68Ga-RM2 PET/MRI in the Evaluation of Patients With Biochemical Recurrence of Prostate Cancer and Non-contributory CT Scans
Phase: PHASE2
Conditions: Prostate Adenocarcinoma
Sponsor: Andrei Iagaru

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68Ga-RM2 PET/MRI in the Evaluation of Patients with Biochemical Recurrence of Prostate 
Cancer and Non-Contributory CT Scans 
Principal Investigator: 
Andrei Iagaru, MD 
300 Pasteur Drive, Room H-2230 
Stanford, CA 94305 
Phone: 650-725-4711 
Fax: 650-498-5047 
Email: aiagaru@stanford.edu  
Co-investigators: 
Bruce Daniel, MD, PhD 
300 Pasteur Dr H1307 MC 5621  
Stanford, CA 94305  
Phone: 650-725-1812 
Email: bdaniel@stanford.edu  
Steven Hancock, MD 
875 Blake Wilbur Dr, Clinic D  
Stanford, CA 94305  
Phone: 650-723-6171 
Email: shancock@stanford.edu  
Andreas Loening, MD, PhD 
300 Pasteur Dr, H1307 MC 5105  
Stanford, CA 94305  
Phone: 650-723-7816 
Email: loaning@stanford.edu  
Guido Davidzon, MD 
300 Pasteur Drive, Room H-2230 
Stanford, CA 94305 
Phone: 650-725-4711 
Email: gdavidzon@stanford.edu  
Geoffrey Sonn, MD 
875 Blake Wilbur Dr, Clinic E  
Stanford, CA 94305 
Phone: 650-725-5544 
Email: gsonn@stanford.edu  
Sandy Srinivas, MD 
875 Blake Wilbur Dr, Clinic E  
Stanford, CA 94305 
Phone: 650-724-8372 
Email: sandysri@stanford.edu  
Shreyas Vasanawala, MD, PhD 
725 Welch Rd, St 1679 MC 5913  
Palo Alto, CA94304 
Phone: 650-724-9824 
Email: vasanawala@stanford.edu 
 
Biostatistician 
Jarrett Rosenberg, PhD 
1201 Welch Road, Room P-280 
Stanford, CA 94305 
Phone: 650-724-3289 
Email: Jarrett.rosenberg@stanford.edu  
Study Coordinator 
Jordan Cisneros, BS 
800 Welch Road 
Phone: 650-725-6409 
Email: jordan.cisneros@stanford.edu  
Protocol IRB-35155  //   PROS0074  //  NCT02624518  
Protocol Version 13/ Version Date: 30 April 2019  

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................ 3 
SCHEMA .................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................... 4 
1. OBJECTIVES ...................................................................................................................... 5 
2. BACKGROUND ................................................................................................................... 5 
2.1 Preliminary information .............................................................................................. 5 
2.2 Study Agent ................................................................................................................. 7 
2.3 Clinicaltrials.gov ......................................................................................................... 7 
2.4 Rationale ...................................................................................................................... 7 
2.5 Study Design ............................................................................................................... 9 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .................................... 9 
3.1 Inclusion Criteria ......................................................................................................... 9 
3.2 Exclusion Criteria...................................................................................................... 10 
3.3 Informed Consent Process ....................................................................................... 10 
3.4 Study Timeline .......................................................................................................... 10 
4. IMAGING AGENT INFORMATION .................................................................................... 10 
4.1 Study Agent ............................................................................................................... 10 
4.2 Specify the source of the study agent. .................................................................... 12 
4.3 Describe how the agent will be requested and provide mailing address and phone 
number. ........................................................................................................................... 12 
4.4 Agent Accountability ................................................................................................ 12 
5. IMAGING SPECIFICS ....................................................................................................... 12 
5.1 
Modality or Modalities to be used ......................................................................... 12 
5.2 
Details of Imaging (i.e. dynamic, static, number of scans, etc.) ......................... 12 
5.3 
Details of processing/analysis .............................................................................. 13 
6. STUDY PROCEDURES .................................................................................................... 13 
6.1 
Criteria for Removal from Study ........................................................................... 13 
6.2 
Alternatives ............................................................................................................ 13 
7. STUDY CALENDAR .......................................................................................................... 13 
8. ADVERSE EVENTS AND REPORTING PROCEDURES .................................................. 13 
8.1 Potential Adverse Events ......................................................................................... 13 
8.2 Adverse Event Reporting ......................................................................................... 14 
9. REGULATORY CONSIDERATIONS ................................................................................. 14 
9.1 Institutional Review of Protocol ............................................................................... 14 
9.2 Data Management Plan ............................................................................................. 14 
10. 
MEASUREMENTS .................................................................................................... 15 
10.1 Primary outcome measure ..................................................................................... 15 
10.2 Measurement Methods ........................................................................................... 15 
10.3 Measurement Time Points ...................................................................................... 15 
11. 
STATISTICAL CONSIDERATIONS ........................................................................... 15 
11.1  Statistical Design ................................................................................................... 15 
11.2  Randomization ....................................................................................................... 15 
11.3  Interim analyses ..................................................................................................... 15 
11.4  Key variables .......................................................................................................... 15 
11.5  Sample Size ............................................................................................................ 15 
11.6  Accrual estimates .................................................................................................. 16 
APPENDIX:  Inclusion/Exclusion Criteria Checklist ........................................................... 16 
REFERENCES: ................................................................................................................ 17 
 

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PROTOCOL SYNOPSIS 
 
TITLE 
68Ga-RM2 PET/MRI in Patients with Biochemically 
Recurrent Prostate Cancer and Non-Contributory 
Conventional Imaging 
STUDY PHASE 
Phase 2-3 
INDICATION 
Prostate cancer 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
68Ga-RM2 
PRIMARY OBJECTIVE(S) 
To evaluate 68Ga-RM2 (formerly known as 
68Ga Bombesin or BAY 86-7548) PET/MRI for 
detection of recurrent prostate cancer after initial 
therapy in patients with elevated PSA and 
non-contributory computed tomography (CT). 
SAMPLE SIZE  
125 participants 
STATISTICAL CONSIDERATIONS 
Prospective single center, single-arm study.  
HYPOTHESES 
1. At least 30% of patients will have one or more 
lesions detected on PET/MR. 
2. PET/MR sensitivity will be higher than MR alone. 
STATISTICAL TEST 
McNemar tests of paired proportions for sensitivity 
and specificity. 
STATISTICAL POWER AND SAMPLE SIZE 
We expect that roughly 50% of patients will have 
lesions (as determined by biopsy or follow-up).  
Assuming a difference in sensitivity for PET/MRI 
and MRI of 20 percentage points (eg, 70% vs 50%), 
a sample of 60 diseased patients will provide 90% 
power at 5% error to detect such a difference.  
Assuming a difference in specificity for PET/MRI 
and MRI of 20 percentage points (eg, 70% vs 90%), 
a sample of 60 non-diseased patients will provide 
98% power at 5% error to detect such a difference. 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Ga-68 
Gallium-68 
IRB 
Institutional Review Board 
IV 
Intravenous 
PET/MRI 
Positron emission tomography – magnetic resonance imaging 
SUV 
Standardized Uptake Value 
GRPr 
Gastrin releasing peptide receptor 
Eligible participant with prostate cancer 
68Ga-RM2 PET/MRI 

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1. OBJECTIVE 
Specific Aim 
To evaluate 68Ga-RM2 (formerly known as DOTA Bombesin or BAY 86-7548) PET/MRI for 
detection of recurrent prostate cancer after initial therapy in patients with elevated PSA and 
non-contributory computed tomography (CT). 
2. BACKGROUND 
2.1 Preliminary information 
Prostate cancer (PC) remains the most-common non-cutaneous cancer diagnosed in American 
males, accounting for an estimated 174,560 estimated new cases and 31,620 estimated deaths in 
2019 (1).   Subsequent treatment is multifaceted and may involve observation, surgery 
(prostatectomy), radiation therapy (external beam or brachytherapy), hormonal therapy, 
chemotherapy, or a combination of these (2-4).  
Up to 40% of the patients with prostate cancer develop biochemical recurrence within 10 years 
after initial treatment (5).  Usually an increase of the PSA-level precedes a clinically detectable 
recurrence by months to years (6).  However, it cannot differentiate between local, regional or 
systemic disease with the necessary precision that is essential for further disease management 
(7).  
Morphological imaging methods exhibit considerable limitations:  sensitivity ranges between 25% 
and 54% for the detection of local recurrence by transrectal ultrasound (TRUS) or 
contrast-enhanced CT and is moderately improved by using functional MRI techniques (7-9).  The 
sensitivity for detection of lymph node metastases of CT or MRI is reported to be 30 to 80% (10). 
Ultra-small particles of iron oxides (USPIOs) proved to be very effective, but are yet to be 
approved by regulatory authorities (11).  Bone metastases presenting as osteoblastic lesions can 
be effectively detected by bone scintigraphy, PET, CT and MRI (12,13). 
Various targets have been addressed by molecular imaging to improve the detection of recurrent 
prostate cancer. PET tracers such as 18F- or 11C-labeled choline and 11C-acetate have been 
investigated for the diagnosis of recurrent (14-16) prostate cancer.  Their feasibility in primary 
diagnosis is limited because of uptake in benign tissue such as benign prostatic hyperplasia or 
inflammatory lymph nodes (17,18).  In addition, fluorinated versions are not available in the United 
States, while 11C-labeled tracers cannot be widely used due to the requirement for an on-site 
cyclotron due to the short half-life.  18F-FACBC, a new synthetic amino acid, might be superior 
when compared to 11C-choline PET/CT (19).  owever, recent work indicates that 18F-FACBC 
uptake in prostate cancer is similar to that in BPH nodules (20). Prostate-specific membrane 
antigen (PSMA) continues to elicit high interest.  This cell surface protein is significantly 
overexpressed in prostate cancer cells when compared to other PSMA-expressing tissues such as 
kidney, proximal small intestine or salivary glands.  It therefore provides a promising target for 
prostate cancer-specific imaging.  
Recently methods have been developed to label PSMA ligands with 68Ga and 18F. Initial 
experience suggests that these novel tracers can detect prostate cancer relapses and metastases 
with high contrast by binding to the extracellular domain of PSMA, followed by internalization 
(21,22). However, these promising agents do not detect all recurrences.  
Consequently, improved imaging of biochemically recurrent prostate cancer continues to be an 
area of unmet clinical need.  68Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-
Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (68Ga-DOTA-Bombesin or 68Ga-RM2, formerly also known as 
BAY86-7548) is a synthetic bombesin receptor antagonist, which targets gastrin-releasing peptide 

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receptors (GRPr) (23).  GRPr proteins are highly overexpressed in several human tumors, 
including prostate cancer (24).  Because of their low expression in BPH and inflammatory prostatic 
tissues (25,26), 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 prostate cancer with high GRPr expression (27). 
We conducted a pilot phase evaluation of 68Ga-RM2 under an RDRC-approved protocol at 
Stanford University.  Ten men (age range:  60 to 83 year-old;  mean ± SD: 73.1 ± 6.9) with 
biochemical recurrence of prostate cancer (PSA range:  3.7 to 36.4; mean ± SD: 12.5 ± 9.8) were 
enrolled.  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.  The uptake of 68Ga-RM2 was 
identified as described in previously published studies referenced above. All participants had 
multiple standard of care imaging studies (CT, MRI, 18F FDG PET/CT, 18F-NaF PET/CT, 99mTc 
MDP bone scan) prior to enrollment that were non-contributory, despite rising PSA values.  The 
time from conventional imaging to enrollment in the protocol ranged 10 to 107 days (mean ± SD:  
43.3 ± 26.0).  One participant also had 11C Acetate and 11C-Choline at other institutions in the 
setting of rising PSA (2.72 ng/mL and 3.63 ng/mL, respectively).  Both scans were negative for 
recurrent prostate cancer lesions.  The participants did not receive treatment in this interval as 
they were managed under a wait and watch strategy due to no identifiable disease.  The interval 
from biochemical recurrence to the 68Ga-RM2 PET/MRI scan ranged 5 to 75 months (mean ± SD:  
30.8 ± 20.4). This pilot data (28) also showed distinct biodistribution and lesion localization 
between 68Ga-RM2 and 68Ga-PSMA11 due to non-overlapping underlying biology. 
Biodistribution and localization of 68Ga-RM2 
All participants tolerated the procedure without immediate or delayed (up to 7 days) complaints or 
complications.  Table 2 shows the 68Ga-RM2 uptake (SUVmax and SUVmean) in normal tissues.  The 
areas with the highest 68Ga-RM2 accumulation are the pancreas (mean SUVmax:  52.0 ± 16.7 
[range:  36.8 to 93.8] and SUVmean:  33.2 ± 17.5 [range:  8.8 to 66.1]) and bladder (mean SUVmax:  
121.6 ± 67.5 [range:  32.6 to 220.7] and SUVmean:  93.8 ± 59.7 [range:  29.8 to 195.7]), while 
moderate uptake was noted in the blood pool (mean SUVmax:  2.3 ± 0.7 [range:  1.8 to 4.0] and 
SUVmean:  1.3 ± 0.7 [range:  0.7 to 2.7]), stomach (mean SUVmax:  2.5 ± 0.7 [range:  1.3 to 3.7] and 
SUVmean:  1.3 ± 0.5 [range:  0.6 to 1.9]), small bowel  (mean SUVmax:  2.4 ± 0.6 [range:  1.7 to 3.3] 
and SUVmean:  1.4 ± 0.5 [range:  0.7 to 2.3])and colon (mean SUVmax:  2.0 ± 0.7 [range:  1.3 to 3.8] 
and SUVmean:  1.0 ± 0.6 [range:  0.5 to 2.3]). The liver had low 68Ga-RM2 uptake with SUVmean of 
less than 1.0. There were no differences between the 68Ga-RM2 biodistribution at 45 minutes 
post-injection among the 10 participants (Figure 1). The pattern of 68Ga-RM2 uptake is similar to 
previous reports (29,30). 
68Ga-RM2 uptake outside the expected physiologic biodistribution 
One case had no focal 68Ga-RM2 uptake outside the expected physiologic biodistribution. The 
remaining 9 participants had 28 areas of high 68Ga-RM2 uptake (up to 10 areas were recorded per 
participant) that corresponded to retroperitoneal lymph nodes (n = 10), bone marrow (n = 7), 
mediastinal lymph nodes (n = 3), pelvic lymph nodes (n = 2), seminal vesicle (n = 2), subclavian 
lymph node (n = 1), mesenteric lymph node (n = 1) and prostate bed (n = 1) on the MRI images. 
These areas of high 68Ga-RM2 uptake had SUVmax of 13.4 ± 8.3 (range:  2.6 to 33.5) and SUVmean 
of 6.7 ± 3.9 (range:  1.7 to 16.1), above the background and easily identifiable given the lack of 
hepato-biliary clearance.  

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Figure 1: Maximum intensity projection (MIP) images from 5 participants in the pilot study conducted at 
Stanford University. Arrows mark suspected recurrent prostate cancer; high uptake in the pancreas is due to 
known over-expression of GRPr. 
The mean diameter of lymph nodes with high 68Ga-RM2 uptake was 1.3 ± 0.8 cm (range: 
0.4 to 2.9 cm).  PSA was 6.7 ng/mL in the patient with no focal 68Ga-RM2 uptake outside the 
expected physiologic biodistribution and ranged 3.7 to 36.4 (mean ± SD: 13.1 ± 10.2) for the other 
patients.  
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) (31). 
These participants will not be evaluated in the current analysis. 
2.2 Study Agent 
We will use 68Ga-RM2, formerly also known as 68Ga-DOTA Bombesin or BAY86-7548 as the PET 
radiopharmaceutical. This is not an FDA-approved product, but we have a FDA-approved IND 
(127137) allowing the use of this tracer in this proposed clinical indication. 
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 
bombesin receptor antagonist, 68Ga-RM2, which has high affinity for gastrin-releasing peptide 

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receptors. GRPr proteins are highly overexpressed in several human tumors, including prostate 
cancer (24). Because of their low expression in BPH and inflammatory prostatic tissues (25,26), 
imaging of GRPr has the potential to improve the lesion detection in prostate cancer. Therefore, 
we propose the following aim: 
 
To evaluate 68Ga-RM2 (68Ga-DOTA-Bombesin) PET/MRI for detection of recurrent prostate 
cancer after initial therapy in patients with elevated PSA (> 2 ng/mL) and non-contributory 
computed tomography (CT). 
 
Figure 2. Chemical structure of 68Ga-DOTA-Bombesin 
 
The first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, 
biodistribution, and radiation dosimetry of 68Ga-RM2.  Five healthy men underwent dynamic 
whole-body PET/CT after an intravenous injection of 68Ga-RM2 (138 ± 5 MBq).  Besides total 
radioactivity, plasma samples were analyzed by radio–high-performance liquid chromatography 
for metabolism of the tracer.  Dosimetry was calculated using the OLINDA/EXM software.  The 
organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the 
pancreas (0.51 mSv/MBq).  The mean effective dose was 0.051 mSv/MBq. 68Ga-RM2 was well 
tolerated by all subjects.  The authors concluded that the intravenously injected 68Ga-RM2 is safe, 
and rapid metabolism is demonstrated.  A 150-MBq injection of 68Ga-RM2 results in an effective 
dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids (29).  
 
Figure 3: Coronal (A) and axial views (B and C) of 68Ga-RM2 PET/CT in patient no. 8 with prostate cancer 
metastasis to multiple lymph nodes. Two normal-sized (less than 10 mm) nodes above the aortic bifurcation 
indicated with red arrow showed increased uptake of tracer, SUVmax 6.2 and 6.3. In addition, one left 
parailiac node, SUVmax 12.7, (B) and two right parailiac nodes, SUVmax 6.1 and 4.7, (C) showed 

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increased uptake of 68Ga-RM2. These five lymph nodes were histologically confirmed as metastases at 
surgery. Green arrows point to ureters, which can be easily distinguished on anatomic CT. 
 
In the first study with 68Ga-RM2 in patients with prostate cancer, 14 men scheduled for radical 
prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) 
were enrolled.  The patients received an intravenous injection of 68Ga-RM2 followed by over 
60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging 
(n = 14).  The visual assessment of PET/CT images included evaluation of intraprostatic (12 
subsextants) and pelvic nodal uptake of 68Ga-RM2 in 11 surgical patients and detection of 
potential metastatic foci in all patients.  In patients with biochemical recurrence, results were 
compared with those of either 11C-acetate (n = 2) or 18F-fluoromethylcholine (n = 1) PET/CT.  The 
authors reported a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for 
detection of primary prostate cancer and sensitivity of 70% for metastatic lymph nodes using 
histology as gold standard (30). 
2.5 Study Design 
This is a prospective, single center, single-arm study enrolling 125 participants with prostate 
cancer.  Eligible participants will undergo baseline assessments at enrollment.  Study participants 
will receive 68Ga-RM2 and undergo a PET/MRI scan.  All patients will first be seen by a Stanford 
Cancer Institute physician and then referred if appropriate on clinical grounds to Dr. Iagaru or his 
colleagues for this study.  The following steps will take place. 
1. Participant will be asked to drink 1 to 2 glasses of water before arrival at the clinic 
2. Participants will be weighed and vital signs (heart rate, blood pressure, respiratory rate, pulse 
oxymetry) will be recorded 
3. Participant will be injected i.v. with 140 MBq of 68Ga-RM2 
4. Participant will void immediately prior to the scan 
5. Approximately 45 minutes after the radiopharmaceutical i.v. 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 3–5 table 
positions at a 4-min acquisition time per table position. 
6. Participants will be given a copy of the consent form s/he signed and will be dismissed. 
7. Vital signs (heart rate, blood pressure, respiratory rate, pulse oxymetry) will be recorded again 
at the completion of the study. 
8. Participants will be contacted at 24 to 48 hours following the scan in order to capture potential 
late occurring Adverse Events. 
The 68Ga-RM2 PET/MRI may be repeated at the completion of treatment to evaluate response to 
therapy, if requested by the treating physician.  
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria 
1. Biopsy proven prostate adenocarcinoma 
2. Rising PSA after definitive therapy with prostatectomy or radiation therapy (external beam 
or brachytherapy) 
a. Post radical prostatectomy (RP) – AUA recommendation (32) 

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i. PSA greater than 0.2 ng/mL measured after at least 6 weeks from radical 
prostatectomy 
ii. Confirmatory persistent PSA greater than 0.2 ng/mL (total of two PSA 
measurements greater than 0.2 ng/mL)  
b. Post-radiation therapy –ASTRO-Phoenix consensus definition (33) 
A rise of PSA measurement  
3. No evidence of metastatic disease on conventional imaging, including a negative bone 
scan for skeletal metastasis and negative CT scan, with or without contrast. NaF PET CT 
can substitute for separate bone scan and CT. CT in Axumin (also known as 18F FACBC 
or 18F Fluciclovine) can substitute for separate CT. 
4. Able to provide written consent 
5. Karnofsky performance status of 50 (or ECOG/WHO equivalent) 
3.2 Exclusion Criteria 
1. Less than 18 years-old at the time of radiotracer administration 
2. Unable to provide informed consent  
3. Inability to lie still for the entire imaging time  
4. Inability to complete the needed investigational and standard-of-care imaging examinations 
due to other reasons (severe claustrophobia, radiation phobia, etc.) 
5. Any additional medical condition, serious intercurrent illness, or other extenuating 
circumstance that, in the opinion of the Investigator, may significantly interfere with study 
compliance 
6. 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 36 months from the time the study opens to accrual. 
3.4.2. Study Completion: 
The study will reach study completion 48 months from the time the study opens to accrual. 
4. IMAGING AGENT INFORMATION 
4.1 Study Agent  
We will use 68Ga-RM2 as the PET radiopharmaceutical. The administered dosage is 140 MBq i.v. 
Effective Doses (ED) of [68Ga]-DOTA Bombesin as calculated using OLINDA for the 
hermaphroditic male model, ranged between 0.028mSv/MBq and 0.051mSv/MBq depending on 
the bladder-voiding interval (0.75h, 1h or 2h). Consequently, the urinary bladder wall was the 
main contributor to the ED followed by the lower large intestinal wall, the gonads and the 

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stomach wall. Based on the fact that human pancreas expresses only low levels of GRPr in 
contrast to mouse and rat pancreas, which demonstrate extremely high expression levels, 
pancreas data of the biodistribution were not taken into account (but contributed to the remainder 
of the body). 
Table 1: Effective Doses and whole body doses for a 140 MBq 68Ga-DOTA-RM2 or 300 MBq 
18F FDG PET scan 
Tracer 
ED (mSv/ MBq) 
Whole Body Dose  
PET scan 
Whole Body Dose 
PET/ CT scan * 
[68Ga]DOTA-RM2  
(0.75h-void.)  
0.028 
3.92 mSv (140 MBq) 
6.92 mSv 
[68Ga]DOTA-RM2 
(1h-void.)  
0.034 
4.76 mSv (140 MBq) 
7.76 mSv 
[68Ga]DOTA-RM2 
(2h-void.)  
0.051 
7.14 mSv (140 MBq) 
10.14 mSv 
[18F]-FDG  
0.019** 
5.70 mSv (300 MBq) 
8.70 mSv 
* Low dose CT yields a dose of appr. 3 mSv (Brix et al.) 
** ICRP-80 
Measured human dosimetry data are available from published data (30) and presented below. 
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 estimations of the absorbed doses are reported in Table 2.  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). 
Table 2: Dose Equivalent estimates (mSv/MBq) after injection of 68Ga-RM2 (n = 5) 
Organ 
Mean 
SD 
Minimum 
Maximum 
Adrenals 
0.011 
0.00080 
0.010 
0.012 
Brain 
0.0056 
0.00051 
0.0049 
0.0061 
Breasts 
0.0060 
0.00048 
0.0053 
0.0064 
Gallbladder wall 
0.011 
0.00054 
0.0099 
0.011 
Lower large intestine wall 
0.014 
0.00036 
0.013 
0.014 
Small intestine 
0.010 
0.00032 
0.0096 
0.010 
Stomach wall 
0.038 
0.0090 
0.027 
0.045 
Upper large intestine wall 
0.0094 
0.00037 
0.0089 
0.0098 
Heart wall 
0.028 
0.0030 
0.023 
0.031 
Kidneys 
0.081 
0.011 
0.067 
0.096 
Liver 
0.023 
0.0035 
0.019 
0.028 
Lungs 
0.0071 
0.00048 
0.0064 
0.0076 
Muscle 
0.0082 
0.00038 
0.0077 
0.0086 
Pancreas 
0.51 
0.16 
0.32 
0.73 
Red marrow 
0.013 
0.0087 
0.0068 
0.026 
Osteogenic cells 
0.013 
0.0051 
0.0092 
0.021 

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Table 2: Dose Equivalent estimates (mSv/MBq) after injection of 68Ga-RM2 (n = 5) 
Organ 
Mean 
SD 
Minimum 
Maximum 
Salivary glands 
0.022 
0.0022 
0.020 
0.026 
Skin 
0.0060 
0.00044 
0.0055 
0.0065 
Spleen 
0.023 
0.0036 
0.017 
0.026 
Testes 
0.010 
0.00045 
0.0097 
0.011 
Thymus 
0.0070 
0.00055 
0.0064 
0.0076 
Thyroid 
0.027 
0.011 
0.014 
0.039 
Urinary bladder wall 
0.61 
0.057 
0.54 
0.68 
Total body 
0.010 
0.00031 
0.0098 
0.011 
Effective dose 
0.051 
0.0072 
0.044 
0.063 
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) (34-37).   
4.2 Specify the source of the study agent.  
Molecular Imaging Program at Stanford 
Satellite Radiochemistry Facility  
300 Pasteur Dr, C21 
Stanford, CA 94305  
4.3 Describe how the agent will be requested and provide mailing address and phone 
number. 
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 (i.e. dynamic, static, number of scans, etc.) 
A localizer MRI scan will be performed at 45 minutes after injection of 140 MBq of 68Ga-RM2 to 
define the table positions.  After correct positioning of the spatial acquisition windows is ensured, 
the combined PET/MRI acquisition will be initiated with 3–5 table positions at a 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 

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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. 
The PET emission scan is corrected using segmented attenuation data of the MRI scan.  The PET 
images are reconstructed with a standard iterative algorithm.  All images are reformatted into 
axial, coronal, and sagittal views and viewed with the software provided by the manufacturer (AW, 
GE Medical Systems). 
5.3 Details of processing/analysis 
The PET/MRI scans will be interpreted by ABNM certified Nuclear Medicine physicians and an 
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 scanner will be conducted. 
6. STUDY PROCEDURES  
6.1 Criteria for Removal from Study 
The Protocol Director may withdraw subjects from the study for one or more of the following 
reasons: failure to follow the instructions of the Protocol Director and/or study staff; determination 
that continuing the participation could be harmful to the subject; the study is cancelled or other 
administrative reasons. 
6.2 Alternatives 
The alternative is to not participate in the study.  
7. STUDY CALENDAR 
 
Pre-Study 
Scan Date 
24 - 48 Hours 
Post-Study 
12 Months 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Follow-up Call to Participant 
 
 
X 
 
68Ga-RM2 
 
X 
 
 
Data analysis 
 
 
 
X 
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 i.v. 
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.  This radiation exposure is for research 
purposes only.  The amount of radiation from one 68Ga-RM2 PET/MR is 4.76 mSv, approximately 

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equal to 10% of the limit that radiation workers (for example, a hospital x-ray technician) are 
allowed to receive in one year.  This amount of radiation involves minimal risk and is necessary to 
obtain the research information desired.  
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 
unanticipated AEs related 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 device effect presents an unreasonable risk to subjects, the study will be terminated as 
soon as possible, but no later than 5 working days after the PI makes the determination and no 
later than 15 working days after first receiving notification of the effect. 
9. REGULATORY CONSIDERATIONS 
9.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to the 
study (eg, advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB.  Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation.  The Protocol Director will disseminate the protocol 
amendment information to all participating investigators. 
9.2 Data Management Plan 
The CRFs will be stored in a locked office in the Cancer Clinical Trials Office.  Records will be kept 
using OnCore.   
During the clinical investigation, the Protocol Director will evaluate the progress of the trial, 
including periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, performance of trial sites, and other factors that can affect 
study outcome.  
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. 
The Research Monitor, Carina Mari Aparici, MD, in the Division of Nuclear Medicine and Molecular 
Imaging is responsible to oversee the safety of the research and report observations/findings to 
the IRB or a designated institutional official.  The Research Monitor will review all unanticipated 
problems involving risks to subjects or others associated with the protocol and provide an 
independent report of the event to the IRB.  The Research Monitor may discuss the research 
protocol with the investigators; shall have authority to stop a research protocol in progress, 
remove individual human subjects from a research protocol, and take whatever steps are 
necessary to protect the safety and well-being of human subjects until the IRB can assess the 
monitor's report; and shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official and the HRPO. 

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10. MEASUREMENTS 
10.1 Primary outcome measure 
The principal goal of this study is to compare the diagnostic performance of 68Ga-RM2 PET/MRI to 
that of MR alone for detecting recurrent prostate cancer in clinically (PSA) recurrent but CT 
negative cases.  The number and location of lesions will be recorded for each modality in each 
patient.  Gold standard will be based on either biopsy or one-year follow-up. 
Specifically, it is hypothesized that: 
1. At least 30% of these patients will have one or more lesions detected on 68Ga-RM2 PET/MRI. 
2. The proportion of patients with detected lesions will be higher for 68Ga-RM2 PET/MRI than for 
MR alone. 
10.2 Measurement Methods 
PET images will be interpreted using dedicated software and the location of uptake will be 
recorded for each patient, blinded to the results of other studies.  MR images will be evaluated for 
detection of areas of abnormal signal or anatomical structures, blinded to the results of PET or 
other studies. 
10.3 Measurement Time Points 
Uptake will be evaluated after the scan completion.  
11. STATISTICAL CONSIDERATIONS 
11.1  Statistical Design 
Prospective single center, single-arm study.  Patients will be scanned with 68Ga-RM2 PET/MRI 
after the CT scan.  MRI and PET/MRI scans will each be evaluated separately by two readers. 
11.2  Randomization 
No randomization will be done. 
11.3  Interim analyses 
No interim analyses are planned. 
11.4  Key variables 
Reference standard: disease status of a lesion will be defined by conventional imaging followed by 
biopsy of suspicious lesions, when clinically feasible.  12-months clinical follow-up will be gold 
standard if biopsy cannot be done.  
Test to be evaluated: 68Ga-RM2 positivity will be determined by the operator as uptake more than 
the liver (malignant) or less (benign).  Visual conspicuity against background on the diffusion 
weighted images and presence of an anatomically corresponding abnormality on the T1w and 
T2w images are the criteria for detecting a lesion on MRI. 
11.4.1  Analysis Population 
All lesions identified by 68Ga-RM2 PET/MRI.  
11.4.2  Analysis Plan 
Sensitivity and specificity of PET/MRI and MR alone will be compared by McNemar tests of paired 
proportions. 
11.5  Sample Size 

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We used the "paired proportions" power analysis procedure in Stata Release 14 to determine the 
sample size (36).  We expect that roughly 50% of patients will have lesions (as determined by 
biopsy or follow-up).  Assuming a difference in sensitivity for PET/MRI and MRI of 20 percentage 
points (eg, 70% vs 50%), a sample of 60 diseased patients will provide 90% power at 5% error to 
detect such a difference.  Assuming a difference in specificity for PET/MRI and MRI of 
20 percentage points (eg, 70% vs 90%), a sample of 60 non-diseased patients will provide 98% 
power at 5% error to detect such a difference. 
--11.6  Accrual estimates 
 
 
We expect to accrue a total of 125 participants for this study.  The 10 patients included in the pilot 
study were enrolled in less than 2 months. The participants evaluated in published data will not be 
included in the analysis. There are approximately 10 prostate cancer patients scanned each week 
using in Nuclear Medicine to evaluate for metastatic disease.  Our enrollment plan is achievable 
given our experience with other protocols and the expected support from the referring physicians, 
Drs. Hancock, Sonn and Srinivas. 

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3. 
Oh WK, Kantoff PW. Treatment of locally advanced prostate cancer: is chemotherapy 
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Jani AB. Management strategies for locally advanced prostate cancer. Drugs & aging. 
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5. 
Isbarn H, Wanner M, Salomon G, et al. Long-term data on the survival of patients with 
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6. 
Van Poppel H, Vekemans K, Da Pozzo L, et al. Radical prostatectomy for locally 
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7. 
Bott SRJ. Management of recurrent disease after radical prostatectomy. Prostate 
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8. 
Panebianco V, Sciarra A, Lisi D, et al. Prostate cancer: 1HMRS-DCEMR at 3&#xa0;T 
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Radiology. 2012;81:700-708. 
 
9. 
Beer AJ, Eiber M, Souvatzoglou M, Schwaiger M, Krause BJ. Radionuclide and hybrid 
imaging of recurrent prostate cancer. Lancet Oncol. 2011;12:181-191. 
 
10. 
Oyen RH, Poppel HPV, Ameye FE, Voorde WAVd, Baert AL, Baert LV. Lymph node 
staging of localized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: 
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11. 
Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive Detection of Clinically Occult 
Lymph-Node Metastases in Prostate Cancer. New England Journal of Medicine. 
2003;348:2491-2499. 
 
12. 
Iagaru A, Young P, Mittra E, Dick DW, Herfkens R, Gambhir SS. Pilot Prospective 
Evaluation of 99mTc-MDP Scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and Whole-Body 
MRI for Detection of Skeletal Metastases. Clinical Nuclear Medicine. 2013;38:e290-e296. 
 
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Iagaru A, Mittra E, Dick D, Gambhir S. Prospective Evaluation of 99mTc MDP 
Scintigraphy, 18F NaF PET/CT, and 18F FDG PET/CT for Detection of Skeletal Metastases. 
Molecular Imaging and Biology. 2012;14:252-259. 
 
14. 
Sandblom G, SÃƒrensen J, Lundin N, HÃƒggman M, MalmstrÃƒm P-U. Positron 
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Oyama N, Miller TR, Dehdashti F, et al. 11C-Acetate PET Imaging of Prostate Cancer: 
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Wachter S, Tomek S, Kurtaran A, et al. 11C-Acetate Positron Emission Tomography 
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Souvatzoglou M, Weirich G, Schwarzenboeck S, et al. The Sensitivity of [11C]Choline 
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Research. 2011;17:3751-3759. 
 
18. 
Rietbergen DDD, van der Hiel B, Vogel W, Stokkel MPM. Mediastinal lymph node 
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19. 
Nanni C, Schiavina R, Boschi S, et al. Comparison of 18F-FACBC and 11C-choline 
PET/CT in patients with radically treated prostate cancer and biochemical relapse: preliminary 
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Turkbey B, Mena E, Shih J, et al. Localized prostate cancer detection with 18F FACBC 
PET/CT: comparison with MR imaging and histopathologic analysis. Radiology. 2014;270:849-
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Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid 68Ga-PSMA Ligand 
PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. Journal of 
Nuclear Medicine. 2015;56:668-674. 
 
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Rowe SP, Gage KL, Faraj SF, et al. 18F-DCFBC PET/CT for PSMA-based Detection 
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Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer J-C, Gugger M. Bombesin Receptor 
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25. 
Markwalder R, Reubi JC. Gastrin-releasing Peptide Receptors in the Human Prostate: 
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26. 
Beer M, Montani M, Gerhardt J, et al. Profiling gastrin-releasing peptide receptor in 
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27. 
Mansi R, Wang X, Forrer F, et al. Development of a potent DOTA-conjugated bombesin 
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28. 
Minamimoto R, Hancock S, Schneider B, et al. Pilot Comparison of (6)(8)Ga-RM2 PET 
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Med. 2016;57:557-562. 
 
29. 
Roivainen A, Kähkönen E, Luoto P, et al. Plasma Pharmacokinetics, Whole-Body 
Distribution, Metabolism, and Radiation Dosimetry of 68Ga Bombesin Antagonist BAY 86-7548 
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30. 
Kähkönen E, Jambor I, Kemppainen J, et al. In Vivo Imaging of Prostate Cancer Using 

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[68Ga]-Labeled Bombesin Analog BAY86-7548. Clinical Cancer Research. 2013;19:5434-5443. 
 
31. 
Minamimoto R, Sonni I, Hancock S, 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;59:803-808. 
 
32. 
Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical 
recurrence in patients treated for localized prostate cancer: the American Urological Association 
Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations 
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33. 
Roach M, 3rd, Hanks G, Thames H, Jr., et al. Defining biochemical failure following 
radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: 
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34. 
Hartmann H, ZÃƒphel K, Freudenberg R, et al. [Radiation exposure of patients during 
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35. 
Pettinato C, Sarnelli A, Di Donna M, et al. 68Ga-DOTANOC: biodistribution and 
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36. 
SandstrÃƒm M, Velikyan I, Garske-RomÃƒn U, et al. Comparative Biodistribution and 
Radiation Dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in Patients with 
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37. 
Kim J, Lee J, Kang K, et al. Whole-body distribution and radiation dosimetry of (68)Ga-
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Inclusion/Exclusion Criteria Checklist  
 
Protocol Title: 
68Ga RM2 PET/MRI in Patients with Biochemically Recurrent Prostate 
Cancer and Non-Contributory Conventional Imaging  
Protocol Number: 
35155 
Principal Investigator: 
Andrei Iagaru, MD 
 
Inclusion Criteria – Yes must be checked to be eligible 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation 
1.  Biopsy proven prostate adenocarcinoma  
☐ 
☐ 
☐ 
2. Rising PSA after definitive therapy with prostatectomy or 
radiation therapy (external beam or brachytherapy) 
a. Post radical prostatectomy (RP)  
ii. PSA greater than 0.2 ng/mL measured after at least 
6 weeks from radical prostatectomy 
ii. Confirmatory persistent PSA greater than 
0.2 ng/mL (total of two PSA measurements greater 
than 0.2 ng/mL)  
b. Post-radiation therapy  
c. i. A rise of PSA measurement of 2 or more ng/mL 
over the nadir 
☐ 
☐ 
☐ 
3. No evidence of metastatic disease on conventional 
imaging, including a negative bone scan for skeletal 
metastasis and negative CT scan, with or without 
contrast. NaF PET CT can substitute for separate bone 
scan and CT. CT in Axumin (also known as 18F FACBC 
or 18F Fluciclovine) can substitute for separate CT. 
☐ 
☐ 
☐ 
4. Able to provide written informed consent  
☐ 
☐ 
☐ 
5. Karnofsky performance status of 50 (or ECOG/WHO 
equivalent) 
☐ 
☐ 
☐ 
 
Exclusion Criteria –No must be checked to be eligible 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation 
1. Patient is < 18 years old at the time of the drug 
administration 
☐ 
☐ 
☐ 
2. Unable to provide informed consent 
☐ 
☐ 
☐ 
3. Inability to lie still for the entire imaging time 
☐ 
☐ 
☐ 
4. Inability to complete the needed investigational and 
standard-of-care imaging examinations due to other 
reasons (severe claustrophobia radiation phobia, etc.) 
☐ 
☐ 
☐ 
5. Any additional medical condition, serious intercurrent 
illness, or other extenuating circumstance that, in the 
opinion of the Investigator, may significantly interfere 
with study compliance. 
☐ 
☐ 
☐ 
6. Metallic implants (contraindicated for MRI) 
☐ 
☐ 
☐ 

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*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.   
 
 
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.   
 
Signature: 
Date: 
Printed Name: 
 
Signature: 
Date: 
Printed Name: 
 
 
Signature: 
Date: 
Printed Name: