A Pilot Study of 68Ga PSMA 11 PET/MRI and 68Ga RM2 PET/MRI for Evaluation of Prostate Cancer Response to HIFU Therapy
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: Andrei Iagaru

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A Pilot Study of 68Ga-PSMA-11 PET/MRI and 68Ga-RM2 PET/MRI for 
Evaluation of Prostate Cancer Response to HIFU Therapy 
Principal Investigator / Protocol Director  
Andrei Iagaru, MD 
300 Pasteur Drive, 
 
Stanford, CA 94305 
Phone:  650-725-4711 
Fax:  650-498-5047 
Email:  aiagaru@stanford.edu 
 
Co-investigators 
Geoffrey Sonn, MD 
875 Blake Wilbur Dr;  
  
Stanford, CA  94305  
Phone:  
;  Fax:  
 
Email:  gsonn@stanford.edu 
Pejman Ghanouni, MD, PhD 
1201 Welch Road, 
 
Stanford, CA  94305  
Phone:  650-498-4485;  
 
Email:  ghanouni@stanford.edu 
Carina Mari Aparici, MD 
300 Pasteur Dr, 
 
Stanford, CA  94305  
Phone:  650-725-4711;  Fax:  650-498-5047 
Email:  drmari@stanford.edu 
Guido Davidzon, MD 
300 Pasteur Dr, 
 
Stanford, CA  94305  
Phone:  650-725-4711;  Fax:  650-498-5047 
Email:   gdavidzon@stanford.edu 
Biostatistician 
, PhD 
Department of Radiology  
Lucas MRS Imaging Center  
1201 Welch Road, 
  
Stanford, CA 94305-
 
  
Study Coordinator  
 
800 Welch Rd 
Palo Alto, CA 94304 
Phone:  
;  Fax:  
 
Email:  
 
Protocol IRB-48213  //  PROS0093  //  NCT- NCT03949517 
Protocol version //  05 January 2021 
SRC Approval Date – 5 March 2019 
 

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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 
10 
2.4 Rationale 
10 
2.5 Study Design 
14 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
16 
3.1 Inclusion Criteria 
16 
3.2 Exclusion Criteria 
16 
3.3 Informed Consent Process 
16 
3.4 Study Timeline 
16 
4. 
IMAGING AGENT INFORMATION 
16 
4.1 Study Agents 68Ga-PSMA-11 and 68Ga-RM2 
16 
4.2 Source of the Study Agent 
17 
4.3 Ordering 
17 
4.4 Agent Accountability 
17 
5. 
IMAGING SPECIFICS 
17 
5.1 Modality or Modalities to be used 
17 
5.2 Details of Imaging (ie, dynamic, static, number of scans, etc) 
17 
5.3 Image interpretation 
18 
6. 
STUDY PROCEDURES 
18 
6.1 Pre-Study 
18 
6.2 Imaging Days 
18 
6.3 Follow-up 
19 
6.4 Criteria for Removal from Study 
19 
6.5 Alternatives 
19 
7. 
STUDY CALENDAR 
19 

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8. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
20 
8.1 Potential Adverse Events 
20 
8.2 Adverse Event Reporting 
20 
9. 
REGULATORY CONSIDERATIONS 
20 
9.1 Institutional Review of Protocol 
20 
9.2 Data Management Plan 
20 
10. Statistical Considerations and Evaluation of Results 
21 
10.1 Study Endpoints 
21 
10.2 Accrual estimates 
22 
10.3 Study Outcomes (ClinicalTrials.gov) 
22 
10.4 Analyses Plans 
22 
10.5 Accrual estimates 
22 
11. REFERENCES: 
23 
3.1 Inclusion Criteria 
28 
3.2 Exclusion Criteria 
28 
 

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PROTOCOL SYNOPSIS 
TITLE 
A Pilot Study of 68Ga-PSMA-11 PET/MRI and 68Ga-RM2 
PET/MRI for Evaluation of Prostate Cancer Response to HIFU 
Therapy 
STUDY PHASE 
Phase 1-2 study (pilot 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  
20 participants 
PRIMARY OBJECTIVE 
To determine feasibility of 68Ga-PSMA-11 PET/MRI and 
68Ga-RM2 PET/MRI for evaluation of HIFU local therapy in 
patients with known prostate cancer 
EXPLORATORY ENDPOINTS 
• 
Comparison of 68Ga-PSMA-11 post-treatment uptake and 
pre-post change in uptake in response to HIFU local therapy 
• 
Comparison of 68Ga-RM2 post-treatment uptake and pre-post 
change in uptake in response to HIFU local therapy 

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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 
HIFU 
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 

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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 
GRPR 
Gastrin releasing peptide receptor 
PRCA 
Prostate cancer 
HIFU 
High-intensity focused ultrasound 
 

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1. OBJECTIVE 
Specific Aim 
To determine the feasibility of 68Ga-PSMA-11 PET/MRI and 68Ga-RM2 PET/MRI for evaluation of 
high-intensity focused ultrasound (HIFU) local therapy in patients with known prostate cancer. 
2. BACKGROUND 
2.1 Preliminary information 
Prostate cancer (PCa) remains the most-common non-cutaneous cancer diagnosed in American 
males, accounting for an estimated 161,360 new cases and 26,730 deaths in 2017 (1).  Historically, 
PCa 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 PCa-specific mortality dropped to 20 per 100,000 by 2012 (2).  While improvements 
in therapy likely play some role, independent groups in the CISNet consortium have shown through 
modeling that 45% to 70% of the decline in PCa mortality can be plausibly attributed to PSA 
screening (3).   
Meanwhile, PSA screening also dramatically increased detection and treatment of slow-growing, 
low-grade PCa 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 PCa mortality in the PSA era, the US Preventive 
Services Task Force (USPTF) recommended in 2011 against routine screening with PSA (4) 
because it deemed that the harms of screening outweighed the benefits.  Accordingly, PSA use and 
early diagnosis PCa have decreased dramatically (5).  The dilemma for patients and 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, cheaper, less invasive 
and fundamentally less risky treatments for localized PCa. 
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 identify metastases.  However most tumors present before 
this stage and are candidates for targeted local therapy. 
Changing paradigms in management of localized PCa.  Not all localized PCa have the same 
biologic 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 (6).  
Low-risk PCa (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 prostate cancer (7, 8).  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 (9).  Newer less 
invasive local therapies seek to offer a treatment options that are faster, less invasive, less risky 
and potentially cheaper than surgery or EBRT.  These include ablation with heating (high-intensity 

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focused ultrasound - HIFU, microwaves, or lasers), freezing (with needle cryoprobes), 
electroporation, stereotactic radiation therapy and brachytherapy.  Such local therapy is 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 PCa is most often multifocal, the 
highest grade, index lesion drives clinical outcomes (10, 11).  Conventional trans-rectal ultrasound 
(TRUS)-guided systematic prostate biopsy consisting of 6 to 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 (12).  MRI-guided biopsies find more 
clinically significant tumor (≥ G7) and less insignificant (G6) tumor than conventional systematic 
biopsies.  MRI use is increasing for: 
• 
MRI prior to biopsy is sometimes used to determine if biopsy is necessary and can enable 
image-targeted biopsy if an abnormality is seen on MRI (12)  
• 
Men contemplating active surveillance:  a normal mpMRI adds confidence that this is a safe 
management option.  An abnormal mpMRI prompts MRI-TRUS fusion biopsy that often 
reveals clinically significant cancer that warrants treatment (13).   
• 
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 (14), the size 
of high grade cancers is underestimated (15), and ~40% of men with a normal MRI have PCa on 
biopsy (16). 
Positron emission tomography (PET) and PCa.  PET tracers, such as 18F- or 11C-labeled choline 
and [11C]-acetate, are used mainly for the diagnosis of recurrent (17-19) or metastatic (20) PCa.  
Their feasibility in primary diagnosis is limited because of uptake in benign tissue such as benign 
prostatic hyperplasia or inflammatory lymph nodes (21, 22).  Although choline based PET/CT is 
widely used outside the US for imaging PCa, there have been numerous studies reporting a low 
sensitivity and specificity, especially at low PSA levels (23, 24).  Consequently, improved molecular 
imaging of PCa is necessary.  One novel method is PET imaging with 18F-FACBC, a synthetic 
amino acid.  Recent evaluations by Nanni et al.  indicate that this tracer might be superior when 
compared to choline PET/CT (25).  However, recent work indicates that 18F-FACBC uptake in PCa 
is similar to that in BPH nodules (26).  Prostate-specific membrane antigen (PSMA) is a 
transmembrane protein that elicits high interest.  This cell surface protein is significantly 
overexpressed in PCa cells when compared to other PSMA-expressing tissues such as kidney, 
proximal small intestine or salivary glands.  PSMA is highly overexpressed on almost all PCa (27-
29).  Only 5-10% of primary PCa lesions have been shown to be PSMA-negative (30, 31), making 
this class of radiopharmaceuticals suitable for diagnosis of primary PCa and for initial staging (32-
37).  Non-invasive tumor grading has also been reported (38).  Recently methods have been 
developed to label PSMA ligands with 68Ga enabling their use for PET imaging and therapy (39).  
Initial experience with PET/CT using Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA-11) 
suggests that it can detect PCa relapses and metastases with high contrast by binding to the 
extracellular domain of PSMA, followed by internalization (40).  Better localization of cancer within 

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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 
(41, 42) and other cancers also express PSMA (43-45).  False positive findings have also been 
reported using PSMA agents (46-49).   
Consequently, improved imaging of PCa 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(50, 51).  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(50, 51).  Studies 
show that GRPr is expressed at very low levels in normal prostate glands but is increased in 
45-100% of human PCa (52, 53).  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 (54).  GRPr proteins are highly overexpressed in several 
human tumors, including PCa (55).  Because of their low expression in BPH and inflammatory 
prostatic tissues (56, 57), 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 PCa with high GRPr expression (58).  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 (59) and mean effective doses comparable with other radiopharmaceuticals (60, 
61).  Preliminary data indicate encouraging potential for their future use at initial diagnosis of PCa 
(59-63). 
Efficacy assessment:  a major unsolved question.  Unlike after prostatectomy, where PSA 
levels fall to zero soon after successful surgery, after local targeted therapy (HIFU) 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 ablation or 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% for clinical recurrence, 
respectively (64).  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 (65).  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.  Cancer recurrence after 
focal ablation can be managed with repeat ablation or whole-gland treatment with surgery or 
radiation.  This potential ability to retreat further highlights the need for sensitive surveillance 
methods after initial treatment. 

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Can mpMRI also help find recurrence or residual tumor after local targeted therapy? It is much 
more difficult to interpret mrMRI after treatment (66).  For example, after ablation, resolving 
hemorrhage and proteinaceous necrosis can cause variable diffusion restriction, and inflammation 
can cause contrast enhancement (67). 
Simultaneous PET/MRI:  PET/MRI is an advanced hybrid 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 (68).  PET/MRI is particularly important 
for accurate localization and assessment of the extent of disease in the pelvis in the initial staging of 
PCa.  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 (69). 
In summary, without ways to answer:  “Was my cancer adequately treated?”, 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. 
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 
. 
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 aim: 
To evaluate 68Ga-PSMA-11 PET/MRI and 68Ga-RM2 PET/MRI for evaluation of HIFU local therapy 
in patients with known prostate cancer. 
68Ga-RM2 PET/MRI at Stanford University:  Under an FDA-approved IND (IND 
) our group 
completed the evaluation of 68Ga-RM2 PET/MRI in 32 patients with biochemical recurrence of PCa 
and negative conventional imaging (bone scintigraphy and CT or MRI) (70).  PET/MRI images were 
acquired at 42-51 minutes (mean ± SD:  47.2 ± 3.2) after injection of 3.6 to 4.1 mCi (mean ± SD:  
3.7 ± 0.2) of 68Ga-RM2.  68Ga-RM2 PET findings were compatible with recurrent PCa in 23 of the 
32 participants (including in the prostate).  Conventional MRI identified findings compatible with 
recurrent PCa in only 11 of the 32 participants.  PET findings were confirmed by biopsy in 
(7 of 23, 30.4%) or clinical follow-up (16 of 23, 69.6%).  The duration of follow-up was 
3 to 25 months (mean ± SD:  17 ± 5.2).  PSA velocity values were 0.32 ± 0.59 ng/mL/year (range:  
0.04 to 1.9) in patients with negative PET scans and 2.51 ± 2.16 ng/mL/year (range:  0.13 to 8.68) 
in patients with positive PET scans (P = 0.006).   

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In addition, we now have pilot data from 12 participants with intermediate or high risk prostate 
cancer scheduled to undergo prostatectomy and nodal dissection who had 68Ga-RM2 PET/CT prior 
to surgery.  Prostate cancer was identified in all 12 patients.
Figure 1:  68 year-old man (participant #2) with recently diagnosed intermediate risk, T1c, Gleason 3+4 
prostate cancer presenting with PSA of 4.53 ng/mL.  Maximum intensity projection (MIP) RM2 PET image (A), 
transaxial PET (B) and fused transaxial PET (C) showed focal uptake in histopathological proven prostate 
cancer (D).
68Ga PSMA-11 PET/MRI 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 conducted a 
prospective study under IND 128379 and enrolled 33 men with intermediate and high risk newly 
diagnosed PCa, scheduled to undergo prostatectomy and pelvic nodal dissection (71).  68Ga 
PSMA-11 PET identified intraprostatic cancer foci in all 33 patients, whereas mpMRI alone 
identified PIRADS 4 or 5 lesions in 26 patients and PIRADS 3 lesions in 4 patients.  68Ga PSMA-11 
PET showed focal uptake in pelvic lymph nodes in five patients.  Final pathology confirmed cancer 
in the prostate of all patients, as well as nodal metastasis in three.  No patient with normal pelvic 
nodes on PET/MRI had metastases on pathology.  An example is shown in Figure 3.

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Figure 2:  74 year-old man (participant #4) with recently diagnosed intermediate risk, T1c, Gleason 4+4 
prostate cancer presenting with PSA of 4.12 ng/mL.  Maximum intensity projection (MIP) PSMA PET image 
(A), early transaxial PET (B) and delayed transaxial PET (C) showed focal uptake in histopathological proven 
prostate cancer (F).  The milder focal uptake in the left lobe was likewise proven to be prostate cancer.  
Transaxial T2-weighted MRI (D) and DWI (B = 800) MRI (E) are also shown. 
68Ga-RM2 vs 68Ga PSMA-11 at Stanford University:  We completed a pilot comparison of 
68Ga-PSMA-11 (IND 
) with 68Ga-RM2 (72).  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.  The fact that 68Ga-RM2 shows similar sensitivity to 
68Ga-PSMA, and provides higher lesion conspicuity due to the lack of significant hepatobiliary 
clearance is a promising result for a radiopharmaceutical that is complementary to 68Ga-PSMA 
(Figure 3).   
While the over-expression of PSMA is ubiquitous in prostate cancer, it is not universal and there will 
be lesions not detected by PSMA-targeted imaging in different risk classes or stages of disease.  
The influence of GRPr expression on cancer grade and stage is not clear.  Nagasaki et al.  (73) 
found that GRPr expression was correlated with higher Gleason score, but another study found that 
it was inversely correlated with Gleason score, preoperative PSA concentration, and tumor size 
(57).  Therefore, the indication (ie, low- vs intermediate- vs high-risk, early- vs late-stage of disease) 
to use PSMA- vs GRPR-targeted imaging or both is an active focus of research.  Until more data is 

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available, scanning using both PET radiopharmaceuticals will ensure appropriate evaluation of PCa 
patients. 
 
Figure 3:  83-year-old man presenting with confirmed Gleason 5+4 PCa and treated with intensity-modulated 
radiotherapy and androgen blockade.  Follow up at 40 months showed positive 68Ga-RM2 and 68Ga-PSMA-11 
(both showing retroperitoneal lymph nodes) while all other studies were negative). 
We also have an example of a patient with local recurrence of PCa treated with brachytherapy 
showing resolution of 68Ga-RM2 uptake in the prostate bed (Figure 4). 
 
Figure 4:  72 year-old man with history of Gleason 3+4 PCa treated with radiation and hormonal therapy, 
presenting with PSA of 3.7 ng/mL.  Maximum intensity projection (MIP) 68Ga-RM2 PET image before (A) and 
after (B) radiation treatment demonstrate resolution of prostate bed uptake (arrow).  

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In summary, GRPr and PSMA expression is increased in PCa.  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 PCa and we will attempt to evaluate response to targeted local therapy. 
Our hypothesis is that the use of 68Ga-RM2 and 68Ga-PSMA-11 PET/MRI will permit accurate 
localization of PCa at initial diagnosis and allow for evaluation of response to treatment.  We will 
use a state of the art simultaneous PET/MRI scanner with time of flight ability whose first world-wide 
installation was at Stanford University in December 2013. 
2.5 Study Design 
This is a pilot study with a total of 20 participants with known prostate cancer, scheduled to undergo 
HIFU local therapy.  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.  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)   

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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. 
The above will be repeated approximately 6 months after HIFU local treatment, prior to standard of 
care biopsy to evaluate for residual disease in the prostate. 
Objectives of the Study 
Primary Objective 
• 
To determine feasibility of 68Ga-PSMA-11 PET/MRI and 68Ga-RM2 PET/MRI for 
evaluation of HIFU local therapy in patients with known prostate cancer. 
Secondary Objective 
• 
None 
ExploratoryObjectives 
• 
Comparison of 68Ga-PSMA-11 post-treatment uptake and pre-post change in uptake in 
response to HIFU local therapy 
• 
Comparison of 68Ga-RM2 post-treatment uptake and pre-post change in uptake in 
response to HIFU local therapy 
Endpoints 
Primary Endpoints 
• 
Number of participants with assessable pre- and post-treatment uptake in response to 
HIFU local therapy 
Secondary Endpoint 
• 
None 
Exploratory Endpoints 
• 
Pre- and post-treatment 68Ga-PSMA-11 SUVmax and pre-post change in SUVmax after 
HIFU local therapy 
• 
Pre- and post-treatment 68Ga-RM2 SUVmax and pre-post change in SUVmax after HIFU 
local therapy 

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3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria 
• 
≥ 18 years-old 
• 
Known prostate cancer 
• 
Planned HIFU local therapy 
• 
Able to provide written consent 
• 
Karnofsky performance status of ≥ 50 (or ECOG/WHO equivalent) 
3.2 Exclusion Criteria 
• 
Patients not capable of getting PET study due to weight, claustrophobia, or inability to 
lay still for the duration of the exam 
• 
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 12 months from the time the the last subject completes the 
first scan. 
3.4.2  Study Completion: 
The study will reach study completion 66 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 
activity of 7 mCi and the higher of the reported dosimetry values.  Therefore, 
259 mBq x 0.0258 mSv/MBq = 6.68 mSv. 

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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) (74-77).   
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 (78).  
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) (74-77). 
4.2 Source of the Study Agent  
Molecular Imaging Program at Stanford (MIPS) 
Satellite Radiochemistry Facility  
300 Pasteur Dr, 
 
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 
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 

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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 HIFU local treatment, prior to standard of 
care biopsy to evaluate for residual disease in the prostate. 
5.3 Image interpretation 
The PET/MRI scans will be interpreted by ABNM certified Nuclear Medicine physicians and an ABR 
certified Radiologists.  Drs Iagaru, Daniel, Davidzon, and Ghanouni 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. 
Additional imaging/biopsy may be performed as a result of the research scan data. 
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 

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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 HIFU 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 12 months from initial scan date.  If a subject transfers clinical 
care from Stanford Healthcare, investigators may request records from the treating physician.  

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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 

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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 Study Endpoints 
Primary endpoint:  
• 
Number of the 20 participants with assessable pre- and post-treatment uptake (on either 
type) in response to HIFU local therapy. 
"Assessable uptake" on a scan is defined as being successfully able to:  
1. Appreciate the presence/absence of localized uptake (a "lesion"), and  
2. Produce an SUVmax measurement for that ROI.  
The rationale is that if both pre- and post-treatment uptake are assessable, then (presumably) 
changes in (1) and (2) have the potential to be used to evaluate treatment response in future trials. 
A patient may be assessable on the 68Ga-PSMA-11 scan but not the 68Ga-RM2-11 scan, and 
vice-versa. 
Thus we will tabulate findings as below: 
SCAN TYPE 
 
                        ------- 68Ga-PSMA-11 ---------                           -------- 68Ga-RM2-11 --------     
                     --- Pre-TX --       --- Post-Tx ---                          --- Pre-TX --     -- Post-Tx ---    
Patient #     Seen? SUVmax?  Seen? SUVmax?                  Seen? SUVmax?  Seen?  SUVmax?  
      1 
      2 
      3 
      . 
      . 
      . 
     20 
The number of patients assessable on either (or both) types of scan is the primary endpoint; if at 
least 10 of the 20 patients are assessable on at least one type of scan, then the study will be 
deemed a success. 
Secondary endpoint:  
• 
None  

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Exploratory endpoints: 
• 
Pre- and post-treatment 68Ga--PSMA--11 SUVmax and pre-post change in SUVmax after 
HIFU local therapy 
• 
Pre- and post-treatment 68Ga-RM2 SUVmax and pre-post change in SUVmax - after HIFU 
local therapy 
10.2 Accrual estimates 
We anticipate enrolling 20 patients in total.  We expect 1 to 2 patients to have residual tumor after 
HIFU.  
10.3 Study Outcomes (ClinicalTrials.gov) 
Primary Outcome 
Title:  Successful PET-based of Assessment of Local Theraeputic Response   
Description:  Therapeutic response to high-intensity focused ultrasound (HIFU) will be 
assessed by 68Ga-PSMA11 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 HIFU is successfully obtained.  
Timeframe:  12 months  
Safety outcome:  No  
Secondary Outcome 
None.  
10.4 Analyses Plans 
This is a pilot study that will not have pre--defined analyses plans, other than the described 
assessment for the number of participants for which a PET--based therapeutic response to HIFU 
successfully obtained.  We will compare the changes in SUVmax after HIFU local thearpy with 
results of biopsy done as standard of care at 6 months post-treatment, as well as with PSA values 
done every 3 months afterwards (ie, a decrease in uptake is expected to predict response, while 
stable or increased uptake is expected to indicate no response to HIFU local therapy).  Data from 
2 arms (68Ga-PSMA11 done first or 68Ga-RM2 done first) will be aggregated.  In the case that the 
treatment has worked to extent that the primary tumor is no longer visible, the disappearance will be 
detectable because of the correspondence between pre and post ROIs.  In that case, we will 
consider the tumor assessable, and record the SUVmax as the ROI background.  
There is no analysis beyond noting whether the total number of assessable patients meets or 
exceeds the threshold for success (10 of 20).  
10.5 Accrual estimates 
We expect the accrual of 5 patients each year for 4 years.  This is achievable given our experience 
with other protocols and the support from the referring physicians, Drs Buyyounouski, Ghanouni, 
and Sonn.   

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Inclusion/Exclusion Criteria Checklist 
Protocol Title: 
A Pilot Study of 68Ga-PSMA-11 PET/MRI and 68Ga-RM2 PET/MRI for 
Evaluation of Prostate Cancer Response to HIFU Therapy  
Protocol Number: 
IRB-48213  /  PROS0093  
Principal Investigator: 
Andrei Iagaru, MD 
3.1 Inclusion Criteria 
Inclusion Criteria  
Yes must be checked to be eligible 
Yes 
No 
Supporting 
Documentation 
1. ≥ 18 years-old 
☐ 
☐ 
 
2. Known prostate cancer 
☐ 
☐ 
 
3. Planned HIFU local therapy 
☐ 
☐ 
 
4. Able to provide written consent 
☐ 
☐ 
 
5. Karnofsky performance status of ≥ 50 (or 
ECOG/WHO equivalent) 
☐ 
☐ 
 
3.2 Exclusion Criteria 
Exclusion Criteria  
No must be checked to be eligible 
Yes 
No 
Supporting 
Documentation 
1. Patients not capable of getting PET study due to 
weight, claustrophobia, or inability to lay still for the 
duration of the exam 
☐ 
☐ 
 
2. 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-48213 
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CONFIDENTIAL 
Protocol version 04 January 2022 
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: