Evaluation of Patients With Low-Risk and Intermediate-Risk Prostate Cancer Scheduled for High-Dose Rate Brachytherapy Using 68-Ga-RM2 PET, 68Ga-PSMA-11 PET and Multi Parametric MRI
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Andrei Iagaru

 
 
 
 
Evaluation of Patients With Low-Risk and Intermediate-Risk Prostate 
Cancer Scheduled for High-Dose Rate Brachytherapy Using 68-Ga-RM2 
PET, 68Ga-PSMA-11 PET and Multi Parametric MRI 
Study Protocol and Statistical Analysis Plan 
NCT04264208 
July 12, 2019 

IRB-51987 
Page 1 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
Evaluation of Patients with Low-Risk and Intermediate-Risk Prostate 
Cancer Scheduled for High-Dose Rate Brachytherapy Using 68Ga-RM2 
PET, 68Ga-PSMA-11 PET and Multi Parametric MRI 
Principal Investigator / Protocol Director  
Andrei Iagaru, MD 
 
Stanford, CA 94305 
Phone:  650-725-4711 
Fax:  
 
Email:  aiagaru@stanford.edu 
 
Co-investigators 
Mark Buyyounouski, MD 
  
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:  mbuyyou@stanford.edu 
Steven Hancock, MD 
 
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:  shancock@stanford.edu 
Andreas Loening, MD, PhD 
 
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:  loening@stanford.edu 
Guido Davidzon, MD 
 
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:   gdavidzon@stanford.edu 
Shreyas Vasanawala, MD, PhD 
 
Stanford, CA  94304  
Phone:  
;  Fax:  
 
Email:  vasanawala@stanford.edu 
Christian Kunder, MD  
 
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:  loening@stanford.edu 
Hilary Bagshaw, MD 
 
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:  hbagshaw@stanford.edu 
Tanya Stoyanova, PhD 
 
Stanford, CA  94305  
Phone:  
 
Email:  stoyanova@stanford.edu 
Biostatistician 
, PhD 
  
Stanford, CA 94305-
 
  
Study Coordinator  
TBD 
Protocol IRB-51987  //  SRC-TBD  //  NCT-TBD 
Protocol version //  12 July 2019 
SRC Approval Date –  
 

IRB-51987 
Page 2 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS 
4 
SCHEMA 
5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6 
1. 
OBJECTIVE 
7 
Specific Aim 
7 
2. 
BACKGROUND 
7 
2.1 Preliminary information 
7 
2.2 Study Agent 
10 
2.3 Clinicaltrials.gov 
11 
2.4 Rationale 
11 
2.5 Study Design 
14 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
17 
3.1 Inclusion Criteria 
17 
3.2 Exclusion Criteria 
17 
3.3 Informed Consent Process 
17 
3.4 Study Timeline 
17 
4. 
IMAGING AGENT INFORMATION 
17 
4.1 Study Agents 68Ga-PSMA-11 and 68Ga-RM2 
17 
4.2 Source of the Study Agent 
18 
4.3 Ordering 
18 
4.4 Agent Accountability 
18 
5. 
IMAGING SPECIFICS 
18 
5.1 Modality or Modalities to be used 
18 
5.2 Details of Imaging (ie, dynamic, static, number of scans, etc) 
18 
5.3 Image interpretation 
19 
6. 
STUDY PROCEDURES 
19 
6.1 Pre-Study 
19 
6.2 Imaging Days 
19 
6.3 Follow-up 
20 
6.4 Criteria for Removal from Study 
20 
6.5 Alternatives 
20 
7. 
STUDY CALENDAR 
20 

IRB-51987 
Page 3 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
8. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
21 
8.1 Potential Adverse Events 
21 
8.2 Adverse Event Reporting 
21 
9. 
REGULATORY CONSIDERATIONS 
21 
9.1 Institutional Review of Protocol 
21 
9.2 Data Management Plan 
21 
10. Statistical Considerations and Evaluation of Results 
22 
10.1 Study Endpoints 
22 
10.2 Accrual estimates 
24 
10.3 Study Outcomes (ClinicalTrials.gov) 
24 
10.4 Analyses Plans 
25 
10.5 Accrual estimates 
25 
11. REFERENCES: 
27 
3.1 Inclusion Criteria 
34 
3.2 Exclusion Criteria 
34 
 

IRB-51987 
Page 4 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
PROTOCOL SYNOPSIS 
TITLE 
Evaluation of Patients with Low-Risk and Intermediate-Risk 
Prostate Cancer Scheduled for High-Dose Rate Brachytherapy 
Using 68Ga-RM2 PET, 68Ga-PSMA-11 PET and Multi Parametric 
MRI 
STUDY PHASE 
Phase 2 study 
INDICATION 
Prostate cancer 
INVESTIGATIONAL 
PRODUCTS  
68Ga-PSMA-11;  also known as: 
• 
DFKZ-11 
• 
HBED-CC PSMA 
• 
The “Heidelberg compound” 
68Ga-RM2;  also known as: 
• 
Bombesin 
• 
BAY86-7548 
SAMPLE SIZE  
100 participants 
PRIMARY OBJECTIVES 
To demonstrate that 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can 
detect additional cancers over mpMRI 
To demonstrate that 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can 
assess changes in response to treatment and predict PFS at 24 
months 

IRB-51987 
Page 5 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
 
SCHEMA 
 
 
Eligible participant with known prostate cancer 
Randomizaton to:  
Schedule A 
68Ga-PSMA11 PET/MRI 
Followed within 2 weeks by 
68Ga-RM2 PET/MRI 
OR 
Schedule B 
68Ga-RM2 PET/MRI 
Followed within 2 weeks by 
68Ga-PSMA11 PET/MRI 
HDR 
At least 3 days later: 
Schedule A 
68Ga-PSMA11 PET/MRI 
Followed within 2 weeks by 
68Ga-RM2 PET/MRI 
OR 
Schedule B 
68Ga-RM2 PET/MRI 
Followed within 2 weeks by 
68Ga-PSMA11 PET/MRI 

IRB-51987 
Page 6 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
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 
GRPR 
Gastrin releasing peptide receptor 
PRCA 
Prostate cancer 
HIFU 
High-intensity focused ultrasound 
HDR 
High-dose rate 
 

IRB-51987 
Page 7 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
1. OBJECTIVE 
Specific Aims 
Aim 1: 68Ga-RM2 PET/MRI and 68Ga PSMA-11 PET/MRI detection of PC. We will investigate the 
performance of the new GRPr-binding PET radiopharmaceutical, 68Ga-RM2, and compare it to the 
currently most widely investigated (but not FDA-approved) PC PET radiopharmaceutical, 68Ga 
PSMA-11, as well as to mpMRI acquired during PET/MRI for the localization and staging of low-risk 
and intermediate-risk PC. New lesions identified on PET/MRI and not known from prior systematic 
prostate biopsy will be confirmed by targeted biopsy and GRPr and PSMA status will be evaluated 
with specific immunohistochemical stains [1, 2]. 
Aim 2: 68Ga-RM2 PET/MRI and 68Ga PSMA-11 PET/MRI prediction of PFS after local targeted 
therapy for PC. We will investigate if the combination of the GRPr-binding PET imaging agent, 68Ga-
RM2, and the most widely investigated (but not FDA-approved) PSMA-binding PET imaging agent, 
68Ga PSMA-11, together with mpMRI can predict PFS after local targeted therapy. We will 
determine if 68Ga-RM2 PET/MRI and 68Ga-PSMA-11 PET/MRI assessment at 6-months follow-up 
will predict PFS at 24 months based on standard clinical follow-up (PSA, imaging, tissue diagnosis). 
 
2. BACKGROUND 
2.1 Preliminary information 
Prostate cancer (PC) remains the most-common non-cutaneous cancer diagnosed in American 
males, accounting for an estimated 164,690 estimated new cases and 29,430 estimated deaths in 
2018 [3]. Historically, PC often presented as painful metastatic disease, and killed up to 40 per 
100,000 men annually in the US between 1991 and 1993. The introduction of widespread PSA 
screening in the early 1990’s led to a profound stage migration with most cancers detected while 
localized to the prostate. Subsequently PC-specific mortality dropped to 20 per 100,000 by 2012 [4]. 
While improvements in therapy likely play some role, independent groups in the CISNet consortium 
have shown through modeling that 45% - 70% of the decline in PC mortality can be plausibly 
attributed to PSA screening [5].  
Meanwhile, PSA screening also dramatically increased detection and treatment of slow-growing, 
low-grade PC that would have otherwise remained asymptomatic. Treating all these cancers with 
radical prostatectomy or external beam radiotherapy (EBRT) is expensive to the healthcare system 
and led to significant short and long-term side effects in hundreds of thousands of men. As a result, 
despite the ~50% reduction in age-specific PC mortality in the PSA era, the US Preventive Services 
Task Force (USPTF) recommended in 2011 against routine screening with PSA [6] because it 
deemed that the harms of screening outweighed the benefits. Accordingly, PSA use and early 
diagnosis PC have decreased dramatically [7]. The dilemma for patients and treating physicians is: 
either continue screening despite the problem of overtreatment and treatment-related side effects, 
or do not screen and miss the opportunity for early diagnosis and cure. To reduce the harms of 
screening while maintaining the benefits, there is a clear need for faster, less invasive and 
fundamentally less risky treatments for localized PC. 
Standard treatment options include observation, surgery (prostatectomy), radiation therapy 
(external beam or brachytherapy), and/or hormonal therapy, depending on the initial stage, the 
patient’s age, co-morbidities, and preferences. If T-stage is greater than 2 or if the PSA > 20 ng/mL 
or if Gleason score is > 8, there is an increased risk of metastatic disease and cross-sectional 
imaging and bone scans are performed to identify metastases. However many cancers are 
diagnosed before this stage and are candidates for targeted local therapy. 
Changing paradigms in management of localized PC. Not all localized PC have the same biologic 

IRB-51987 
Page 8 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
potential; most men with small, non-aggressive (Gleason 3+3) cancers can be safely followed by 
‘active surveillance’ – a strategy that has gained acceptance in the last 5 years [8]. Low-risk PC 
(Gleason score ≤6, pretreatment PSA level <10 ng/mL, and clinical stage T1–T2a) is a group that 
accounts for 35% to 70% of all patients with PC [9, 10]. But for the remaining patients with higher 
grade, clinically significant cancers still merit treatment. They face a difficult choice: aggressive 
whole-gland treatment that risks life-altering side effects, vs. no treatment and the risk of cancer 
progression, metastasis and potential death [11]. Newer less invasive local therapies seek to offer 
treatment options that are faster, less invasive, less risky and potentially cheaper than surgery or 
EBRT. These include ablation with heating (high-intensity focused ultrasound - HIFU, microwaves, 
or lasers), freezing (with needle cryoprobes), electroporation, stereotactic radiation therapy and 
brachytherapy. Such localized therapies are becoming popular despite limited long-term evidence 
of tumor control, especially for ablation modalities.  
The role of multi-parametric MRI (mpMRI) for guiding care. While PC is most often multifocal, the 
highest grade, index lesion drives clinical outcomes [12, 13]. Conventional trans-rectal ultrasound 
(TRUS)-guided systematic prostate biopsy consisting of 6-12 biopsy cores is limited by under-
diagnosis of index lesions and over-diagnosis of small, non-aggressive tumors that pose little threat 
to a man’s life. Use of mpMRI is increasing rapidly due to its ability to improve detection of clinically 
significant index tumors using MRI-guided biopsy [14]. MRI-guided biopsies find more clinically 
significant tumors (≥G7) and less insignificant (G6) tumor than conventional systematic biopsies. 
MRI is increasingly used for the following: 
• 
Prior to biopsy, MRI can be used to determine if biopsy is necessary and can enable image-
targeted biopsy if an abnormality is seen on MRI [14]  
• 
Men contemplating active surveillance: a normal mpMRI adds confidence that this is a safe 
management option. An abnormal mpMRI prompts a conventional MRI-transrectal ultrasound 
(MRI-TRUS) fusion biopsy that often reveals clinically significant cancer that warrants treatment 
[15].  
• 
Men deciding between whole-gland treatment (surgery or radiation) and partial-gland focal 
ablation. Finding a single tumor on MRI prompts consideration of focal ablation. Finding multiple 
and/or bilateral tumors prompts consideration of whole-gland treatment (surgery or radiation). 
Finding extracapsular disease (T3 / T4) prompts workup for potential metastatic cancer. 
It should be noted that mpMRI has limitations: ~20% of all index lesions are missed [16], the size of 
high-grade cancers is underestimated [17], and ~40% of men with a normal MRI have PC on 
biopsy [18]. 
Positron emission tomography (PET) and PC. PET tracers, such as 18F- or 11C-labeled choline and 
[11C]-acetate, are used mainly for the diagnosis of recurrent [19-21] or metastatic [22] PC. Their 
feasibility in primary diagnosis is limited because of uptake in benign tissue such as benign 
prostatic hyperplasia or inflammatory lymph nodes [23, 24]. Although choline based PET/CT is 
widely used outside the US for imaging PC, there have been numerous studies reporting a low 
sensitivity and specificity, especially at low PSA levels [25, 26]. Consequently, improved molecular 
imaging of PC is necessary. One novel method is PET imaging with 18F-FACBC, a synthetic amino 
acid. Nanni et al. indicate that this tracer might be superior when compared to choline PET/CT [27]. 
However, others shown that 18F-FACBC uptake in PC is similar to that in BPH nodules [28]. 
Prostate-specific membrane antigen (PSMA) is a transmembrane protein of high interest in PC. 
This cell surface protein is significantly overexpressed in PC cells when compared to other PSMA-
expressing tissues such as kidney, proximal small intestine or salivary glands. PSMA is highly 
overexpressed on almost all PC [29-31]. Only 5-10% of primary PC lesions have been shown to be 
PSMA-negative [32, 33], making this class of radiopharmaceuticals suitable for diagnosis of primary 
PC and for initial staging [34-39]. Non-invasive tumor grading has also been reported [40]. PSMA 
ligands can be labeled with 68Ga for PET imaging [41]. Experience with PET/CT using Glu-NH-CO-
NH-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA-11) indicates that this compound can detect PC 
relapses and metastases with high contrast by binding to the extracellular domain of PSMA, 

IRB-51987 
Page 9 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
followed by internalization [42]. Better localization of cancer within the prostate itself would also 
have a clinical impact by guiding image-targeted biopsy and patient selection for local targeted 
therapy. However, these promising agents do not detect all recurrences [43, 44] and other cancers 
also express PSMA [45-47]. False positive findings have also been reported using PSMA agents 
[48-51].  
Consequently, improved imaging of PC continues to be an area of unmet clinical need. Gastrin-
releasing peptide (GRP) is a 27-amino acid neuropeptide that is the mammalian homologue of the 
linear tetradecapeptide bombesin. It shares homology with bombesin at the C-terminal amidation 
sequence in the final 7 amino acids [52, 53]. The GRP receptor (GRPr) is the only well 
characterized receptor to which GRP and bombesin bind with a high affinity. GRPr belongs to a 
family of G-coupled protein receptors, and the GRP binds selectively to the GRPr [52, 53]. Studies 
show that GRPr is expressed at very low levels in normal prostate glands but is increased in 45-
100% of human PCa [54, 55]. 68Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-
Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (68Ga-RM2, formerly also known as BAY86-7548 or 68Ga-DOTA-
Bombesin) is a synthetic bombesin receptor antagonist, which targets GRPr [56]. GRPr proteins are 
highly overexpressed in several human tumors, including PC [57]. Because of their low expression 
in BPH and inflammatory prostatic tissues [58, 59], imaging of GRPr has potential advantages over 
current choline- and acetate-based radiotracers. Indeed, preclinical studies using BAY86-7548 have 
shown a high and persistent tracer uptake in mice bearing PC-3 tumor xenografts, which represent 
androgen-independent human PC with high GRPr expression [60]. Clinically translated GRPr 
antagonists PET radiopharmaceuticals include 68Ga-RM2, 68Ga-SB3, 68Ga-NeoBOMB1, 18F-BAY-
864367 and 64Cu-CB-TE2A-AR06. They have been shown to have stable biodistribution in healthy 
volunteers [61] and mean effective doses comparable to other radiopharmaceuticals [62, 63]. 
Published data indicate encouraging results for use at initial diagnosis of PC [61-65] or at 
biochemical recurrence [66]. 
While the PSMA is over-expressed in prostate cancer, this is not universal; there are lesions 
undetected by PSMA-targeted imaging in different risk classes or stages of disease. The influence 
of GRPr expression on cancer grade and stage has been evaluated by several groups. Nagasaki 
et al. found that GRPr expression is correlated with higher Gleason score [67]. Most recently, 
Michaud et al. showed that GRPr expression in PC is independent from PSMA expression. In 
some cases GRPr expression occurred in the absence of detectable PSMA expression on IHC [2]. 
Evolution of Radiotherapy. Localized PC is effectively treated with external beam radiation therapy 
(EBRT) to 78 to 80 Gy, a non-invasive, outpatient treatment regimen. It requires approximately 40 
fractions, or treatments, delivered 5 days/week over 2 months, necessitating a significant time 
commitment from patients. Potential side effects include urinary urgency, dysuria, hematuria, 
urinary retention, impotence, and GI toxicity. Biochemical failure (rising PSA after treatment) may 
occur in as many as 20-30% of men after EBRT for intermediate risk PC [68]. Low dose rate (LDR) 
brachytherapy with trans-perineal radioactive seed implantation can deliver potentially higher local 
doses which is important for local tumor control. However, seed placement is challenging with real-
time planning and seed placement resulting in variable dosimetry, and the radioactive seeds 
mandate contact restrictions for patients. Recently, high dose rate (HDR) brachytherapy has been 
utilized as an alternative. Although usually done under general anesthesia, HDR is minimally 
invasive, enables real time treatment planning, the ability to preferentially boost dominant tumor 
locations, and has favorable dosimetry [69]. Local control after HDR is excellent [70], the treatment 
is more convenient for patients and side effects are less common than after EBRT as the radiation 
is delivered with a sharp fall-off minimizing dose to surrounding pelvic structures. At Stanford, we 
have an active, well-established HDR brachytherapy program led by Dr. Mark Buyyounouski who 
consistently treats at least 6 patients per week with this technique. Since initiation of the program 
approximately 3 years ago, we have treated over 500 patients with this modality either as part of a 
boost treatment in addition to EBRT (325 patients) or as HDR monotherapy (175 patients) for 
definitive treatment of their PC. These include 45 patients to date in 2018 with low or intermediate 

IRB-51987 
Page 10 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
risk PC. 
Efficacy assessment: a major unsolved question. Unlike after prostatectomy, where PSA levels 
fall to zero soon after successful surgery, after local targeted therapy (HDR) PSA levels are poor 
measures of efficacy. PSA falls to a variable nadir due to continued production by residual prostate 
tissue as well as potential occult non-index tumor that was outside the boost region. Even the 
Phoenix criterion for radiation failures (2 ng/ml rise above nadir), now a de facto standard, has a 
sensitivity and specificity of only ~65% and ~77%, respectively, for clinical recurrence [71]. False 
negatives may occur early because it takes time for tumor to grow back fast enough to generate 2 
ng/ml of PSA. False positives may be due to residual BPH, regeneration of normal prostate tissue, 
and prostatitis. PSA is especially problematic for ablation because some portions of the gland are 
left entirely untreated. The potential for residual under-treated target tumor, or occult non-target 
tumor to progress, and potentially become clinically significant, highlights the unmet need for 
sensitive surveillance methods after local targeted therapy.  
Therapeutic options after local treatment. Evidence from salvage treatment for post-prostatectomy 
recurrence reveals that success is more likely when treatment is initiated early [72]. One theoretical 
advantage of local treatments is that tissue damage is restricted to the prostate. This enables 
options for local retreatment and second line therapy after failure. After brachytherapy, local 
recurrence can potentially be retreated with more brachytherapy. This ability to retreat further 
highlights the need for sensitive surveillance methods after initial treatment. 
Can mpMRI also help find recurrence or residual tumor after local targeted therapy? It is much 
more difficult to interpret mrMRI after treatment [73]. For example, after radiation therapy, 
decreased exocrine function, and fibrosis can cause low signal on T2-weighted images and variable 
diffusion restriction that mimic tumor [74]. Similarly, after ablation, resolving hemorrhage and 
proteinaceous necrosis can cause variable diffusion restriction, and inflammation can cause 
contrast enhancement [75]. 
Simultaneous PET/MRI: PET/MRI is an advanced hybrid imaging technology that can provide both 
biological and morphological information of various biological pathways, as discussed in more 
details in “Approach”. Compared to PET/CT, simultaneous PET/MRI has advantages resulting from 
reduced radiation exposure and higher soft tissue contrast [76]. PET/MRI is particularly important 
for accurate localization and assessment of the pelvic extent of disease at the initial staging of PC. 
In fact, the majority of pathologic findings leading to up-staging are microscopic, requiring the high 
resolution of intraprostatic anatomy and adjacent structures afforded by co-registration with MRI 
rather than CT [77]. In addition, the silicon photomultipliers (SiPM) based PET detectors in SIGNA 
PET/MRI or digital PET/CT scanners are more sensitive than photomultiplier tubes (PMT) based 
PET detectors in standard PET/CT [78-80]. The knowledge we propose to acquire can be 
generalized to separately acquired PET/CT and mpMRI, although motion artefacts and other factors 
may prevent accurate fusion of the data. 
In summary, some men could undergo ineffective local treatment and miss the chance for effective 
local salvage treatment before metastasis occurs. 
2.2 Study Agent 
This study will use 68Ga-RM2.  This PET radiopharmaceutical has previously been identified as 
68Ga-DOTA Bombesin or BAY86-7548.  This is not an FDA-approved product.  This protocol is 
submitted to IND
, the IND to which this protocol is submitted. 

IRB-51987 
Page 11 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
This study will also use 68Ga-PSMA11.  This PET radiopharmaceutical has previously been 
identified as DFKZ-11;  HBED-CC PSMA;  or the “Heidelberg compound.”  This is not an 
FDA-approved product, and is described in detail in IND 128379. 
2.3 Clinicaltrials.gov  
This study will be registered on ClinicalTrials.gov. 
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) and a GRPR ligand (ie, 68Ga-RM2) that have high affinity for 
prostate specific membrane antigen and gastrin releasing peptide receptors, respectively.  
Therefore, we propose the following goals: 
1. To demonstrate that 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can detect additional cancers over 
mpMRI. 
2. To demonstrate that 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can assess changes in response to 
treatment and predict PFS at 24 months. 
68Ga-RM2 at Stanford University: Under an FDA-approved IND (# 
) our group currently 
uses 68Ga-RM2 in 2 clinical scenarios, either prior to prostatectomy in patients with intermediate or 
high-risk PC or at biochemical recurrence after definitive treatment (prostatectomy or radiation 
therapy). 
68Ga-RM2 identified primary PC lesions in all 15 
patients scheduled for prostatectomy included in 
our pilot study [81]. An example is shown in 
Figure 1. 
We recently published our results using 68Ga-
RM2 PET/MRI in 32 patients with biochemical 
recurrence of PC and negative conventional 
imaging (bone scintigraphy and CT or MRI) [66]. 
Currently, we have 80 participants scanned at 
BCR and our data indicates a 70% detection rate 
in this population with a mean PSA of 8.0 ng/dl 
and negative conventional imaging. The lowest 
PSA in a patient with positive 68Ga-RM2 PET was 
0.24. One third of the lesions found on 68Ga-
RM2 PET were biopsied; all results were true 
positive. Examples are shown in Figure 2. More 
importantly in our opinion, PSA velocity values 
were 0.32±0.59 ng/ml/year (range: 0.04-1.9) in 
patients 
with 
negative 
PET 
scans 
and 
2.51±2.16 ng/ml/year (range: 0.13-8.68) in patients with positive PET scans (P=0.006), 
suggesting the ability to detect more aggressive PC.  
 
 
 

IRB-51987 
Page 12 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
 
68Ga PSMA-11 at Stanford University: 68Ga PSMA-11 is under clinical investigation in the US, 
although it is widely used elsewhere despite lack of regulatory approval. We are currently 
conducting prospective studies under IND #128379 in the same indications as for 68Ga-RM2 (prior 
to prostatectomy in patients with intermediate or high-risk PC or at biochemical recurrence after 
definitive treatment).  
To date we enrolled 49 men with intermediate and high risk newly diagnosed PC, scheduled to 
undergo prostatectomy and pelvic nodal dissection [82]. 68Ga PSMA-11 PET identified intraprostatic 
cancer in all 49 patients, while mpMRI alone identified PIRADS 4 or 5 lesions in ¾ of patients. 68Ga 
PSMA-11 PET showed focal uptake in pelvic lymph nodes in 9 patients. Final pathology confirmed 
cancer in the prostate of all patients. No 
patient 
with 
normal 
pelvic 
nodes 
on 
PET/MRI had metastases on pathology. An 
example is shown in Figure 3. 
 
In addition, we now have data from 62 
patients with BCR PC who had 68Ga PSMA-
11 PET/CT at our institution [83]. 
68Ga 
PSMA-11 detected sites of recurrence in 73% of patients, with the lowest PSA and a positive scan 

IRB-51987 
Page 13 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
at 0.05 ng/mL. Examples are shown in Figure 4. 
 
68Ga-RM2 vs. 68Ga PSMA-11 at Stanford University: We first published a pilot comparison of 
68Ga-PSMA-11 with 68Ga-RM2 at BCR [84]. There were 45 areas of high 68Ga-PSMA uptake that 
corresponded 
to 
metastases 
shown on the CT 
images 
in 
the 
bone 
marrow 
(n=13), 
retroperitoneal 
lymph 
nodes 
(n=12), 
mediastinal lymph 
nodes 
(n=8), 
pelvic 
lymph 
nodes 
(n=9), 
seminal 
vesicle 
(n=2), 
and 
subclavian lymph 
node (n=1). 68Ga-
RM2 uptake was high in all these areas, except for one pelvic lymph node and seminal vesicle in 
the same patient. 68Ga PSMA-11 uptake and/or clearance in the bowel made assessment of small 
retroperitoneal lymph nodes more difficult compared to 68Ga-RM2 in 2 participants. 68Ga-RM2 
shows similar sensitivity to 68Ga-PSMA and provides higher lesion conspicuity in selected patients 
due to no significant hepatobiliary clearance (Figure 5).  
At this time, we enrolled 9 patients with intermediate and high risk newly diagnosed PC, scheduled 
to undergo prostatectomy and pelvic nodal dissection, in a prospective comparison of 68Ga-RM2 
and 68Ga-PSMA-11. At least one lesion in the prostate was identified by each radiopharmaceutical 
in every participant, but the results did not overlap, as shown in Figure 6. 
Another study at our institution enrolled 29 
patients with BCR PC in a direct comparison of 
68Ga-RM2 and 
68Ga-PSMA-11. 
68Ga-PSMA 
found sites of disease in 22/29 patients and 
68Ga-RM2 
identified 
recurrent 
prostate 
cancer in 20/29 patients. 68Ga-PSMA-11 was 
positive and 68Ga-RM2 was negative in 3 
patients; 68Ga-PSMA-11 was negative and 
68Ga-RM2 was positive in 2 patients. More 
lesions were seen on 68Ga-PSMA-11 than 
on 68Ga-RM2 in 4 patients, while 68Ga-RM2 
identified more lesions than 68Ga-PSMA-11 
in 3 patients. PSA was 0.4-36.4 ng/mL; 
mean±SD: 8.3±8.8) in patients with positive 
68Ga-PSMA-11 and 0.3-36.4 ng/mL; mean±SD: 

IRB-51987 
Page 14 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
8.8±9.1) in patients with positive 68Ga- RM2 (P: 0.86). PSA was 0.2-8.2 ng/mL; mean±SD: 2.5±3.2) 
in patients with negative 68Ga-PSMA-11 and 0.2-8.2 ng/mL; mean±SD: 2.7±2.9) in patients with 
negative 68Ga- RM2 (P: 0.90). Examples are shown in Figure 7. 
PSMA is over-expressed in many but not all PC; some lesions will not be detected by PSMA-
targeted imaging 
in 
different 
risk 
classes or stages 
of disease. The 
influence of GRPr 
expression on PC 
grade and stage 
has 
been 
evaluated 
by 
several 
groups. 
Nagasaki 
et al. 
found that GRPr 
expression 
is 
correlated with higher Gleason score [67]. GRPr expression in PC is independent from PSMA 
expression and GRPr expression can occurr in the absence of detectable PSMA expression on 
IHC [2]. Therefore, GRPr PET is complementary to 
PSMA PET for detection of PC. The use of both 
PET 
radiopharmaceuticals 
will 
ensure 
appropriate evaluation of PC patients. 
Figure 8 shows a patient with local recurrence of PC 
identified with 68Ga-RM2 and subsequently treated 
with HDR brachytherapy, showing resolution of 68Ga-
RM2 uptake in the prostate bed. 
In summary, GRPr and PSMA expression is 
increased in PC, due to different underlying biological 
processes. By using a novel approach combining 
both 68Ga-RM2 and 68Ga-PMSA-11 PET/MRI within 
each patient, we will be able to accurately identify PC 
and we will attempt to predict PFS after targeted 
therapy. 
We hypothesize that the use of 68Ga-RM2 and 68Ga-
PSMA-11 PET/MRI will permit accurate localization 
of PC at initial diagnosis and allow for evaluation of 
response to treatment and prediction of PFS at 24 
months after local targeted therapy. We will use a 
state-of-the-art simultaneous PET/MRI scanner with time of flight capability that was first-ever 
installed system at Stanford University in December 2013. There are now more than 200 
simultaneous PET/MRI systems world-wide and we collaborate with many of these sites. 
2.5 Study Design 
This is a NCI-funded phase II study with a total of 100 participants with known prostate cancer, 
scheduled to undergo HDR local therapy.  All patients will first be seen by a Stanford Cancer 

IRB-51987 
Page 15 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
Institute physician and then referred if appropriate on clinical grounds to Dr Iagaru or his colleagues 
for this study.  Eligible participants will undergo baseline assessments at enrollment.  The following 
steps will take place after the participant has signed the written consent (participants will be 
randomized to have 68Ga-RM2 first followed by 68Ga-PSMA11 within 2 weeks or 68Ga-PSMA11 first 
followed by 68Ga-RM2 within 2 weeks [50/50 chance for each schedule]).  After the 1st scan, the 
2nd scan will only occur after the follow-up with the patient for the 1st scan, and after a minimum of 
3 days have elapsed.   
Scan 1 
1. Participants will be given a copy of the consent form s/he signed  
2. Participant will be asked to drink 1 to 2 glasses of water before arrival at the clinic 
3. Vital signs (heart rate, blood pressure) will be recorded 
4. Participant will be injected IV with 140 ± 20% mBq of 68Ga-RM2  OR  3 to 7 mCi of 
68Ga-PSMA11.  
5. Participant will void immediately prior to the scan 
6. Approximately 45 minutes after the radiopharmaceutical IV administration, data acquisition 
will begin in the pelvic region and move toward the head.  First, localizer MRI scans will be 
performed to define the table positions.  After correct positioning of the spatial acquisition 
windows is ensured, the combined PET/MRI acquisition will be initiated with 3 to 5 table 
positions at a 2 to 4-min acquisition time per table position. 
7. Participants will be dismissed. 
8. Vital signs (heart rate, blood pressure) will be recorded again at the completion of the study 
9. Participants will be contacted at 24 to 72 hours following the scan in order to capture 
potential occurring Adverse Events. 
Scan 2 
1. Participant will be asked to drink 1 to 2 glasses of water before arrival at the clinic 
2. Vital signs (heart rate, blood pressure) will be recorded 
3. Participant will be injected IV with 3 to 7 mCi of 68Ga-PSMA11  OR  140 ± 20% mBq of 
68Ga-RM2 (ie, the radiopharmaceutical not administered for Scan 1)   
4. Participant will void immediately prior to the scan 
5. Approximately 45 to 60 minutes after the radiopharmaceutical IV administration, data 
acquisition will begin in the pelvic region and move toward the head.  First, localizer MRI 
scans will be performed to define the table positions.  After correct positioning of the spatial 
acquisition windows is ensured, the combined PET/MRI acquisition will be initiated with 
3 to 5 table positions at a 2 to 4 minute acquisition time per table position.  Only MR 
sequences required for attenuation correction of PET data will be acquired. 
6. Vital signs (heart rate, blood pressure) will be recorded again at the completion of the study. 
7. Participants will be contacted at 24 to 72 hours following the scan in order to capture 
potential occurring Adverse Events. 

IRB-51987 
Page 16 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
The above will be repeated approximately 6 months after HIFU or HDR local treatment, prior to 
standard of care biopsy to evaluate for residual disease in the prostate. 
Objectives of the Study 
Primary Objectives 
• 
To demonstrate that 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can detect additional 
cancers over mpMRI. 
• 
To demonstrate that 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can assess changes in 
response to treatment and predict PFS at 24 months. 
Secondary Objective 
• 
None 
 
Endpoints 
Primary Endpoints 
• 
Number of participants with assessable additional prostate cancedr lesions over mpMRI 
• 
Number of participants with assessable pre- and post-treatment uptake in response to 
HIFU or HDR local therapy 
Secondary Endpoint 
• 
None 

IRB-51987 
Page 17 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria 
• 
Patients must be at least 18 years of age;  
• 
Patients must be able to provide informed consent;  
• 
Histologically proven low-grade or intermediate-grade PC;  
• 
Scheduled to undergo targeted local therapy (HDR brachytherapy). 
3.2 Exclusion Criteria 
• 
Inability to lie still for the entire imaging time;  
• 
Inability to complete the needed investigational and standard-of-care imaging 
examinations due to other reasons (severe claustrophobia, radiation phobia, etc.);  
• 
Any additional medical condition, serious intercurrent illness, or other extenuating 
circumstance that, in the opinion of the Investigator, may significantly interfere with study 
compliance;  
• 
Metallic implants (contraindicated for MRI). 
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 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 24 months from the time the the last subject completes the 
first scan. 
3.4.2  Study Completion: 
The study will reach study completion 84 months from the time the study opens to accrual. 
4. IMAGING AGENT INFORMATION 
4.1 Study Agents 68Ga-PSMA-11 and 68Ga-RM2  
68Ga-PSMA-11  
This study 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.”  
The administered dosage of 68Ga-PSMA-11 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 

IRB-51987 
Page 18 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
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) [85-88].   
68Ga-RM2  
This study will also use 68Ga-RM2 as the PET radiopharmaceutical.  The administered dosage is 
140 ± 20% mBq IV.  Measured human dosimetry data are available from published data [89].  
68Ga-RM2 is rapidly excreted through the kidneys to the urinary bladder and accumulated 
predominantly in the pancreas and liver.  Maximum peak uptake of the total injected radioactivity was 
seen in the urinary bladder contents and the liver, with approximately 36% and 14%, respectively. 
The organ with the highest absorbed dose was the urinary bladder wall at 0.61 mSv/MBq, followed by 
the pancreas at 0.51 mSv/MBq.  The mean effective dose (14) was 0.051 mSv/MBq.  Thus, the 
effective dose from a 140 MBq injected radioactivity is 7.7 mSv, which could be reduced to roughly 
4.76 mSv with frequent bladder voiding (1-h voids). 
To summarize the results of the published human dosimetry study, there were no observed adverse 
events to the radiopharmaceutical.  The measured dosimetry showed that the critical organ with 
68Ga-RM2 is the urinary bladder, followed by the pancreas.  The effective dose of 68Ga-RM2 reported 
(0.051 mSv/MBq) is approximately twice as much as 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) [85-88]. 
4.2 Source of the Study Agent  
Molecular Imaging Program at Stanford (MIPS) 
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/MRI 
5.2 Details of Imaging (ie, dynamic, static, number of scans, etc) 
A localizer MRI scan will be performed at 45 minutes after injection of 140 ± 20% mBq of 68Ga-RM2 
(or 3 to 7 mCi of 68Ga-PSMA11, depending on randomization) to define the table positions.  After 

IRB-51987 
Page 19 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
correct positioning of the spatial acquisition windows is ensured, the combined PET/MRI acquisition 
will be initiated with 3 to 5 table positions at a 2 to 4 min acquisition time per table position.  A 
volumetric T1 acquisition with fat-water separation and motion correction to enable free-breathing 
will be obtained at each table position and used for the generation of attenuation maps and for 
anatomic allocation of the PET results.  Simultaneously with the start of the T1 MRI sequence, the 
PET acquisition will start at the same table position, thus ensuring optimal temporal and regional 
correspondence between MRI and PET data.  The PET acquisition time will be 4 min per table 
position, taking delayed acquisition times and radioactive decay into account.  As the T1 will take 
less than 4 minutes, a rapid diffusion weighted MRI will also be performed.  After completion of the 
PET acquisition, the table will be moved to the next table position and the procedure will be 
repeated.  Upon completion of the PET acquisition for all stations, volumetric post-contrast T1- and 
T2-weighted MR images may be obtained at multiple stations as needed. 
A localizer MRI scan will be performed at 45 minutes after injection of 3 to 7 mCi of 68Ga-PSMA11 
(or 68Ga-RM2, depending on randomization)  to define the table positions.  After correct positioning 
of the spatial acquisition windows is ensured, the combined PET/MRI acquisition will be initiated 
with 3 to 5 table positions at a 2 to 4 min acquisition time per table position.  Only MR sequences 
required for attenuation correction of PET data will be acquired. 
Participants will be randomized to have 68Ga-RM2 first followed by 68Ga-PSMA11 within 2 weeks or 
68Ga-PSMA11 first followed by 68Ga-RM2 within 2 weeks (50/50 chance for each schedule). 
The above will be repeated approximately 6 months after HDR local treatment. 
5.3 Image interpretation 
The PET/MRI scans will be interpreted by ABNM certified Nuclear Medicine physicians and ABR 
certified Radiologists.  Drs Iagaru, Davidzon, Loening and Vasanawala have significant clinical 
experience and will be blinded to the participants’ medical history and the results of other imaging 
modalities.  Consensus read will be obtained for each scan.  Each lesion will be tabulated and a 
comparison of lesion detection by each tracer will be conducted. 
The study team will communicate the results of the scans to the referring (treating) physicians. 
6. STUDY PROCEDURES  
6.1 Pre-Study 
Potential subjects will be referred by treating physicians for participation in this imaging study.  The 
following procedures will occur pre-study: 
• 
Review of eligibility criteria 
• 
Obtain informed consent 
• 
Collect demographics 
• 
Review medical history, including any concomitant medication.   
6.2 Imaging Days 
Subjects will undergo 2 separate clinic visits not less than 3 days apart for imaging before therapy 
and two separate clinic visits for imaging after therapy.  After the 1st scan, the 2nd scan will only 
occur after the follow-up with the patient for the 1st scan, and after a minimum of 3 days have 
elapsed.  On each imaging day, subjects will receive an intravenous (IV) injection of investigational 

IRB-51987 
Page 20 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
imaging agent (68Ga-RM2 or 68Ga-PMSA11) and undergo PET/MRI image collection as described 
above.   
6.3 Follow-up 
Active subject participation ends after the 24 to 72 hour Safety Follow-up after the 2nd post-therapy 
scan.  Investigators will follow subjects by chart review for 12 months post-scan to record any 
standard of care biopsies or imaging results.  The investigators will assist with identification of 
lesions that can be biopsied, based on 68Ga-RM2 and/or 68Ga-PMSA11 PET/MRI findings. 
If a subject transfers clinical care outside of Stanford Healthcare during the chart review clinical 
follow-up period, investigators will request permission to contact the treating physician. 
6.4 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.   
6.5 Alternatives 
The alternative is to not participate in the study.  
7. STUDY CALENDAR 
 
Pre-Study 
Scan 
Date 
24 to 72 hours 
Post-Scan 
12 months 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
68Ga-RM2 
 
X a 
 
 
68Ga-PSMA11 (≥ 3 days and ≤ 2 weeks) 
 
X a 
 
 
Follow-up call to participant (24 to 72 hours) 
 
 
X 
 
Chart review b 
 
 
 
X 
a:  Subjects will undergo either 68Ga-RM2 PET/MRI followed within 2 weeks by 68Ga-PMSA11 PET/MRI, or 
68Ga-PMSA11 PET/MRI followed within 2 weeks by 68Ga-RM2 PET/MRI.  After the 1st scan, the 2nd scan 
will only occur after the follow-up with the patient for the 1st scan, and after a minimum of 3 days have 
elapsed.  This will be repeated approximately 6 months after HDR local treatment, prior to standard of care 
biopsy to evaluate for residual disease in the prostate. 
b:  Subjects will be followed by chart review for 24 months from initial scan date.  If a subject transfers clinical 
care from Stanford HealthCare, investigators may request records from the treating physician.  

IRB-51987 
Page 21 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
8. ADVERSE EVENTS AND REPORTING PROCEDURES 
8.1 Potential Adverse Events 
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 two (before and after treatment) 
68Ga-PSMA-11 PET/MRI.  There is no radiation exposure from MRI.  The effective dose from one 
typical maximum of 259 mBq (range:  3 to 7 mCi) administration of 68Ga-PSMA-11 is 6.68 mSv.  
Therefore, the effective dose from two 68Ga-PSMA-11 PET/MRI is 13.36 mSv, approximately equal 
to 26% of the limit that radiation workers (eg, a hospital X-ray technician) are allowed to receive in 
one year.  
This research study also involves exposure to radiation from two (before and after treatment) 
68Ga-RM2 PET/MRI.  There is no radiation exposure from MRI.  The amount of radiation from one 
administration of 140 mBq of 68Ga-RM2 is 4.76 mSv.  Therefore, the effective dose from two 
68Ga-RM2 PET/MRI is 9.52 mSv, approximately equal to 20% 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 resulted in 
death) using the Adverse Events Communication Form.  If the principal investigator determines the 
unanticipated adverse 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 

IRB-51987 
Page 22 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
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 the appropriate regulatory authorities at the time 
of continuing review, or in an expedited fashion, as needed.  
10. Statistical Considerations and Evaluation of Results 
10.1 Aim 1 
Participants: 100 patients with low- or intermediate-risk prostate cancer, as described in the 
inclusion/exclusion criteria. 
Design: Patients will have both 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI, including mpMRI. mpMRI 
and PET images will each be evaluated separately. For each of the 12 prostate regions, between 1-
3 imaging-positive samples will be taken, and 1 sample will be taken from each imaging-negative 
region. 
Outcome measures: Number and location of lesions will be recorded for each modality in each 
patient. Gold standard will be based on the biopsy of lesions found on 68Ga-RM2 and 68Ga-PSMA-
11 PET and prior systematic prostate biopsy, including IHC stains for GRPr and PSMA. 
Hypothesis: 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI sensitivity, either alone or in combination, will 
be higher than that of mpMRI alone. 
Reference standard: disease status of a lesion will be defined by biopsy of lesions found on 68Ga-
RM2 and 68Ga-PSMA-11 PET and from prior saturation prostate biopsy. Tissue samples will be 
evaluated for GRPr and PSMA 
expression 
as 
previously
reported [1, 2] and results will 
be 
compared 
to 
imaging
findings. For GRPr staining, 
immunohistochemistry will be 
performed 
using 
standard
protocols with primary rabbit 
polyclonal 
antibody 
(OPA1-
15619, 1:200 dilution; Affinity 
Bioreagents, 
Golden,
Colorado). For PSMA, a rabbit 
polyclonal anti-PSMA antibody 
(D7I8E; 
Cell 
Signaling 
technology, 
#12815, 
1:100
dilution) we be used following 
the 
manufacturer's 
immunohistochemistry protocol. 
We already successfully used 

IRB-51987 
Page 23 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
these, as shown on page 11. 
Drs. Kunder (clinical pathologist), Stoyanova and Dalm will perform all histopathological analyses. 
Clinical follow-up will be gold standard if biopsy cannot be done. 
Test to be evaluated: All T1w, T2w, DWI and DCE 
MR images will first be analyzed and graded by two-
board 
certified 
abdominal 
radiologists 
with 
subspecialty training in body MRI and extensive 
clinical experience in prostate MRI (Drs. Loening 
and Vasanawala) using the PI-RADS version 2 
scoring system, blinded to the clinical information 
and pathology. The PET images will be corrected 
using the attenuation data from the MRI scan, and 
Drs. Iagaru and Davizon who already have extensive 
experience with 68Ga-RM2 and 68Ga-PSMA-11 from 
our clinical trials, will perform blinded and random 
interpretation of the PET scans. Areas of focally 
increased 
68Ga-RM2 and 
68Ga-PSMA-11 uptake 
above surrounding background will be considered 
positive for PC (Figures 9 and 10). This approach is 
based on recently published guidelines for standard 
image interpretation developed for 68Ga-PSMA-11 
image 
interpretation 
[90]. 
In 
addition, 
semi-
quantitative measurements of tracer uptake (SUVmax) 
will be recorded for each lesion. 
 
Statistical Analysis: The following statistical considerations have the full support of a 
biostatistician (Dr. Jarrett Rosenberg) within the Department of Radiology, who has been 
specifically assigned to the project and can provide continuous support throughout the data 
collection and data analysis process. He has also carefully reviewed the study design and was fully 
involved in the writing of this grant proposal. 
Because there may be multiple lesions per-patient and an indefinite number of non-lesions, the 
primary analysis will be per-region. Each of the 12 regions will have gold-standard positive or 
negative information, as well as imaging positive or negative assessments. Predictive accuracy of 
PI-RADS composite score (mpMRI) and SUVmax PET uptake values will be assessed by ROC 
analysis using univariable logistic regression for the presence of PC. Areas under the entire ROC 
curve, and partial area at fixed 90% specificity will be compared. Additional benefit of the other 
modalities over mpMRI alone will be tested by a multivariable logistic regression. All analyses will 
be adjusted for clustering within patient. 
Statistical Power and Sample Size: Based on our clinical experience at Stanford, we expect an 
average of 2 PC-positive regions and 10 PC-negative regions per patient. Assuming mpMRI has 
sensitivity of 80% and specificity of 80-90% [91], a sample size of 1200 regions with 20% 
prevalence will provide 90% power at 5% error to demonstrate non-inferiority of a PET sensitivity of 
90% at 80-90% specificity [62, 92, 93]. 
The per-lesion analysis will depend on the number of lesions found but will be similar. We will also 
explore whether specific imaging findings are especially accurate in detection of specific subtypes 
of PC or prostate regions (i.e., peripheral versus transitional zones). It may also be the case that 

IRB-51987 
Page 24 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
predictive failures in imaging may be associated with a particular subtype. Given the small sample, 
we acknowledge that this analysis will be exploratory. 
10.2 Aim 2 
Participants: Those enrolled in Aim 1. 
Design: Patients will be scanned with both 68Ga-RM2 PET/MRI and 68Ga-PSMA-11 PET/MRI at six 
months after initiation of therapy. MRI and PET images will each be evaluated separately. 
Outcome measures: Changes in MRI features and/or changes in radiopharmaceutical uptake in 
lesions will be recorded for each modality in each patient. Gold standard of response to treatment 
and of PFS will be based on standard clinical follow-up (PSA, imaging, tissue diagnosis including 
IHC stains for GRPr and PSMA) 
Test to be evaluated: All T1w, T2w, DWI and DCE MR images will first be analyzed and graded by 
two-board certified abdominal radiologists with subspecialty training in body MRI and extensive 
clinical experience in prostate MRI (Drs. Loening and Vasanawala), before and after treatment. 
Areas of focally increased 68Ga-RM2 or 68Ga-PSMA-11 uptake above surrounding background on 
pre-therapy scans will be evaluated for changes in uptake by Drs. Davidzon and Iagaru. 
Hypotheses 
Primary: Change in 68Ga-RM2 or 68Ga-PSMA-11 uptake from baseline (T0) to 6 months after start 
of treatment (T1) will predict treatment response better than T0-T1 changes in MRI. 
Secondary: T0-T1 change in 68Ga-RM2 or 68Ga-PSMA-11 uptake will predict progression-free 
survival (PFS) better than MRI. 
Statistical Analysis:  
Primary: (a) logistic regression of response/non-response at T6 on T1-T0 change in PET/MRI 
measures; (b) McNemar tests of MRI and PET predictions of T6 response. 
Secondary: (a) log-rank tests of PFS time (length of drug response) on patients dichotomized as 
above/below the median change in PET/MRI measures; (b) Cox proportional-hazards regressions 
of PFS on amount of T1-T0 change in PET/MRI measures. 
Statistical Power and Sample Size: We expect a 70-80% response rate to treatment, and 20% of 
responders progressing by two years. 
A sample size of ~75 responders and ~25 non-responders will provide 90% power at one-sided 5% 
error to detect sensitivity low as 80% at fixed 90% specificity, and to demonstrate a difference in 
sensitivities of 10 percentage points (e.g., 80% vs 90%). 
Median-change groups of ~40 each among the responders will provide 90% power at one-sided 5% 
error to detect differences in PFS hazard ratios as small as 2.5.  
10.3 Study Outcomes (ClinicalTrials.gov) 
Primary Outcomes 
Title:  68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can detect additional cancers over mpMRI   
Description:  Detection of PC lesions will be assessed by 68Ga-PSMA-11 and 68Ga-RM2 
PET scans.  The outcome is the number of participants without dispersion, by randomization 
schedule, for which an assessment of PET-based PC lesions is successfully obtained.  
Timeframe:  60 months  
Safety outcome:  No  

IRB-51987 
Page 25 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
 
Title:  68Ga-RM2 and 68Ga-PSMA-11 PET/MRI can assess changes in response to 
treatment and predict PFS at 24 months   
Description:  Therapeutic response to HDR will be assessed by 68Ga-PSMA-11 and 
68Ga-RM2 PET scans.  The outcome is the number of participants without dispersion, by 
randomization schedule, for which an assessment of PET-based therapeutic response to 
HDR is successfully obtained.  
Timeframe:  84 months  
Safety outcome:  No  
Secondary Outcome 
None.  
 
10.4 Accrual estimates 
We expect the accrual of 20 patients each year for 5 years.  This is achievable given our 
experience with other protocols and the support from the referring physicians, Drs Buyyounouski, 
Bagshaw and Hancock who run the HDR Brachytherapy Clinic at the Stanford Cancer Institute.   
Potential difficulties and limitations: All patients will first be seen by a Stanford Cancer Institute 
physician and then referred if 
appropriate on clinical grounds 
for this study. SCI has a 
substantial volume of men with 
PC. We do not anticipate any 
difficulty in recruiting 100 men 
at Stanford with PC over the 
period 
of 
the 
grant 
since 
referring 
physicians 
from 
Radiation 
Oncology 
are 
supporting 
the 
study. 
We 
previously enrolled 10 patients 
included in a prior PET/MRI 
pilot study in less than 2 
months.  
Based 
on 
our 
preliminary 
experience in patients with PC 
we do not expect any technical 
problems. We already hold 
FDA-approved INDs for 68Ga-
RM2 PET imaging (IND # 
) and 
68Ga-PSMA-11 
PET imaging (IND # 128379). 
We have already imaged 38 PC 
patients 
at 
initial 
diagnosis 

IRB-51987 
Page 26 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
(n=9) or BCR (n=29) with both 68Ga-RM2 PET and 68Ga-PSMA-11 PET. Therefore, we do not 
anticipate problems enrolling participants in this study. 
Lastly, we successfully tested in-house the PSMA and GRPr IHC stains both in benign prostate 
tissue and PC, as shown in Figure 11. Therefore, we do not anticipate issues with the IHC 
analyses of tissue samples from the enrolled participants. 

IRB-51987 
Page 27 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
11. REFERENCES: 
1. 
Rybalov M, Ananias HJ, Hoving HD, van der Poel HG, Rosati S, de Jong IJ. PSMA, EpCAM, 
VEGF and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy. Int J 
Mol Sci. 2014;15:6046-61. doi:10.3390/ijms15046046. 
2. 
Michaud L, Kossatz S, Gopalan A, Yarilin D, Lyashchenko S, Hricak H, et al. 
Immunohistochemical analysis of Gastrin-Releasing-Peptide receptor (GRPr) and Prostate-
Specific- Membrane Antigen (PSMA) in primary prostate cancer: comparison with radiolabeled 
GRPr antagonist (68Ga-RM2) PET/CT. Journal of Nuclear Medicine. 2018;59:89. 
3. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 
2018;68:7-30. doi:doi:10.3322/caac.21442. 
4. 
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and 
survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220-41. doi:10.3322/caac.21149. 
5. 
Berg CD. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: the prostate 
cancer screening results in context. Acta Oncol. 2011;50 Suppl 1:12-7. 
doi:10.3109/0284186X.2010.531283. 
6. 
Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task 
Force recommendation statement. Ann Intern Med. 2012;157:120-34. doi:10.7326/0003-4819-157-
2-201207170-00459. 
7. 
Penson DF. The Pendulum of Prostate Cancer Screening. JAMA. 2015;314:2031-3. 
doi:10.1001/jama.2015.13775. 
8. 
Cooperberg MR, Carroll PR. Trends in Management for Patients With Localized Prostate 
Cancer, 1990-2013. JAMA. 2015;314:80-2. doi:10.1001/jama.2015.6036. 
9. 
Shao YH, Demissie K, Shih W, Mehta AR, Stein MN, Roberts CB, et al. Contemporary risk 
profile of prostate cancer in the United States. J Natl Cancer Inst. 2009;101:1280-3. 
doi:10.1093/jnci/djp262. 
10. 
Hayes JH, Ollendorf DA, Pearson SD, Barry MJ, Kantoff PW, Stewart ST, et al. Active 
surveillance compared with initial treatment for men with low-risk prostate cancer: a decision 
analysis. JAMA. 2010;304:2373-80. doi:10.1001/jama.2010.1720. 
11. 
Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-Year 
Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. New England 
Journal of Medicine. 2016;375:1415-24. doi:10.1056/NEJMoa1606220. 
12. 
Ahmed HU, Arya M, Freeman A, Emberton M. Do low-grade and low-volume prostate 
cancers bear the hallmarks of malignancy? The Lancet Oncology. 2012;13:e509-e17. 
doi:10.1016/s1470-2045(12)70388-1. 
13. 
Ahmed HU. The index lesion and the origin of prostate cancer. N Engl J Med. 
2009;361:1704-6. doi:10.1056/NEJMcibr0905562. 
14. 
Puech P, Rouviere O, Renard-Penna R, Villers A, Devos P, Colombel M, et al. Prostate 
cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion 
guidance versus systematic biopsy--prospective multicenter study. Radiology. 2013;268:461-9. 
doi:10.1148/radiol.13121501. 
15. 
Hoeks CM, Schouten MG, Bomers JG, Hoogendoorn SP, Hulsbergen-van de Kaa CA, 
Hambrock T, et al. Three-Tesla magnetic resonance-guided prostate biopsy in men with increased 

IRB-51987 
Page 28 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound 
biopsies: detection of clinically significant prostate cancers. Eur Urol. 2012;62:902-9. 
doi:10.1016/j.eururo.2012.01.047. 
16. 
Le JD, Tan N, Shkolyar E, Lu DY, Kwan L, Marks LS, et al. Multifocality and prostate cancer 
detection by multiparametric magnetic resonance imaging: correlation with whole-mount 
histopathology. Eur Urol. 2015;67:569-76. doi:10.1016/j.eururo.2014.08.079. 
17. 
Priester A, Natarajan S, Khoshnoodi P, Margolis DJ, Raman SS, Reiter RE, et al. Magnetic 
Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds 
to Correlate Images with Whole Mount Pathology. J Urol. 2017;197:320-6. 
doi:10.1016/j.juro.2016.07.084. 
18. 
Sonn GA, Chang E, Natarajan S, Margolis DJ, Macairan M, Lieu P, et al. Value of targeted 
prostate biopsy using magnetic resonance-ultrasound fusion in men with prior negative biopsy and 
elevated prostate-specific antigen. Eur Urol. 2014;65:809-15. doi:10.1016/j.eururo.2013.03.025. 
19. 
Sandblom G, Sorensen J, Lundin N, Haggman M, Malmstrom PU. Positron emission 
tomography with C11-acetate for tumor detection and localization in patients with prostate-specific 
antigen relapse after radical prostatectomy. Urology. 2006;67:996-1000. 
doi:10.1016/j.urology.2005.11.044. 
20. 
Oyama N, Miller TR, Dehdashti F, Siegel BA, Fischer KC, Michalski JM, et al. 11C-Acetate 
PET Imaging of Prostate Cancer: Detection of Recurrent Disease at PSA Relapse. Journal of 
Nuclear Medicine. 2003;44:549-55. 
21. 
Wachter S, Tomek S, Kurtaran A, Wachter-Gerstner N, Djavan B, Becherer A, et al. 11C-
acetate positron emission tomography imaging and image fusion with computed tomography and 
magnetic resonance imaging in patients with recurrent prostate cancer. J Clin Oncol. 2006;24:2513-
9. doi:10.1200/JCO.2005.03.5279. 
22. 
Kotzerke J, Volkmer BG, Glatting G, van den Hoff J, Gschwend JE, Messer P, et al. 
Intraindividual comparison of [11C]acetate and [11C]choline PET for detection of metastases of 
prostate cancer. Nuklearmedizin. 2003;42:25-30. doi:10.1267/NUKL03010025. 
23. 
Souvatzoglou M, Weirich G, Schwarzenboeck S, Maurer T, Schuster T, Bundschuh RA, et 
al. The sensitivity of [11C]choline PET/CT to localize prostate cancer depends on the tumor 
configuration. Clin Cancer Res. 2011;17:3751-9. doi:10.1158/1078-0432.CCR-10-2093. 
24. 
Rietbergen DD, van der Hiel B, Vogel W, Stokkel MP. Mediastinal lymph node uptake in 
patients with prostate carcinoma on F18-choline PET/CT. Nucl Med Commun. 2011;32:1143-7. 
doi:10.1097/MNM.0b013e32834b76fa. 
25. 
Heinisch M, Dirisamer A, Loidl W, Stoiber F, Gruy B, Haim S, et al. Positron emission 
tomography/computed tomography with F-18-fluorocholine for restaging of prostate cancer patients: 
meaningful at PSA < 5 ng/ml? 
26. 
Vees H, Buchegger F, Albrecht S, Khan H, Husarik D, Zaidi H, et al. 18F-choline and/or 
11C-acetate positron emission tomography: detection of residual or progressive subclinical disease 
at very low prostate-specific antigen values (<1 ng/mL) after radical prostatectomy. 
27. 
Nanni C, Schiavina R, Boschi S, Ambrosini V, Pettinato C, Brunocilla E, et al. Comparison of 
18F-FACBC and 11C-choline PET/CT in patients with radically treated prostate cancer and 
biochemical relapse: preliminary results. Eur J Nucl Med Mol Imaging. 2013;40 Suppl 1:S11-7. 
doi:10.1007/s00259-013-2373-3. 
28. 
Turkbey B, Mena E, Shih J, Pinto PA, Merino MJ, Lindenberg ML, et al. Localized prostate 
cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic 
analysis. Radiology. 2014;270:849-56. doi:10.1148/radiol.13130240. 

IRB-51987 
Page 29 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
29. 
Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane 
antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3:81-5. 
30. 
Mannweiler S, Amersdorfer P, Trajanoski S, Terrett JA, King D, Mehes G. Heterogeneity of 
prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant 
metastasis. Pathol Oncol Res. 2009;15:167-72. doi:10.1007/s12253-008-9104-2. 
31. 
Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP. Prostate specific membrane antigen 
expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. 
1998;82:2256-61. 
32. 
Budaus L, Leyh-Bannurah SR, Salomon G, Michl U, Heinzer H, Huland H, et al. Initial 
Experience of (68)Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical 
Prostatectomy. Eur Urol. 2016;69:393-6. doi:10.1016/j.eururo.2015.06.010. 
33. 
Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G, et al. Diagnostic 
Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging 
for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate 
Cancer. J Urol. 2016;195:1436-43. doi:10.1016/j.juro.2015.12.025. 
34. 
Koerber SA, Utzinger MT, Kratochwil C, Kesch C, Haefner M, Katayama S, et al. 68Ga-
PSMA11-PET/CT in newly diagnosed carcinoma of the prostate: correlation of intraprostatic PSMA 
uptake with several clinical parameters. J Nucl Med. 2017. doi:10.2967/jnumed.117.190314. 
35. 
Schmuck S, Mamach M, Wilke F, von Klot CA, Henkenberens C, Thackeray JT, et al. 
Multiple Time-Point 68Ga-PSMA I&T PET/CT for Characterization of Primary Prostate Cancer: 
Value of Early Dynamic and Delayed Imaging. Clin Nucl Med. 2017;42:e286-e93. 
doi:10.1097/RLU.0000000000001589. 
36. 
Fendler WP, Schmidt DF, Wenter V, Thierfelder KM, Zach C, Stief C, et al. 68Ga-PSMA 
PET/CT Detects the Location and Extent of Primary Prostate Cancer. J Nucl Med. 2016;57:1720-5. 
doi:10.2967/jnumed.116.172627. 
37. 
Giesel FL, Sterzing F, Schlemmer HP, Holland-Letz T, Mier W, Rius M, et al. Intra-individual 
comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate 
cancer. Eur J Nucl Med Mol Imaging. 2016;43:1400-6. doi:10.1007/s00259-016-3346-0. 
38. 
Eiber M, Weirich G, Holzapfel K, Souvatzoglou M, Haller B, Rauscher I, et al. Simultaneous 
68Ga-PSMA HBED-CC PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 
2016;70:829-36. doi:10.1016/j.eururo.2015.12.053. 
39. 
Sachpekidis C, Kopka K, Eder M, Hadaschik BA, Freitag MT, Pan L, et al. 68Ga-PSMA-11 
Dynamic PET/CT Imaging in Primary Prostate Cancer. Clin Nucl Med. 2016;41:e473-e9. 
doi:10.1097/RLU.0000000000001349. 
40. 
Koerber SA, Utzinger MT, Kratochwil C, Kesch C, Haefner M, Katayama S, et al. 68Ga-
PSMA11-PET/CT in newly diagnosed carcinoma of the prostate: correlation of intraprostatic PSMA 
uptake with several clinical parameters. Journal of Nuclear Medicine. 2017. 
doi:10.2967/jnumed.117.190314. 
41. 
Hillier SM, Maresca KP, Femia FJ, Marquis JC, Foss CA, Nguyen N, et al. Preclinical 
evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen 
as molecular imaging pharmaceuticals for prostate cancer. Cancer Res. 2009;69:6932-40. 
doi:10.1158/0008-5472.CAN-09-1682. 
42. 
Afshar Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, et al. PET 
imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: 
biodistribution in humans and first evaluation of tumour lesions. 

IRB-51987 
Page 30 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
43. 
Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 
(6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical 
Prostatectomy. J Nucl Med. 2015;56:668-74. doi:10.2967/jnumed.115.154153. 
44. 
Rowe SP, Gage KL, Faraj SF, Macura KJ, Cornish TC, Gonzalez-Roibon N, et al. (1)(8)F-
DCFBC PET/CT for PSMA-Based Detection and Characterization of Primary Prostate Cancer. J 
Nucl Med. 2015;56:1003-10. doi:10.2967/jnumed.115.154336. 
45. 
Sathekge M, Lengana T, Modiselle M, Vorster M, Zeevaart J, Maes A, et al. 68Ga-PSMA-
HBED-CC PET imaging in breast carcinoma patients. Eur J Nucl Med Mol Imaging. 2017;44:689-
94. doi:10.1007/s00259-016-3563-6. 
46. 
Rhee H, Blazak J, Tham CM, Ng KL, Shepherd B, Lawson M, et al. Pilot study: use of 
gallium-68 PSMA PET for detection of metastatic lesions in patients with renal tumour. EJNMMI 
Res. 2016;6:76. doi:10.1186/s13550-016-0231-6. 
47. 
Patel D, Loh H, Le K, Stevanovic A, Mansberg R. Incidental Detection of Hepatocellular 
Carcinoma on 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT. Clin Nucl Med. 2017. 
doi:10.1097/RLU.0000000000001832. 
48. 
Hermann RM, Djannatian M, Czech N, Nitsche M. Prostate-Specific Membrane Antigen 
PET/CT: False-Positive Results due to Sarcoidosis? Case Rep Oncol. 2016;9:457-63. 
doi:10.1159/000447688. 
49. 
Sasikumar A, Joy A, Nanabala R, Pillai MR, T AH. 68Ga-PSMA PET/CT False-Positive 
Tracer Uptake in Paget Disease. Clin Nucl Med. 2016;41:e454-5. 
doi:10.1097/RLU.0000000000001340. 
50. 
Noto B, Vrachimis A, Schafers M, Stegger L, Rahbar K. Subacute Stroke Mimicking 
Cerebral Metastasis in 68Ga-PSMA-HBED-CC PET/CT. Clin Nucl Med. 2016;41:e449-51. 
doi:10.1097/RLU.0000000000001291. 
51. 
Demirkol MOMD, Kiremit MCMD, Acar OMD, Sag AAMD, Kapran YMD. False-Positive 
Pancreatic Uptake Detected on 68Ga-PSMA PET/CT: A Priority Changing Incidental Finding While 
Assessing the Need for a Prostate Biopsy. Clinical Nuclear Medicine. 
52. 
Erspamer V, Erspamer GF, Inselvin.M. Some Pharmacological Actions of Alytesin and 
Bombesin. J Pharm Pharmacol. 1970;22:875-&. 
53. 
Ischia J, Patel O, Shulkes A, Baldwin GS. Gastrin-releasing peptide: different forms, 
different functions. BioFactors. 2009;35:69-75. doi:10.1002/biof.10. 
54. 
Ischia J, Patel O, Bolton D, Shulkes A, Baldwin GS. Expression and function of gastrin-
releasing peptide (GRP) in normal and cancerous urological tissues. BJU international. 2014;113 
Suppl 2:40-7. doi:10.1111/bju.12594. 
55. 
Korner M, Waser B, Rehmann R, Reubi JC. Early over-expression of GRP receptors in 
prostatic carcinogenesis. The Prostate. 2014;74:217-24. doi:10.1002/pros.22743. 
56. 
Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. 
Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions 
in normal and disease states. Pharmacol Rev. 2008;60:1-42. doi:10.1124/pr.107.07108. 
57. 
Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer J-C, Gugger M. Bombesin Receptor 
Subtypes in Human Cancers: Detection with the Universal Radioligand 125I-[d-TYR6, β-ALA11, 
PHE13, NLE14] Bombesin(6–14). Clinical Cancer Research. 2002;8:1139-46. 
58. 
Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation 
to neoplastic transformation. Cancer Res. 1999;59:1152-9. 

IRB-51987 
Page 31 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
59. 
Beer M, Montani M, Gerhardt J, Wild PJ, Hany TF, Hermanns T, et al. Profiling gastrin-
releasing peptide receptor in prostate tissues: clinical implications and molecular correlates. The 
Prostate. 2012;72:318-25. doi:10.1002/pros.21434. 
60. 
Mansi R, Wang X, Forrer F, Waser B, Cescato R, Graham K, et al. Development of a potent 
DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours. Eur J Nucl Med Mol 
Imaging. 2011;38:97-107. doi:10.1007/s00259-010-1596-9. 
61. 
Roivainen A, Kahkonen E, Luoto P, Borkowski S, Hofmann B, Jambor I, et al. Plasma 
pharmacokinetics, whole-body distribution, metabolism, and radiation dosimetry of 68Ga bombesin 
antagonist BAY 86-7548 in healthy men. J Nucl Med. 2013;54:867-72. 
doi:10.2967/jnumed.112.114082. 
62. 
Kahkonen E, Jambor I, Kemppainen J, Lehtio K, Gronroos TJ, Kuisma A, et al. In vivo 
imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548. Clin Cancer Res. 
2013;19:5434-43. doi:10.1158/1078-0432.CCR-12-3490. 
63. 
Wieser G, Mansi R, Grosu AL, Schultze-Seemann W, Dumont-Walter RA, Meyer PT, et al. 
Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide 
receptor antagonist--from mice to men. Theranostics. 2014;4:412-9. doi:10.7150/thno.7324. 
64. 
Nock BA, Kaloudi A, Lymperis E, Giarika A, Kulkarni HR, Klette I, et al. Theranostic 
Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist 
NeoBOMB1: Preclinical and First Clinical Results. J Nucl Med. 2017;58:75-80. 
doi:10.2967/jnumed.116.178889. 
65. 
Sah BR, Burger IA, Schibli R, Friebe M, Dinkelborg L, Graham K, et al. Dosimetry and first 
clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with 
prostate cancer. J Nucl Med. 2015;56:372-8. doi:10.2967/jnumed.114.147116. 
66. 
Minamimoto R, Sonni I, Hancock S, Vasanawala S, Loening A, Gambhir SS, et al. 
Prospective Evaluation of 68Ga-RM2 PET/MRI in Patients with Biochemical Recurrence of Prostate 
Cancer and Negative Findings on Conventional Imaging. Journal of Nuclear Medicine. 
2018;59:803-8. doi:10.2967/jnumed.117.197624. 
67. 
Nagasaki S, Nakamura Y, Maekawa T, Akahira J, Miki Y, Suzuki T, et al. 
Immunohistochemical analysis of gastrin-releasing peptide receptor (GRPR) and possible 
regulation by estrogen receptor betacx in human prostate carcinoma. Neoplasma. 2012;59:224-32. 
68. 
Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-Year 
Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med. 
2016;375:1415-24. doi:10.1056/NEJMoa1606220. 
69. 
White EC, Kamrava MR, Demarco J, Park SJ, Wang PC, Kayode O, et al. High-dose-rate 
prostate brachytherapy consistently results in high quality dosimetry. Int J Radiat Oncol Biol Phys. 
2013;85:543-8. doi:10.1016/j.ijrobp.2012.03.035. 
70. 
Demanes DJ, Ghilezan MI. High-dose-rate brachytherapy as monotherapy for prostate 
cancer. Brachytherapy. 2014;13:529-41. doi:10.1016/j.brachy.2014.03.002. 
71. 
Roach M, 3rd, Hanks G, Thames H, Jr., Schellhammer P, Shipley WU, Sokol GH, et al. 
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with 
clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus 
Conference. International journal of radiation oncology, biology, physics. 2006;65:965-74. 
doi:10.1016/j.ijrobp.2006.04.029. 
72. 
Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus 
deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical 
prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7:472-9. doi:10.1016/S1470-

IRB-51987 
Page 32 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
2045(06)70700-8. 
73. 
Kirkham AP, Emberton M, Hoh IM, Illing RO, Freeman AA, Allen C. MR imaging of prostate 
after treatment with high-intensity focused ultrasound. Radiology. 2008;246:833-44. 
doi:10.1148/radiol.2463062080. 
74. 
Zattoni F, Kawashima A, Morlacco A, Davis BJ, Nehra AK, Mynderse LA, et al. Detection of 
recurrent prostate cancer after primary radiation therapy: An evaluation of the role of 
multiparametric 3T magnetic resonance imaging with endorectal coil. Pract Radiat Oncol. 
2017;7:42-9. doi:10.1016/j.prro.2016.06.003. 
75. 
Kim CK, Park BK, Lee HM, Kim SS, Kim E. MRI techniques for prediction of local tumor 
progression after high-intensity focused ultrasonic ablation of prostate cancer. AJR Am J 
Roentgenol. 2008;190:1180-6. doi:10.2214/AJR.07.2924. 
76. 
Antoch G, Bockisch A. Combined PET/MRI: a new dimension in whole-body oncology 
imaging? Eur J Nucl Med Mol Imaging. 2009;36 Suppl 1:S113-20. doi:10.1007/s00259-008-0951-6. 
77. 
Engeler CE, Wasserman NF, Zhang G. Preoperative assessment of prostatic carcinoma by 
computerized tomography. Weaknesses and new perspectives. Urology. 1992;40:346-50. 
78. 
Minamimoto R, Levin C, Jamali M, Holley D, Barkhodari A, Zaharchuk G, et al. 
Improvements in PET Image Quality in Time of Flight (TOF) Simultaneous PET/MRI. Molecular 
Imaging and Biology. 2016;18:776-81. doi:10.1007/s11307-016-0939-8. 
79. 
Baratto L, Park SY, Hatami N, Davidzon G, Srinivas S, Gambhir SS, et al. 18F-FDG silicon 
photomultiplier PET/CT: A pilot study comparing semi-quantitative measurements with standard 
PET/CT. PLOS ONE. 2017;12:e0178936. doi:10.1371/journal.pone.0178936. 
80. 
Iagaru A, Mittra E, Minamimoto R, Jamali M, Levin C, Quon A, et al. Simultaneous Whole-
Body Time-of-Flight 18F-FDG PET/MRI: A Pilot Study Comparing SUVmax With PET/CT and 
Assessment of MR Image Quality. Clinical Nuclear Medicine. 2015;40:1-8. 
doi:10.1097/rlu.0000000000000611. 
81. 
Baratto L, Harrison C, Davidzon G, Yohannan T, Iagaru A. 68Ga-RM2 PET/MRI Detection of 
Recurrent Prostate Cancer in Patients with Negative Conventional Imaging. Journal of Nuclear 
Medicine. 2018;59:453. 
82. 
Park SY, Zacharias C, Harrison C, Fan RE, Kunder C, Hatami N, et al. Gallium 68 PSMA-11 
PET/MR Imaging in Patients with Intermediate- or High-Risk Prostate Cancer. Radiology. 
2018;288:495-505. doi:10.1148/radiol.2018172232. 
83. 
Park S, HATAMI N, Baratto L, Yohannan T, Davidzon G, Iagaru A. Dual-Time 68Ga-PSMA-
11 Imaging for Biochemically Recurrent Prostate Cancer Using LYSO and SiPM-Based Detectors 
PET/CT. Journal of Nuclear Medicine. 2018;59:431. 
84. 
Minamimoto R, Hancock S, Schneider B, Chin FT, Jamali M, Loening A, et al. Pilot 
Comparison of (6)(8)Ga-RM2 PET and (6)(8)Ga-PSMA-11 PET in Patients with Biochemically 
Recurrent Prostate Cancer. J Nucl Med. 2016;57:557-62. doi:10.2967/jnumed.115.168393. 
85. 
Hartmann H, Zophel K, Freudenberg R, Oehme L, Andreeff M, Wunderlich G, et al. 
[Radiation exposure of patients during 68Ga-DOTATOC PET/CT examinations]. Nuklearmedizin. 
2009;48:201-7. doi:10.3413/nukmed-0214. 
86. 
Pettinato C, Sarnelli A, Di Donna M, Civollani S, Nanni C, Montini G, et al. 68Ga-
DOTANOC: biodistribution and dosimetry in patients affected by neuroendocrine tumors. Eur J Nucl 
Med Mol Imaging. 2008;35:72-9. doi:10.1007/s00259-007-0587-y. 
87. 
SandstrÃƒm M, Velikyan I, Garske-RomÃƒn U, SÃƒrensen J, Eriksson B, Granberg D, et al. 
Comparative Biodistribution and Radiation Dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in 

IRB-51987 
Page 33 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
Patients with Neuroendocrine Tumors. The Journal of nuclear medicine. 2013;54:1755-9. 
88. 
Kim JH, Lee JS, Kang KW, Lee HY, Han SW, Kim TY, et al. Whole-body distribution and 
radiation dosimetry of (68)Ga-NOTA-RGD, a positron emission tomography agent for angiogenesis 
imaging. Cancer Biother Radiopharm. 2012;27:65-71. doi:10.1089/cbr.2011.1061. 
89. 
Kähkönen E, Jambor I, Kemppainen J, Lehtiö K, Grönroos TJ, Kuisma A, et al. In Vivo 
Imaging of Prostate Cancer Using [68Ga]-Labeled Bombesin Analog BAY86-7548. Clinical Cancer 
Research. 2013;19:5434-43. doi:10.1158/1078-0432.ccr-12-3490. 
90. 
Fanti S, Minozzi S, Morigi JJ, Giesel F, Ceci F, Uprimny C, et al. Development of 
standardized image interpretation for 68Ga-PSMA PET/CT to detect prostate cancer recurrent 
lesions. Eur J Nucl Med Mol Imaging. 2017;44:1622-35. doi:10.1007/s00259-017-3725-1. 
91. 
Turkbey B, Brown AM, Sankineni S, Wood BJ, Pinto PA, Choyke PL. Multiparametric 
prostate magnetic resonance imaging in the evaluation of prostate cancer. CA Cancer J Clin. 
2016;66:326-36. doi:10.3322/caac.21333. 
92. 
Zamboglou C, Drendel V, Jilg CA, Rischke HC, Beck TI, Schultze-Seemann W, et al. 
Comparison of 68Ga-HBED-CC PSMA-PET/CT and multiparametric MRI for gross tumour volume 
detection in patients with primary prostate cancer based on slice by slice comparison with 
histopathology. Theranostics. 2017;7:228-37. doi:10.7150/thno.16638. 
93. 
Kesch C, Vinsensia M, Radtke JP, Schlemmer HP, Heller M, Ellert E, et al. Intra-individual 
comparison of 18F-PSMA-1007-PET/CT, multi-parametric MRI and radical prostatectomy specimen 
in patients with primary prostate cancer - a retrospective, proof of concept study. Journal of nuclear 
medicine : official publication, Society of Nuclear Medicine. 2017. doi:10.2967/jnumed.116.189233. 
 

IRB-51987 
Page 34 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
Inclusion/Exclusion Criteria Checklist 
Protocol Title: 
Evaluation of Patients with Low-Risk and Intermediate-Risk Prostate 
Cancer Scheduled for High-Dose Rate Brachytherapy Using 68Ga-RM2 
PET, 68Ga-PSMA-11 PET and Multi Parametric MRI 
Protocol Number: 
IRB-51987  /  SRC-TBD  
Principal Investigator: 
Andrei Iagaru, MD 
3.1 Inclusion Criteria 
Inclusion Criteria  
Yes must be checked to be eligible 
Yes 
No 
Supporting 
Documentation 
1. Patients must be at least 18 years of age 
☐ 
☐ 
 
2. Patients must be able to provide informed consent 
☐ 
☐ 
 
3. Histologically proven low-grade or intermediate-
grade PC 
☐ 
☐ 
 
4. Scheduled to undergo targeted local therapy (HDR 
brachytherapy) 
☐ 
☐ 
 
3.2 Exclusion Criteria 
Exclusion Criteria  
No must be checked to be eligible 
Yes 
No 
Supporting 
Documentation 
1. Inability to lie still for the entire imaging time 
☐ 
☐ 
 
2. Inability to complete the needed investigational and 
standard-of-care imaging examinations due to other 
reasons (severe claustrophobia, radiation phobia, 
etc.) 
☐ 
☐ 
 
3. Any additional medical condition, serious 
intercurrent illness, or other extenuating 
circumstance that, in the opinion of the Investigator, 
may significantly interfere with study compliance 
☐ 
☐ 
 
4. Metallic implants (contraindicated for MRI) 
☐ 
☐ 
 
*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.   

IRB-51987 
Page 35 of 35 
CONFIDENTIAL 
Protocol version 12 July 2019 
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: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: