Clinical trial NCT02673151
Conditions: Prostate Adenocarcinoma PSA Failure Recurrent Prostate Carcinoma
Sponsor: Andrei Iagaru
Start date: 2017-05-20; Completion date: 2019-04-27
Enrollment: 61 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to see if recurrent prostate cancer can be identified using a special procedure called a positron emission tomography (PET) scan. PET/CT is used to describe information regarding the function, as well as location and size of a tumor.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate 68Ga-PSMA-11 PET/CT for detection of recurrent prostate cancer after initial therapy in patients with elevated PSA. PSMA refers to prostate-specific membrane antigen.

Eligible participants will undergo baseline assessments at enrollment. Study participants will receive 68Ga-PSMA-11 and undergo a PET/CT. Participants will be contacted at 24 to 72 hours following the scan in order to capture potential late occurring adverse events. Clinical follow up of participant at 3 to 12 months following the scan in order to analyze secondary endpoints.

Arms: arm 1: Patients receive 68gallium-labeled prostate-specific membrane antigen-11 (68-Ga-PSMA-11). Participant will be injected IV with 3 to 7 millicurie (mCi) of 68Ga-PSMA-11. Beginning 50 to 100 minutes later, a low-dose computed tomography (CT) scan will be obtained from vertex to mid thighs; followed by a static positron emission tomography (PET) scan over the same .
Interventions: intervention 1: Computed Tomography (CT) scan intervention 2: 68Ga-PSMA-11 intervention 3: Positron Emission Tomography (PET)
Intervention descriptions: intervention 1: PET/CT scan using 68gallium-labeled prostate-specific membrane antigen-11 (68-Ga-PSMA-11). intervention 2: 68gallium-labeled prostate-specific membrane antigen-11 (68-Ga-PSMA-11), administered by intravenous (IV) injection. intervention 3: PET/CT scan using 68gallium-labeled prostate-specific membrane antigen-11 (68-Ga-PSMA-11).

Protocol documents:
Prot_SAP_000.pdf: 
IRB-35932 
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CONFIDENTIAL 
Amendment 3, 12 July 2018 
68Ga-PSMA-11 PET/CT for detection of recurrent prostate cancer after initial therapy in 
patients with elevated PSA   
Principal Investigator / Protocol Director  
Andrei Iagaru, MD 
300 Pasteur Drive, Room H-2230 
Stanford, CA 94305 
Phone:  xxx-xxx-xxxx 
Fax:  xxx-xxx-xxxx 
Email:  aiagaru@stanford.edu  
Co-investigators  
Steven Hancock, MD 
875 Blake Wilbur Dr;  Stanford, CA  94305  
Phone:  xxx-xxx-xxxx 
Email:  shancock@stanford.edu  
Guido Davidzon, MD 
300 Pasteur Dr,  
Stanford, CA  94305  
Phone xxx-xxx-xxxx  Email:   
gdavidzon@stanford.edu   
Sandy Srinivas, MD 
875 Blake Wilbur Dr;   
Stanford, CA  94305  
Phone:  :  xxx-xxx-xxxx 
Email:  sandysri@stanford.edu 
Carina Mari Aparici, MD 
300 Pasteur Dr,  
Stanford, CA  94305  
Phone:  xxx-xxx-xxxx 
Email:  drmari@stanford.edu 
Biostatistician 
Jarrett Rosenberg, PhD 
1201 Welch Road,  
Stanford, CA 94305 
Phone: xxx-xxx-xxxx 
Email:  Jarrett.rosenberg@stanford.edu  
Study Coordinator  
Jordan Cisneros or designate 
Phone:  :  xxx-xxx-xxxx 
Email:  jdcis@stanford.edu  
 
Protocol IRB-35932  //   PROS0076  //  NCT02673151 
Protocol Amendment 3  //  12 July 2018   
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................. 3 
SCHEMA ...................................................................................................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 3 
1. OBJECTIVES ........................................................................................................................ 5 
2. BACKGROUND ..................................................................................................................... 5 
2.1 Preliminary information ................................................................................................ 5 
2.2 Study Agent ................................................................................................................... 8 
2.3 Clinicaltrials.gov ........................................................................................................... 8 
2.4 Rationale ........................................................................................................................ 8 
2.5 Study Design ................................................................................................................. 9 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................................... 10 
3.1 Inclusion Criteria ......................................................................................................... 10 
3.2 Exclusion Criteria ........................................................................................................ 11 
3.3 Informed Consent Process ........................................................................................ 12 
3.4 Study Timeline ............................................................................................................. 13 
4. IMAGING AGENT INFORMATION...................................................................................... 13 
4.1 Study Agent ................................................................................................................. 13 
4.2 Specify the source of the study agent. ..................................................................... 13 
4.3 Ordering ....................................................................................................................... 13 
4.4 Agent Accountability .................................................................................................. 13 
5. IMAGING SPECIFICS ......................................................................................................... 13 
5.1 Modality or Modalities to be used ............................................................................. 13 
5.2 Details of Imaging (ie, dynamic, static, number of scans, etc) .............................. 13 
5.3 Details of processing/analysis .................................................................................. 14 
6. STUDY PROCEDURES ...................................................................................................... 14 
6.1 Criteria for Removal from Study ............................................................................... 14 
6.2 Alternatives ................................................................................................................. 14 
7. STUDY CALENDAR ............................................................................................................ 14 
8. ADVERSE EVENTS AND REPORTING PROCEDURES ................................................... 14 
8.1 Potential Adverse Events ........................................................................................... 14 
8.2 Adverse Event Reporting ........................................................................................... 15 
9. REGULATORY CONSIDERATIONS................................................................................... 15 
9.1 Institutional Review of Protocol ................................................................................ 15 
9.2 Data Management Plan ............................................................................................... 15 
10. 
MEASUREMENTS ...................................................................................................... 16 
10.1 Primary outcome measure ....................................................................................... 16 
10.2 Measurement Methods ............................................................................................. 16 
10.3 Measurement Time Points ........................................................................................ 16 
10.4 Primary Endpoint…………………………………………………………………………..16 
10.5 Secondary Endpoint................................................................................................  17 
10.6 Measurement Time Points………………………………………………………….........17 
11. 
GOALS ........................................................................................................................ 17 
APPENDIX:  Inclusion/Exclusion Criteria Checklist ............................................................ 18 
REFERENCES: .................................................................................................................. 20 


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PROTOCOL SYNOPSIS 
TITLE 
68Ga-PSMA-11 PET/CT for detection of recurrent prostate cancer 
after initial therapy in patients with elevated PSA 
STUDY PHASE 
Phase 2-3 
INDICATION 
Prostate cancer 
INVESTIGATIONAL 
PRODUCT  
68Ga-PSMA-11;  also known as: 
• 
DFKZ-11 
• 
HBED-CC PSMA 
• 
The “Heidelberg compound” 
PRIMARY OBJECTIVE 
To evaluate 68Ga-PSMA-11 PET/CT for detection of recurrent 
prostate cancer after initial therapy in patients with elevated PSA  
SAMPLE SIZE  
200 participants 
GOALS 
Prospective single-center, single-arm study.  
HYPOTHESES 
1. At least 30% of these patients will have one or more lesions 
detected on 68Ga-PSMA-11 PET/CT. 
2. 68Ga-PSMA-11 PET/CT will have sensitivity and specificity of at 
least 70% in this context. 
STATISTICAL TEST 
We will calculate point estimates and 95% confidence intervals for: 
1. Percentage of patients who had true lesions. 
2. Sensitivity and specificity of 68Ga-PSMA-11 PET/CT. 
STATISTICAL POWER AND SAMPLE SIZE 
We expect to recruit 200 patients over the course of this trial.  The 
number of lesions cannot be predicted at this time, however,  if our 
expectation of a 30% discovery rate is correct, the resulting 
confidence interval would be roughly +/- 7 percentage points, and 
confidence intervals for specificity/sensitivity would be roughly 
+/- 10 percentage points. 
SCHEMA 
 
 
 
 
 
 
 
 
Eligible participant with prostate cancer 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ga-68; 68Ga 
Gallium-68 
IRB 
Institutional Review Board 
IV 
Intravenous 
MRI 
Magnetic resonance imaging 
NPV 
Negative predictive value  
PPV 
Positive predictive value  
PET 
Positron emission tomography 
SUV 
Standardized Uptake Value 
PSMA 
Prostate Specific Membrane Antigen 


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1. OBJECTIVE 
Specific Aim 
To evaluate 68Ga-PSMA-11 PET/CT for detection of recurrent prostate cancer after initial 
therapy in patients with elevated SA.  
2. BACKGROUND 
2.1 Preliminary information 
Data from the American Cancer Society suggests that for 2015 in the United States prostate 
cancer will continue to be the leading non-cutaneous cancer diagnosis in males with 
220,800 estimated new cases, and has the second highest mortality (after lung) with 27,540 
estimated deaths (1).  Subsequent treatment is multifaceted and may involve observation, 
surgery (prostatectomy), radiation therapy (external beam or brachytherapy), hormonal 
therapy, chemotherapy, or a combination of these (2-4).   
Up to 40% of the patients with prostate cancer develop biochemical recurrence within 10 
years after initial treatment (5).  Usually an increase of the PSA-level precedes a clinically 
detectable recurrence by months to years (6).  However, it cannot differentiate between 
local, regional or systemic disease with the necessary precision that is essential for further 
disease management (7).   
Morphological imaging methods exhibit considerable limitations:  sensitivity ranges between 
25% and 54% for the detection of local recurrence by transrectal ultrasound (TRUS) or 
contrast-enhanced CT and is moderately improved by using functional MRI techniques (7-9).  
The sensitivity for detection of lymph node metastases of CT or MRI is reported to be 
30-80% (10).  Ultra-small particles of iron oxides (USPIOs) proved to be very effective, but 
are yet to be approved by regulatory authorities (11).  Bone metastases presenting as 
osteoblastic lesions can be effectively detected by bone scintigraphy, PET, CT and MRI (12, 
13). 
Various targets have been addressed by molecular imaging to improve the detection of 
recurrent prostate cancer.  PET tracers such as 18F- or 11C-labeled choline and 11C-acetate 
have been investigated for the diagnosis of recurrent (14-16) prostate cancer.  Their 
feasibility in primary diagnosis is limited because of uptake in benign tissue such as benign 
prostatic hyperplasia or inflammatory lymph nodes (9, 17).  In addition, fluorinated versions 
are not available in the United States, while 11C-labeled tracers cannot be widely used due 
to the requirement for an on-site cyclotron due to the short half-life.  18F-FACBC, a new 
synthetic amino acid, might be superior when compared to 11C-choline PET/CT (18).   
However, recent work indicates that 18F-FACBC uptake in prostate cancer is similar to that 
in BPH nodules (19).  Prostate-specific membrane antigen (PSMA) continues to elicit high 
interest.  This cell surface protein is significantly overexpressed in prostate cancer cells 
when compared to other PSMA-expressing tissues such as kidney, proximal small intestine 
or salivary glands.  It therefore provides a promising target for prostate cancer-specific 
imaging.  Recently methods have been developed to label PSMA ligands with 68Ga and 18F.  
Initial experience suggests that these novel tracers can detect prostate cancer relapses and 


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metastases with high contrast by binding to the extracellular domain of PSMA, followed by 
internalization (20, 21).  However, these promising agents do not detect all recurrences. 
Although choline-based PET/CT is widely used outside the US for imaging prostate cancer, 
there have been numerous studies reporting a low sensitivity and specificity, especially at 
low prostate specific antigen (PSA) levels (22, 23).  Consequently, improved imaging of 
prostate cancer is necessary.  One novel promising method is PET imaging with 
18F-FACBC, a new synthetic amino acid.  Recent evaluations by Nanni et al.  indicate that 
this tracer might be superior when compared to choline PET/CT (24).  However, recent work 
indicates that 18F-FACBC uptake in prostate cancer is similar to that in BPH nodules (25). 
In addition, prostate-specific membrane antigen (PSMA) recently has received increased 
attention (26).  This cell surface protein is significantly overexpressed in prostate cancer 
cells when compared to other PSMA-expressing tissues such as kidney, proximal small 
intestine or salivary glands (27).  It therefore provides a promising target for prostate 
cancer-specific imaging (28).  Recently methods have been developed to label PSMA 
ligands with 68Ga enabling their use for PET imaging and therapy (29).  Initial experience 
with PET/CT using Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA-11) as a 
68Ga-labelled PSMA ligand suggests that this novel tracer can detect prostate cancer 
relapses and metastases with high contrast by binding to the extracellular domain of PSMA, 
followed by internalization (30).  Improved detection of occult metastatic disease will improve 
treatment efficacy by enabling better patient selection for treatment and prompting more 
extended pelvic node treatment with surgery or radiation for patients with evidence of nodal 
metastases outside the normal lymph node treatment area. 
We conducted a pilot phase evaluation of 68Ga-PSMA-11 under an RDRC-approved 
protocol at Stanford University.  Ten men (age range:  67 to 83 year-old; mean ± SD:  
73.1 ± 5.7) with biochemical recurrence of prostate cancer (PSA range:  2.6-36.4; 
mean ± SD:  12.4 ± 10.6) were enrolled.  PET/CT images were acquired at 51 to 68 minutes 
(mean ± SD:  57.4 ± 6.3) after injection of 3.7 to 4.0 mCi (mean ± SD:  3.8 ± 0.1) of 
68Ga-PSMA.  The uptake of 68Ga-PSMA-11 was identified as described in previously 
published studies referenced above.  
All participants had multiple standard of care imaging studies (CT, MRI, 18F-FDG PET/CT, 
18F-NaF PET/CT, 99mTc MDP bone scan) prior to enrollment that were non-contributory, 
despite rising PSA values.  The participants did not receive treatment in this interval as they 
were managed under a wait and watch strategy due to no identifiable disease.  The interval 
from biochemical recurrence to the 68Ga-PSMA-11 PET/CT scan ranged 5 to 75 months 
(mean ± SD:  30.8 ± 20.4). 
Biodistribution and localization of 68Ga-PSMA-11 
All participants tolerated the procedure without immediate or delayed (up to 7 days) 
complaints or complications.  The areas with the highest 68Ga-PSMA-11 accumulation are 
the lacrimal grand (mean SUVmax:  9.3 ± 3.3 [range:  4.6 to 14.9] and SUVmean:  5.2 ± 2.3 
[range:  2.5 to 8.8]), the parotid grand (mean SUVmax:  14.2 ± 2.6 [range:  9.9 to 19.1] and 
SUVmean:  11.8 ± 2.6 [range:  7.2 to 16.1]), the submandibular grand (mean SUVmax:  


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16.8 ± 3.3 [range:  12.3 to 22.7] and SUVmean:  13.5 ± 2.9 [range:  9.8 to 18.1]), small 
intestine (mean SUVmax:  14.6 ± 4.6 [range:  8.2 to 23.4] and SUVmean:  11.0 ± 3.9 [range:  
5.6 to 18.5]), kidney (mean SUVmax:  35.1 ± 9.9 [range:  14.4 to 46.2] and SUVmean:  
25.8 ± 7.5 [range:  12.0 to 36.0]) and bladder (mean SUVmax:  35.0 ± 24.7 [range:  
9.6 to 78.5] and SUVmean:  26.5 ± 17.4 [range:  7.8 to 67.9]), while moderate uptake was 
noted in the sublingual grand (mean SUVmax:  5.0 ± 2.4 [range:  1.9 to 10.6] and SUVmean:  
3.3 ± 1.6 [range:  1.5 to 7.1]), liver (mean SUVmax:  6.0 ± 1.3 [range:  4.1 to 9.0] and 
SUVmean:  4.1 ± 0.8 [range:  3.2 to 5.7]) and spleen (mean SUVmax:  8.0 ± 3.3 [range:  
2.6 to 12.3] and SUVmean:  6.4 ± 2.7 [range:  2.0 to 10.5]).  Other tissues analyzed had low 
68Ga-PSMA-11 uptake, with SUVmean of less than 1.7.  There were no differences between 
the 68Ga-PSMA-11 biodistribution at 45 minutes post-injection among the 10 participants 
(Figure 2).  The pattern of 68Ga-PSMA-11 uptake is similar to previous reports. 
68Ga-PSMA-11 uptake outside the expected physiologic biodistribution 
There were 45 areas of high 68Ga-PSMA-11 uptake that corresponded on the CT images to 
bone marrow (n = 13), retroperitoneal lymph nodes (n = 12), mediastinal lymph nodes 
(n = 8), pelvic lymph nodes (n = 9), seminal vesicle (n = 2), subclavian lymph node (n = 1).   
 
Figure 1:  Maximum intensity projection (MIP) images from 10 participants in the pilot study 
conducted at Stanford University. 


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2.2 Study Agent 
We will use 68Ga-PSMA-11 as the PET radiopharmaceutical.  This agent has previously 
been identified as DFKZ-11;  HBED-CC PSMA;  or the “Heidelberg compound.”  This is not 
an FDA-approved product.  This protocol is submitted to IND 128379. 
2.3 Clinicaltrials.gov  
Since 68Ga-PSMA-11 is not an FDA-approved product, we will register the study on 
clinicaltrials.gov once all approvals will be in place. 
2.4 Rationale 
In this study, we propose to use a well-established PET isotope, Gallium-68 (68Ga), bound 
to a PSMA ligand, (ie, 68Ga-PSMA-11), which has high affinity for prostate specific 
membrane antigen.  68Ga-PSMA-11 has been shown to be superior to other PET tracers 
used in prostate cancer such as 18F-Fluoroethylcholine (FECH) and 
18F-Fluoromethylcholine (31, 32).  Therefore, we propose the following aim:  to evaluate 
68Ga-PSMA-11 PET/CT for detection of recurrent prostate cancer after initial therapy in 
patients with elevated PSA.   
A prior first-in-human study investigated the biodistribution of 68Ga-PSMA-11 and its ability 
to detect lesions.  Thirty-seven men with prostate cancer underwent whole-body PET/CT 
after an intravenous injection of 68Ga-PSMA-11 (median 121.0 MBq, range 52–212 MBq).  
Within healthy organs, kidneys and salivary glands demonstrated the highest radiotracer 
uptake.  Lesions suspicious for PC presented with excellent contrast as early as 1 hour 
post-injection with high detection rates even at low PSA levels (30).  In another study, a total 
of 78 lesions characteristic for prostate cancer were detected in 32 patients using 
68Ga-PSMA-11 PET/CT and 56 lesions were detected in 26 patients using choline PET/CT 
(32).  The higher detection rate in 68Ga-PSMA-11 PET/CT was statistically significant 
(P = 0.04).  All lesions detected by 18F-fluoromethylcholine PET/CT were also seen by 
68Ga-PSMA-11 PET/CT.  In conclusion, 68Ga-PSMA-11 PET/CT can detect prostate cancer 
lesions with improved contrast when compared to 18F-fluoromethylcholine PET/CT, 
especially at low PSA levels.   


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Figure 2:  Red arrows point to a nodular pelvic wall metastasis (a, b, histologically-confirmed) and to 
small lymph nodes (c, d) which present with clearly pathological tracer uptake in 68Ga-PSMA-11 
PET/CT (b and d) only.  Yellow arrows point to both catheterized ureters (c, d).  Patient presented 
with a minimal PSA value (0.01 ng/mL) despite visible tumor lesions.  The PSMA-11 ligand is 
therefore able to detect poorly differentiated PC.  a + c Fusion of 18F-fluoromethylcholine PET and 
CT;  b + d fusion of 68Ga-PSMA-11 PET and CT. 
Our initial analysis evaluated the first 32 participants enrolled in the study (33). Excluding 
one patient with a very high PSA of 1170 ng/mL, the mean PSA at time of scan was 7.3 
ng/mL. 68Ga-PSMA-11 PET detected sites of recurrence in 24/32 (75 %) patients, including 
8/12 (66.7%) patients with PSA below 1 ng/mL, and the lowest PSA value associated with a 
positive scan was 0.21 ng/mL.  An example is shown in Figure 3.  
 
Figure 3: 73 year-old man with rising PSA (0.9 ng/dl) after initiat treatment of prostate cancer.  
68Ga-PSMA-11 PET identifies recurrent prostate cancer in a left pelvic lymph node. 


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2.5 Study Design  
This is a phase 2-3 study with a total of 200 participants with biochemically recurrent 
prostate cancer.  Eligible participants will undergo baseline assessments at enrollment.  
Study participants will receive 68Ga-PSMA-11 and undergo a PET/CT.  All patients will first 
be seen by a Stanford Cancer Institute physician and then referred if appropriate on clinical 
grounds to Dr Iagaru or his colleagues for this study.  The following steps will take place. 
1. 
After signed the informed consent document, participants will be given a copy of the 
signed form. 
2. 
Participant will be asked to drink 1 to 2 glasses of water before arrival at the clinic 
3. 
Participants will be weighed and vital signs (heart rate, blood pressure, respiratory 
rate, pulse oxymetry) will be recorded 
4. 
Study personnel (eg, technologist) will verify subject identify;  radiopharmaceutical 
identity;  dose;  and administration route.  Participant will be injected IV with 3 to 7 mCi 
of 68Ga-PSMA-11 
5. 
A dose of 20 mg of furosemide is recommended to be injected 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 that 
can occur with 68Ga-PSMA-11.  However, this is not needed if the scanner can reduce 
such artifacts during image reconstruction 
6. 
Participant will void immediately prior to the scan 
7. 
Approximately 50 to 100 minutes later, a low-dose CT will be obtained from vertex to 
mid-thighs; this will use 120 kV and dose modulation based on body habitus, ranging 
10 to 105 mA.  This will be followed by a static PET emission scan over the same 
area. 
8. 
If participant agrees, immediately after first scan and without reinjecting 
68Ga-PSMA-11, a second PET/CT will be acquired to compare standard vs digital 
PET/CT.  The CT will be done for attenuation correction only. 
9. 
Vital signs (heart rate, blood pressure, respiratory rate, pulse oxymetry) will be 
recorded again at the completion of the study. 
10. Participants be dismissed. 
11. Participants will be contacted at 24 to 72 hours following the scan in order to capture 
potential late occurring Adverse Events. 
12. Clinical follow-up of participant at 3 to 12 months following the scan in order to analyze 
secondary endpoints. 
The 68Ga-PSMA-11 PET/CT may be repeated at the completion of treatment to evaluate 
response to therapy, if requested by the treating physician.   


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3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria 
• 
≥ 18 years-old 
• 
Histopathological-proven prostate adenocarcinoma 
• 
Rising PSA after definitive therapy with prostatectomy or radiation therapy (external 
beam or brachytherapy) 
a. Post radical prostatectomy (RP) – AUA recommendation (34) 
i. PSA greater than 0.2 ng/mL measured after at least 6 weeks from radical 
prostatectomy 
ii. Confirmatory persistent PSA greater than 0.2 ng/mL (total of two PSA 
measurements greater than 0.2 ng/mL) 
b. Post-radiation therapy –ASTRO-Phoenix consensus definition (35) 
i. A rise of PSA measurement of 2 or more ng/mL over the nadir 
• 
Able to provide written consent 
• 
Karnofsky performance status of  50 (or ECOG/WHO equivalent) 
3.2 Exclusion Criteria 
• 
Investigational therapy for prostate cancer. 
• 
Unable to lie flat, still or tolerate the study scan. 
• 
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. 


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3.3 Informed Consent Process 
All participants will be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any study 


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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 
medical record or research file.   
3.4 Study Timeline 
3.4.1 Primary Completion: 
The study will reach primary completion 36 months from the time the study opens to 
accrual. 
3.4.2.  Study Completion: 
The study will reach study completion 48 months from the time the study opens to 
accrual. 
4. IMAGING AGENT INFORMATION  
4.1 Study Agent  
The administered dosage is 111 to 259 MBq (3 to 7 mCi) IV.  We will use 68Ga PSMA-11 as 
the PET radiopharmaceutical. There are 2 publications on dosimetry for 68Ga-PSMA-11 
(PMID: 27260521; 28012435).  The first lists 0.0236 mSv/MBq for the mean effective dose, 
while the other indicates 0.0258 mSv/MBq.  We used the maximum potential administered 
activity of 7 mCi and the higher of the reported dosimetry values.  Therefore, 
259 MBq x 0.0258 mSv / MBq = 6.68 mSv. 
To summarize the results of the published human studies, there were no observed adverse 
events to the radiopharmaceutical.  The measured dosimetry showed that the critical organ 
with 68Ga-PSMA-11 is the spleen, followed by the stomach wall, pancreas and bladder wall.  
The effective dose of 68Ga-PSMA-11 reported (0.0258 mSv/MBq) is similar to those of 
68Ga-DOTA-TOC (0.023 mSv/MBq);  68Ga-DOTA-NOC (0.025 mSv/MBq);  
68Ga-DOTA-TATE (0.021 mSv/MBq);  and 68Ga-NOTA-RGD (0.022 mSv/MBq) (36-39). 
4.2 Source of the Study Agent  
Molecular Imaging Program at Stanford 
Satellite Radiochemistry Facility  
300 Pasteur Dr, C21 
Stanford, CA 94305  
4.3 Ordering 
Ordered in Radiology Information System (RIS), address per above. 
4.4 Agent Accountability 
RIS is password protected and part of the electronic medical records. 
5. IMAGING SPECIFICS  
5.1 Modality or Modalities to be used 
PET/CT 


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5.2 Details of Imaging (ie, dynamic, static, number of scans, etc) 
Whole-body (skull base to mid-thighs) PET/CT images will be obtained using the GE 
PET/CT 600 or 690 scanners.  In brief, PET/CT images will be acquired in 3D mode at 
50 to 100 minutes after injection of 3 to 7 mCi of 68Ga-PSMA-11.   
The PET emission scan is corrected using segmented attenuation data of the CT scan.  PET 
images are reconstructed using ordered subset expectation maximization (OSEM) with 
2 iterations and 32 subsets for the Discovery 600 scanner and with 2 iterations and 
24 subsets for the Discovery 690 scanner.  These are the vendor-recommended 
reconstruction parameters.  Images will be reviewed and analyzed using Advantage 
Workstation version 4.6 (GE Healthcare). 
5.3 Details of processing/analysis 
The lesions will be analyzed by Nuclear Medicine physicians blinded to the diagnosis and 
results of the other scan, in a randomized order to avoid bias.  68Ga-PSMA-11 PET data will 
be interpreted by 3 different readers in a random order at separate reading sessions.  Cross 
sectional imaging from the PET will be available for anatomic correlate.   
6. STUDY PROCEDURES  
6.1 Criteria for Removal from Study 
The Protocol Director may withdraw subjects from the study for one or more of the following 
reasons:  failure to follow the instructions of the Protocol Director and/or study staff; 
determination that continuing the participation could be harmful to the subject; the study is 
cancelled or other administrative reasons. 
6.2 Alternatives 
The alternative is to not participate in the study.   
7. STUDY CALENDAR 
 
Pre-Study 
Scan 
Date 
24 - 48 Hours 
Post-Scan 
3-12 Months 
Post-Scan 
12 Months 
(End-of-Study) 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
68Ga-PSMA-11 
 
X 
 
 
 
Follow-up Call to Participant 
 
 
X 
 
 
Clinical Follow-up 
 
 
 
X 
 
Data analysis 
 
 
 
 
X 
8. ADVERSE EVENTS AND REPORTING PROCEDURES 
8.1 Potential Adverse Events 


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The administration of the radioactive substance will feel like a slight pinprick when given by 
IV injection.  Patients who are claustrophobic may feel some anxiety while positioned in the 
scanner.  Also, some patients find it uncomfortable to hold one position for more than a few 
minutes.  The subjects will not feel anything related to the radioactivity of the substance in 
their body.  Because the radioactivity is very short-lived, the radiation exposure is low.  The 
substance amount is so small that it does not affect the normal processes of the body.   
This research study involves exposure to radiation from one 68Ga-PSMA PET/CT. The 
effective dose from one typical maximum of 259 MBq (range: 3-7 mCi) administration of 
68Ga-PSMA is 6.68 mSv. The effective dose from one CT attenuation scan is 3 mSv.  
Therefore, the total effective dose from the 68Ga-PSMA PET/CT scan is 9.68 mSv, 
approximately equal to 19.4% of the limit that radiation workers (for example, a hospital 
x-ray technician) are allowed to receive in one year.     
8.2 Adverse Event Reporting 
We do not anticipate hazardous situations for the subjects as a result of this protocol.  
However, standard of care procedures will be in place for verification of correct 
radiopharmaceutical dose and route of administration.  The study Principal Investigator (PI) 
or his designee will report all serious adverse events (per 21CFR§312.32) to the Stanford 
CCTO Safety Coordinator within 10 working days of becoming aware of the event (5 days if 
the event is life-threatening or results in death) using the Adverse Events Communication 
Form.  If the Principal Investigator determines the unanticipated adverse device effect 
presents an unreasonable risk to subjects, the study will be terminated as soon as possible, 
but no later than 5 working days after the PI makes the determination, and no later than 
15 working days after first receiving notification of the effect. 
9. REGULATORY CONSIDERATIONS 
9.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (eg, advertisements used to recruit participants) will be reviewed and approved 
by the Stanford IRB.  Any changes made to the protocol will be submitted as a modification 
and will be approved by the IRB prior to implementation.  The Protocol Director will 
disseminate the protocol amendment information to all participating investigators. 
9.2 Data Management Plan 
The CRFs will be stored in a locked office in the Nuclear Medicine clinic.  Records will be 
kept using OnCore.   
During the clinical investigation, the Protocol Director will evaluate the progress of the trial, 
including periodic assessments of data quality and timeliness, participant recruitment, 
accrual and retention, participant risk versus benefit, performance of trial sites, and other 
factors that can affect study outcome.  Monitoring of the trial will occur every 8 weeks and a 
record of monitoring activities will be maintained by the study team.   
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will audit 
study related activities to determine whether the study has been conducted in accordance 
with the protocol, local standard operating procedures, FDA regulations, and Good Clinical 
Practice (GCP).  This may include review of regulatory binders, case report forms, eligibility 
checklists, and source documents.  In addition, the DSMC will regularly review serious 
adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of DSMC audits will be communicated to the IRB and 


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the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
10. MEASUREMENTS 
10.1 Outcome Measures 
The principal goal of this study is to compare, in the setting of suspected prostate cancer 
recurrence, the diagnostic performance of 68Ga-PSMA-11 PET/CT in cases where 
conventional imaging for detecting recurrent prostate cancer is likely to have false 
negatives. Sites of suspected disease will be evaluated by 68Ga-PSMA-11 PET/CT and 
conventional imaging by region for all patients.  Specifically, it is hypothesized that the 
diagnostic performance of the 68Ga-PSMA-11 PET/CT will be superior to anatomical 
imaging, and that 68Ga-PSMA-11 PET/CT will provide complementary information. 
10.1.1 Primary Outcome 
Primary Outcome Title:  Confirmation of Prostate Cancer Recurrence  
Description:  Prostate cancer patients with suspected prostate cancer recurrence will be 
evaluated with 68Ga-PSMA-11 PET/CT and conventional imaging.  The outcome will be 
reported as the percentage of participants for whom tumor lesions are identified by 
68Ga-PSMA-11 PET/CT, and for whom tumor lesions are identified by 
histopathology/biopsy and/or conventional imaging follow-up.  The outcome is reported 
as percentages without dispersion.   
Time Frame:  1 year 
10.1.2 Secondary Outcomes 
Secondary Outcome Title:  68Ga-PSMA-11 PET/CT Sensitivity and Specificity by 
Participant  
Description:  The sensitivity and specificity of 68Ga-PSMA-11 PET/CT for detection of 
tumor by participant will be determined, as confirmed by conventional imaging follow-up 
and/or histopathology/biopsy, within the following 1 year.  The sensitivity and specificity 
of 68Ga-PSMA-11 PET/CT for detection of tumor lesions is reported with the 95% 
confidence interval.  
Time Frame:  12 months 
Secondary Outcome Title:  68Ga-PSMA-11 PET/CT Sensitivity and Specificity by Region  
Description:  The sensitivity and specificity of 68Ga-PSMA-11 PET/CT for tumor 
detection by location will be determined, as confirmed by conventional imaging follow-up 
and/or histopathology/biopsy, within the following 1 year.  The regions evaluated will be 
the prostate bed;  pelvis outside of prostate bed including lymph nodes;  extrapelvic soft 
tissue;  lymph nodes;  and organ metastases (non bone);  and bone metastases.  The 


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sensitivity and specificity of 68Ga-PSMA-11 PET/CT for detection at the specified tumor 
locations is reported with the 95% confidence interval.  
Time Frame:  12 months 
Secondary Outcome Title:  68Ga-PSMA-11 PET/CT Predictive Value by Participant  
Description:  The predictive value of 68Ga-PSMA-11 PET/CT for detection of tumor, as 
confirmed by conventional imaging follow-up and/or histopathology/biopsy, within the 
following 1 year, is assessed by participant.  Positive predictive value (PPV) is the 
probability that participants identified by 68Ga-PSMA-11 PET/CT as having prostate 
cancer recurrence, do have prostate cancer recurrence.  Negative predictive 
value (NPV) is the probability that participants not identified by 68Ga-PSMA-11 PET/CT 
as having prostate cancer recurrence, do not have prostate cancer recurrence.  The 
outcome is reported as the PPV and the NPV of 68Ga-PSMA-11 PET/CT for 
confirmation of prostate cancer recurrence by participant, with 95% confidence interval.   
Time Frame:  12 months 
Secondary Outcome Title:  68Ga-PSMA-11 PET/CT Predictive Value by Region 
Description:  The predictive value of 68Ga-PSMA-11 PET/CT for detection of tumor 
location, as confirmed by conventional imaging follow-up and/or histopathology/biopsy, 
within the following 1 year, is assessed by region [prostate bed;  pelvis outside of 
prostate bed including lymph nodes;  extrapelvic soft tissue;  lymph nodes;  and organ 
metastases (non bone);  and bone metastases].  Negative predictive value (NPV) is the 
probability that participants not identified by 68Ga-PSMA-11 PET/CT as having prostate 
cancer recurrence, do not have prostate cancer recurrence.  The outcome is reported as 
the PPV and the NPV of 68Ga-PSMA-11 PET/CT for confirmation of prostate cancer 
recurrence by region, with 95% confidence interval. 
Time Frame:  12 months 
Secondary Outcome Title:  68Ga-PSMA-11 PET/CT Per-patient Tumor Detection Rates  
Description:  68Ga-PSMA-11 PET/CT tumor detection rates by patient, stratified by 
PSA value in ng/mL (0.2 to < 0.5;  0.5 to < 1.0;  1.0 to < 2.0;  2.0 to < 5.0;  ≥ 5.0), are 
reported with mean  SD and 95% confidence interval. 
Time Frame:  12 months 
10.2 Measurement Methods 
Visually PET positive lymph nodes will be considered greater than blood pool (adjacent or 
mediastinal blood pool); PET positive bone lesions will be considered greater than 
physiologic bone marrow; PET positive prostate, prostate bed and visceral lesions will be 
considered greater than physiologic background activity of the involvement organ or 
anatomic site. 


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Sites of suspected metastatic disease will be graded as positive or negative on two separate 
analysis, for a more sensitive or specific visual read respectively. 
10.3 Primary Endpoint 
The primary endpoint is sensitivity and PPV on a per-patient and per-region-basis (Table 1) 
of 68Ga-PSMA-11 PET for detection of tumor location confirmed by histopathology/biopsy.   
Table 1:  Region Definition 
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 
10.4 Secondary endpoints: 
1. PPV and negative predictive value (NPV) on a per-patient and per-region-basis (Table 1) 
of 68Ga-PSMA-11 PET for detection of tumor location confirmed by 
histopathology/biopsy and conventional imaging follow-up. 
2. Sensitivity and specificity on a per-patient basis of 68Ga-PSMA-11 PET for detection of 
tumor location confirmed by histopathology/biopsy and conventional imaging follow-up. 
3. Detection rates on a per-patient basis of 68Ga-PSMA-11 PET stratified by PSA value in 
ng/mL (0.2 to < 0.5;  0.5 to < 1.0;  1.0 to < 2.0;  2.0 to < 5.0;  ≥ 5.0). 
10.5 Exploratory Endpoints  
1. Impact of 68Ga-PSMA-11 PET on clinical management in patients with recurrence of 
prostate cancer. 
2. Inter-reader reproducibility 
10.6 Measurement Time Points 
Uptake will be evaluated after the scan completion.   
11. STATISTICAL CONSIDERATIONS 
11.1 Statistical Design 
Prospective single center, single-arm study.  Patients will be scanned with 68Ga-PSMA-11 
PET/MRI.  MRI and PET/MRI scans will each be evaluated separately by 3 readers. 
11.2 Randomization 
No randomization will be done. 
11.3 Key variables 
11.3.1 Analysis Population 
All lesions identified by 68Ga-PSMA-11 PET/CT. 


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11.3.2 Analysis Plan 
We will calculate point estimates and 95% confidence intervals for:  
1. Percentage of patients who had true lesions. 
2. Sensitivity and specificity of 68Ga-PSMA-11 PET/CT. 
11.4 Sample Size 
We expect to recruit 200 patients over the course of this trial.  The number of lesions cannot 
be predicted at this time, however, if our expectation of a 30% discovery rate is correct, the 
resulting confidence interval would be roughly ± 7 percentage points, and confidence 
intervals for specificity/sensitivity would be roughly ± 10 percentage points. 
11.5 Accrual estimates 
We expect the accrual of 40 patients each year for 5 years. 


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Inclusion/Exclusion Criteria Checklist  
Protocol Title: 
68Ga PSMA-11 PET/CT for detection of recurrent prostate cancer after initial 
therapy in patients with elevated PSA and non-contributory bone scintigraphy, 
computed tomography (CT) or magnetic resonance imaging (MRI) 
Protocol Number: 
IRB-35932  /  PROS0076 
Principal Investigator: 
Andrei Iagaru, MD 
 
Inclusion Criteria – Yes must be checked to be eligible 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation 
1. ≥ 18 year-old 
☐ 
☐ 
☐ 
2. Histologically-proven prostate adenocarcinoma 
 
 
 
3. 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 after 
at least 6 weeks from radical prostatectomy 
ii. Confirmatory persistent PSA greater than 
0.2 ng/mL (total of two PSA measurements greater 
than 0.2 ng/mL) 
b. Post-radiation therapy –ASTRO-Phoenix consensus 
definition  
i. A rise of PSA measurement of 2 or more ng/mL 
over the nadir 
☐ 
☐ 
☐ 
4. Able to provide written consent 
☐ 
☐ 
☐ 
5. Karnofsky performance status of 50 (or ECOG/WHO 
equivalent) 
☐ 
☐ 
☐ 
 
Exclusion Criteria –No must be checked to be eligible 
(From IRB approved protocol) 
Yes 
No 
Supporting 
Documentation 
1. Investigational therapy for prostate cancer 
☐ 
☐ 
☐ 
2. Unable to lie flat, still or tolerate the study 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. 
☐ 
☐ 
☐ 
 
*All subject files must include supporting documentation to confirm subject eligibility.  The method of confirmation can 
include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record 
review.   


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Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [☐eligible / ☐ ineligible] for participation in the 
study.  This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford 
IRB, and has finalized financial and contractual agreements as required by Stanford School of Medicine’s 
Research Management Group.   
 
Treating Physician Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
 


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