Clinical trial NCT03831711
Conditions: Breast Carcinoma Estrogen Receptor Positive
Sponsor: Andrei Iagaru
Start date: 2019-03-19; Completion date: 2021-11-15
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial studies how well 68-Ga RM2 works with PET/MRI in imaging patients with estrogen receptor-positive breast cancer. 68-Ga-RM2 is an agent used in diagnostic imaging.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the feasibility of 68-Ga RM2 PET/MRI for identification of estrogen receptor positive primary breast cancer and metastases

OUTLINE:

Patients receive 68-Ga-RM2 intravenously (IV) and after 45 minutes undergo PET/MRI over 30-60 minutes.

After completion of study, patients are followed up at 24-72 hours, and then for 12 months.

Arms: arm 1: Patients receive 68-Ga RM2 IV and after 45 minutes undergo PET/MRI over 30-60 minutes.
Interventions: intervention 1: Gallium Ga 68-labeled GRPR Antagonist BAY86-7548 intervention 2: Magnetic Resonance Imaging intervention 3: Positron Emission Tomography intervention 4: Investigational software and coils in PET/MR scan
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo PET/MRI intervention 3: Undergo PET/MRI intervention 4: General Electric (GE) Healthcare non-approved PET scanner coils and software

Protocol documents:
Prot_SAP_000.pdf: 
IRB-48150 
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CONFIDENTIAL 
Protocol version 4   10 July 2019  
A Pilot Study of 68Ga-RM2 PET/MRI in the Evaluation of Patients with 
Estrogen Receptor-positive Breast Cancer 
 
 
Principal Investigator / Protocol Director  
 
Andrei Iagaru, MD 
300 Pasteur Dr, 
 
Stanford, CA 94305 
Phone:  650-725-4711 
Fax:  650-498-5047 
Email:  aiagaru@stanford.edu  
Co-investigators 
Bruce Daniel, MD, PhD 
300 Pasteur Dr;  
  
Stanford, CA  94305  
Phone:  650-725-1812;  Fax:  
 
Email:  bdaniel@stanford.edu 
Suleiman Alfred Massarweh, MD 
900 Blake Wilbur Dr 
Palo Alto, CA  94304  
Phone:  
 
Email:  
 
Andreas Loening, MD, PhD 
300 Pasteur Dr, 
  
Stanford, CA  94305  
Phone:  
;  Fax:  650-723-1909 
Email:  loaning@stanford.edu 
Carina Mari Aparici, MD 
300 Pasteur Dr, 
 
Stanford, CA  94305  
Phone:  650-725-4711;  Fax:  650-498-5047 
Email:  drmari@stanford.edu 
Statistician  
, PhD 
 
Palo Alto, CA 94305 
Phone:  
 
Fax:  
 
Email:  
 
Study Coordinator  
 
800 Welch Rd,  
Palo Alto, CA  94304 
Phone:  
;  Fax:  
 
Email:  
  
Protocol IRB-48150  //   BRS0098  //  NCT03831711 
Protocol Version 4 // 10 July 2019  
SRC Approval Date:  11 February 2019 (for version v30 January 2019)  


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Table of Contents 
PROTOCOL SYNOPSIS ........................................................................................................................ 4 
SCHEMA ............................................................................................................................................ 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................................ 6 
1. OBJECTIVE .................................................................................................................................. 7 
2. BACKGROUND ............................................................................................................................ 7 
2.1 Preliminary information ................................................................................................................ 7 
2.2 Clinicaltrials.gov ............................................................................................................................. 9 
2.3 Rationale ........................................................................................................................................ 9 
2.4 Study Design ................................................................................................................................ 10 
2.4.1 Objectives of the Study ............................................................................................................ 10 
2.4.2 Endpoints .................................................................................................................................. 10 
2.4.3 ClinicalTrials.gov Outcomes ...................................................................................................... 10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ...................................................... 11 
3.1 . Inclusion Criteria ......................................................................................................................... 11 
3.2 Exclusion Criteria ......................................................................................................................... 11 
3.3 Informed Consent Process ........................................................................................................... 11 
3.4 Study Timeline ............................................................................................................................. 11 
4. IMAGING AGENT INFORMATION .............................................................................................. 11 
4.1 Study Agent 68Ga-RM2 ................................................................................................................. 11 
4.2 Source of the Study Agent ........................................................................................................... 12 
4.3 Ordering ....................................................................................................................................... 12 
4.4 Agent Accountability ................................................................................................................... 12 
5. IMAGING SPECIFICS .................................................................................................................. 12 
5.1 . Modality or Modalities to be used.............................................................................................. 12 
5.2 . Details of Imaging (ie, dynamic, static, number of scans, etc) ................................................... 13 
5.3 . Image interpretation ................................................................................................................... 13 
6. STUDY PROCEDURES ................................................................................................................. 13 
6.1 Pre-Study ..................................................................................................................................... 13 
6.2 Imaging Days ................................................................................................................................ 13 
6.3 Follow-up ..................................................................................................................................... 13 
6.4 . Criteria for Removal from Study ................................................................................................. 14 


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6.5 . Alternatives ................................................................................................................................. 14 
7. STUDY CALENDAR ..................................................................................................................... 14 
8. ADVERSE EVENTS AND REPORTING PROCEDURES ..................................................................... 14 
8.1 Potential Adverse Events ............................................................................................................. 14 
8.2 Adverse Event Reporting ............................................................................................................. 14 
9. REGULATORY CONSIDERATIONS ............................................................................................... 15 
9.1 Institutional Review of Protocol .................................................................................................. 15 
9.2 Data Management Plan ............................................................................................................... 15 
10. Statistical Considerations and Evaluation of Results .................................................................. 15 
10.1 Study Endpoints ......................................................................................................................... 15 
10.2.  Accrual estimates..................................................................................................................... 15 
10.3 Analyses Plans ........................................................................................................................... 15 
10.4 Accrual estimates ...................................................................................................................... 16 
11. REFERENCES: ............................................................................................................................ 17 
3.1 Inclusion Criteria .......................................................................................................................... 18 
3.2 Exclusion Criteria ......................................................................................................................... 18 
 


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PROTOCOL SYNOPSIS 
 
TITLE 
A Pilot Study of 68Ga-RM2 PET/MRI in the Evaluation of Patients 
with Estrogen Receptor-positive Breast Cancer 
STUDY PHASE 
Pilot study 
INDICATION 
Breast cancer 
INVESTIGATIONAL 
PRODUCTS  
68Ga-RM2;  also known as: 
• 
Bombesin 
• 
BAY86-7548 
SAMPLE SIZE  
20 participants 
PRIMARY OBJECTIVE 
To evaluate the feasibility of 68Ga-RM2 PET/MRI for identification 
of estrogen receptor positive primary breast cancer and 
metastases 
 


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Protocol version 4   10 July 2019 
SCHEMA
Eligible participant with breast cancer
68Ga-RM2 PET/MRI


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ga-68;  68Ga 
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 
ER 
Estrogen receptor 
 


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1. OBJECTIVE 
Specific Aim 
To evaluate the feasibility of 68Ga-RM2 PET/MRI for identification of estrogen receptor positive 
primary breast cancer and metastases. 
2. BACKGROUND 
2.1 Preliminary information 
Breast cancer is a leading cause of cancer-related death found in women worldwide, with a 
steadily increasing incidence in many countries over the past 30 years (1). Thus, early detection 
and thorough evaluation of primary breast cancer and its metastases may lead to a higher rate 
of successful treatment and extend the patient’s life span. Currently, the diagnosis of breast 
cancer is usually determined using anatomical imaging, such as x-ray mammography, 
ultrasound, and MRI, and is confirmed via biopsy.  
With the advent of molecular imaging, nuclear medicine techniques are considered to hold 
promise for the early detection of tumors through a functional perspective, providing information 
on molecular characteristics.  
GRPR is known as a G-protein-coupled receptor that is expressed in a series of cancer types, 
including breast cancer, small cell lung cancer, prostate cancer, glioma, and neuroblastoma. 
According to literature, 62% to 96% of estrogen receptor positive (ER+) breast cancers express 
GRPR (2). Gastrin-releasing peptide receptor is heterogeneously expressed in neoplastic 
epithelial mammary cells, ductal carcinomas in situ, and invasive carcinoma. GRPR is also 
expressed in metastatic lymph nodes from breast cancer, whereas the level of GRPR 
expression in normal lymph node tissue is very low.  
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 receptors 
(GRPR) (3).  Stoykow and colleagues reported the use of 68Ga-RM2 in 15 patients with breast 
cancer.  A total of 13 of 18 tumors demonstrated strongly increased 68Ga-RM2 uptake 
compared to normal breast tissue (defined as PET-positive).  All PET-positive primary tumors 
were ER- and PR-positive (13 of /13) in contrast to only 1 of 5 PET-negative tumors.  Mean 
SUVmax of ER-positive tumors was 10.6 ± 6.0 compared to 2.3 ± 1.0 in ER-negative tumors 
(P = 0.016).  In a multivariate analysis including ER, PR, HER2/neu and MIB-1, only ER 
expression predicted 68Ga-RM2 uptake (model:  r2 = 0.55, p = 0.025).  Normal breast tissue 
showed inter- and intraindividually variable, moderate GRPR binding (SUVmax 2.3 ± 1.0), while 
physiological uptake of other organs was considerably less except pancreas.  Of note, 
68Ga-RM2-PET/CT detected internal mammary lymph nodes with high 68Ga-RM2 uptake (n = 8), 
a contralateral axillary lymph node metastasis (verified by biopsy) and bone metastases (n = 1;  
not detected by bone scan and CT).  This study demonstrated that 68Ga-RM2-PET/CT is a 
promising imaging method in ER-positive breast cancer.  In vivo GRPR binding assessed by 
68Ga-RM2-PET/CT correlated with ER expression in primary tumors of untreated patients (4). 
We conducted a pilot phase evaluation of 68Ga-RM2 in prostate cancer patients 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 


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42 to 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.   
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 (5). 
 
Figure 1:  Maximum intensity projection (MIP) images from 10 participants in the prostate cancer pilot 
study conducted at Stanford University.   


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The sponsor-investigator Dr Iagaru holds an Investigational New Drug application (IND) for 
68Ga-RM2 (IND 127137), and the group has significant experience using the tracer in currently 
ongoing clinical studies in prostate cancer at our institution, including 81 patients with 
biochemically recurrent prostate cancer and 16 patients with newly diagnosed prostate cancer. 
We propose to extend the use in patients with estrogen receptor positive (ER+) breast cancer. 
2.2 Clinicaltrials.gov  
This protocol will be registered on Clinicaltrials.Gov.  ClinicalTrials.gov outcomes are described 
at Section 2.4.3.  
2.3 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 
receptors.  GRPR proteins are highly overexpressed in several human tumors, including breast 
cancer (2).  The following aim is proposed: 
To evaluate the feasibility of 68Ga-RM2 PET/MRI for identification of ER+ primary breast 
cancer and metastases. 
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 (5). 
 
Figure 2:  74-year-old patient with a bilateral tumor with an ER/PR-positive tumor on the right side (PET-positive) 
and an ER/PR-negative tumor on the left side (PET-negative).  Maximum intensity projection (left);  CT (upper 
row);  68Ga-RM2-PET (lower row);  primary tumors indicated by red arrows (4). 


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2.4 Study Design 
This is a pilot study enrolling up to 20 participants with ER+ breast cancer, either at initial 
diagnosis prior to surgery or at suspected recurrence.  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. Participants will be given a copy of the consent form s/he signed. 
2. Participant will be asked to drink 1 to 2 glasses of water before arrival at the clinic 
3. Vital signs (heart rate, blood pressure) will be recorded 
4. Participant will be injected IV with 140 ± 20% mBq of 68Ga-RM2 
5. Participant will void immediately prior to the scan 
6. Data acquisition will begin with a dedicated scan of the breasts, followed by a vertex to 
mid-thighs scan.  First, localizer MRI scans will be performed to define the table 
positions and then MR structural imaging and diffiusion weigted imaging will be 
performed simultaneousely with PET imaging.  After the dedicated scan of the breasts, a 
whole-body combined PET/MRI acquisition will be initiated with 3 to 5 table positions at 
a 2 to 4 minute acquisition time per table position. 
7. Vital signs (heart rate, blood pressure) will be recorded again at the completion of the 
study, and the patient will be dismissed. 
8. Participants will be contacted at 24 to 72 hours following the scan in order to collect 
record any adverse events. 
2.4.1 Objectives of the Study 
Primary Objective 
• 
To evaluate the feasibility 68Ga-RM2 PET/MRI for identification of estrogen receptor 
positive primary breast cancer and metastases  
2.4.2 Endpoints 
Primary Endpoints 
• 
Number of lesions identified on 68Ga-RM2 PET/MRI 
• 
Correlation of 68Ga-RM2 uptake and ER positivity on biopsy (when done as clinically 
indicated) 
2.4.3 ClinicalTrials.gov Outcomes 
Primary Outcome 
Title:  Number of lesions identified on 68Ga-RM2 PET/MRI 
Description:  Findings deemed as compatible with breast cancer 
The outcome will be reported as the number of participants with successful PET-based 
detection of ER-positive breast cancer and metastases  
Timeframe:  12 months  
Safety outcome:  No 


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Secondary Outcome 
None 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 Inclusion Criteria 
1. ≥ 18 years-old 
2. Biopsy proven ER+ breast cancer, either at initial diagnosis prior to surgery or at 
suspected recurrence. 
3. Able to provide written consent 
4. Karnofsky performance status of ≥ 50 (or ECOG/WHO equivalent) 
5. Females must be not be pregnant per urine pregnancy test 
3.2 Exclusion Criteria 
1. Inability to lie still for the entire imaging time Inability to lie still for the entire imaging 
time  
2. Inability to complete the needed investigational and standard-of-care imaging 
examinations due to other reasons (severe claustrophobia, radiation phobia, etc.) 
3. Any additional medical condition, serious intercurrent illness, or other extenuating 
circumstance that, in the opinion of the Investigator, may significantly interfere with 
study compliance 
4. Metallic implants (contraindicated for MRI) 
3.3 Informed Consent Process 
All participants will be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.  
3.4 Study Timeline 
3.4.1 Primary Completion: 
The study will reach primary completion 24 months from the time the study opens to accrual. 
3.4.2.  Study Completion: 
The study will reach study completion 36 months from the time the study opens to accrual. 
4. IMAGING AGENT INFORMATION 
4.1 Study Agent 68Ga-RM2  
The PET radiopharmaceutical 68Ga-RM2 has previously been identified as 
68Ga-DOTA Bombesin or BAY86-7548.  This is not an FDA-approved product,and is described 
within IND 127137, the IND to which this protocol is submitted.  The structure of 68Ga-RM2 is 
represented in Figure 3. 


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Protocol version 4   10 July 2019  
 
Figure 3:  Chemical structure of 68Ga-RM2 
The administered dosage of 68Ga-RM2 will be 140 mBq ± 20%, administered IV.  The 
administered dosage is 140 mBq i.v.  Measured human dosimetry data are available from 
published data (5).  68Ga-RM2 is rapidly excreted through the kidneys to the urinary bladder and 
accumulated predominantly in the pancreas and liver.  Maximum peak uptake of the total 
injected radioactivity was seen in the urinary bladder contents and the liver, with approximately 
36% and 14%, respectively. 
The organ with the highest absorbed dose was the urinary bladder wall at 0.61 mSv/MBq, 
followed by the pancreas at 0.51 mSv/MBq.  The mean effective dose (14) was 
0.051 mSv/MBq.  Thus, the effective dose from a 140 MBq injected radioactivity is 7.7 mSv, 
which could be reduced to roughly 4.76 mSv with frequent bladder voiding (1-h voids).   
To summarize the results of the published human dosimetry study, there were no observed 
adverse events to the radiopharmaceutical.  The measured dosimetry showed that the critical 
organ with 68Ga-RM2 is the urinary bladder, followed by the pancreas.  The effective dose of 
68Ga-RM2 reported (0.051 mSv/MBq) is approximately twice as much as those of 
68Ga-DOTA-TOC (0.023 mSv/MBq), 68Ga-DOTA-NOC (0.025 mSv/MBq), 68Ga-DOTA-TATE 
(0.021 mSv/MBq) and 68Ga-NOTA-RGD (0.022 mSv/MBq) (6-9). 
4.2 Source of the Study Agent  
Molecular Imaging Program at Stanford (MIPS) 
Satellite Radiochemistry Facility  
300 Pasteur Dr, 
 
Stanford, CA 94305  
4.3 Ordering 
Ordered in Radiology Information System (RIS), address per above. 
4.4 Agent Accountability 
The RIS is password-protected and part of the electronic medical records. 
5. IMAGING SPECIFICS  
5.1 Modality or Modalities to be used 
PET/MRI 


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5.2 Details of Imaging (ie, dynamic, static, number of scans, etc) 
First a standard breast MRI will be done, at the discretion of the investigator.  After correct 
positioning of the spatial acquisition windows is ensured, the combined PET/MRI acquisition will 
be initiated with 3 to 5 table positions at a 2 to 4 min acquisition time per table position.  A 
volumetric T1 acquisition with fat-water separation and motion correction to enable 
free-breathing 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 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 Image interpretation 
The PET/MRI scans will be interpreted by ABNM certified Nuclear Medicine physicians and 
ABR certified Radiologists.  Drs Iagaru, Daniel, Loening and Mari 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 Pre-Study 
Potential subjects will be referred by treating physicians for participation in this imaging study.  
The following procedures will occur pre-study: 
• 
Review of eligibility criteria 
• 
Obtain informed consent 
• 
Collect demographics 
• 
Review medical history, including any concomitant medication.   
6.2 Imaging Days 
Subjects will undergo one clinic visit for imaging.  Subjects will receive an intravenous (IV) 
injection of investigational imaging agent (68Ga-RM2) and undergo PET/MRI image collection as 
described above.   
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 (chart review of 
medical records at approximately 6 months post scan and 12 months post scan) to record any 


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standard of care biopsies or imaging results.  The investigators will assist with identification of 
lesions that can be biopsied, based on 68Ga-RM2 findings, if requested by treating physicians. 
If a subject transfers clinical care outside of Stanford Healthcare during the chart review clinical 
follow-up period, investigators will request permission to contact the treating physician 
6.4 Criteria for Removal from Study 
The Protocol Director may withdraw subjects from the study for one or more of the following 
reasons:  failure to follow the instructions of the Protocol Director and/or study staff;  
determination that continuing the participation could be harmful to the subject;  the study is 
cancelled or other administrative reasons.  
6.5 Alternatives 
The alternative is to not participate in the study.   
7. STUDY CALENDAR 
 
Pre-Study 
Scan Date 
24 to 72 Hours 
Post-Scan 
12 Months 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
68Ga-RM2 
 
X  
 
 
Safety Follow-up Call to 
Participant 
 
 
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 equal to 10% of the limit that radiation workers (for example, a hospital x-ray 
technician) are allowed to receive in 1 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 all 
serious adverse events (per 21CFR§312.32) to the Stanford CCTO Safety Coordinator within 10 
working days of becoming aware of the event (5 days if the event is life-threatening or resulted 


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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 study charts will be stored in a locked office in the Cancer Clinical Trials Office.  
Demographic information 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.  
10. Statistical Considerations and Evaluation of Results 
10.1 Study Endpoints 
Primary endpoint:   
• 
Number of participants with successful PET-based detection of ER-positive breast 
cancer and metastases  
Other endpoints:   
None 
10.2.  Accrual estimates 
We anticipate enrolling 20 patients in total.  
10.3 Analyses Plans 
As this is an initial feasibility pilot, and we have no control over the biopsy process, we will only 
estimate the per-lesion sensitivity of 68Ga-RM2 PET-based in detecting the known ER+ lesions. 


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There will be at least 20 ER+ lesions, and we expect that the PET sensitivity will be at least 
80%. A sample of 20 will provide 90% power at one-sided 5% error to demonstrate that a 
sensitivity of 80% is greater than chance performance. A sample of 25 will provide 80% power 
to demonstrate sensitivity of 75%, which we believe is the minimum that would justify further 
study. 
10.4 Accrual estimates 
We expect the accrual of 10 patients each year for 2 years.  This is achievable given our 
experience with other protocols and the support from the referring physicians, Drs Masarweh 
and Telli.   


IRB-48150 
Page 17 of 18 CONFIDENTIAL 
Protocol version 4   10 July 2019  
11. REFERENCES: 
1. 
Siegel RL, Miller KD, Jemal A.  Cancer statistics, 2018.  CA:  A Cancer Journal for 
Clinicians.  2018;68(1):7-30. 
2. 
Morgat C, MacGrogan G, Brouste V, et al.  Expression of Gastrin-Releasing Peptide 
Receptor in Breast Cancer and Its Association with Pathologic, Biologic, and Clinical 
Parameters:  A Study of 1,432 Primary Tumors.  Journal of Nuclear Medicine.  
2017;58(9):1401-7. 
3. 
Jensen RT, Battey JF, Spindel ER, Benya RV.  International Union of Pharmacology.  
LXVIII.  Mammalian Bombesin Receptors:  Nomenclature, Distribution, Pharmacology, 
Signaling, and Functions in Normal and Disease States.  Pharmacological Reviews.  
2008;60(1):1-42. 
4. 
Stoykow C ET, Maecke HR, Bulla S, Bartholomä M, Mayer S, Drendel V, Bronsert P, 
Werner M, Gitsch G, Weber WA, Stickeler E, Meyer PT.  Gastrin-releasing Peptide 
Receptor Imaging in Breast Cancer Using the Receptor Antagonist 68Ga-RM2 And PET.  
Theranostics.  2016;6(10):1641-50. 
5. 
Kähkönen E, Jambor I, Kemppainen J, et al.  In Vivo Imaging of Prostate Cancer Using 
[68Ga]-Labeled Bombesin Analog BAY86-7548.  Clinical Cancer Research.  
2013;19(19):5434-43. 
6. 
Hartmann H, Zophel K, Freudenberg R, et al.  [Radiation exposure of patients during 
68Ga-DOTATOC PET/CT examinations].  Nuklearmedizin.  2009;48(5):201-7. 
7. 
Pettinato C, Sarnelli A, Di Donna M, et al.  68Ga-DOTANOC:  biodistribution and dosimetry 
in patients affected by neuroendocrine tumors.  Eur J Nucl Med Mol Imaging.  
2008;35(1):72-9. 
8. 
Sandstrőm M, Velikyan I, Garske-Román U, et al.  Comparative Biodistribution and 
Radiation Dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in Patients with 
Neuroendocrine Tumors.  The Journal of nuclear medicine.  2013;54(10):1755-9. 
9. 
Kim JH, Lee JS, Kang KW, et al.  Whole-body distribution and radiation dosimetry of 
(68)Ga-NOTA-RGD, a positron emission tomography agent for angiogenesis imaging.  
Cancer Biother Radiopharm.  2012;27(1):65-71. 
10. Connor RJ.  Sample Size for Testing Differences in Proportions for the Paired-Sample 
Design.  Biometrics.  1987;43(1):207-11. 
 


IRB-48150 
Page 18 of 18 CONFIDENTIAL 
Protocol version 4   10 July 2019  
Inclusion/Exclusion Criteria Checklist 
Protocol Title: 
A Pilot Study of 68Ga-RM2 PET/MRI in the Evaluation of Patients with Estrogen 
Receptor-positive Breast Cancer 
Protocol Number: 
IRB-48150  /  BRS0098   
Principal Investigator: 
Andrei Iagaru, MD 
3.1 Inclusion Criteria 
Inclusion Criteria  
Yes must be checked to be eligible 
Yes No 
Supporting 
Documentation 
1. ≥ 18 years-old 
☐ 
☐ 
 
2. Biopsy proven ER+ breast cancer, either at initial diagnosis prior to 
surgery or at suspected recurrence. 
☐ 
☐ 
 
3. Able to provide written consent 
☐ 
☐ 
 
4. Karnofsky performance status of ≥50 (or ECOG/WHO equivalent) 
☐ 
☐ 
 
5. Females must be not be pregnant per urine pregnancy test 
 
 
 
3.2 Exclusion Criteria 
Exclusion Criteria  
No must be checked to be eligible 
Yes No 
Supporting 
Documentation 
1. Inability to lie still for the entire imaging time  
☐ 
☐ 
 
2. Inability to complete the needed investigational and standard-of-care 
imaging examinations due to other reasons (severe claustrophobia, 
radiation phobia, etc) 
☐ 
☐ 
 
3. Any additional medical condition, serious intercurrent illness, or other 
extenuating circumstance that, in the opinion of the Investigator, may 
significantly interfere with study compliance. 
☐ 
☐ 
 
4. Metallic implants (contraindicated for MRI) 
☐ 
☐ 
 
*All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, 
and medical record review.  
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.   
 
Principal Investigator or Sub-Investigator: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
x 
Secondary Reviewer Signature: 
Date: 
Printed Name: