HBED-CC 
 
 
5 mCi 
 
 
 
20 mg IV furosemide 
 
 
X 
 
 
 
HR, BP, Temp 
 
 
supinee 
supinee 
 
 
voiding 
 
 
 
Xf 
 
 
Adverse event queryg 
 
X 
X 
Xg 
 
 
 
 
 
 
 
 
 
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 HR, BP, temp performed with subject supine immediately before and after injection and post-imaging of the scan 
f subject should void immediately prior to the scan. 
g final adverse event assessment is done 1 to 3 days post-injection but no earlier than 24 hours post-injection 
 
 
 


page 21 of 35 
 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. Trained 
readers 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 22 of 35 
12.1. 
68Ga-PSMA-HBED-CC PET Results Definition 
Imaging interpretation 68Ga-PSMA-HBED-CC PET: 
Local Interpretations:  PET images will initially 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 at the institution that the study is being 
performed. These interpretations will not be used for evaluation of the primary 
endpoint.  
Blinded Read Logistics: Imaging data will be de-identified. PET data will be 
interpreted by two different readers in a random order at separate reading sessions. 
Cross sectional imaging (CT or MRI) from the 68Ga-PSMA-HBED-CC PET will be 
available for anatomic correlate. The blinded readers will be blinded to all other 
imaging results and all other clinical data. 
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 
blinded reader (0=Negative or 1= Positive). A region will be judged as positive 
if at least one lesion in this region is visually positive. 
 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. 
 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 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. 
 Bone lesions will be considered positive if the 68Ga-PSMA-


page 23 of 35 
HBED-CC uptake is focal and greater than physiologic bone 
marrow. 
- 
Bone lesions will be classified by 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 
primary or secondary endpoints, but for exploratory analysis.  
 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 involvement 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. 
 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. 
 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. 


page 24 of 35 
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. 
- 
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. 
 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 diagnoses that is 
known to be 68Ga-PSMA-HBED-CC positive (eg 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. 
 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. 
 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.  If no follow-up imaging has been performed within 
the 9 months following the 68Ga-PSMA-HBED-CC scan, then the research 
study will pay for an additional follow-up CT scan to be performed in the 9-12 


page 25 of 35 
month window post-68Ga-PSMA-HBED-CC scan. Follow up imaging 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 
of follow-up imaging will be performed by local read. 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.  
Conventional imaging 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: 
 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). 


page 26 of 35 
ii. 
Negative for disease: 
- 
Conventional Imaging follow-up will not be used for 
assessment of negativity for disease. 
iii. 
Indeterminate for disease 
- 
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. 
 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% 


page 27 of 35 
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 
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. 
 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 ≤ 30 days 
before or after the PET/CT. 
- 
Focal uptake on the baseline bone scan performed within one 
month of 68Ga-PSMA-HBED-CC PET. 
- 
Any MRI lesion in bone read as positive on the initial MRI 
performed within one month 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 


page 28 of 35 
- 
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. 
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. 
 STATISTICAL CONSIDERATIONS  
13.1. 
Statistical Justification 
This study is a pilot study to determine target sensitivity for 68Ga PSMA-HBED-CC 
for the detection of prostate cancer in the pre-prostatectomy population. Based upon 
literature, we anticipate sensitivities of > 80% in this patient population, but there are 
uncertainties, particularly related to the proposed reference standard. We plan to use 
the results of this pilot study, potentially combined with reported results from other 
sites across the US performing similar studies (same patient population, same 
methods, same reference standard definitions…) to determine most-appropriate 
primary endpoint sensitivities for a larger University of Iowa study to follow this one, 
so as to appropriately statistically power the larger study. 
The primary objective of this pilot study is to obtain preliminary information on the 
sensitivity of physician reads for Ga-68 PSMA pre-prostatectomy; physicians’ ability 
to correctly identify prostate cancer and metastates via Ga-68 PSMA relative to our 
pathology/conventional imaging reference standard. Due to the lack of clinical 
experience with this radiopharmaceutical, this pilot study is meant to gain meaningful 
information of the sensitivity of this agent in this patient population to generate 
hypotheses for further trials. 
To evaluate sensitivity, patients must undergo both Ga-68 PSMA imaging and 
evaluation for prostate cancer by pathology, follow-up conventional imaging, or both. 
Sensitivity is defined as: 
 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑡𝑡𝑡𝑡=
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (𝑇𝑇𝑇𝑇)
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (𝑇𝑇𝑇𝑇) + 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 (𝐹𝐹𝐹𝐹) 
 


page 29 of 35 
The table below provides 95% confidence interval half-widths for a range of 
sensitivity values based on a planned sample size of 30 patients using a normal 
approximation.   
.   
Sensitivity 
Half-Width 
70% 
16.4% 
75% 
15.5% 
80% 
14.3% 
85% 
12.8% 
90% 
10.7% 
13.2. 
Primary Endpoint:  
The sensitivity, specificity, positive and negative predictive values of 68Ga PSMA-
HBED-CC PET/CT for the detection of disease on a per patient basis will be 
summarized by descriptive statistics.  
No statistical significance will be generated due to the pilot nature of the project. 
The below criteria will be used for evaluation of a per patient basis with nodal 
regional correlation (Primary endpoint 1): 
13.2.1. True positive patient: 
 
68Ga PSMA-HBED-CC PET/CT positive for a regional node 
by internal blind reader: pathology at prostatectomy is positive 
for a regional node that correlates in location to the PET images 
(location on pathology is determined by the urologist at the time 
of the surgery). Only one node needs to correspond between 
imaging and pathology for a patient to be considered a true 
positive. 
 
68Ga PSMA-HBED-CC PET/CT positive for regional nodes 
by internal blind reader, pathology negative for regional nodes, 
imaging after prostatectomy demonstrates the same node was not 
removed at surgery, and follow-up biopsy or imaging 
demonstrates presence of nodal disease as defined in Section 
12.2.1.2 . 
 Conventional imaging criteria for positive node on follow-up 
imaging: imaging within 3-12 months, the node decreases by 
more than 30% (for patients undergoing systemic treatment or 
focal therapy at this site) or increase by more than 20% in short 
axis diameter in the absence of treatment (with a minimum of 3 
mm in change in size) as defined in Section 12.2.2.1 . 
13.2.2. True negative patient: 
 
68Ga PSMA-HBED-CC PET/CT negative for regional nodes 
by internal blind reader; pathology at prostatectomy negative 
for regional nodes as defined in Section 12.2.1.2 . 
13.2.3. False positive patient: 
 
68Ga PSMA-HBED-CC PET/CT positive for regional nodes 


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by internal blind reader, pathology at prostatectomy is 
negative, and imaging after prostatectomy demonstrates that 
node is no longer present as defined in Section 12.2.1.2. 
 
68Ga PSMA-HBED-CC PET/CT positive for regional node 
by internal blind reader, but pathology at prostatectomy is 
positive for node but in a different nodal region than the node 
seen on PSMA PET. 
13.2.4. False negative patient: 
 
68Ga PSMA-HBED-CC PET/CT negative for regional nodes 
by internal blind reader, but pathology at prostatectomy is 
positive for regional nodes. 
13.2.5. Non-evaluable patient:  
 Any subject that does not have sufficient data to meet the criteria 
for definition of true positive patient, true negative patient, false 
positive patient, or false negative will be classified as non-
evaluable. 
 Patients with extrapelvic nodal metastases will not be included in 
this analysis for the primary endpoint if patients do not undergo 
prostatectomy. 
13.3. 
Secondary Endpoints:     
Analysis plan for Secondary Endpoints: We will report the sensitivity, specificity, 
positive and negative predictive value of 68Ga PSMA-HBED-CC PET/CT over all 
imaged regions as well as sub-classified by the following regions:  
• 
extra-pelvic nodal metastases 
• 
visceral metastases 
• 
osseous metastases 
No statistical significance will be generated due to the pilot nature of the project. 
Follow-up for extra-pelvic nodal metastases, visceral metastases and osseous 
metastases are defined as below: 
13.3.1. True positive region 
 
68Ga PSMA-HBED-CC PETCT positive for extra-pelvic node 
metastases by internal blind reader – and pathology (if 
available) positive for that node, or, extra-pelvic node positive 
for disease by imaging as defined in Section 12.2.2.1. 
 
68Ga PSMA-HBED-CC PET/CT positive for visceral 
metastases by internal blind reader – 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. 
 
68Ga PSMA-HBED-CC PET/CT positive for osseous 
metastases by internal blind reader - and pathology (if 
available) positive for that osseous lesion, or, osseous lesion 


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positive for disease by imaging as defined in Section 12.2.2.3. 
13.3.2.  True negative region 
 
68Ga PSMA-HBED-CC PET negative for extra-pelvic node 
metastases by internal blind reader – and pathology (if 
available) negative for disease, and, extra-pelvic node not 
positive for disease by imaging. 
 
68Ga PSMA-HBED-CC PET negative for visceral metastases 
by internal blind reader – and pathology (if available) negative 
for disease, and, visceral lesion not positive for disease by 
imaging. 
 
68Ga PSMA-HBED-CC PET negative for osseous metastases 
by internal blind reader - and pathology (if available) negative 
for disease, and, osseous lesion not positive for disease by 
imaging. 
13.3.3. False positive region: 
 
68Ga PSMA-HBED-CC PET positive for extra-pelvic nodes 
by internal blind reader, pathology (if available) is negative, 
and imaging after prostatectomy demonstrates that node is not 
positive for disease. 
 
68Ga PSMA-HBED-CC PET positive for 
regional node by internal blind reader, but 
pathology (if available) is positive for node but in 
a different nodal region than the node seen on 
PSMA PET. 
 PSMA-HBED-CC PET positive for visceral lesion by internal 
blind reader, pathology (if available) is negative, and imaging 
after prostatectomy demonstrates that the visceral lesion is not 
positive for disease. 
 
68Ga PSMA-HBED-CC PET positive for 
visceral lesion by internal blind reader, but 
pathology (if available) is positive for visceral 
lesion but in a different region than the visceral 
region seen on PSMA PET. 
 
68Ga PSMA-HBED-CC PET positive for osseous lesion by 
internal blind reader, pathology (if available) is negative, and 
imaging after prostatectomy demonstrates that the osseous lesion 
is not positive for disease  
 
68Ga PSMA-HBED-CC PET positive for 
osseous lesion by internal blind reader, but 
pathology (if available) is positive for osseous 
lesion but in a different region than the osseous 
region seen on PSMA PET. 
13.3.4. False negative region: 
 
68Ga PSMA-HBED-CC PET negative for extra-pelvic nodes 


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by internal blind reader, and pathology (if available) positive 
for that node, or, extra-pelvic node positive for disease by 
imaging as defined in Section 12.2.2.1. 
 
68Ga PSMA-HBED-CC PET negative for extra-pelvic nodes 
by internal blind reader, 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. 
 
68Ga PSMA-HBED-CC PET negative for extra-pelvic nodes 
by internal blind reader, 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. 
13.3.5. Non-evaluable region:  
 Any region that is 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. 
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