Clinical trial NCT03396874
Conditions: Prostate Cancer Prostate Adenocarcinoma Prostate Cancer Metastatic Prostate Cancer Recurrent
Sponsor: University of Michigan
Start date: 2018-02-09; Completion date: 2022-08-09
Enrollment: 1435 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the value of Gallium-68 labeled PSMA (68Ga-PSMA) for PET/CT imaging of prostate cancer recurrence. 68Ga-PSMA is a radioactive molecule, which binds to prostate cancer cells. Together with a PET/CT scanner, the distribution of 68Ga-PSMA can be determined in the body.

To test this new drug, participants will receive an intravenous injection of Ga-68-PSMA and then have a PET/CT scan. The scan results will be made available to study participants and treating physicians.

Detailed description:
This study evaluates Gallium-68 labelled PSMA-11 (also called Gallium-68 labelled PSMA-HBED-CC, or Gallium-68 labelled PSMA N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid), abbreviated here as 68Ga-PSMA. This molecule (or radiotracer) binds to receptors that are often present on prostate cancer cells. Using 68Ga-PSMA together with a positron emission tomography (PET) scanner (with computed tomography, called PET/CT), it is therefore possible to find prostate cancer lesions in the body. The study will test whether 68Ga-PSMA will identify prostate cancer more precisely than normal imaging methods (for example CT, MRI, or bone scan). A more precise identification of the location of the disease is important. Knowing where the disease is located will help to decide on the best course of action to treat the disease.

Men who have elevated tumor markers of prostate cancer are eligible for this study. Participants undergo a 68Ga-PSMA PET/CT scan before further treatment. Based on clinical information, including any prior imaging and biopsy/surgery information and follow-up information, we will determine whether 68Ga-PSMA PET/CT imaging was more accurate than the standard imaging. The study team will collect this information for up to 1 year after the 68Ga-PSMA PET/CT scan.

The results of the 68Ga-PSMA PET/CT scan will be shared with the participating patients. Also, results will be entered into the participant's medical record and shared with the treating physicians.

Arms: arm 1: PET/CT imaging
Interventions: intervention 1: 68Ga-PSMA
Intervention descriptions: intervention 1: PET/CT imaging with 68Ga-PSMA:

68Ga-PSMA is an investigational radioactive drug that binds to receptors on prostate cancer cells. The intravenously administered drug dose will be about 5 mCi (range 3-7 mCi).

Protocol documents:
Prot_SAP_000.pdf: 
 
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68Ga-PSMA-11 
 
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Gallium-68 PSMA-11 PET in patients with biochemical recurrence 
Study Drug:  Gallium-68 PSMA-11 
Version Date:  09/13/2019 
 
 
 
 
 
Principle investigator  
Morand Piert, M.D. Ph.D. 
Co-investigators 
 
Ajjai Alva, M.D. 
Matthew Davenport, M.D. 
 
 
 
 
Issam El Naqa, Ph.D. 
Kirk Frey, M.D. Ph.D. 
 
 
 
 
Jason Hearn, M.D. 
 
 
 
 
Jeffrey Montgomery, M.D. 
 
 
 
 
Peter Scott, Ph.D. 
 
 
 
 
Monica Gerst, M.D. 
Statistician 
 
 
Timothy Johnson, Ph.D. 
Study coordinator 
 
James Pool Jr. 
 
Rogel Cancer Center #: 
2017.016 
IND Number: 
IND 133858 
NCT Number: 
NCT03396874 
 
 
 
 


 
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Note: 
This study is a site-specific single center study; however together with other participating sites, 
the University of Michigan investigators will share obtained data regarding the performance of 
68Ga-PSMA-11 PET/CT in biochemical recurrence in order to allow for a future NDA filing for 
68Ga-PSMA-11 to the FDA. The study protocol has been designed in consultation with the FDA. 
The entire study process is organized by the Clinical Trials Network (CTN) of the Society of 
Nuclear Medicine. Specifically, data capture procedures and data management is organized by 
the CTN. The University of California at San Francisco (UCSF) site will host an electronic 
database for central anonymized data capture. 
 
 


 
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SCHEMA 
 
 
 


 
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Abstract 
Title 
Gallium-68 PSMA-11 PET in patients with biochemical recurrence 
Study 
population 
Arm 1 (Prostate cancer patients): 
Rising PSA after definitive therapy with prostatectomy or radiation therapy 
(external beam or brachytherapy): 
Post radical prostatectomy (RP) – AUA recommendation   
PSA greater than 0.2 ng/mL measured more than 6 weeks after 
RP and, 
Confirmatory persistent PSA greater than 0.2 ng/mL  
Post-radiation therapy – ASTRO-Phoenix consensus definition  
Nadir + greater than or equal to 2 ng/mL rise in PSA 
Arm 2 (Physicians/practitioners): 
Ordering physicians/practitioners of study arm 1 patients will be surveyed 
whether 68Ga PSMA-HBED-CC PET/CT has an impact on the clinical 
management of their respective patients. 
 
Rationale for 
Study 
68Ga PSMA-HBED-CC (68Ga-PSMA-11) has been shown to have a higher 
sensitivity for the detection of metastatic prostate cancer compared to 
choline based imaging. 
Primary 
Objectives 
Determine the positive predictive value (PPV) of 68Ga PSMA-11 PET/CT for 
detecting prostate cancer on a per-patient basis, confirmed by 
histopathology 
Secondary 
Objectives 
Determine sensitivity and PPV on a per-patient and per-region-basis of 
68Ga-PSMA-11 PET/CT for detection of tumor location confirmed by 
conventional imaging, clinical follow-up, and histopathology/biopsy where 
available 
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) 
Determine the impact of 68Ga PSMA-HBED-CC PET/CT on clinical 
management in patients who have prostate cancer with biochemical 
recurrence 
Continue to evaluate safety of 68Ga PSMA-HBED-CC injection as 
categorized by CTCAE 4.0 


 
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Study Design 
Single-center, open label phase 2.  
Number of 
subjects 
Study arm 1: The total number of patients at the University of Michigan is 
750. The data will be shared with other sites within the CTN. The total 
population of patients will be 1,500 patients across all participating 
institutions. 
Study arm 2: the total number of physicians/practitioners ordering PET/CT 
scans will be small, but theoretically be as high as 750. 
Duration of 
Therapy 
The study will involve a single imaging study. 
Duration of 
Safety Follow 
up 
The patients will be followed-up by phone after PET/CT imaging. 
Duration of 
study 
The study will reach completion of recruitment 3 years from the time the 
study opens to accrual. 
Study Drugs 
Gallium-68 labeled PSMA-11 (PSMA-HBED-CC) 
Safety 
Assessments 
Patient vital signs will be taken immediately before and after the 
administration of the radiopharmaceutical. The patients will also be asked to 
report adverse events. 
 
 


 
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List of Abbreviations 
68Ga-PSMA 
Glu-NH-CONH-Lys-(Ahx)-[68Ga(HBED-CC)], also called 68Ga-PSMA-11 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
BCR 
Biochemical Recurrence 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTN 
Clinical Trials Network (of the Society of Nuclear Medicine) 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
F/u 
Follow-up 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
LN 
Lymph node 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NRC 
Nuclear Regulatory Commission 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PPV 
Positive Predictive Value 
PRC 
Protocol Review Committee 
PSA 
Prostate-specific Antigen 
PSMA 
Prostate-specific Membrane Antigen 
RDRC 
Radioactive Drug Research Committee 


 
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List of Abbreviations 
RECIST 
Response Evaluation Criteria In Solid Tumors (Version 1.1) 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SHUR 
Subcommittee on the Human Use of Radioisotopes 
SUV 
Standardized Uptake Value 
UaP 
Unanticipated Problem 
WHO 
World Health Organization 
VOIs 
Volumes of interest 
 
 


 
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Contents 
Schema 
3 
Abstract 
4 
List of Abbreviations ...................................................................................................................... 6 
1 
Introduction ........................................................................................................................... 9 
1.1 
Overview ............................................................................................................... 9 
1.2 
Background ......................................................................................................... 10 
1.3 
Patient Population ................................................................................................ 15 
2 
Objectives of the Study........................................................................................................ 15 
2.1 
Primary ................................................................................................................ 15 
2.2 
Secondary ............................................................................................................ 15 
2.3 
Endpoints ............................................................................................................. 16 
2.3.1 
Primary Endpoints ........................................................................................... 16 
2.3.2 
Secondary Endpoints ....................................................................................... 16 
3 
Study Design........................................................................................................................ 16 
3.1 
Characteristics ..................................................................................................... 16 
3.1 
Number of Subjects ............................................................................................. 16 
3.2 
Eligibility Criteria ................................................................................................ 16 
3.2.1 
Inclusion Criteria ............................................................................................. 17 
3.2.2 
Exclusion Criteria ............................................................................................ 17 
3.3 
Duration of Follow Up ........................................................................................ 17 
3.3.1 
Active Safety Follow-up .................................................................................. 17 
3.3.2 
Long-term Follow-up ...................................................................................... 17 
3.4 
Study Timeline .................................................................................................... 17 
3.4.1 
Primary Completion ........................................................................................ 17 
3.4.2 
Study Completion ............................................................................................ 18 
4 
Study Drugs ......................................................................................................................... 18 
4.1 
Description, Supply and Storage of Investigational Drugs ................................. 18 
4.1.1 
Investigational Drug #1 ................................................................................... 18 
5 
Treatment Plan ..................................................................................................................... 18 
5.1 
Dosage and Administration ................................................................................. 18 
5.1.1 
Other Modality(ies) or Procedures .................................................................. 18 
5.2 
Monitoring and Toxicity Management ................................................................ 19 
5.3 
Follow-up Standard of Care Imaging .................................................................. 19 
5.4 
General Concomitant Medication and Supportive Care Guidelines ................... 20 
6 
Study Procedures and Observations .................................................................................... 20 
See also appendix 2 and 3. ............................................................................................................ 20 
6.1 
Schedule of Procedures and Observations .......................................................... 20 
6.1.2 
Treatment Period ............................................................................................. 20 
6.1.3 
Post-treatment Safety Follow Up .................................................................... 21 
6.2 
Prohibited Medications ........................................................................................ 21 
7 
Reporting and Documentation of Results ............................................................................ 21 
7.1 
Evaluation of Efficacy (or Activity) .................................................................... 21 


 
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7.2 
Evaluation of Safety ............................................................................................ 21 
7.3 
Definitions of Adverse Events ............................................................................ 21 
7.3.1 
Adverse Event.................................................................................................. 21 
7.3.2 
Adverse reaction .............................................................................................. 21 
7.4 
Recording of an Adverse Event ........................................................................... 22 
7.5 
Data and Safety Monitoring ................................................................................ 23 
7.6 
Expedited Reporting ............................................................................................ 24 
8 
Statistical Considerations and Evaluation of Results .......................................................... 24 
8.1 
Study Endpoints .................................................................................................. 24 
8.1.1 
Randomization ................................................................................................. 24 
8.2 
Determination of Sample Size and Accrual Rate ................................................ 24 
8.2.1 
Sample Size and Power Estimate .................................................................... 24 
8.3 
Analyses Plans ..................................................................................................... 25 
8.3.1 
Analysis Population ......................................................................................... 25 
8.3.2 
Scan Interpretations ......................................................................................... 25 
8.3.3 
Central Data Analysis ...................................................................................... 26 
8.3.4 
Analysis of Primary Endpoints ........................................................................ 26 
8.3.5 
Central Analysis of Secondary Endpoints ....................................................... 30 
9 
Study Management .............................................................................................................. 31 
9.1 
Pre-study Documentation .................................................................................... 31 
9.2 
Institutional Review Board Approval .................................................................. 31 
9.3 
Informed Consent ................................................................................................ 31 
9.4 
Changes in the Protocol ....................................................................................... 31 
10 
Protection of Human Subjects ............................................................................................. 31 
10.1 
Protection of Privacy ........................................................................................... 31 
Appendices 
32 
Appendix 1 
Performance Status Criteria ................................................................................. 32 
Appendix 2 
Schedule of Study Procedures and Assessments ................................................. 33 
Appendix 3 (Flow chart) ............................................................................................................... 34 
References  ………………………………………………………………………………………35 
 
1 Introduction 
1.1 Overview 
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 (more commonly called 68Ga-PSMA-11) in order to demonstrate its utility.   We plan to 
utilize this data to obtain further approvals of the 68Ga-PSMA-11 compound, so that this agent 
will become available for clinical imaging in prostate cancer patients.   
This compound has been shown to be superior to choline based PET agents for the staging of 
prostate cancer, both Carbon-11 and Fluorine-18 compounds.  But this compound was not 
patented and therefore no company or private entity will make the investment required to bring 
HBED-CC PSMA to market.  In the vacuum of availability, academic groups must take the lead 
in order to collect the necessary data for future FDA approval.  This protocol was developed in 


 
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collaboration with the Clinical Trials Network of the Society of Nuclear Medicine and Molecular 
Imaging.  The inclusion criteria and study endpoints have been aligned so that inter-institutional 
sharing of data can be performed in order to pool data for final NDA submission. 
1.2 Background 
Prostate cancer is the most commonly diagnosed cancer and second leading cause of cancer 
death in American men 1. Biochemical recurrence (BCR) of prostate cancer is defined as a 
confirmed PSA value of ≥ 0.2 ng/dL if the patient has had a radical prostatectomy (RP) with or 
without postoperative radiation therapy (adjuvant or salvage).  If the initial local therapy was 
definitive radiation therapy (RT), biochemical recurrence is defined as the nadir PSA value plus 
2 ng/mL, since some benign PSA-producing tissue may remain.  Patients with BCR after RP 
who have not received postoperative RT are frequently treated with salvage RT to the prostate 
bed, which can be curative for some. Patients with BCR after initial definitive RT may be 
salvaged with brachytherapy or in some cases with surgery.  However, for patients with BCR 
and no further local therapy options, there is no consensus as to optimal management.   
Typical management of BCR involves serial clinical and laboratory monitoring 2 with eventual 
initiation of androgen deprivation therapy (ADT) in many patients as the PSA rises. The risk of 
developing BCR is 15–20% at 5 and 25–30% at 10 years after initial therapy of prostate cancer 
3,4.  The best threshold at which to initiate systemic androgen deprivation therapy (ADT) in 
patients with BCR remains controversial. In one retrospective cohort of over 5,000 patients 
treated with primary prostatectomy or radiotherapy, ADT was not associated with an all-cause 
mortality or prostate cancer-specific mortality benefit in the prostatectomy cohort. However, ADT 
did show improvement in all-cause and prostate-cancer specific mortality in patients with a PSA 
doubling time less than 9 months. This suggests that there is a potential role for aggressive, 
earlier intervention in the setting of BCR in select patients, and systemic therapy may also be 
necessary in these patients 5.  Recently, a randomized trial of early versus delayed use of ADT 
in men with BCR after local therapy showed a small improvement in survival with early ADT 6. 
Nonetheless, the toxicity of ADT is not trivial, and the authors recommended a thorough 
discussion of the risks and benefits of early versus late ADT with each patient rather than 
blanket use of early ADT. 
Current standard imaging of early recurrent prostate cancer is insufficient. Accurate detection of 
tumor locations is essential as the clinical management varies from active surveillance to 
targeted local to systemic therapy 7. Per NCCN guidelines at the time of biochemical recurrence, 
imaging is performed to detect and characterize the disease to determine treatment or guide 
change in management. Imaging can evaluate anatomic or functional parameters and 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). 
More specifically, Current U.S. guidelines recommend either a radionuclide bone scan, 
abdominopelvic CT, multi-parameter MRI or – where available - choline PET/CT for patients 
with rising PSA or clinical symptoms 7. The probability of a positive bone scan is reported to be 
<5% with a serum PSA level of <7 ng/mL. A CT scan will only be positive in 11–14% of patients 


 
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with BCR 8. Additionally, in a study with 132 patients, the mean PSA level of patients with a 
positive CT scan was 27.4 ng/ml 8.  
Due to this limitation, of existing conventional imaging 9, numerous approaches to stage patients 
have been evaluated. Choline imaging has been frequently used, as prostate cancer exhibits 
increase choline uptake that has been associated with the presence of choline kinase 10.  
Choline uptake is increased in comparison to FDG in both androgen dependent and 
independent prostate cancer patients 11.  Choline has also been shown to be sensitive for the 
detection of recurrent tumor in patients with PSA (prostate specific antigen) values of less than 
1.0 ng/ml 12.  There are two forms of choline that are used in imaging prostate cancer, 11C - and 
18F-choline.  11C-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.  18F-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 13. 
11C-choline has limited sensitivity for osseous metastasis, possibly due to the decreased uptake 
time 14.  Additionally, the sensitivity of 11C -choline is limited in patients with PSA values < 1.0 
ng/ml 15-17.  Although choline PET may be limited in sensitivity, it clearly delineates more lesions 
than cross section imaging or bone scan in patients with known disease 18. In 2012, the Mayo 
Clinic obtained NDA approval from the FDA for the use of 11C-choline. MRI and choline PET/CT 
have been reported to have similar sensitivities in detecting bone metastasis 19. However, the 
sensitivity for lymph node detection remains low. Choline PET/CT have shown variable results 
with the detection rates ranging between 11% and 75%, largely depending on serum PSA 
levels. For PSA levels <1.0 mg/ml, the detection rates range from 5% to 44%. The main 
limitation is the low sensitivity for micro-metastatic disease 20. 
A different approach is to image the prostate specific membrane antigen (PSMA).  PSMA is 
expressed on the majority of prostate cancer cells. The initial imaging approach to PSMA 
imaging was to target the intracellular domain of PSMA using Indium-111-capromab 
(Prostascint), a murine monoclonal antibody 21.  Although there was early promise for the 
detection of nodal metastasis 22, the agent was never able to adequately visualize osseous 
metastasis 23.  One main limitation to Indium-111-capromab is that it takes a prolonged time to 
localize to the target tissue, which likely relates to both the size of the monoclonal antibody and 
the fact that agent targets the intracellular domain of the PSMA protein. 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 Indium-111 capromab, there has been continued effort to develop 
agents that target the extracellular domain of the PSMA protein. 68Ga-PSMA has become of 
particular interest in biochemical recurrent prostate cancer. Afshar-Oromieh et al. demonstrated 
that 68Ga-PSMA-11 has a higher sensitivity for the detection of disease than 18F-choline in a 
head-to-head intra-patient comparison that included 37 patients 24. Later the same group 
demonstrated a high sensitivity of 68Ga-PSMA-11 in the detection of metastatic lesions at the 
time of recurrent prostate cancer 25. 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 12. Newer extensive retrospective data of more than 1600 patients further support 
these earlier data suggesting that 68Ga-PSMA is an excellent radiotracer for biochemically 
recurrent prostate cancer with particular benefits over choline PET/CT at very low PSA levels (< 
0.5 ng/mL) 26-29. 68Ga-PSMA has also been shown in head-to-head comparisons to outperform 
conventional imaging for detection of nodal metastatic disease by a large margin 30.  
Factors influencing the probability for a positive 68Ga-PSMA PET/CT study have been evaluated 
in larger retrospective patient populations 31. These factors including the absolute level of PSA 


 
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at the time of scanning, PSA doubling time, PSA velocity, initial Gleason score, ongoing 
androgen deprivation therapy, patient age and amount of injected tracer activity in cohorts of 
319, 248 and 1007 patients with BCR 25,27,29. All studies suggested that the absolute PSA level 
and androgen deprivation therapy were associated with a positive 68Ga-PSMA scan, while the 
PSA doubling time and Gleason score at initial presentation were not a significant predictors of 
scan positivity. 
Improvements in the detection of recurrent prostate cancer have profound effects on patient 
management 28. In a recently published Australian multi-center trial including 323 patients with 
biochemical evidence of recurrent disease and equivocal conventional imaging, 68Ga-PSMA 
PET/CT changed the management of prostate cancer in 62% of cases. In this study, a 
substantial impact was documented with a significant reduction in the number of men in whom 
the site of disease recurrence was unknown and significant increases in the detection of 
presumed oligometastatic and polymetastatic disease. Compared to standard of care 
diagnostics (including imaging), additional sites of disease were detection in 32% as local 
recurrence, 43% as nodal disease and 20% as metastatic (mostly to bone) 32. 68Ga-PSMA has a 
significantly higher sensitivity and specificity than 99mTc-bone scanning in 126 patients with 
prostate cancer, of whom 75 were found to present with osseous metastatic disease 33. 
 
Overtreatment and undertreatment of BCR occurs 34. Due to the lack of accurate imaging, 
salvage RT of prostate bed without identification of the disease location is commonly performed. 
The lack of targeted focal treatment of metastatic disease may limit the success of such 
treatment. Also, 68Ga-PSMA identifies a high detection rate of prostate cancer recurrence 
outside of the prostatic fossa 35. This clearly indicates the need for prospective trials to evaluate 
the changes in RT volumes or disease management and their outcomes. 
Earlier detection of macroscopic metastatic disease in castration sensitive prostate cancer by 
novel highly sensitive molecular imaging techniques could lead to detection of prostate cancer 
metastases at lower tumor burdens presenting as oligometastatic prostate cancer rather than as 
diffusely metastatic prostate cancer. While the definition of oligometastatic disease varies, the 
addition of locoregional ablative therapies directed at sites of macroscopic disease to 
conventional systemic therapy has shown promise with respect to delaying progression of 
disease in other cancer types. A recent randomized trial in oligometastatic non-small cell lung 
cancer demonstrated that the addition of locoregional therapy to systemic therapy improved 
progression-free survival 36. More importantly, the addition of locoregional therapy doubled the 
time to the appearance of disease at new sites, indicating that the overall natural history of the 
disease was altered.  
In prostate cancer, multiple studies suggest a benefit from locoregional therapy in 
oligometastatic disease. Given that maximally effective use of locoregional therapy requires 
accurate knowledge of disease extent, further investigation of the clinical impact of highly 
sensitive molecular imaging is critical. Incorporation of additional focal or targeted therapeutic 
modalities could be valuable in this patient population, but is currently limited by the low 
sensitivity of standard imaging modalities. The STOMP trial is an ongoing randomized phase 
study utilizing metastases-directed therapy with either surgery or sterotactic body radiotherapy, 
with less than or equal to 3 metastases defining oligometastatic disease diagnosed on choline 
PET/CT 37. The ORIOLE trial is also an ongoing randomized phase II study assessing the 
efficacy of stereotactic ablative radiotherapy in patients who have failed primary treatment and 
have developed oligometastatic disease with three or fewer bone metastases 38. 


 
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Based on the available data, it is evident that the full extent of metastatic disease patients with 
biochemically recurrent prostate cancer is frequently underestimated on conventional imaging 
when compared to advanced molecular imaging techniques. Importantly, the utility of 68Ga-
PSMA PET/CT to identify such metastatic lesions earlier prior their appearance on standard 
imaging has not yet been evaluated in the randomized setting.  
In HUM00106254, a small pilot trial, we are currently evaluating 68Ga-PSMA for the detection of 
primary prostate cancer and BCR. Examples of the potential of this excellent radiotracer for the 
identification of significant primary disease (Figure 1), and low-volume metastatic disease are 
given in figures 2-3. 
 
 


 
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Because of the improved resolution and image quality with PET, ability to quantitate uptake, 
increased sensitivity compared to choline PET/CT, we intend to evaluate the utility of 68Ga-


 
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PSMA-11 in patient with BCR. We expect that the data from this study will support an NDA 
application to the FDA, which may ultimately lead to FDA approval for the United States.  
 
1.3 Patient Population 
Arm 1 (Prostate cancer patients) 
Patients with biochemical recurrence after prostatectomy or radiation therapy: 
- 
Post radical prostatectomy (RP) – AUA recommendation * 
− 
PSA greater than 0.2 ng/mL measured more than 6 weeks after RP and, 
− 
Confirmatory persistent PSA greater than 0.2 ng/mL. 
- 
Post-radiation therapy –ASTRO-Phoenix consensus definition ** 
− 
Nadir + greater than or equal to 2 ng/mL rise in PSA. 
* Biochemical recurrence will be defined using the AUA and ASTRO-Phoenix definitions. 
Specifically, post radical prostatectomy (RP) – AUA recommendation39 is PSA greater 
than 0.2 ng/mL measured 6–13 weeks after RP and confirmatory persistent PSA greater 
than 0.2 ng/mL.  
** Post-radiation therapy – ASTRO-Phoenix consensus definition40 nadir + greater than 
or equal to 2 ng/mL rise in PSA. 
 
Arm 2 (Physicians/practitioners) 
Physicians/practitioners of study arm 1 patients will be surveyed to assess whether 68Ga PSMA-
HBED-CC PET/CT has an impact on the clinical management of their respective patients. 
 
2 Objectives of the Study 
2.1 Primary 
- 
Determine the positive predictive value (PPV) of 68Ga PSMA-11 PET/CT for detecting 
prostate cancer on a per-patient basis, confirmed by histopathology. 
2.2 Secondary 
- 
Determine sensitivity and PPV on a per-patient and per-region-basis of 68Ga-PSMA-11 
PET/CT for detection of tumor location confirmed by conventional imaging, clinical 
follow-up, and histopathology/biopsy where available. 
- 
Determine detection rates on a per-subject basis of 68Ga PSMA-11 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). 
- 
Determine the impact of 68Ga PSMA-11 PET/CT on clinical management in patients who 
have prostate cancer with biochemical recurrence. 


 
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- 
Continue to evaluate safety of 68Ga-PSMA-11. 
 
2.3 Endpoints 
2.3.1 Primary Endpoints 
• 
Per patient 68Ga-PSMA-11 positivity. 
• 
Histological correlation with 68Ga-PSMA-11 lesion results. 
2.3.2 Secondary Endpoints 
• 
Per patient and per region detection sensitivity and PPV using a combined histology and 
conventional imaging correlate. * 
• 
Change in management: survey based results. * 
• 
Safety: blood pressure, heart rate, self-reported adverse events. * 
Note: * secondary endpoints are assessed at central data analysis in the entire patient 
population (n=1500) across participating institutions (see section 8.3.3) 
3 Study Design 
3.1 Characteristics 
This is a prospective, phase 2, open-label study in patients with prostate cancer performed at 
the University of Michigan. Eligible participants will undergo baseline assessments at 
enrollment. Study participants will receive a one-time administration of Gallium-68 PSMA-11 
and undergo a PET/CT imaging study.  
3.1  Number of Subjects 
It is anticipated that in study arm 1 up to 750 patients will be enrolled at the University of 
Michigan in this study. Total population of patients will be 1,500 patients across participating 
institutions. 
The total number of physicians/practitioners (study arm 2) will be small, but theoretically be as 
high as 750. 
3.2 Eligibility Criteria 
Patients must have baseline evaluations performed prior to the administration of the 
radiopharmaceutical and must meet all inclusion and exclusion criteria.  In addition, the patient 
must be thoroughly informed about all aspects of the study, including the study visit schedule 
and required evaluations and all regulatory requirements for informed consent.  The written 
informed consent must be obtained from the patient prior to enrollment.  The following criteria 
apply to all patients enrolled onto the study unless otherwise specified. 
Table 1 
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 


 
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3.2.1 Inclusion Criteria 
1. Histopathological proven prostate adenocarcinoma. 
2. Rising PSA after definitive therapy with prostatectomy or radiation therapy (external 
beam or brachytherapy).  
a. Post radical prostatectomy (RP) – AUA recommendation   
i. PSA greater than 0.2 ng/mL measured more than 6 weeks after RP and, 
ii. Confirmatory persistent PSA greater than 0.2 ng/mL  
b. Post-radiation therapy –ASTRO-Phoenix consensus definition  
i. Nadir + greater than or equal to 2 ng/mL rise in PSA 
3. Karnofsky performance status of ≥ 50 (or ECOG/WHO equivalent). 
4. Age ≥ 18. 
5. Ability to understand a written informed consent document, and the willingness to sign it. 
3.2.2 Exclusion Criteria 
1. Current investigational therapy for prostate cancer. 
2. Unable to lie flat, still or tolerate a PET scan. 
3. Prior history of any other malignancy within the last 2 years, other than skin basal cell or 
cutaneous superficial squamous cell carcinoma that has not metastasized and 
superficial bladder cancer. 
4. Prisoner. 
3.3 Duration of Follow Up 
3.3.1 Active Safety Follow-up 
Patients will be followed for acute adverse events for one day (allowed range 1 to 3 calendar 
days) after the administration of the radiopharmaceutical. 
3.3.2 Long-term Follow-up 
After the active safety 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. 
3.4 Study Timeline 
3.4.1 Primary Completion 
The study is expected to reach completion of active recruitment 36 months from the time the 
study opens to accrual. 


 
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3.4.2 Study Completion 
The study is expected to reach its final completion 48 months from the time the study opens to 
accrual. 
4 Study Drugs 
4.1 Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug #1 
Gallium-68 labeled PSMA-11 (or PSMA-HBED-CC) is a radiopharmaceutical that will be 
produced under cGMP at the Cyclotron Radiochemistry of the University of Michigan as 
described in IND #133858. Inventory recordkeeping requirements, disposition, handling, etc. of 
the radioactive product is regulated by the NRC. The local regulatory body is the SHUR 
committee as part of the IRB process. 
4.1.2 Furosemide (optional) 
Description of furosemide (Trade name: Lasix) Source: Sanofi-Aventis. 
A dose of 20 mg of furosemide (Lasix) may be injected i.v. together with, shortly before or 
after administration of the radiotracer 68Ga-PSMA in order to minimize PET scatter artifacts 
from excreted radiotracer accumulation in the kidney and urinary bladder. Patients with 
known adverse effects to furosemide may participate in the study but will not receive 
Furosemide IV. Potential adverse effects of furosemide include urticaria, rash, and 
anaphylaxis (rare). 
5 Treatment Plan 
5.1 Dosage and Administration 
The imaging agent (68Ga-PSMA-11) will be administered.  It will be administered a single time 
intravenously prior to the PET imaging.  The one-time nominal injected dose will be 3 to 7 mCi 
of 68Ga-PSMA-11. 
5.1.1 Other Modality(ies) or Procedures 
5.1.1.1 Change in Management Surveys 
Referring clinicians will be required to fill out a pre-imaging survey prior to imaging. Additionally, 
within 30 days of the completion of imaging, the referring physician will be requested to fill out a 
post-imaging physician survey, and finally six months (allowed range 3 – 12 months) after 
imaging, a third physician survey will be filled out. 
5.1.1.2 PET Imaging 
a) 68Ga-PSMA-11 PET preparation and injection:   
The injected dose will be 111-259 MBq (3-7 mCi) of 68Ga-PSMA-11 PET.  PET imaging 
will begin 50-100 minutes after injection (target 75 minutes).  Scan time per bed position 
will be determined based on expected count statistics related to the administered dose. 


 
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b) Patient preparation: no fasting is required. Participants will be asked to void prior to 
radiotracer injection. 
c) Furosemide administration: A single dose of 20 mg of furosemide (Lasix) may be 
administered i.v. together with, shortly before or after administration of the radiotracer in 
order to minimize PET scatter artifacts from excreted radiotracer accumulation in the 
kidney and urinary bladder. Furosemide should not be administered in subjects with 
medical contraindications to furosemide administration including allergies and adverse 
reactions including sulfa allergies.  
d) PET protocol: 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. Additional body parts may be included as deemed necessary based on 
clinical information, including information from prior diagnostic scans. Scan time per bed 
position will be determined based on expected count statistics, which is determined 
mainly by the administered dose.  Scan time will therefore be between 15 and 40 
minutes.  
 
e) Patient monitoring: Vital signs will be assessed immediately before and after injection of 
68Ga-PSMA-11 (HR and supine BP).  Patients will be monitored for adverse events 
during injection and for two hours after radiotracer administration.   Additionally, patient’s 
vitals (HR and supine BP) will be checked at the completion of the imaging study prior to 
leaving the imaging center. 
f) Results dissemination. Scan results will be shared with the subject's clinician and will be 
reported and stored in the electronic medical record. 
 
5.2 Monitoring and Toxicity Management 
Each patient receiving 68Ga-PSMA-11 will be evaluable for safety. The safety parameters 
include physical findings and spontaneous reports of adverse events reported to the investigator 
by patients. 
5.3 Follow-up Standard of Care 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 68Ga-PSMA-11 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-11 positive findings will be 
validated as true positive or false positive as outlined in greater detail below.  
 
5.3.1.1 PSMA-positive Lymph Nodes  
68Ga-PSMA-11 positive nodes will be assessed for change in size using standard of 
care follow-up imaging. 


 
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5.3.1.2 PSMA-positive Osseous or Metastatic Lesions  
68Ga-PSMA-11 positive osseous or distant metastatic lesions will be followed by other 
imaging (bone scan, 18F-NaF PET, CT or MRI) at the treating physician’s discretion 
and local standard of care. 
5.3.1.3 Biopsy 
Biopsies are performed to determine presence of absence of prostate cancer at the 
discretion of treating physicians according to standard of care. 
5.4 General Concomitant Medication and Supportive Care Guidelines 
In general, subjects may receive full concomitant and supportive care throughout this trial. 
 
6 Study Procedures and Observations 
See also appendix 2 and 3. 
6.1 Schedule of Procedures and Observations 
Screening assessments must be performed within 30 days prior to the first dose of 
investigational product.  Any results falling outside of the reference ranges may be repeated at 
the discretion of the investigator.  Treatment or visit delays for public holidays or weather 
conditions do not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the electronic medical record.  The original will be kept on file with the study records. 
6.1.1.1 Screening Assessments  
The Screening procedures and assessments must be completed within 30 days of the day 1 
Visit.  
• 
Laboratory values: all patients should have a recent PSA (within 30 days prior to study 
enrollment) consistent with BCR 
• 
Pathology: all patients must have histopathology/biopsy of the prostate with a 
documented Gleason score  
• 
Performance status: all patients must have their Karnofsky performance status (or 
ECOG/WHO equivalent) evaluated (Appendix 1). 
6.1.2 Treatment Period 
6.1.2.1 Study Procedures, Imaging Day 1 
• 
Vital signs 
• 
Evaluation of adverse events 


 
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6.1.3 Post-treatment Safety Follow Up 
Patients will be followed for acute adverse events for one day (allowed range 1 to 3 calendar 
days) after the administration of the radiopharmaceutical. 
• 
 Evaluation of adverse events 
6.2 Prohibited Medications 
There are no prohibited medications. 
 
7 Reporting and Documentation of Results 
7.1 Evaluation of Efficacy (or Activity) 
7.1.1.1 Definitions 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of 68Ga-PSMA-11 administration. 
7.2 Evaluation of Safety 
Analyses will be performed for all patients receiving 68Ga-PSMA-11.  The study will use the 
CTCAE v4.0 for reporting of adverse events. 
7.3 Definitions of Adverse Events 
7.3.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
7.3.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 


 
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7.3.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, 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.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
7.4 Recording of an Adverse Event 
All grade 3 and above adverse events will be recorded using the NCI CTCAE v4.0.   The 
Investigator will assign attribution of the possible association of the event with use of the 
investigational drug.  


 
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Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 
3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 
4: 
Life-threatening consequences; urgent intervention indicated 
Grade 
5: 
Death related to AE 
7.5 Data and Safety Monitoring 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected cases in which the injection of the 
investigational radiotracer was stopped (for instance partial or complete paravenous injection), a 
repeat injection of the subject with the investigational radiotracer may be conducted if 
considered both safe and ethical by the Investigator. 
This trial will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan. The study team will meet every 3 months or 
more frequently depending on the activity of the protocol. The discussion will include matters 
related to the safety of study participants (SAE/UaP reporting), validity and integrity of the data, 
enrollment rate relative to expectations, characteristics of participants, retention of participants, 
adherence to the protocol (potential or real protocol deviations) and data completeness. At 
these regular meetings, the protocol specific Data and Safety Monitoring Report form will be 
completed and signed by the Principal Investigator or by one of the designated co-investigators. 
Data and Safety Monitoring Reports will be submitted to the University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Committee every 3 months for independent review. 


 
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7.6 Expedited Reporting  
Reporting to the Institutional Review Board 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the University of 
Michigan IRB within 1 business day of knowledge of the event.  The contact may be by phone 
or e-mail. 
Expedited Reporting to the Food and Drug Administration 
As the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions:  
• 
Suspected adverse reaction (as defined in 7.3.2.1) 
• 
Unexpected (as defined in 7.3.2.2) 
• 
Serious (as defined in 7.3.2.3) 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
8 Statistical Considerations and Evaluation of Results 
8.1 Study Endpoints 
• 
Per patient 68Ga-PSMA-11 positivity. 
• 
Histological correlation with 68Ga-PSMA-11 lesion results. 
8.1.1 Randomization 
There will be no randomization performed.  There will be no blinding performed. 
8.2 Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
The primary endpoint is to evaluate the positive predictive value (PPV) (true positives / (true 
positives + false positives)) of 68Ga-PSMA-11 PET for presence or absence of prostate cancer 


 
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confirmed by histopathology on a per-patient basis. It is anticipated that – on a per-patient basis 
- the PPV of conventional imaging ranges between 30-50%. An overall PPV for 68Ga-PSMA-11 
PET of at most 50% will be considered as unacceptably low. Hence, the null hypothesis that the 
PPV is at most 50% will be tested against the alternative hypothesis that the PPV is greater 
than 50%.  
Given recently published data from 68Ga-PSMA-11 indicating a substantially higher PPV than 
previously assumed 41, we now hypothesize that 68Ga-PSMA-11 PET imaging will substantially 
increase the PPV to at least 75% in our patient population.  
We previously expected that approximately 25% of the accrued patients will undergo a biopsy 
and 95% of the biopsied patients will have positive 68Ga-PSMA-11 PET scan at the biopsied site 
(about 5% of patients may receive a biopsy of a 68Ga-PSMA-11 negative site, which was 
however identified on conventional imaging). However, we were able to obtain biopsies from 
68Ga-PSMA-11 positive lesions in only 13 of 316 evaluable subjects, and no biopsies of 68Ga-
PSMA-11 negative lesions identified by conventional imaging were obtained.  
When 750 (instead of 375) patients are accrued at the University of Michigan, we now expect 
that about 24 patients who are to receive a biopsy will receive the biopsy of a 68Ga-PSMA-11 
positive lesion. Then, the attainable power is estimated at 80% for detecting an increase in the 
PPV from 50% to 75% at the one-sided 0.05 significance level. 
Within the first secondary objective, the region-specific PPV will be determined (confirmed by 
conventional imaging, clinical follow-up, and/or histopathology/biopsy where available). Based 
on the results of previous studies, the following distribution of biopsied disease across the four 
regions are anticipated 1,2: 
a) Prostate bed: 30% 
b) Pelvis: 15% 
c) Extrapelvic soft tissue: 20% 
d) Bone metastases: 35% 
 
In summary, a sample size of 750 UM patients would be sufficient to achieve adequate power 
for detecting an increase in the per-patient PPV from 50% to 75% for the primary objective. 
Regarding the first secondary objective (region-specific PPV), the per-region tests would have 
adequate power in the 1,500 pooled sample from all participating sites. 
 
8.3 Analyses Plans 
8.3.1 Analysis Population 
Patients with histopathology correlates will be analyzed for the primary aim.  All remaining 
patients will be analyzed for the secondary endpoints.  
8.3.2 Scan Interpretations 
68Ga-PSMA-11 PET/CT images will initially be interpreted by a board certified nuclear medicine 
physician or a board-certified radiologist experienced in reading PET/CT at the time of the 
imaging study at the institution that the study is being performed. These interpretations will be 
made available to the treating physician and will become part of the patient’s electronic record. 
These interpretations will however not be used for final evaluation.   


 
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8.3.3 Central Data Analysis 
Anonymized coded patient information (case report forms) will be captured in a central REDCap 
database hosted at the University of California at San Francisco (UCSF).  
Anonymized and de-identified imaging data will be uploaded to a central website hosted at the 
Clinical Trials Network (CTN). PET data will be interpreted by three different readers in a 
random order at separate reading sessions.  Cross sectional imaging (CT) obtained with the 
68Ga PSMA-11 PET will be available as anatomic correlate.   
Central Read Interpretation: Final reads by the central read physicians for each subject will be 
interpreted as positive or negative for the presence of disease in the regions defined in section 
8.2.1 (see table).  
Reader Positivity and Negativity Definition: 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. Criteria for visual interpretation is described 
in section 8.3.3. 
Reader Training: 68Ga PSMA-11 PET/CT reading training set and guides will be provided and 
completion of this training will be required for all central review readers.  
Case report forms will be provided to the FDA for review, when requested. 
8.3.4 Analysis of Primary Endpoints 
Primary endpoint: PPV on a per-patient basis of 68Ga-PSMA-11 PET for detection of prostate 
cancer confirmed by histopathology 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.  
a) Imaging interpretation 68Ga-PSMA-11 PET: 
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 University of Michigan. These interpretations will not be used for final evaluation. 
Upon request, anonymized 68Ga-PSMA PET/CT imaging data are sent to the FDA for 
further review. 
Visual interpretation:  
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. 
i) 
Lymph nodes will be considered positive if the 68Ga-PSMA-11 uptake is focal and 
greater than blood pool (adjacent or mediastinal blood pool). Pelvic lymph nodes 
will be subclassified according to their localization as follows: R/L obturator, R/L 
external iliac, R/L internal iliac and other (total of 7 subgroups). 
ii) Visceral lesions will be considered positive if the 68Ga-PSMA-11 uptake is focal 
and greater than physiologic background activity of the involvement organ or 
anatomic site. 


 
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iii) Bone lesions will be considered positive if the 68Ga-PSMA-11 uptake is focal and 
greater than physiologic bone marrow. 
iv) Prostate bed and prostate lesions will be considered positive if the 68Ga-PSMA-
11 uptake is focal and greater than physiologic background activity of the 
involvement organ or anatomic site. 
b) Follow-up Imaging: 
All patients are expected to be followed up as part of clinical care within 3-12 months 
with conventional imaging (dedicated CT, MRI and/or bone scan).  Interpretation of 
follow-up imaging will be performed by local read. The follow-up conventional imaging 
should be the same modality/modalities as the initial staging work-up to allow 
reproducible and accurate comparisons. 
68Ga-PSMA-11 PET positive findings will be validated as true or false positive as 
outlined in more detail below. False negative 68Ga-PSMA-11 PET findings may be 
determined based on biopsies obtained from lesion identified on conventional imaging 
that are negative on 68Ga-PSMA-11.  
Rationale for applied response criteria:  
RECIST 1.1 defines a size decrease of at least 30% as response (either partial or 
complete), while an increase of at least 20% is considered progressive disease 42,43. The 
decline of serum PSA of 50% or more is a commonly used criterion for treatment 
response following systemic treatment of metastatic prostate cancer 44-46.  
Following the 68Ga-PSMA-11 PET/CT scan, focal therapies of metastatic lesions may be 
performed without systemic treatment. Therefore, anatomic size variations can be 
suitable endpoints in absence of histological verification. In patients with solitary lesions, 
PSA reductions following focal treatment may indicate a true positive scan finding even 
in absence of significant size changes. 
 
68Ga-PSMA-11 PET validation based on follow-up imaging: 
i) 
Lymph nodes will be assessed by change in size. 68Ga-PSMA-11 positive lymph 
nodes will be considered: 
(1) True positive:  
- If on follow-up imaging within 3-12 months, lymph nodes seen on CT or MRI 
decrease by more than 30% (for patients undergoing systemic treatment of 
focal therapy at this site) or increase by more than 20% in short axis diameter 
(with a minimum of 3 mm in change in size). 
- If patients with solitary lymph node regions show a decrease of PSA by 
greater than 50% after targeted treatment (i.e. external beam radiation) and 
the lymph nodes do not change in size (less than 30% decrease or less than 
20% increase in short axis diameter). 
 
(2) False positive:  


 
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- If on follow-up imaging within 3-12 months, sites of initial 68Ga-PSMA-11 
positive lymph node lesions seen on CT or MRI decrease by more than 30% 
without systemic therapy or focal therapy at this site. 
- If 68Ga-PSMA-11 positive lymph node lesions do not meet the criteria for 
above false positive or true positive findings. 
ii) Visceral lesions (non-lymph node soft tissue or organ) will be assessed by 
change in size. 68Ga-PSMA-11 positive visceral lesions will be considered: 
(1) True positive:  
- If on follow-up imaging within 3-12 months, visceral lesions seen on CT or 
MRI decrease by 30% (for patients undergoing systemic treatment of focal 
therapy at this site) or increase by 20% in largest diameter. 
- If patients with solitary visceral metastasis show a decrease of PSA by 
greater than 50% after targeted treatment (i.e. external beam radiation) and 
lesions do not change in size (less than 30% decrease or 20% increase in 
largest diameter). 
(2) False positive:  
- If on follow-up imaging within 3-12 months, sites of initial 68Ga-PSMA-11 
positive lymph node lesions seen on CT or MRI decrease by more than 30% 
without systemic therapy or focal therapy at this site. 
- If 68Ga-PSMA-11 positive lymph node lesions do not meet the criteria for 
above false positive or true positive findings. 
iii) 68Ga-PSMA-11 positive bone lesions will be considered: 
(1) True positive: 
- If there was a corresponding positive sclerotic lesion on the CT portion of 
the 68Ga-PSMA-11 PET. 
- If there is focal uptake seen on the baseline bone scan performed within 
one month of 68Ga-PSMA-11 PET. 
- If there is a lesion noted on the initial MRI performed within one month of 
68Ga-PSMA-11 PET. 
- If within 12 months follow-up CT demonstrates development of sclerosis. 
- If within 12 months follow-up MRI demonstrates a new bone lesion. 
- If within 12 months follow-up bone scan demonstrates new focal uptake. 
(2) False positive: 
- If 68Ga-PSMA-11 positive bone lesions do not meet the criteria for true 
positive findings. 
iv) 68Ga-PSMA-11 positive prostate bed and prostate lesions will be considered: 


 
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(1) True positive: 
- If on follow-up imaging within 12 months, lesions seen on CT or MRI 
decrease by 30% (for patients undergoing systemic treatment of focal therapy 
at this site) or increase by 20% in largest diameter. 
- If patients with prostate bed lesions show a decrease of PSA by greater 
than 50% after targeted treatment (i.e. external beam radiation) and lesions 
do not change in size (less than 30% decrease or 20% increase in largest 
diameter). 
(2) False positive:  
- If on follow-up imaging within 3-12 months, sites of initial 68Ga-PSMA-11 
positive lymph node lesions seen on CT or MRI decrease by more than 30% 
without systemic therapy or focal therapy at this site. 
- If 68Ga-PSMA-11 positive lymph node lesions do not meet the criteria for 
above false positive or true positive findings. 
c) Histopathology/Biopsy: 
i) 
Localization of lesions for histopathology/biopsy will be a classified according to the 
regions in table 1. 
ii) 
68Ga-PSMA-11 positive findings are aimed to be confirmed by histopathology/biopsy 
if clinically feasible.  
iii) Histopathological procedures and biopsies will be performed as clinically indicated 
and as per institutional protocol.   
(1) Positive HP/Biopsy: Confirmed sites of metastatic or tumor involvement by 
histopathology/biopsy will be discussed with the responsible physician/surgeon.   
(2) Negative Biopsy: Patients with suspected tumor recurrence on 68Ga-PSMA-11 
PET with negative histopathology/biopsy will be handled as outlined below: 
(a) Lymph nodes: 
− 
For patients undergoing nodal dissection: Patients will be rescanned with 
dedicated CT or MRI to determine if the suspicious 68Ga-PSMA-11 
positive node was removed.   
1. If 68Ga-PSMA-11 positive lymph node is still present, a repeat biopsy 
can be pursued if clinically feasible and applicable, or follow-up using 
imaging as described above will be performed. 
2. If the corresponding node was removed, then this will be considered a 
False Positive. 
− 
For patients undergoing needle biopsy: Images of the procedure will be 
reviewed to determine if the correct node was biopsied.   
1. If the correct node was biopsied, then a negative biopsy will be 
considered a False Positive. 


 
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68Ga-PSMA-11 
 
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2. If the incorrect node was biopsied, then follow-up imaging as 
described above will be performed. 
(b) Bone lesions:  Given the high rate of false negative biopsies for osseous 
metastases in patients with prostate cancer, patients with negative bone 
biopsies of PSMA PET positive lesions will be further evaluated: 
− 
If pathology demonstrates an alternative diagnosis that is known to be 
PSMA positive (eg Renal Cell Carcinoma metastases, Paget’s disease), 
then this will be considered a False Positive. 
− 
If pathology is indeterminate, then follow-up imaging as described above 
will be performed to determine if the lesion is a True Positive or False 
Positive. 
− 
Additionally, a repeat 68Ga-PSMA-11 can also be obtained, as allowable, 
in addition to repeat conventional imaging (CT and/or MRI) in cases of 
negative biopsy to determine if the biopsy was true negative or false 
negative. 
(3) 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. 
8.3.5 Central Analysis of Secondary Endpoints 
1. PPVs on a per-patient and per-region-basis of 68Ga-PSMA-11 PET 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. 
2. Sensitivity on a per-patient and per-region basis of 68Ga-PSMA-11 PET for detection of 
tumor location confirmed by histopathology/biopsy will be summarized in tabular format. 
Ninety-five percent confidence intervals of sensitivity and PPV will be calculated using the 
Wilson score method.  
3. Detection rates on a per-patient basis of 68Ga-PSMA-11 PET 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.  
4. The impact of 68Ga-PSMA-11 PET on clinical management in BCR patients will be 
evaluated using surveys of the treating physician or practitioner before, at 1 (2-30 days) 
and 6 (range 3 - 12) months after the 68Ga-PSMA-11 PET scan (see data collection 
sheet, section 44 eResearch). The results will be analyzed and provided in coded form 
for central analysis.  
5. Safety will be reported descriptively as rates of patient reported adverse events. 
 
 


 
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9 Study Management 
9.1 Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
9.2 Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the University of Michigan Institutional Review Board (IRB) including the Protocol 
Review Committee (PRC). The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.   
9.3 Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the research file and a 
copy may be stored in the electronic medical record.  
9.4 Changes in the Protocol 
Once the protocol has been approved by the University of Michigan IRB, any changes to the 
protocol must be documented in the form of an amendment.  The amendment must be 
submitted by the Investigator and approved by PRC and IRB prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, the 
study will be halted and the IRB will be informed within five (5) working days.  
10 Protection of Human Subjects 
10.1 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the informed consent document. The original signed document will become part of the 
patient’s medical records, and each patient will receive a copy of the signed document. The use 
and disclosure of protected health information will be limited to the individuals described in the 
informed consent document. 


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


 
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Appendix 2 
Schedule of Study Procedures and Assessments 
 
 
 
 
 
 
 
 
Schedule of Study Procedures and Assessments 
Period/ 
Procedure 
Screening 
Imaging day 
1 
One day post 
imaging 
Follow-up 
surveys 
Study Day/Visit Day 
-30 to 1 
1 
2 (allowed  
range day 2-4) 
 
Informed consent 
X 
 
 
 
Laboratory values, 
history from medical 
record 
X 
 
 
 
Pre-survey 
X 
 
 
 
Performance status 
X 
 
 
 
Blood Pressure, HR 
X 
X 
 
 
Imaging Procedure 
68Ga-PSMA-11 
 
X 
 
 
PET/CT or PET/MRI  
 
X 
 
 
Furosemide 20 mg IV 
 
X 
 
 
Follow-up 
Adverse event 
reporting 
 
 
X 
 
1. Post-survey (within 
2-30 days of PET) 
 
 
 
X 
2. Post-survey (within 
3-12 months of PET) 
 
 
 
X 


 
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Appendix 3 (Flow chart) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCa BCR Study Entry Criteria: 
• 
Post-Prostatectomy (AUA criteria) – PSA >0.2 ng/mL x 2 measured more than 6 weeks after RP,  and 
confirmatory persistent PSA greater than 0.2 ng/mL 
• 
Post-Radiation Therapy -  (ASTRO-Phoenix criteria) Nadir + ≥ 2 ng/mL 
• 
Contraindications to furosemide administration including allergies and adverse reactions(including sulfa drugs); Note: 
furosemide can be omitted if second-generation scatter correction PET imaging is utilized. 
Bone: Further 
imaging of 
suspected bone 
metastasis by MRI 
(and/or repeat 
68Ga-PSMA-11 as 
allowable). 
 
Target Lesion(s) - 
HP/Biopsy 
Positive  
68Ga-PSMA-11 PET 
Positive Regions 2-4  
(see Table 1) 
Target Lesion(s) –
HP/Biopsy 
Negative  
LN: If LN was resected, repeat 
dedicated CT or MRI (and/or 
repeat 68Ga-PSMA-11 PET as 
allowable) to determine if the 
PSMA PET positive node was 
removed.  If LN is still present on 
imaging then biopsy is 
considered false negative.  A 
repeat biopsy  can be pursued. 
• 3-12 month f/u conventional 
imaging similar to initial 
staging modality (CT, bone 
scan and/or MRI) 
68Ga-PSMA-11 PET 
Negative Regions 2-4 
68Ga-PSMA-11 
PET Positive in 
Region 1 s/p -
Prostatectomy? 
Yes 
No 
• In case of Salvage Radiation 
Therapy of the prostate bed: 
monitor PSA level to 6 months 
post-radiation to confirm PSA 
nadir < 0.05 ng/mL  
• In case of no salvage radiation 
therapy: 
HP/Biopsy or 3-12 month f/u 
conventional imaging similar to 
initial staging modality (CT, 
bone scan and/or MRI) 
• 3-12 month f/u conventional imaging 
similar to initial staging modality (CT, 
bone scan and/or MRI) 
• 3-12 month f/u 
conventional imaging 
similar to initial staging 
modality (CT, bone scan 
and/or MRI) 
• 
Document change in clinical management 
68Ga-PSMA-11 PET Imaging   
Positive imaging findings are aimed to be confirmed by histopathology(HP)/biopsy, if clinically feasible, and 
imaging follow-up.  
HP/Biopsy of accessible site(s)  


 
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