Clinical trial NCT03698370
Conditions: Prostate Adenocarcinoma PSA Progression Recurrent Prostate Carcinoma
Sponsor: Andrei Iagaru
Start date: 2020-12-15; Completion date: 2022-02-11
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This phase II trial studies how well gallium Ga 68 DOTA-NeoBOMB1 and gallium Ga 68 PSMA-R2 positron emission tomography (PET)/magnetic resonance imaging (MRI) work in diagnosing participants with prostate cancer that has come back. Diagnostic procedures, such as gallium Ga 68 DOTA-NeoBOMB1 and gallium Ga 68 PSMA-R2 PET/MRI, may help find and diagnose prostate cancer and find out how far the disease has spread.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate gallium Ga 68 DOTA-NeoBOMB1 (68Ga-NeoBOMB1) and gallium Ga 68 PSMA-R2 (68Ga-PSMA R2) PET/MRI for detection of recurrent prostate cancer after initial therapy in patients meeting the criterion of biochemical recurrence.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM I: Participants receive gallium Ga 68 DOTA-NeoBOMB1 intravenously (IV) and 45 minutes later, undergo PET/MRI. Within 2 weeks, participants receive gallium Ga 68 PSMA-R2 IV then undergo PET/MRI 45-60 minutes later.

ARM II: Participants receive gallium Ga 68 PSMA-R2 IV and 45-60 minutes later undergo PET/MRI. Within 2 weeks, participants receive gallium Ga 68 DOTA-NeoBOMB1 IV then undergo PET/MRI 45 minutes later.

After completion of study, participants are followed up at 12 months.

Arms: arm 1: Participants receive gallium Ga 68 DOTA-NeoBOMB1 IV and 45 minutes later, undergo PET/MRI. Within 2 weeks, participants receive gallium Ga 68 PSMA-R2 IV then undergo PET/MRI 45-60 minutes later. arm 2: Participants receive gallium Ga 68 PSMA-R2 IV and 45-60 minutes later undergo PET/MRI. Within 2 weeks, participants receive gallium Ga 68 DOTA-NeoBOMB1 IV then undergo PET/MRI 45 minutes later.
Interventions: intervention 1: Gallium Ga 68 DOTA-NeoBOMB1 intervention 2: Gallium Ga 68 PSMA-R2
Intervention descriptions: intervention 1: Administered intravenously (IV) intervention 2: Administered intravenously (IV)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
68Ga-NeoBOMB1 and 68Ga-PSMA R2 PET/MRI in the Evaluation of 
Patients With Biochemical Recurrence of Prostate Cancer 
Study Protocol and Statistical Analysis Plan 
NCT03698370 
March 18, 2020 


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68Ga-NeoBOMB1 and 68Ga-PSMA R2 PET/MRI in the Evaluation of Patients with 
Biochemical Recurrence of Prostate Cancer 
 
 
Principal Investigator: 
 
Andrei Iagaru, MD 
300 Pasteur Drive, 
 
Stanford, CA 94305 
Phone: 650 725 4711 
Fax: 650 498 5047 
Email: aiagaru@stanford.edu 
 
Co-investigators: 
 
Guido Davidzon, MD 
300 Pasteur Drive, 
 
Stanford, CA 94305 
Phone: 650 725 4711 
Email: gdavidzon@stanford.edu 
 
Andreas Loening, MD, PhD 
300 Pasteur Dr, 
  
Stanford, CA 94305  
Phone: 
 
Email: loaning@stanford.edu 
 
Shreyas Vasanawala, MD, PhD 
725 Welch Rd, 
  
Palo Alto, CA94304 
Phone: 
 
Email: 
 
 
 
Study Coordinator: 
, BS 
Cancer Clinical Trials Office 
300 Pasteur Dr. 
 
Stanford, CA 94305 
Phone: 
 
Fax: 
 
Email: 
 
 
Biostatistician 
, PhD 
Email: 
 
 
SRC Protocol / Version 2/ Version Date: 18 Mar 2020 
IRB protocol #46258 
SRC Approval Date: 27 July 2018 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES .......................................................................................................... 4 
PROTOCOL SYNOPSIS .............................................................................................................. 5 
SCHEMA ...................................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 7 
1. OBJECTIVES ........................................................................................................................ 8 
2. BACKGROUND ..................................................................................................................... 8 
2.1 Preliminary information ................................................................................................ 8 
2.2 Study Agent ................................................................................................................... 9 
2.3 Clinicaltrials.gov ........................................................................................................... 9 
2.4 Rationale ........................................................................................................................ 9 
2.5 Study Design ............................................................................................................... 12 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................................... 13 
3.1 Inclusion Criteria ......................................................................................................... 13 
3.2 Exclusion Criteria ........................................................................................................ 13 
3.3 Informed Consent Process ........................................................................................ 13 
3.4 Study Timeline ............................................................................................................. 13 
4. IMAGING AGENT INFORMATION...................................................................................... 14 
4.1 Study Agent ................................................................................................................. 14 
4.2 Specify the source of the study agent. ..................................................................... 16 
4.3 Describe how the agent will be requested and provide mailing address and 
phone number. .................................................................................................................. 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 
Details of processing/analysis ................................................................................ 18 
6. STUDY PROCEDURES ...................................................................................................... 18 
6.1 
Pre-Study .................................................................................................................. 18 
6.2 
Imaging Days ............................................................................................................ 18 
6.3 
Follow-up .................................................................................................................. 18 
6.4 
Criteria for Removal from Study ............................................................................. 18 
6.5 
Alternatives ............................................................................................................... 19 
7. STUDY CALENDAR ............................................................................................................ 19 
8. ADVERSE EVENTS AND REPORTING PROCEDURES ................................................... 19 
8.1 Potential Adverse Events ........................................................................................... 19 
8.2 Adverse Event Reporting ........................................................................................... 20 
9. REGULATORY CONSIDERATIONS................................................................................... 20 
9.1 Institutional Review of Protocol ................................................................................ 20 
9.2 Data Management Plan ............................................................................................... 20 
10. 
MEASUREMENTS ...................................................................................................... 20 
10.1 Primary outcome measure ....................................................................................... 20 
10.2 Measurement Methods ............................................................................................. 21 
10.3 Measurement Time Points ........................................................................................ 21 
11. 
STATISTICAL CONSIDERATIONS ............................................................................ 21 
11.1  Statistical Design ..................................................................................................... 21 
11.2  Randomization ......................................................................................................... 21 
11.3  Interim analyses ....................................................................................................... 21 


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11.4  Key variables ............................................................................................................ 22 
11.5  Sample Size .............................................................................................................. 22 
11.6  Accrual estimates .................................................................................................... 22 
APPENDIX:  Inclusion/Exclusion Criteria Checklist ............................................................ 23 
REFERENCES: .................................................................................................................. 24 


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Summary of Changes 
 
Version 2 
Added new source for 68Ga-NeoBOMB1  
 


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PROTOCOL SYNOPSIS 
 
TITLE 
68Ga-NeoBOMB1 and 68Ga-PSMA R2 
PET/MRI in Patients with Biochemically 
Recurrent Prostate Cancer and 
Non-Contributory Conventional Imaging 
STUDY PHASE 
Phase II 
INDICATION 
Prostate cancer 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
68Ga-NeoBOMB1 
68Ga-PSMA R2 
PRIMARY OBJECTIVE(S) 
To evaluate 68Ga-NeoBOMB1 PET/MRI and 
68Ga-PSMA R2 PET/MRI for detection of 
recurrent prostate cancer after initial therapy 
in patients with biochemical recurrence 
SAMPLE SIZE  
50 participants 
STATISTICAL CONSIDERATIONS 
Prospective single center, single-arm study.  
 


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SCHEMA 
 
 
 
 
 
 
Eligible participant with prostate cancer 
68Ga-NeoBOMB1 PET/MRI  
followed within 2 weeks by 
 68Ga-PSMA R2 PET/MRI 
OR 
68Ga-PSMA R2 PET/MRI 
followed within 2 weeks by 
 68Ga- NeoBOMB1 PET/MRI 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
BPH 
Benign prostatic hyperplasia 
Ga-68 
Gallium-68 
GRPR 
Gastrin releasing peptide receptor 
IRB 
Institutional Review Board 
IV 
Intravenous 
PC 
Prostate cancer 
PET/MRI 
Positron emission tomography – magnetic resonance imaging 
PSA 
Prostate-specific antigen 
PSMA 
Prostate specific membrane antigen 
SUV 
Standardized Uptake Value 
TRUS 
Transrectal ultrasound 
 
 
 


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1. OBJECTIVE 
Specific Aim 
To evaluate 68Ga-NeoBOMB1 and 68Ga-PSMA R2 PET/MRI for detection of recurrent 
prostate cancer after initial therapy in patients meeting the criterion of biochemical 
recurrence. 
2. BACKGROUND 
2.1 Preliminary information 
Data from the American Cancer Society suggests that prostate cancer (PC) will continue to 
be the leading non-cutaneous cancer diagnosis in males in 2016 in the US with 180,980 
estimated new cases, and has the second highest mortality with 26,120 estimated deaths 
(1).  Subsequent treatment is multifaceted and may involve observation, surgery 
(prostatectomy), radiation therapy (external beam or brachytherapy), hormonal therapy, 
chemotherapy, or a combination of these (2-4).  
Up to 40% of the patients with prostate cancer develop biochemical recurrence within 10 
years after initial treatment (5).  Usually an increase of the PSA-level precedes a clinically 
detectable recurrence by months to years (6).  However, it cannot differentiate between 
local, regional or systemic disease with the necessary precision that is essential for further 
disease management (7).  
Morphological imaging methods exhibit considerable limitations: sensitivity ranges between 
25% and 54% for the detection of local recurrence by transrectal ultrasound (TRUS) or 
contrast-enhanced CT and is moderately improved by using functional MRI techniques (7-9).  
The sensitivity for detection of lymph node metastases of CT or MRI is reported to be 
30-80% (10).  Ultra-small particles of iron oxides (USPIOs) proved to be very effective, but 
are yet to be approved by regulatory authorities (11).  Bone metastases presenting as 
osteoblastic lesions can be effectively detected by bone scintigraphy, PET, CT and MRI 
(12,13). 
Various targets have been addressed by molecular imaging to improve the detection of 
recurrent prostate cancer.  PET tracers such as 18F- or 11C-labeled choline and 11C-acetate 
have been investigated for the diagnosis of recurrent (14-16) prostate cancer.  Their 
feasibility in primary diagnosis is limited because of uptake in benign tissue such as benign 
prostatic hyperplasia (BPH) 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).  
However, 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 


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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.  
Gastrin-releasing peptide receptors (GRPR) are highly overexpressed in several human 
tumors, including PC (23).  GRP receptor was detected in 63-100 % of human prostate 
cancer tissue (24,25).  Moreover, because of their low expression in BPH and inflammatory 
prostatic tissues (25), imaging of GRPR has potential advantages over current choline- and 
acetate-based radiotracers. 
Maina and colleagues evaluated 68Ga-SB3 in 8 patients with breast cancer and 9 patients 
with prostate cancer.  All patients had disseminated disease and had received previous 
therapies (26).  68Ga-SB3 did not produce adverse effects and identified cancer lesions in 4 
out of 8 (50 %) with breast cancer and 5 out of 9 (55 %) with PC.  An improved version of 
this radiopharmaceutical, 68Ga-NeoBOMB1, is showing promising results in preliminary 
studies (27,28).  68Ga-NeoBOMB1 has undergone extensive pre-clinical testing confirming 
specific and high affinity GRPR targeting (IC50: 1-2 nM), both in vitro and in vivo, as well as 
an appropriate pharmacokinetic profile compatible with a diagnostic use and a favorable 
safety profile.  68Ga-NeoBOMB1 specifically and strongly bound on the cell-membrane of 
PC-3 cells displaying low internalization, as expected for receptor antagonists.  During a 
translational study in prostate cancer patients 68Ga-NeoBOMB1 rapidly localized in 
pathological lesions achieving high contrast imaging (29). 
A phase 1-2 clinical study (MITIGATE trial) aimed to evaluate 68Ga-NeoBOMB1 safety, 
tolerability, biodistribution, dosimetry and preliminary diagnostic performance is ongoing in 
GIST patients at Innsbruck University.  The safety assessment on the first 6 patients 
enrolled in the study confirmed good tolerance, with no AEs reported.  Uptake in tumors was 
fast with good visibility of the metastasis already at 1h after administration, associated with 
rapid renal and blood clearance (30). 
PET/MRI is an advanced multimodality technology that can provide both biological and 
morphological information of various biological processes.  Compared to PET/CT, 
simultaneous PET/MRI has advantages resulting from reduction in the radiation exposure 
and improvements in diagnostic ability due to better soft tissue contrast (31). 
2.2 Study Agent 
We will use 68Ga-NeoBOMB1 and 68Ga-PSMA R2 as the PET radiopharmaceuticals.  These 
are not FDA-approved products, but we have letters of cross-reference for FDA-approved 
INDs allowing the use of these tracers in this proposed clinical indication under a Stanford 
investigator sponsored IND (
). 
2.3 Clinicaltrials.gov  
Since 68Ga-NeoBOMB1 and 68Ga-PSMA R2 are not FDA-approved products, we will register 
the study on clinicaltrials.gov once initial FDA, IRB and SRC approvals are in place. 
2.4 Rationale 
In this study, we propose to use a well-established PET isotope, Gallium-68 (68Ga), bound to 
a bombesin receptor antagonist, NeoBOMB1, which has high affinity for gastrin-releasing 
peptide receptors (GRPR), and to PSMA R2 which has high affinity for prostate specific 


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membrane antigen (PSMA).  GRPR proteins are highly overexpressed in several human 
tumors, including prostate cancer (23) and its overexpression has been demonstrated in 
patients with biochemically recurrent prostate cancer (32,33).  Therefore, imaging GRPR 
has the potential to improve the lesion detection in prostate cancer.  
68Ga and 18F labeled PSMA ligands can detect prostate cancer relapses and metastases 
with high contrast by binding to the extracellular domain of PSMA, followed by internalization 
(21,22).  
Therefore, we propose the following aim: 
• 
To evaluate 68Ga-NeoBOMB1 and 68Ga-PSMA R2 PET/MRI for detection of recurrent 
prostate cancer after initial therapy in patients with biochemical recurrence. 
Imaging gastrin releasing peptide receptors using 68Ga-NeoBOMB1 
 
Figure 1.  Chemical structure of 68Ga-NeoBOMB1 
Four prostate cancer patients were imaged with 68Ga-NeoBOMB1 PET/CT by Nock et al 
(28).  The tracer was well-tolerated by all participants and no side-effect was registered from 
the administration of 68Ga-NeoBOMB1.  Successful visualization of prostate cancer lesions 
in man was described by the authors for applying 68Ga-NeoBOMB1PET/CT. 
 
Figure 2: 65-year-old man with pT3b (G3) pN1c M0, Gleason score 7 prostate cancer.  Multiple 
mediastinal, para-oesophageal, abdominal and pelvic lymph node metastases are strongly positive 
for 68Ga-NeoBOMB1 uptake. 


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Preliminary results from MITIGATE trial after completion of phase-I part of the study (6 
patients included) showed that 68Ga-NeoBOMB1 presents a favorable safety and tolerability 
profile, with no adverse events (AEs) related with the compound.  Overall, two subjects 
experienced adverse events, none of which were causally linked to the study drug.  Uptake 
in tumor was fast with good imaging performance already at 1h after administration, 
associated with rapid renal and blood clearance (30). 
Imaging prostate specific membrane antigen using 68Ga-PSMA R2 
Prostate specific membrane antigen (PSMA) is a type II integral membrane glycoprotein 
identified on human prostatic carcinoma cell lines.  The PSMA protein has a unique 3-part 
structure consisting in a 19-amino-acid internal portion, a 24-amino-acid transmembrane 
portion, and a 707-amino-acid external portion.  The PSMA gene is located on the short arm 
of chromosome 11 in a region that is not commonly deleted in prostate cancer.  PSMA 
triggers a signal that allows internalization of the protein on the cell surface into an 
endosomal compartment.  This characteristic seems to be useful for diagnostic and 
therapeutic (theragnostic) approach in which PSMA could be used as an antigenic target or 
as a specific docking-station for tailored small molecules (34). 
Increased PSMA expression has been detected most notably in prostate cancer; though, it 
was also detected in the peritumoral and endotumoral capillaries of a variety of 
malignancies including renal cell carcinomas, transitional cell carcinomas, and colon 
carcinomas (35).  Nearly all adenocarcinomas of the prostate demonstrate PSMA 
expression in most primary and metastatic lesions (36).  Immuno-histochemical studies have 
shown that PSMA expression increases in cases of de-differentiated, metastatic, or 
hormone-refractory disease (37) and its expression level is a significant prognosticator for 
disease outcome (38).  
Several urea-based PSMA ligands have already been successfully tested in prostate cancer 
patients confirming good imaging performance and favorable safety profile.  In line with 
existing guidelines, the diagnostic doses of the 68Ga-PSMA ligands range 120-200 
MBq/patient (approximately 2 to 3 MBq/kg).  Considering the half-life of 68Ga, as well as the 
foreseen imaging and blood sampling schedule in early phase trials (up to ¾ h for imaging 
acquisition or 6h for PK sampling), a dose of 3 MBq/kg, but not less than 150 MBq and not 
more than 250 MBq, is considered adequate to obtain good quality imaging using 
68Ga-PSMA R2.  The proposed dose is also consistent with the one applied in the two 
marketed AAA diagnostic products Somakit and NETSpot.  
The safety of the cold compound present in a single dose of 68Ga-PSMA R2 is supported by 
the preclinical data obtained in GLP single and repeated dose toxicity studies performed in 
rats and mini-pigs showing good tolerability of the compound and no toxicity signs at the 
highest tested dose (in single dose studies: 8000 (rats) and 3500 (mini-pigs) times the 
maximum foreseen human dose; in repeated dose studies:  2600 (rats) and 1150 (mini-pigs) 
times the maximum foreseen human dose).  Similarly, no adverse effects have been 
observed in the safety pharmacology studies performed in rats and mini-pigs at any of the 
tested doses  which were 4000 (studies on effects on CNS and respiratory function in rats) 
or 1150 times higher (study on effects on cardiovascular function in mini-pigs) than the dose 
foreseen in human for the imaging drug product. 


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2.5 Study Design 
This is a prospective, single center, single-arm phase II study enrolling 50 participants with 
biochemically recurrent prostate cancer.  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-NeoBOMB1 first followed by 
68Ga-PSMA R2 within 2 weeks or 68Ga-PSMA R2 first followed by 68Ga-NeoBOMB1 within 
2 weeks [50/50 chance for each schedule]). 
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 IV with 150 to 250 MBq of 68Ga-NeoBOMB1 
4. Vital signs (heart rate, blood pressure, respiratory rate, pulse oxymetry) will be recorded 
after the injection 
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 4-min acquisition time per table position. 
7. Participants will be given a copy of the consent form s/he signed and will be dismissed. 
8. Vital signs (heart rate, blood pressure, respiratory rate, pulse oxymetry) 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. 
The same will be repeated for 68Ga-PSMA R2 (within 2 weeks of 68Ga-NeoBOMB1): 
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 IV with 150 to 250 MBq of 68Ga-PSMA R2 
4. Vital signs (heart rate, blood pressure, respiratory rate, pulse oxymetry) will be recorded 
after the injection 
5. Participant will void immediately prior to the scan 
6. 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 4-min acquisition time per table position.  Only 
MR sequences required for attenuation correction of PET data will be acquired. 
7. Participants will be given a copy of the consent form s/he signed and will be dismissed. 
8. Vital signs (heart rate, blood pressure, respiratory rate, pulse oxymetry) 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. 


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3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria 
• 
Biopsy proven prostate adenocarcinoma 
• 
Rising PSA after definitive therapy with prostatectomy or radiation therapy (external 
beam or brachytherapy) 
a. Post radical prostatectomy (RP) – AUA recommendation (39) 
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 (40) 
i. A rise of PSA measurement of 2 or more ng/mL over the nadir 
• 
Able to provide written consent 
• 
Karnofsky performance status of ≥50 (or ECOG/WHO equivalent) 
3.2 Exclusion Criteria 
• 
Less than 18 years old at the time of radiotracer administration 
• 
Inability to lie still for the entire imaging time  
• 
Inability to complete the needed investigational and standard-of-care imaging 
examinations due to other reasons (severe claustrophobia, radiation phobia, etc.) 
• 
Any additional medical condition, serious intercurrent illness, or other extenuating 
circumstance that, in the opinion of the Investigator, may significantly interfere with 
study compliance 
• 
Known allergy, hypersensitivity, or intolerance to the investigational product or its 
excipients 
• 
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 (all 50 participants enrolled) 24 months from the 
time the study opens to accrual.   
3.4.2 Study Completion: 
The protocol will reach study completion when all participants will have 12 months of 
clinical follow-up completed. 


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4. IMAGING AGENT INFORMATION 
4.1 Study Agent  
We will use 68Ga-NeoBOMB1 and 68Ga-PSMA R2 as the PET radiopharmaceuticals.  These 
will be provided as ready-to-inject unit doses from a commercial radiopharmacy (Sofie 
Biosciences, previously dba Zevacor).  No manufacturing will take place at Stanford 
University. 
The administered dosage of 68Ga-NeoBOMB1 is 150 to 250 MBq IV.  The in vivo distribution 
of 68Ga-NeoBOMB1 was studied by Dalm et al in Balb c nu/nu mice bearing the PC-3 
tumor-xenograft, injected with ~13 MBq/250 pmol 
68Ga-NeoBOMB1 (specific activity 
~ 50 MBq/nmol) (41).  At 6 time-points (15 min;  30 min;  60 min;  2 h;  4 h;  and 6 h) 
post-injection (p.i.), tumor and organ uptake was determined using a gamma counter.  To 
assess receptor-specificity additional groups of animals were co-injected with an excess of 
unlabelled NeoBOMB1 (40 nmol).  Results of the biodistribution studies were also used to 
determine pharmacokinetics parameters and to perform dosimetry calculations.  The highest 
tumor uptake of 12.4 ± 2.3 %ID/g tissue was measured at 2 h p.i.  At that time point, the 
uptake in the pancreas was 22.7 ± 3.3 %ID/g tissue.  Uptake values in kidney and liver were 
5.7 ± 2.4 and 8.3 ± 1.8 % ID/g tissue, respectively, indicating renal and hepatobiliary 
excretion.  When receptors were blocked by co-injection with an excess of unlabelled 
NeoBOMB1, uptake in GRPR-expressing tissues decreased, as observed in tumor and 
pancreas, where relative uptake reached 1.0 ± 0.1 and 0.7 ± 0.1 %ID/g tissue, respectively.  
Pharmacokinetic calculations resulted in a tumor clearance half-life of 6.9 ± 2.8 h and a 
pancreas clearance half-life of 12.9 ± 4.0 h.  Clearance from blood proceeded according to a 
bi-phasic pattern: 66 ± 9 % with half-life of 8±5 min and 34% with half-life of 50 ± 15 min. 
Using the OLINDA/EXM for 68Ga and assuming equal uptake per organ in human and mice, 
extrapolation to humans was performed obtaining an effective dose of 0.039 mSv/MBq.  
Estimated absorbed doses extrapolated from animal study showed that the critical organ is 
the pancreas (0.341 mGy/MBq).  However, it is important to note that the contribution to the 
effective dose (calculated using the ICRP-60 weighting factors) for this organ is 0.002 
mSv/MBq.  Therefore, with an administered dose of 250 MBq (max dose), the resulting 
expected dose in the pancreas will be 0.43 mSv (50 mSv is the organ radiation dose limit for 
adults receiving a single administration, as per the Guidance for Industry and Researchers; 
“The Radioactive Drug Research Committee: Human Research Without an Investigational 
New Drug Application”, August 2010). 
The estimated effective dose for total human body, for an injected dose of 150 to 250 MBq 
is between 5.85 to 9.75 mSv, which is below the FDA limit of 30 mSv for adult research 
subjects receiving a single dose (Guidance for Industry and Researchers; “The Radioactive 
Drug Research Committee: Human Research Without an Investigational New Drug 
Application”, August 2010). 


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Table 1:  Absorbed dose estimates for 68Ga-NeoBOMB1 in humans (mGy/MBq).  
Effective dose and contributions to the effective (ED Cont.) are also reported 
(mSv/MBq). 
 
The administered dosage of 68Ga-PSMA R2 is 150 to 250 MBq IV.  The effective dose is 
expected to be similar to that from 68Ga-PSMA-617. 
Within healthy organs, the kidneys and salivary glands showed the highest 68Ga-PSMA-617 
uptake.  The average radiation exposure (effective dose) was approximately 0.021 
mSv/MBq. 


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Table 3: Absorbed Organ Doses of 68Ga-PSMA-617 PET: 
Absorbed organ dose (mGy/MBq) for patient 
Target organ 
16 
17 
18 
19 
Adrenals 
0.015 
0.014 
0.015 
0.015 
Brain 
0.010 
0.011 
0.010 
0.011 
Breasts 
0.010 
0.011 
0.010 
0.010 
Gallbladder 
0.015 
0.014 
0.016 
0.015 
Lower colon 
0.013 
0.014 
0.013 
0.013 
Small intestine 
0.019 
0.015 
0.024 
0.015 
Stomach 
0.013 
0.013 
0.013 
0.013 
Upper colon 
0.053 
0.045 
0.064 
0.017 
Heart 
0.012 
0.012 
0.012 
0.012 
Kidneys 
0.239 
0.085 
0.305 
0.196 
Liver 
0.033 
0.022 
0.032 
0.028 
Lungs 
0.011 
0.012 
0.011 
0.012 
Muscle 
0.011 
0.012 
0.011 
0.012 
Pancreas 
0.014 
0.014 
0.015 
0.015 
Red marrow 
0.010 
0.010 
0.010 
0.010 
Osteogenic cells 
0.015 
0.017 
0.015 
0.016 
Skin 
0.009 
0.010 
0.009 
0.010 
Spleen 
0.040 
0.020 
0.015 
0.039 
Testes 
0.011 
0.012 
0.011 
0.012 
Thymus 
0.011 
0.012 
0.011 
0.012 
Thyroid 
0.011 
0.012 
0.011 
0.011 
Urinary bladder 
0.098 
0.121 
0.062 
0.080 
Total body 
0.013 
0.013 
0.013 
0.013 
Effective dose (mSv/MBq) 
0.023 
0.018 
0.022 
0.020 
The estimated effective dose for total human body, for an injected dose of 150 – 250 MBq is 
between 3.15-5.25 mSv, which is below the FDA limit of 30 mSv for adult research subjects 
receiving a single dose (Guidance for Industry and Researchers; “The Radioactive Drug 
Research Committee: Human Research Without an Investigational New Drug Application”, 
August 2010).  The effective dosage from 68Ga-PSMA-617 (and the expected effective dose 
from 
68Ga-PSMA-R2) 
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) (42-45). 
4.2 Source of the study agent  
68Ga-PSMA-R2 
Sofie Biosciences (local manufacturer for Advanced Accelerator Applications) 
Attn: 
 
5900B Obata Way 


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Gilroy, CA, 95020 
Phone: 408-842-0520 
 
68Ga-NeoBOMB1 
Cardinal Health (local manufacturer for Advanced Accelerator Applications) 
254 E. Gish Rd. 
San Jose, CA, 95112 
Phone: 408-573-7819 
 
4.3 Describe how the agent will be requested and provide mailing address and phone 
number. 
Ordered in Radiology Information System (RIS). 
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 150 to 250 MBq of 
68Ga-NeoBOMB1 (or 68Ga-PSMA R2, 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 3–5 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 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 150 – 250 MBq of 
68Ga-PSMA R2 (or 68Ga-NeoBOMB1, 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 3–5 table positions at a 4-min acquisition 
time per table position.  -----Only MR sequences required for attenuation correction of PET 
data will be acquired.  


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Participants will be randomized to have 68Ga-NeoBOMB1 first followed by 68Ga-PSMA R2 
within 2 weeks or 68Ga-PSMA R2 first followed by 68Ga-NeoBOMB1 within 2 weeks (50/50 
chance for each schedule). 
5.3 Details of image 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. 
The study team will communicate the results of the scans to the referring (treating) 
physicians who can decide what to do with the findings, including making treatment 
decisions. 
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.  Record past prostate 
cancer diagnosis and treatment details. 
6.2. 
Imaging Days 
Subjects will undergo two separate clinic visits for imaging.  On each imaging day, subjects 
will receive an intravenous (IV) injection of investigational imaging agent (68Ga-NeoBOMB1 
or 68Ga-PMSA-R2) and undergo PET/MRI image collection as described in Section 2.5.  
6.3. 
Follow-up 
Active subject participation ends after the 24 to 72 hour post-scan Safety Follow-up.  
Investigators will follow subjects by chart review for 12 months post-scan to record any 
standard of care biopsies or imaging results.  If required by treating physicians for 
standard of care biopsies, the investigators will assist with identification of lesions that 
can be biopsied, based on 68Ga-NeoBOMB1 and/or 68Ga-PMSA-R2 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 to review medical records. 
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; 


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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 - 72 Hours 
Post-Scan 
12 Months 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
68Ga-NeoBOMB1 
 
X a 
 
 
68Ga-PSMA R2 
(within 2 weeks) 
 
X a 
 
 
Follow-up Call to 
Participant 
 
 
X 
 
Chart reviewb 
 
 
 
X 
a: Subjects will undergo either 68Ga-NeoBOMB1 PET/MRI followed within 2 weeks by 68Ga-PMSA-R2 
PET/MRI, or 68Ga-PMSA-R2 PET/MRI followed within 2 weeks by 68Ga-NeoBOMB1 PET/MRI 
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. 
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.  Because the radioactivity is very short-lived, the expected radiation exposure of 
the whole body and critical organs is low.  The substance amount (PSMA R2 and 
NeoBOMB1) is so small that it does not affect the physiological processes of the body.  
This research study involves exposure to radiation from one 68Ga-NeoBOMB1 PET/MRI.  
There is no radiation exposure from MRI.  The estimated effective dose for total human 
body, for an injected dose of 150 to 250 MBq is between 5.85 to 9.75 mSv, approximately 
equal to 11.7 to 19.5% of the limit that radiation workers (for example, a hospital X-ray 
technician) can receive in one year.  
This research study also involves exposure to radiation from one 68Ga-PSMA-R2 PET/MRI.  
There is no radiation exposure from MRI.  The effective dose from 68Ga-PSMA-R2 PET is 
similar to 68Ga-PSMA-11 or 68Ga-PSMA-617.  The estimated effective dose for total human 
body, for an injected dose of 150 to 250 MBq, is between 3.15 to 5.25 mSv, approximately 
equal to 6.3-10.5% of the limit that radiation workers (for example, a hospital X-ray 
technician) can receive in one year.  


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8.2 Adverse Event Reporting 
We do not anticipate hazardous situations for the subjects because of this protocol.  
However, procedures will be in place for verification of correct radiopharmaceutical dose 
and route of administration (ie, each dose will be double checked for dosimetry and quality 
by a researcher and technologist).  The study Principal Investigator (PI) or his designee will 
report unexpected 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 effect presents an unreasonable risk to subjects, the 
study will be terminated as soon as possible, but no later than 5 working days after the PI 
makes the determination and no later than 15 working days after first receiving notification of 
the effect. 
9. REGULATORY CONSIDERATIONS 
9.1 Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (eg, advertisements used to recruit participants) will be reviewed and approved 
by the Stanford IRB.  Any changes made to the protocol will be submitted as a modification 
and will be approved by the IRB prior to implementation.  The Protocol Director will 
disseminate the protocol amendment information to all participating investigators. 
9.2 Data Management Plan 
The CRFs will be stored in a locked office in the Nuclear Medicine clinic.  Records will be 
kept using OnCore.  
During the clinical investigation, the Protocol Director will evaluate the progress of the trial, 
including periodic assessments of data quality and timeliness, participant recruitment, 
accrual and retention, participant risk versus benefit, performance of trial sites, and other 
factors that can affect study outcome.  Monitoring of the trial will occur every 8 weeks and a 
record of monitoring activities will be maintained by the study team.  
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will audit 
study related activities to determine whether the study has been conducted in accordance 
with the protocol, local standard operating procedures, FDA regulations, and Good Clinical 
Practice (GCP).  This may include review of regulatory binders, case report forms, eligibility 
checklists, and source documents.  In addition, the DSMC will regularly review serious 
adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of DSMC audits will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
10. MEASUREMENTS 
10.1 Primary outcome measure 
The principal goal of this study is to compare the diagnostic performance of 
68Ga-NeoBOMB1 PET/MRI and 68Ga-PSMA R2 PET/MRI to that of MR alone in clinically 
(PSA) recurrent but CT-negative prostate cancer patients.  The gold standard will be based 
on either biopsy or one-year follow-up with imaging. 


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Specifically, it is expected that: 
1.  At least 30% of these patients will have one or more lesions detected on 68Ga- 
NeoBOMB1 PET/MRI or 68Ga-PSMA R2 PET/MRI. 
2.  The proportion of patients with detected lesions will be higher for 68Ga-NeoBOMB1 
PET/MRI or 68Ga-PSMA R2 PET/MRI than for MR alone. 
• 
Primary Outcome measure: Number of lesions detected by investigational imaging 
agent 
• 
Timeframe: Within 30 days 
• 
Description: The number of lesions detected on 68Ga- NeoBOMB1 PET/MRI, 
68Ga-PSMA R2 PET/MRI, and conventional MR will be compared.  Outcome will be 
reported as number of lesions detected per patient for each imaging method. 
10.2 Measurement Methods 
PET images will be interpreted using the AW software (GE Healthcare) 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.  
10.4  Secondary Outcome Measure 
• 
Secondary Outcome measure: Predictive value of malignancy 
• 
Timeframe: After 1 year clinical follow-up 
• 
Description: The predictive value of 68Ga- NeoBOMB1 PET/MRI and 68Ga-PSMA R2 
PET/MRI imaging will be evaluated based on biopsy and/or imaging results during 12 
month standard clinical follow-up.  Outcome will be reported as- percentage of 
detected lesions that were confirmed to be malignant for each imaging method. 
11. STATISTICAL CONSIDERATIONS 
11.1  Statistical Design 
Prospective single center, single-arm study.  Patients will be scanned with 68Ga-NeoBOMB1 
PET/MRI and 68Ga-PSMA R2 PET/MRI.  MRI and PET/MRI scans will each be evaluated 
separately by two readers. 
11.2  Randomization 
Patients will be randomized equally between having the 68Ga-NeoBOMB1 PET/MRI scan 
done first or the 68Ga-PSMA R2 PET/MRI. 
11.3  Interim analyses 
We will evaluate if 68Ga-NeoBOMB1 and 68Ga-PSMA R2 will have the same findings as 
what was noted with Ga68 PSMA-11 and Ga68 RM2 (bombesin), ie, about 2/3 same 
findings, while 1/3 will show different findings.  We will do the interim analysis after 
enrollment of 20 participants.  If all participants will have the same findings or if one 


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radiopharmaceutical will outperform the other (no additional lesions found by one vs 
another), the study will be discontinued. 
11.4  Key variables 
Reference standard: disease status of a lesion will be defined by biopsy of suspicious 
lesions, when clinically feasible.  12-months clinical follow-up with imaging will be gold 
standard if biopsy cannot be done. 
Test to be evaluated: 68Ga-NeoBOMB1 and 68Ga-PSMA R2 positivity will be determined by 
the operator as uptake more than the adjacent background (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-NeoBOMB1 PET/MRI and 68Ga-PSMA R2 PET/MRI.  
11.4.2  Analysis Plan 
• 
Sensitivity, specificity, and positive and negative predictive value of imaging modalities 
will be estimated. 
• 
Sensitivity and specificity of PET/MRI and MR alone will be compared by McNemar tests 
of paired proportions. 
• 
The number and type of discrepancies between 68Ga-NeoBOMB1 and 68Ga-PSMA R2 
will be tabulated. 
• 
We will explore hypotheses about the reasons for such discrepancies, such as PSA 
level/velocity, Gleason score, and location. 
11.5  Sample size justification  
 
The following estimate is for a per-lesion analysis.  We expect approximately 70% of 
patients (~35) to have one or more PET-positive findings and approximately 1/3 to be 
biopsied.  Our existing data for 68Ga PSMA-11 and 68Ga-RM2 (please see attached 
publications) indicate no false positive findings based on biopsy.  We cannot predict an 
average number of lesions per patient given small data available to date, but if only half of 
the positive patients have more than one lesion, this will easily yield 50 lesions.  We also 
expect the sensitivity of MR alone to be roughly 40%, while that of PET to be roughly 60% or 
more.  A sample size of 50 patients will provide 90% power at one-sided 5% error to detect 
such a difference.  Participants who complete only one PET/MRI scan (either due to 
withdrawal of consent or loss to follow-up) will not be replaced with additional subjects. 
11.6  Accrual estimates  
 
We expect the accrual of 50 patients over 24 months.  There are approximately 10 prostate 
cancer patients scanned each week in Nuclear Medicine to evaluate for metastatic disease.  
We plan to enroll 50 participants over 24 months and this 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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Inclusion/Exclusion Criteria Checklist 
Protocol Title: 
68Ga NeoBOMB1 and 68Ga-PSMA R2 PET/MRI PET/MRI in Patients with 
Biochemically Recurrent Prostate Cancer  
Protocol Number: 
46258 
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)  
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  
       i. A rise of PSA measurement of 2 or more ng/mL over the 
nadir 
☐ 
☐ 
☐ 
3. Able to provide written consent  
☐ 
☐ 
☐ 
4. Karnofsky performance status of ≥50 (or ECOG/WHO 
equivalent) 
☐ 
☐ 
☐ 
 
*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.   
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
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. Inability to lie still for the entire imaging time 
☐ 
☐ 
☐ 
3. Inability to complete the needed investigational and 
standard-of-care imaging examinations due to other reasons 
(severe claustrophobia radiation phobia, etc.) 
☐ 
☐ 
☐ 
4. Any additional medical condition, serious intercurrent illness, 
or other extenuating circumstance that, in the opinion of the 
Investigator, may significantly interfere with study 
compliance. 
☐ 
☐ 
☐ 
5. Metallic implants (contraindicated for MRI) 
☐ 
☐ 
☐ 
6. Known allergy, hypersensitivity, or intolerance to the 
investigational product or its excipients. 
☐ 
☐ 
☐ 
Secondary Reviewer Signature: 
Date: 
Printed Name: 


SRC Version #2, 18 Mar 2020 
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