A Phase II Study of 68Ga-RM2 for PET/CT of Gastrin Releasing Peptide Receptor (GRPr) Expression in Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
 
Approval date: 05-Sep-2018 
A Phase II Study of 68Ga-RM2 for PET/CT of Gastrin 
Receptor (GRPr) Expression in Prostate 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTO 
Principal Investigator/Department: 
Hebert A. Vargas Alvarez , MD, 
Releasing Peptide 
Cancer 
COL 
Radiology 
Co-Principal 
Karim Touijer, MD 
Investigator(s)/Department: 
Anuradha Gopalan, MD 
Surgery 
Pathology 
Investigator(s)/Department: 
Hedvig Hricak, MD, PhD 
Jorge A. Carrasquillo, MD 
Neeta Pandit-Taskar, MD 
Josef Fox, MD 
Peter T. Scardino, MD 
James A. Eastham, MD 
Vincent Laudone, MD 
Brett Carver, MD 
Jonathan Coleman, MD 
Behfar Ehdaie, MD 
Laure Michaud, MD 
Lewis, Jason, PhD 
Serge Lyashchenko, Pharm 
Mithat Gonen, PhD 
Brad Beattie, PhD 
Radiology 
Radiology 
Radiology 
Radiology 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Radiology 
Radiochemistry 
Epidemiology/Biostatistics 
Medical Physics 
Consenting 
Karim Touijer, MD 
Professional(s)/Department: 
Peter T Scardino, MD 
James A. Eastham, MD 
Vincent Laudone, MD 
Brett Carver, MD 
Jonathan Coleman, MD 
Behfar Ehdaie, MD 
Hedvig Hricak, MD, PhD 
Jorge A. Carrasquillo, MD 
Neeta Pandit-Taskar, MD 
Josef Fox, MD 
Hebert A. Vargas Alvarez, MD 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Radiology 
Radiology 
Radiology 
Radiology 
Radiology 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 4 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 4 
2.2 
Primary Objective ......................................................................................................... 4 
2.3 
Secondary Objectives ...................................................................................................... 4 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 5 
3.1 
The Problem Being Addressed ..................................................................................... 5 
3.2. 
Existing Imaging Modalities in Prostate Cancer ................................................................ 6 
3.3 
Gastrin Releasing Peptide Receptor (GRPr) in Prostate Cancer ...................................... 8 
3.4 
Properties of 68Ga-RM2 (BAY 86-7548) ............................................................................. 10 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 12 
4.1 
Design .............................................................................................................................. 12 
4.2 
Intervention ............................................................................................................................ 13 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 14 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 14 
6.1 
Subject Inclusion Criteria .................................................................................................. 14 
6.2 
Subject Exclusion Criteria ................................................................................................. 14 
7.0 
RECRUITMENT PLAN ................................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 15 
Drug Accountability ......................................................................................................................... 16 
9.1 
PET/CT imaging ............................................................................................................. 16 
PET/CT imaging will be performed within two weeks prior to the planned prostatectomy ............ 16 
Package Labeling and Formulation ............................................................................................ 16 
9.2 
PET/MR coregistration .................................................................................................... 17 
9.3 
Immunohistochemistry and gene expression analysis ...................................................... 17 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 18 
Laboratory Safety Assessments ................................................................................................ 18 
Physical examination ................................................................................................................. 18 
Vital Signs ....................................................................................................................................... 18 
Image data analysis ................................................................................................................... 19 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 20 
Assessment for Toxicity ............................................................................................................. 22 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 22 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 22 
14.0 
BIOSTATISTICS ............................................................................................................... 22 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES24 
15.1 Research Participant Registration ......................................................................................... 24 
15.2 
Randomization ................................................................................................................... 24 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 24 
16.1 
Quality Assurance .............................................................................................................. 25 
16.2 
Data and Safety Monitoring .................................................................................................... 25 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 25 
17.1 
Privacy ............................................................................................................................... 26 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................... 26 
17.2.1.........................................................................................................................................28 
18.0 
INFORMED CONSENT PROCEDURES ............................................................................... 29 
19.0 
REFERENCES ...................................................................................................................... 30 
20.0 
APPENDICES ................................................................................................................... 33 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
Primary Objective 
 
• 
To determine the sensitivity and specificity of 68Ga-RM2 PET/CT to detect foci of 
primary prostate cancer using whole mount step sections of the prostate as a 
reference standard. 
(68Ga-RM2 is a Galium-68 labeled, gastrin releasing peptide receptor RM2 [DOTA-4-amino-1- 
carboxymethylpiperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2]). 
2.2 
Secondary Objectives 
 
• 
To compare the findings on 
68 Ga-RM2 PET/CT in the prostate with 
multiparametric MRI. 
• 
To study biological correlates for the increased GRPr (gastrin releasing peptide 
receptor) expression of prostate cancer. 
Correlation of PET/CT findings with: 
• Whole mount step sections of the prostate 
• Histology of resected lymph nodes 
• Multiparametric MRI of the prostate 
Radical prostatectomy and lymph node 
dissection 
PET/CT imaging with 68Ga-RM2 
Multiparametric MRI as part of standard of care 
Eligible patients with newly diagnosed prostate 
cancer, scheduled to undergo prostatectomy 
will be registered to study 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
2.3. 
Exploratory Analysis 
• 
To obtain preliminary data on the ability of 
68Ga-RM2 PET/CT to detect lymph 
node metastases. Because of the limited number of high risk patients included 
(n=6) we expect only few lymph node metastases. The ability of 68Ga-RM2 PET 
to detect these metastases will be reported in a descriptive fashion. 
• 
To obtain further descriptive data on the safety of 68 Ga-RM2. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
The Problem Being Addressed: 
 
In 2013, an estimated 238,540 US men will receive a diagnosis of prostate cancer and 29,170 are 
expected to succumb to the disease (1). If we compare this to 1988, the incidence today is 2.4 times 
higher but the mortality estimate is the same. The Swedish randomized trial of radical prostatectomy 
versus watchful waiting demonstrated a 50% reduction in metastasis and cancer specific mortality 
(2). In our experience of about 1700 patients treated with surgery alone, 15-year estimates for PSA 
progression and death from disease were 26% and 7% respectively. Despite these excellent rate of 
cancer control, perioperative morbidity (e.g., acute surgical and anesthetic complications, need for 
transfusions, incision pain, and time away from normal activities) is still too common. While some of 
these events have improved with minimally invasive surgery, other key outcomes measures such as 
positive surgical margins, urinary incontinence and erectile dysfunction remain unacceptably high. A 
patient with clinically localized cancer who is unlikely to harbor an indolent tumor and is 
contemplating surgery must have a clear understanding of the treatment goal: complete removal of 
the prostate, seminal vesicles and nodes (if indicated) with a negative margin and complete 
preservation of continence and potency. This is no easy task. The operation is technically 
challenging and its outcomes are highly sensitive to fine nuances in the surgical technique. 
Knowledge of cancer location, aggressiveness, size and extent are essential if treatment is to be 
tailored to individual patients. 
 
The need for individualized therapy of prostate cancer has been underlined by a large multicenter 
study on the mortality of prostate cancer (3). In this study the 15-year prostate cancer specific 
mortality rate was estimated at 7%, with poorly differentiated cancer and seminal vesicle invasion. In 
contrast, patients with Gleason score 6 or less had the lowest risk of prostate cancer specific 
mortality (0.03%). This data clearly demonstrates the wide range risk spectrum of prostate cancer 
and forms a strong impetus for a risk-adjusted management for prostate cancer. 
 
Advances in imaging have potential for achieving the goal of individualized treatment. As most 
cancers treated today are not palpable, the information from imaging will help the surgeon improve 
preoperative staging and deliver a more efficient surgical strategy. Imaging is also necessary for 
focal therapies of prostate cancer, such as radiotherapy or focused ultrasound (4). 
 
Management of patients with these low-risk tumors could be significantly improved by imaging 
techniques that accurately visualize the tumor in the prostate and allow for serial non-invasive 
imaging studies. Current active surveillance strategies require repeated biopsies in addition to digital 
rectal examination and PSA testing (5, 6). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
Thus there are four unmet medical needs that could be addressed by improved imaging 
technologies: (i) better identification of clinically significant prostate cancers, (ii) better delineation for 
prostate cancer for focal therapies, (iii) accurate non-invasive detection of lymph node metastases 
and (iv) non-invasive ways to monitor patients during active surveillance. The goal of this trial is to 
obtain initial clinical data whether PET/CT with a new ligand, targeting the gastrin releasing peptide 
receptor (GRPr) can address these needs. 
3.2. 
Existing Imaging Modalities in Prostate Cancer 
 
The cross-sectional imaging modalities that are used to evaluate prostate cancer include transrectal 
ultrasound (TRUS), x-ray computed tomography (CT), magnetic resonance imaging ( MRI), magnetic 
resonance spectroscopy (MRS) as well as positron emission tomography with fluorodeoxyglucose 
(FDG) or choline. 
3.2.1 
Computed tomography (CT) 
 
CT generally cannot detect disease that is confined to the prostate because of the limited 
contrast between tumor and normal prostate. In patients with high risk disease CT is used to 
exclude macroscopic lymphadenopathy. However, the sensitivity of CT to detect lymph node 
metastases is limited, because metastases frequently do not cause a significant enlargement of 
the node at the time of diagnosis. A meta-analysis of 24 studies has concluded that the pooled 
sensitivity of CT for detection of lymph node metastases was 42% at a specificity of 82% (7). 
3.2.2 
Transrectal Ultrasound (TRUS) 
 
Transrectal ultrasound was introduced in the 1970s and is used to localize areas suspicious for 
prostate cancer and directing transrectal biopsies (8). TRUS visualizes the seminal vesicles and 
the ampulla of the vas deferens. TRUS imaging also allows to differentiate the peripheral 
hyperechogenic zone from the central hypoechogenic zone. These anatomical features are used 
to guide systematic transrectal biopsies. Prostate cancer is typically visualized as hypoechogenic 
area within the prostate. However, up to 50% of prostate cancer show a similar echogenicity  
than the peripheral zone which limits the sensitivity of the technique for prostate cancer  
detection. Biopsies of prostate cancer guided by TRUS have shown only a poor correlation with 
the highest Gleason score as determined from systematic biopsies or prostatectomy specimens. 
In a multicenter study including almost 4000 patients, prostate cancer was detected in 25% of  
the hypoechogenic and in 25% of the isoechogenic lesions (8). 
3.2.3 
Magnetic resonance imaging and spectroscopy (MRI/MRS) 
 
Magnetic resonance imaging has been extensively studied for the detection and staging of 
prostate cancer as well as for differentiating clinically significant prostate cancers from 
insignificant cancers (9). Commonly used MRI techniques include T2 weighted and diffusion 
weighted images as well as contrast enhanced, T1 weighted images. The sensitivity and 
specificity for detection of prostate cancer varies with the used techniques and higher diagnostic 
accuracy is obtained by combining different imaging features (multiparametric MRI). MRI 
provides excellent soft-tissue resolution and is the most sensitive anatomic imaging modality 
available for the detection and staging of localized prostate cancer. A standard prostate 
examination includes at least multi-planar T1 - and T2 -weighted imaging and diffusion-weighted 
MRI (DW-MRI). These sequences are frequently complemented by T1 weighted contrast 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
enhanced study (dynamic contrast enhanced MRI, DCE-MRI). On T2 weighted images, prostate 
cancer usually demonstrates decreased signal intensity within the high-signal-intensity peripheral 
zone. However, the detection of prostate cancer can be hampered by the presence of 
confounding factors, such as post-biopsy hemorrhage and chronic prostatitis (9). 
 
DW-MRI allows for the measurement of water diffusivity. The degree of water diffusivitiy can be 
quantified by the apparent diffusion coefﬁcient (ADC), a measure of average molecular motion in 
the intra- and extracellular space (10). Generally, prostate cancer is detected as an area of low 
ADC. DCE-MRI involves the assessment of changes in signal intensity over time after contrast 
injection. During DCE-MRI, the contrast agent gadopentetate dimeglumine (Gd-DTPA) is  
injected intravenously and passes from the intravascular space to the interstitial space at a rate 
that depends on perfusion, vascularity, extracellular volume and vascular permeability. Prostate 
cancer typically demonstrates rapid initial uptake and rapid clearance of the contrast agent. The 
signal from  DCE MRI can quantified by various parameters including Ktrans  a parameter 
describing the transfer of contrast from the vascular space to the extracellular space and kep 
which describes the transport from the extracellular space to the vascular space (9). 
 
Magnetic resonance spectroscopy (MRS) provides maps of the distribution of choline, creatine, 
citrate and polyamines. Prostate cancer typically shows an increased concentration of choline 
and creatine relative to citrate (9). 
 
While multiparametric, multiplanar MRI is currently the most accurate technique to detect 
prostate cancer, sensitive and specific detection of prostate cancer remains challenging, 
especially for tumors with low Gleason scores. Furthermore, MRI signals do not accurately 
reflect Gleason scores. 
 
Detection of lymph node metastases on MRI is based on the size of the lymph node and 
therefore faces similar limitations than CT. A meta-analysis reported a pooled sensitivity and 
specificity of 39% and 82% (7). MRI is highly accurate for the diagnosis of bone metastases of 
prostate cancer and is frequently used to corroborate bone scintigraphy findings (particularly 
when the earliest involvement is thought to be present in the bone marrow). MRI is most 
sensitive in the axial skeleton and pelvis, and is less effective in the ribs, chest wall, and skull. 
3.2.4 
Radionuclide bone scanning 
 
In prostate cancer, bone scintigraphy is highly sensitive for detection of bone metastases, 
because prostate cancer metastases typically induce strong osteoblastic response. However, 
radionuclide bone scanning does not image tumor, but the reaction of the normal bone matrix to 
the metastasis. Thus it provides only a direct measure of cancer activity. Furthermore, the bone 
tissue reacts in a similar way to trauma, infection and non-physiologic stress. Consequently the 
specificity of radionuclide bone scanning is low. In addition, the common occurrence of the flare 
phenomenon (a paradoxical increase in intensity after successful therapy due to healing of the 
bone matrix) complicates the interpretation of scans on a serial basis. 
3.2.5 
Positron Emission Tomography (PET) 
 
PET has advantages over other imaging methods because it quantitatively assesses biologic 
processes in vivo and can assess different processes using specific radiotracers. Processes that 
can be analyzed with currently available reagents include glucose and amino acid metabolism 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
and proliferation, blood flow, and receptor status (i.e., androgen receptor). However, most 
studies have focused on the accumulation radiolabeled choline or choline analogs and FDG. 
 
3.2.5.1 FDG PET 
 
During the past decade, investigators at MSKCC have shown that PET imaging in prostate 
cancer can be tested prospectively using rigorous, carefully controlled standard clinical trial 
designs traditionally reserved for therapeutics. FDG PET has been shown to be clinically 
valuable to differentiate between active and inactive/treated metastases in castration 
resistant prostate cancer (11, 12). FDG PET was also found useful for monitoring 
chemotherapy in patients with metastatic prostate cancer. However, FDG uptake of primary 
prostate cancer is typically low, and the sensitivity of FDG PET for detection of primary 
prostate cancer is therefore limited. 
3.2.5.2 Choline PET 
 
11C-Choline has recently been FDA approved for detection of recurrent prostate cancer. 11C- 
Choline as well 18F labeled choline analogs (fluoroethylcholine and fluoromethylcholine) are 
commonly used in Europe for restaging of prostate cancer in patients with rising prostate 
specific antigen (PSA) levels following radical prostatectomy or radiotherapy for prostate 
cancer(13, 14). Choline PET has also been studied for detection of primary prostate cancer 
and of lymph node metastases at the time of initial diagnosis. While initial studies reported a 
high sensitivity and specificity for detection of prostate cancer, more recent studies have 
indicated that choline is also significantly accumulated by benign prostate hyperplasia and in 
chronic prostatitis (15). Systematic studies correlating choline uptake in the prostate with 
step-section whole mount histology found only a low sensitivity and specificity for detection of 
prostate cancer. Focal choline uptake in regional lymph nodes is quite specific for metastatic 
disease (specificity 94%), but the sensitivity was only 56% in a recent study including more 
than 200 patients with newly diagnosed prostate cancer (16). 
 
In summary, a variety of clinically available imaging modalities have been studied for imaging of 
prostate cancer. Currently MRI is the most accurate imaging technology for detection and 
regional staging of prostate cancer. However, even MRI demonstrated significant limitations in 
the detection and delineation of prostate cancer as well as in the accurate detection of regional 
lymph node metastases. Consequently, there is a clear clinical need for novel approaches for 
prostate cancer imaging. 
3.3 
Gastrin Releasing Peptide Receptor (GRPr) in Prostate Cancer 
 
An attractive target for a more sensitive and specific imaging of prostate cancer is the gastrin 
releasing peptide receptor (GRPr), a G protein coupled receptor that is a member of the bombesin 
receptor family. The bombesin family receptor is named after 14 amino acid peptide bombesin which 
was initially detected in the skin of the toad bombina. The bombesin receptor family comprises of 
four receptors, the BB1 or neuromedin receptor, the BB2 or GRPr receptor, the BB3 receptor which 
is not found in humans and the BB4 receptor for which the natural ligand is currently unknown (17). 
 
GRPr and its human ligand, gastrin releasing peptide (GRP), are physiologically expressed in the 
central nervous system and the gastrointestinal tract (17). GRPr overexpression has been observed 
in a variety of malignant tumors including breast cancer, small cell lung cancer and (17), but most 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
consistently in prostate cancer. An autoradiographic study found markedly increased binding of 
radiolabeled bombesin by prostatic intraepithelial neoplasia (PIN) and all 38 primary prostate 
cancers studied. In contrast, normal and hyperplastic prostate tissue demonstrate no or very low 
binding of bombesin (18). 
 
The potential of radiolabeled peptides in nuclear medicine to target tumor receptors has been 
investigated for many years and has been proven to be successful especially in the case of 
somatostatin. The radiotracer [68 Ga]DOTA-D-Phe1-Tyr3-Octreotid (DOTATOC) is used for the 
diagnosis of neuroendocrine tumors in clinical routine (19). Peptides provide excellent 
characteristics for PET-imaging because they can easily be synthesized, have fast and specific 
targeting features and are rapidly cleared from the body mainly via the renal pathway. In particular, 
peptides targeting G-protein coupled receptors are effective in accumulating in tumors in vivo. 
Peptides can also easily be labeled with therapeutic radionuclides for radiopeptide therapy of 
metastatic tumors. This ―theranostic‖ concept has been highly successful for imaging and treatment 
of neuoroendocrine tumors with the combination of 
68Ga-DOTATOC PET imaging 
90 Y-DOTA-TOC 
therapy (19). 
 
The physiologic ligand of GRPr in humans is gastrin releasing peptide (GRP), a 27 amino acid 
peptide. Both bombesin and GRPr are highly unstable in human plasma and therefore cannot be 
used as imaging or therapeutic agents. Several groups have therefore developed more metabolically 
stable bombesin analogs. Most of the compounds are GRPr agonists that have been tested in 
preclinical models of prostate cancer as well as in preliminary clinical trials (20). However, most of 
these ligands demonstrated high gastrointestinal uptake and insufficient metabolic stability in-vivo. 
Furthermore, GRPr agonists can cause acute side effects (abdominal cramps, vomiting) when 
administered at higher doses, as needed for radionuclide therapy (21). These limitations can 
potentially be overcome by radiolabeled GRPr antagonists. Non-radioactive labeled GRPr 
antagonists have been developed as anti-cancer agents, since GRP is involved in mitogenic auto- 
and paracrine signaling loops (17). These compounds were found to cause only minimal side effects 
in clinical trials (22). 
 
Our group has developed several radiolabeled GRPr antagonists for imaging and radionuclide 
therapy of prostate cancer. In mice these tracers showed higher tumor uptake than GRPr agonists.  
In addition, the antagonists showed rapid clearance from tissues with physiologic expression 
(gastrointestinal tract and pancreas) while they were retained for more than 24 h in GRPr expressing 
prostate tumor xenografts (23, 24). 
Of the studied GRPr antagonists, 64Cu-AR-CBC-TE2A demonstrated the most favorable 
characteristics with respect to tumor uptake and tumor-to-organ-ratios (23). Because of the 64Cu 
label (T1/2=12.7 h) pharmacokinetics of 64Cu-CBC-TE2A can be studied over several hours. Based 
on these encouraging characteristics we selected this compound for initial clinical studies. 
 
In a pilot 64Cu-AR-CBC-TE2A biodistribution and tumor uptake were in 4 patients with newly 
diagnosed prostate cancer at the University of Freiburg. Patient characteristics are summarized in 
table 1. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
 
Nr. 
Age 
Result core needle biopsy: Gleason score, 
TNM classification, tumor site and extension 
PSA 
(ng/ml) 
Therapy 
1 
64 
4/6 biopsies positive in left lobe (Gleason 6, T2), 
right lobe negative, tumor fraction 2% 
10,0 
125I seed implantation 
 
2 
77 
3/4 biopsies positive in right lobe (Gleason 7, 
T2a), left lobe negative, tumor fraction up to 
40% 
4,6 
percutaneous radiotherapy 
and androgen deprivation 
therapy 
 
3 
70 
Biopsies positive in right lobe (Gleason 7, T2b), 
left lobe negative, tumor fraction 10% 
9,9 
percutaneous radiotherapy 
and interstitial after- 
loading 
 
4 
73 
Biopsies positive in both sides of the prostatic 
gland (Gleason 7b, T2b), tumor fraction >90% in 
left lobe, <1% in right lobe 
26,2 
prostatectomy and 
lymphadenectomy 
 
 
Table 1. Characteristics of patients studied with 
64Cu-AR-CBC-TE2A 
 
All 4 tumors were visualized on the PET/CT images. Importantly, good contrast between the 
tumor and normal prostate tissue was achieved with 20 min to 4 hours post injection. These 
data therefore indicate that a long lived radionuclide is not necessary for PET/CT imaging of 
GRPr expressing tumors. 
For radiolabeling of peptides the positron emitter Gallium-68 (68 Ga) is particularly attractive. 
68Ga can be produced in radionuclide generator from the long lived parent radionuclide 
Germanium-68. This a significant advantage when compared to 64Cu which is produced in a 
cyclotron with an expensive solid target that is difficult to handle. 64Cu is therefore only 
produced at a few centers within the US. The physical half-live of 68 Ga is only 68 minutes 
which results in a low radiation exposure of the patients as compared to 64Cu (physical half- 
life 12 h). 68Ga labeling of peptides is performed with the commonly used Chelator DOTA 
(diethylentetraaminopentaacetat). 68Ga labeled peptides are in broad clinical use for imaging 
of neuroendocrine tumors in Europe. 
Because of these favorable characteristics we are evaluating a 68 Ga labeled GRPr binding peptide 
68Ga-RM2 for imaging of prostate cancer. 
3.4 
Properties of 68Ga-RM2 (BAY 86-7548) 
3.4.1 
Receptor affinity in-vitro 
 
In vitro, RM2 demonstrated high and selective binding affinity to the GRPr (IC 50  7.7-9.3nM, 
K d  2.5-3.1nM) whereas no binding was detected to other bombesin receptor subtypes such 
as neuromedin B (25). RM2 showed antagonistic properties due to inhibition of GRPr 
receptor internalization in GRPr-transfected HEK-cells and Ca2+ mobilization in PC-3 cells. 
No species differences in GRPr binding affinity between mouse, rat and human receptors 
was found (25). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
3.4.2 
Tumor uptake and biodistribution in mice 
 
High and specific tumor uptake of RM2 was found in mice bearing GRPr expressing human 
prostate cancer models: the androgen-independent PC-3 xenograft (14% ID/g at 1h p.i.) and 
the androgen-dependent LNCaP xenograft (6% ID/g at 1h p.i.). Low uptake in non-target 
organs resulted in high tumor-to-tissue (T/T) ratios at 1h p.i. favorable for PET imaging (e.g. 
T/Blood = 25, T/Muscle = 130 for PC3 tumors). RM2 was mainly excreted via the urinary 
pathway (~70% ID after 1h, >80% after 2h). (25) 
3.4.3 
Pharmacokinetics and Metabolism in mice 
 
In vitro, it was shown that the compound has a high stability in serum and liver microsomes. 
Negligible degradation of [177 Lu]-labeled RM2 was detected in vitro when incubated in   
human serum over a time period of 96 h as analyzed by radio-HPLC. After 96h incubation 
70% of the peptide was still intact. Microsomal stability of radioactive RM2 tested in human 
and mouse liver microsomes showed minor but cofactor-independent degradation of the 
tracer after 60 min incubation as analyzed by radio-HPLC (BAY 86-7548 investigators 
brochure). Metabolic profiling of BAY 86-7548 showed that 2 metabolites in minor amounts 
are generated in the presence of liver microsomes and hepatocytes of both rat and human. 
After intravenous administration of the non-radioactive precursor of 68Ga-RM2 in rat the 
compound distributes rapidly into the tissues with an alpha half-life of t 1/2 of 0.07 h and is 
also rapidly eliminated with a beta half-life of 0.19 h.  After intravenous administration of  
[
68Ga] labeled RM2 to mice it was shown that the radioactivity is mainly excreted renally via 
urine. In vivo evaluation of metabolism of the radioactive RM2 was performed in mouse using 
radio HPLC. In this study minor amounts of polar metabolites were found in plasma. In urine, 
one of these polar metabolites was also identified as dominant degradation product which 
increased over time, while intact peptide was still detected in the urine after 10-15 min. 
3.4.4 
Safety pharmacology studies 
 
The pharmacological safety of 68 Ga-RM2 bombesin analog was subject to studies addressing 
effects on the central nervous system (integrated into extended single dose toxicity study), 
cardiovascular system and respiratory system. Since the studies were intended to address 
the effects of the chemical entity only, a mixture (500:1) of RM2 and stable Ga-RM2) which 
are the precursor and the non-radioactive analogue of 68 Ga-RM2 was dissolved in 0.9% NaCl 
and given to rats as a single intravenous injection. Doses were 0 (vehicle), 0.11, 1.05 and 
10.5 mg/kg. The overall results of the in vivo safety pharmacology showed no adverse 
effects on central nervous system function and pulmonary function in rats. A transient slight 
increase in systolic and diastolic blood pressure was found immediately after administration 
of the high dose. The no observed  effect level (NOEL) was 1.05 mg/kg suggesting a safety 
factor of 300 to the planned maximal human mass dose of 30 µg of the mixture of RM2 and 
68Ga-RM2 per patient (conversion based on body surface area). 
3.4.5 
Safety, pharmacokinetics metabolism in humans 
 
The safety, pharmacokinetics and metabolism of 
68Ga-RM2 were studied in 5 male 
volunteers (26). The 68Ga radioactivity was rapidly excreted through the kidneys to the 
urinary bladder and accumulated predominantly in the pancreas and liver. Maximum peak 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
uptake of the total injected radioactivity was seen in the urinary bladder contents and the 
liver, with approximately 36% and 14%, respectively. The proportion of intact RM2 on total 
radioactivity in venous plasma declined over time, and 3 metabolites were detected by radio- 
HPLC. The proportions of unchanged 68Ga-RM2 were 92%±9%, 68%±9%, 47%±6%, 
29%±6%, 19%±2%, 16%±4%, and 15%±2% at 1, 10, 20, 40, 65, 100, and 150 min after 
injection, respectively. The in vitro investigations applying human hepatocytes revealed the 
metabolic pathways. Metabolite M-1 (68 Ga-DOTA chelate) appeared to be major, and M-2 
(cleavage of amide bond at alanine–valine) and M-3 (hydrolysis of glutamine residue) were 
minor constituents of total radioactivity. 
 
The unchanged tracer reached maximum plasma concentration after about 10 min and was 
eliminated from the circulation, with a terminal half-life of about 80 min. The total clearance 
was estimated to be about 55 L/h. No significant changes in vital signs, EKG and routine 
laboratory parameters were observed (26). 
3.4.6 
Uptake in human prostate cancer 
 
A recent study of 68Ga-RM2 in 11 patients with newly diagnostic prostate cancer reported a 
sensitivity of 88% and a specificity of 81% for detection of prostate cancer foci in 132 
prostate regions (27). This study did not include detailed comparisons with multiparametric 
MRI and no detailed correlative studies, such as correlation with ETS transcription factor 
rearrangements, was performed. 68Ga-RM2 also identified tumor recurrence in two of three 
patients with biochemical recurrence (27). 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
Patients with newly diagnosed prostate cancer scheduled to undergo radical prostatectomy 
are eligible to register for this study, providing all other eligibility criteria are met. Patients can 
be co-registered to therapeutic clinical trials, but may not receive any treatment between the 
PET study and the prostatectomy. 6 patients with low-risk, 8 patients with intermediate-risk 
and 6 patients with high-risk tumors according to NCCN guidelines (2.2014) will be included. 
Patients in ―very low‖, ―locally advanced‖, ―very high‖, and ―metastatic‖ risk categories of the 
NCCN guidelines will not be included in this study. We expect the information of RM-2 
PET/CT to be most clinically relevant in the ―low‖, ―intermediate‖, and ―high risk‖ patients. 
The classification of patients as low, intermediate and high risk is based on Gleason score, 
clinical T stage and serum PSA level. All of these parameters are routinely known before the 
planned surgical procedure and documented in the patient‘s medical record. We will create a 
spreadsheet with the number of patients in each risk group. As soon as the planned number 
of patients in a specific risk group has been accrued we will no longer screen for patients in 
this risk group. 
The goal of this proposal is to systematically evaluate a 
68 Ga labeled GRPr antagonist for 
imaging of primary prostate cancer using whole mount step section pathology as the 
reference standard. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
The primary objective (specific aim 1) is to determine the sensitivity and specificity of 
PET/CT with the GRPr antagonist 
68Ga-RM2 to detect foci of primary prostate cancer. 
Approach: we will include 20 patients with newly diagnosed prostate cancer (Gleason score 
6 to 8) scheduled to undergo radical prostatectomy. Localization will be defined using a total 
of 12 regions within the prostate. To facilitate correlation of radiotracer uptake with histology 
and MRI findings, PET/CT images will be coregistered with a T2 weighted MR images of the 
prostate (see specific aim 2). Radiotracer uptake within each region (expressed as 
standardized uptake value, SUV) will be assessed without knowledge of other imaging or 
clinical patient characteristics. 
Secondary objective 1 (specific aim 2) is to compare GRPr PET/CT for localizing prostate 
cancer with MRI and to determine if the combination of 68 Ga-PET and MRI is more accurate 
for detection of prostate cancer than either 
68 Ga-PET and MRI alone. Approach: MR imaging 
(established as standard of care at our institution) will include T2-weighted as well as  
diffusion weighted imaging. MR images will be read (i) blinded to the results of GRPr PET/CT 
and (ii) using fusion images of MR and PET. The level of suspicion for prostate cancer for 
both approaches will be recorded on a 5 point scale. We will compare the ROC curves, 
sensitivity and specificity of GRPr PET/CT, MRI and GRPr PET/MR using a McNemar‘s test 
adjusted for multiple regions. 
Secondary objective 2 (specific aim 3) is to perform exploratory analyses of histological, 
immunohistochemical, genetic and gene expression features of the resected tumors in order 
to identify factors influencing 68Ga-RM2 uptake. Appr oach: we will correlate 68 Ga-RM2 uptake 
with Gleason score, GRPr expression (as determined by immunohistochemistry), as well as 
the presence of ERG and ETV1 rearrangements. These rearrangements have recently been 
shown to be associated with increased GRPr RNA expression in patients with prostate 
cancer, but their relationship to GRPr protein expression and GRPr ligand binding is currently 
unknown. In order to undertand the relationship between AR signaling and uptake of 
68Ga- 
RM2 we also determine the correlation between AR staining on immunohistochemistry and 
an AR gene expression signature. 
In an exploratory analysis we will record the frequency of lymph node metastases on 
histopathology and the diagnostic accuracy of 68Ga-RM2-PET/CT to detect these 
metastases. Analysis will be performed on the basis of lymph node regions that can be 
identified on the PET/CT images to ensure that findings on PET are correctly matched with 
positive nodes on histopathology. Lymph node regions will include: internal iliac, obturator, 
presacral, external iliac, common iliac (each on the left and right side). For each of these 
anatomical lymph node regions an assessment will be made on the PET/CT images if there 
is focal 68Ga-RM2 uptake (above regional background) on PET in a lymph node identified on 
CT. 
 
4.3 
Intervention 
 
The intervention is the administration of a single dose of 150-200 MBq 68Ga-RM2 (mass <= 
30 µg) for imaging purposes. This will be followed by a 30-40 min PET/CT study after a 
waiting period of 60 min (+/- 10 min). Prior clinical experience suggests that imaging can be 
performed within 1 hour post injection (27, 28). MR imaging and prostatectomy will be 
performed as standard of care at MSKCC. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
If less than 150 MBq of 68Ga-RM2 are synthesized due to technical difficulties, patient can be 
injected with that amount. However, only a limited PET/CT will be performed over the region 
of interest, over the pelvis with acquisition time per bed position adjusted to the lower amount 
of injected radioactivity. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
The investigational product in this study is 
68Ga-RM2 (RM2), a [
68 Ga] labeled peptide antagonist of 
the bombesin GRPr receptor, for positron emission tomography (PET) imaging of tumors. 68Ga-RM2 
will be synthesized, formulated and tested for release as described in section 7 of this IND 
application. The synthetic precursor for 68Ga-RM2, RM2 (DOTA-4-amino-1-carboxymethylpiperidine- 
D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is provided by Piramal Life Sciences, Imaging Division 
(Berlin, Germany, http://www.piramal.com). Radiolabeling will be performed  in the Radiochemistry & 
Molecular Imaging Probes (RMIP) Core Facility at MSKCC. A Letter of Authorization from Eckert & 
Ziegler Eurotope, granting FDA access to the Drug Master File (DMF) for the Ga- generator is 
provided in section 7 of this IND. 
 
 
 
 
 
 
 
 
 
 
Figure 1. Chemical structure of 68Ga-RM2 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Age ≥18 years 
• 
Biopsy proven adenocarcinoma of the prostate 
• 
Patients with low-risk, intermediate-risk and high-risk tumors according to NCCN 
guidelines (2.2014) will be included 
• 
Planned radical prostatectomy at MSKCC 
• 
Multiparametric MRI of the pelvis (performed or planned) as routine care 
 
6.3 
Subject Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria will not be eligible for study entry: 
• 
Hematologic 
o Platelets <75K/mcL 
o ANC <1.0 K/mcL 
• 
Hepatic laboratory values 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
o Bilirubin >2.0 x ULN (institutional upper limits of normal) 
o AST/ALT >2.5 x ULN 
• 
Renal laboratory values 
o Creatinine > 2.0 x ULN 
• 
Claustrophobia interfering with MRI and PET/CT imaging 
• 
Prior pelvic radiation 
• 
Prior androgen deprivation therapy 
• 
Patients deemed not surgical candidates due to prohibitive co-morbidities 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Potential study participants will be identified by a member of the patient‘s treatment team at MSKCC. 
Men of all races and ethnic groups will be considered for study participation. Candidates must 
conform to all inclusion and exclusion criteria to be accepted into the study. 
 
If the investigator is a member of the treatment team, s/he will screen their patients‘ medical records 
for suitable research study participants and discuss the study and their potential for enrolling in the 
research study. Potential subjects contacted by their treating physician will be referred to the 
investigator/ research staff of the study. 
 
During the initial conversation between the investigator/ research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/ research staff may also review portions of their medical 
records at MSKCC in order to further assess eligibility. They will use the information provided by the 
patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment. If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation and 
medical records review. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
• 
History and physical examination 
• 
Vital signs 
• 
Laboratory studies (within 2 weeks before study entry): 
o Complete blood count 
o PSA 
o Serum BUN, creatinine, AST, ALT, total bilirubin, alkaline phosphatase, 
and albumin 
• 
Prostate MR imaging 
 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
Drug Accountability 
 
The investigator is obliged to keep sufficient documentation of the delivery and use of the 
investigational product. The documentation will include administration date/ time, calibration 
date/time, quantity, patient code, lot number and date of destruction. The investigator should 
maintain records that document adequately that the patients were provided the dose specified in the 
protocol and reconcile the medication received for the study. The label of each vial will contain the 
patient code and lot number, patient and radiopharmaceutical information will be entered in the 
radiopharmacy drug accountability forms. The investigator may assign some or all of the 
investigator‘s duties for drug accountability to an appropriate individual such as pharmacist or 
nuclear medicine technician who is under the supervision of the investigator. 
9.2 
PET/CT imaging 
 
PET/CT imaging will be performed within two weeks prior to the planned prostatectomy. 
 
No specific patient preparation is required before 68Ga-RM2 injection. One intravenous 
catheter (Hep-Lock) will be placed by staff in the Molecular Imaging and Therapy Service for 
radiopharmaceutical  administration. 
68Ga-RM2 preparation 
Radiolabeling of 68Ga-RM2. Labeling will be performed in accordance with the IND. The 
study will be performed under an FDA approved IND for 
68Ga-RM2; no studies will be 
performed until the IND is approved. The final product will contain 150-200 MBq 68Ga and a 
total mass of less than 40 µg RM2. The investigational product label will include the patient 
name, MRN and the calibration date and time. The investigational product is to be used 
within 60 minutes after manufacturing. 
 
Package Labeling and Formulation 
 
Each vial will contain the following information on the label: 
 
 
 
Images will be corrected for attenuation and scatter and adjusted for system sensitivity and 
providing parametric images in terms of standardized uptake values (SUV) (= MBq found/gm 
tissue / (MBq injected/gm body mass). 
PET scanning: In order to provide reproducible clinical data, we will acquire all 68 Ga RM2 
PET scans on a PET-CT scanner at MSKCC (same or a newer generation scanner). 
Intravenous injection of 68 Ga-RM2 (maximum of 200 MBq) will be given as a bolus. A PET- 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
CT scan extending from top of skull to mid thighs will be performed to determine the 
biodistribution 60 min (+/- 10 min) after injection. The low dose CT portion of the study will 
utilize 80 mA. 
If less than 150 MBq of 68Ga-RM2 is acquired and injected, only a limited PET/CT will be 
performed over the pelvis and acquisition times per bed position will be increased. 
 
Because the diagnostic accuracy of RM2-PET/CT for detection of prostate cancer and 
prostate cancer metastases is currently not known, the result of the RM2-PET/CT will in 
general have no impact on patient management. However, in the special case of focal RM2 
uptake in the bone marrow (outside the field of view of the prostate MRI), a dedicated MRI of 
the involved region will be discussed with the referring clinician and the patient. Because 
bone marrow is a frequent site for prostate cancer metastases and studies in normal 
volunteers have not shown any relevant RM2 uptake in the bone marrow, focal RM2 uptake 
in the bone marrow has to be considered as suspicious for metastatic prostate cancer. MRI 
is highly sensitive and specific for bone marrow metastases and is not associated with an 
additional risk for the patient. If bone marrow metastases are seen on MRI, patients are 
generally no longer treated with radical prostatectomy. Because radical pros tatectomy is 
associated with significant morbidity, we would therefore consider it as ethically problematic 
not to further evaluate focal RM2 uptake in the bone marrow by MRI. 
9.3 
PET/MR coregistration 
 
Mirada (www.mirada-medical.com) provides dedicated software to permit manual rigid and 
deformable registrations to align images acquired in separate sessions. We have used this 
software to register PET and MR datasets through anatomical co-registration of the low-dose 
CT scan of the PET/CT and MR data. The resultant transformation was then applied to the 
PET data. This co-registration capability will allow us to meet our primary objective of 
determining the distribution of radiolabeled bombesin in the prostate within a ―sextant‖ model 
used previously by our group (29).  In this model the prostate is divided in left/right base, 
left/right midgland and left/right apex. Each of these sextants is further divided into peripheral 
and transition zones. We acknowledge the imperfect nature of the ―sextant‖ approach for 
localization, particularly on PET/CT where the normal anatomy is less well-delineated, but 
co-registration with MRI based on anatomical landmarks such as the urethra, verumontanum 
and ejaculatory ducts should minimize localization errors and improve imaging to pathology 
correlation. 
9.4 
Immunohistochemistry and gene expression analysis 
 
The expression of GRPr by prostate tumors will be assessed with immunohistochemical 
staining as previously described (30, 31). Preliminary data in prostate tumor xenografts 
treated with androgen deprivation therapy suggest that GRPr expression is AR regulated (32, 
33). Conversely, GRPr expression can induce androgen independent growth of prostate 
cancer cells (34). We will therefore stain the tumors for nuclear AR as well as for PSA 
(positively regulated by AR) and PSMA (negatively regulated by AR, (35)) in order to 
interrogate the relationship between GRPr expression, in vivo 68Ga-RM2 binding, and AR 
signaling. Semiquantitative assays for AR and PSA are established at the prostate SPORE 
core lab. The relationship of GRPr and PSMA expression is also interesting from an imaging 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
perspective, because radiolabeled PSMA inhibitors have shown encouraging results in 
metastatic prostate cancer (36-38). Staining for PSMA and GRPr will allow us to evaluate 
whether PSMA and GRPr based PET imaging provide complementary information about 
tumor biology. This is suggested by previous studies which found that Gleason scores are 
negatively correlated with GRPr expression but positively with PSMA expression (18, 39). A 
recent study indicated that GRPr is a shared target gene of two ETS transcription factors that 
are involved in the development and progression of prostate cancer (ERG and ETV1) (40). 
ETS rearrangements are considered an early event in prostate carcinogenesis, which may 
explain the overexpression of GRPr in PIN and low-grade prostate cancers. Nuclear 
expression of ERG is a sensitive and specific marker for the presence of the TMPRSS2-ERG 
rearrangement and ERG mRNA expression (41). We will therefore stain the tumors for 
nuclear ERG using established protocols at MSKCC (41) and correlate the staining with  
GRPr immunohistochemistry as well as in vivo 
68Ga-RM2 binding. Loss of PTEN is closely 
linked to aberrant gene expression by ERG transcription factor rearrangements (42). Staining 
for PTEN will therefore also be included in our analysis. 
FISH analysis: In order to further investigate the relationship between ETS and AR signaling, 
we will use FISH for the TMPRSS2-ERG fusion gene (43) to assess the type of 
rearrangement (i.e., whether it is by deletion or translocation). We will also use FISH to 
assess the tumors for ETV1 rearrangements and AR amplification using established 
protocols at the prostate SPORE core lab. 
 
Gene expression analysis: We will determine GRPr mRNA levels of the tumors, normal 
prostate and benign prostate tumors and correlate those with GRPr immunohistochemistry 
and in vivo uptake of 68Ga-RM2. We will also determine the RNA expression levels for AR 
regulated genes including PSA, HK2 TMPRSS2, FKBP5, STEAP and PSMA as a readout for 
AR output. This ―AR signature‖ will be correlated with uptake of 68Ga-RM2. 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Laboratory Safety Assessments 
 
Hematology and blood chemistry assessments (CBC, PSA, serum BUN, creatinine, AST, ALT, total 
bilirubin, alkaline phosphatase, albumin, blood glucose levels, and serum testosterone level) will be 
done at the time points described in Table 2. Additional blood tests may also be performed at the 
discretion of the investigator for the purposes of investigation and follow-up of adverse events. 
 
Physical examination 
 
A physical examination including, but not limited to, general appearance, skin, neck, eyes, ears, 
throat,  lungs, heart, abdomen, lymph nodes, extremities, and nervous system will be performed. 
The physical examination will include examination of known and suspected sites of disease. 
Physical examination results, height and weight will be recorded at baseline . 
 
Vital Signs 
 
Blood pressure and heart rate will be obtained at the time points outlined in the flowchart. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
 
Table 2 
Schedule of Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1  CBC, PSA, serum BUN, creatinine, AST, ALT, total bilirubin, alkaline phosphatase, albumin, 
blood glucose, serum testosterone 
 
 
Image data analysis 
 
PET and MRI exams will be evaluated by a nuclear medicine physician (W. Weber) and an 
experienced radiologist (H.A. Vargas), respectively, blinded to the findings of the other imaging test, 
the biopsy results or any other clinical data except for the fact that the patient has prostate cancer. 
PET/CT. The reader will record the level of suspicion for the presence of cancer in each sextant of 
the peripheral and transition zones using a 5-point index scale. The minimum intensity of uptake for a 
positive lesion (score > 1 on the 5 point scale) will be defined as mean uptake in normal prostate 
tissue plus two-times the standard deviation in prostate tissue without focal radiotracer uptake. Mean 
and maximum standardized uptake values will be recorded for each suspicious focus on PET. We 
will use ROC analysis to determine the sensitivity/specificity for prostate cancer detection by various 
visual scores and quantitative thresholds for lesion ―positivity‖. Quantitative thresholds will be based 
on SUVs as well as lesion-to-background ratios. In addition to this analysis of the prostate, focal 
68Ga-RM2 uptake in lymph nodes, bones or other organs that is not explained by the normal 
biodistribution will be recorded. 
MRI. Standard of care MRI studies at the Department of radiology are performed using a 3T whole- 
body unit. Transverse T1-weighted and transverse, coronal, and sagittal T2-weighted fast spin-echo 
sequences are obtained. Diffusion-weighted MRI is acquired in the transverse plane using a single 
shot spin-echo echo-planar imaging sequence with multiple b-values (b 0-1000). Dynamic contrast- 
enhanced MRI is performed using a transverse 3D T1-weighted spoiled gradient-echo sequence 
with a temporal resolution <7 seconds. Images are acquired after i.v. injection of 0.1 mmol/kg body 
weight gadolinium-DTPA at a rate of 2 mL/s.Based on these images the likelihood of prostate will be 
scored on a 5-point scale as described in several previous publication of the Department of 
Radiology, for example  (29). 
Screening 
Day 1 
(day of 
PET/CT) 
Day 2 
(after 
PET/CT) 
Within 4 
weeks before 
PET/CT 
Within 14 
days before 
PET/CT 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concomitant  medications 
X 
Physical exam 
X 
Performance  status 
X 
Vital signs 
X 
X 
Routine MRI 
X 
Laboratory  studies1 
X 
Follow-up over phone 
X 
68Ga-RM2 tracer 
administration 
X 
68Ga-RM2 PET/CT scan 
X 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
Joint analysis of PET and MR images. Following this independent reading of the MRI and PET 
images, a joint reading of PET and MR will be performed. This will allow us to localize the findings 
on PET to the prostate zonal anatomy on MRI. We will then also record the likelihood of cancer in 
each prostate region but now based on the combined information from the PET and MRI. This 
analysis is performed in order to evaluate if the combination of PET and MR imaging is more 
accurate than PET and MR alone. Since combined PET/MR scanners have recently been 
introduced it is clinically relevant to evaluate if the combination of 68 Ga-RM2-PET and MR is 
potentially more accurate for detection of prostate cancer than either  68Ga-RM2-PET/CT or MR 
alone. 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
Risks 
 
68Ga-RM2 PET/CT Scans 
 
As part of this scan there is radiation delivered from the 68 Ga and from the low dose CT scan that 
are performed as part of the PET/CT for attenuation correction and co-registration. Although any 
exposure to ionizing radiation has the potential to cause some harm to tissue, the radiation 
exposures in this study are comparable to the low-level exposures associated with common 
diagnostic procedures such as CT scanning. There remains a low theoretical risk of developing a 
cancer at some point later in life as a result of the radiation exposure received in this study. This risk 
is much smaller than the clinical risks posed by the patient‘s current cancer. Participants should not 
father a baby while on this study. Acceptable birth control methods include abstinence, double 
barrier method, surgically sterilized patient or partner. 
RM2 
 
A recent study of 6 8Ga-RM2 in 5 normal male volunteers reported no drug related adverse effects 
after administration of up to 28 µg 68 Ga-RM2 (26) . There were also no drug related adverse effects 
in a study of 14 patients with prostate cancer imaged with 
68Ga-RM2 (27). Other non-radioactive 
GRPr antagonists have been studied for treatment of prostate cancer and were well tolerated at 
several degrees of magnitude higher doses. In a phase I study the GRPr antagonists RC3095 was 
administered at doses ranging from 8-96 µg/kg once or twice daily, i.e. approximately 560 µg/day – 
13440 µg/day. In this study the only discomfort observed was local discomfort at the injection site. 
There is a potential small risk of infection at the site of injection. 
Radiation Dosimetry 
 
 
68Ga-RM2 Radiation Doses in the 70 -kg Standard Man 
68Ga  Administered Activity: 
200 
MBq 
# of 80-mA CT scans: 
1 
Organ dose per 80-mA CT scan:   
9  
mSv  
Absorbed Dose s 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
68Ga-RM2 
68Ga-RM2+CT 
 
 
mSv/MBq 
mSv/scan 
mSv 
Adrenals 
0.011 
2.2 
11.2 
Brain 
0.0056 
1.12 
10.12 
Gallbladder Wall 
0.011 
1.2 
10.2 
LLI Wall 
0.014 
2.2 
11.2 
Small Intestine 
0.01 
2.8 
11.8 
Stomach Wall 
0.038 
2 
11 
ULI Wall 
0.0094 
7.6 
16.6 
Heart Wall 
0.028 
1.88 
10.88 
Kidneys 
0.081 
5.6 
14.6 
Liver 
0.023 
16.2 
25.2 
Lungs 
0.0071 
4.6 
13.6 
Muscle 
0.0082 
1.42 
10.42 
Pancreas 
0.51 
1.64 
10.64 
Red Marrow 
0.013 
102 
111 
Osteogenic Cells 
0.013 
2.6 
11.6 
Skin 
0.022 
2.6 
11.6 
Spleen 
0.006 
4.4 
13.4 
Teste s 
0.023 
1.2 
10.2 
Thymus 
0.01 
4.6 
13.6 
Thyroid 
0.007 
2 
11 
Urinary Bladder Wall 
0.027 
122 
131 
Total Body 
0.61 
2 
11 
Effective Dose (mSv/MBq) 
0.051 
10.2 
19.2 
 
 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
Table 3. 68Ga-RM2 absorbed Doses in 70-kg Standard Man per MIRD (OLINDA) Formalism Based 
on data from 5 volunteers. The calculations assume a bladder voiding interval of 3.5 h (26). Effective 
dose would be reduced by 25% by frequent bladder voiding (1h interval). 
Assessment for Toxicity 
 
Safety Outcome Measures (CTCAE v4) 
Infusion Reaction 
Patients will be monitored during and after 68 Ga-RM2 infusion for 120 minutes  after the infusion. 
The safety and tolerability of 68Ga-RM2 w i l l  be assessed using the following primary safety 
outcome measure: 
 
• 
Incidence,  nature, and severity of adverse events up to 1 day following peptide 
administration. 
• 
Change in vital signs during administration 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Tumor response will not be assessed as part of the study. 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Participation in the study is strictly voluntary. Patients have the right to withdraw from the study at 
any time. If a patient chooses to withdraw, he or she must inform the investigator immediately. In 
addition, the investigator has the right to terminate participation of any patient at any time if it is 
deemed in the patient‘s best interest. The reason and circumstances for premature discontinuation 
will be documented in the patient‘s medical records. Possible examples for reasons of premature 
study withdrawal include withdrawal of consent, SAE or intolerable AE, or any other medical illness 
at investigator‘s discretion. 
 
 
14.0 
BIOSTATISTICS 
Accrual Rate 
The  Urology  Service  performs  on  average  600-700  radical  prostatectomies  per  year  of  which 
patients  with intermediate or high-risk disease represent the majority.This imaging study does not 
compete with therapeutic studies and there is also no competing imaging study for primary prostate 
cancer. Therefore, we expect an accrual rate of one patient per week. 
Primary objective (specific aim 1) 
 
The primary objective of this proposal is to estimate the sensitivity and specificity of PET using a 
gastrin releasing peptide receptor antagonist for localizing tumors of the prostate. Localization will be 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
defined using a total of 12 regions within the prostate: right and left base, midgland and apex in both 
peripheral and transition zones. The uptake on each region will be assessed by a radiologist blinded 
to standard of care imaging and clinical characteristics. Histopathological confirmation will be used 
as the gold standard. 
 
Unit of analysis will be region and the correlation between regions of the same prostate will be 
handled statistically using a variance inflation factor (VIF) as described before (44). Primary analysis 
will involve an ROC curve for the uptake and calculation of the area under it. We will also report 
sensitivity and specificity in selected operating points from the ROC curve. With 20 patients and a 
total of 240 regions we will be able to estimate the sensitivity to within approximately +/- 11.4% and 
specificity to within +/- 8.1% with 95% confidence. These calculations are informed by a recent 
investigation of the use of 3T DW-MR imaging for the same disease at our institution (29). 
Specifically we used presumed values of 65% and 80% for sensitivity and specificity respectively, a 
VIF of 1.22 and a region-based prevalence of 40% which corresponds to approximately 100 tumor- 
bearing regions. 
Secondary objective 1 (specific aim 2) 
 
We will construct ROC curves separately for PET and MR, based on blinded five-point scale 
readings using histopathology as the gold standard. Curves will be compared using the Obuchowski 
method adjusted for clustering. We will also dichotomize the readings (0 and 1 as negative, and 2 or 
up as positive) and compare sensitivity and specificity of standard of care MR imaging with PET 
using a McNemar‘s test adjusted for multiple regions. The same comparisons will also be made for 
the joint analysis of PET and MR imaging vs. PET alone and MR imaging alone, respectively. 
 
With 20 patients contributing 12 regions each we will have approximately 80% power to detect an 
absolute difference of 10% (e.g. 65% vs 75%) between the sensitivities and specificities (45) while 
controlling the Type I error rate at 5%. 
Secondary objective 2 (specific aim 2) 
 
Because of the limited knowledge on the relationship between uptake of 68Ga-RM2 on the hand and 
AR  signaling  and  ETS  rearrangements  on  the  other  hand,  we  will  perform  descriptive, 
hypothesis generating analyses for this aim. Specifically, we will determine the 68Ga-RM2 SUVs for 
tumors with and without ETS rearrangement, AR amplification, AR gene expression signature, and 
PTEN loss in a descriptive fashion. We will also study the relationship between SUVs  and 
semiquantitative  immunohistochemical  parameters, such  as  GRPr  and  nuclear  AR  expression 
levels using Spearman rank correlation. 
Exploratory analyses 
 
Detection of lymph node metastases 
 
The frequency of lymph node and distant metastases in the studied patient population is expected to 
be small (a total of 20 patients will be studied, only 6 of whom will be high risk patients). Therefore, 
sensitivity and specificity for detection metastatic disease will only be recorded in a descriptive way 
and not further analyzed. 
Safety and tolerability of 
68Ga-RM2 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
The safety and tolerability of 68Ga-RM2 will be assessed using the following primary safety outcome 
measures: Incidence and nature of DLTs; incidence, nature, and severity of adverse events; and 
change in vital signs and clinical laboratory results. Incidence and severity of DLTs and adverse 
events will be estimated with sample proportions and 95% confidence intervals while changes in 
vital signs and laboratory parameters will be tested using the signed-ranks test and summarized with 
descriptive statistics. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. 
During the registration proc ess registering individuals will be required to complete a protocol 
specific Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether 
or not the participant is eligible to enroll in the study. Study staff are responsible for ensuring 
that all institutional requirem ents necessary to enroll a participant to the study have been 
completed. See related Clinical Research Polic y and Procedure #401 (Protocol Participant 
Registration). 
 
 
15.3 
Randomization 
 
This research study does not require randomization procedures. 
 
 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. 
The data collected for this study will be entered into a secure database. Source documentation will 
be available to support the computerized patient record. 
Study personnel will record clinical data in each patient‘s source documents (i.e., the patient‘s 
medical record). 
 
The investigator will maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified. After study closure, the 
investigator will maintain all source documents, study-related documents, and the data stored in the 
database used for data collection. Records will be retained and securely stored for a minimum of 2 
years after the completion of all study activities. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
Data will be entered throughout the duration of the trial as patients are enrolled. Accrual is expected 
to last 2 years. 
 
 
16.2 
Quality Assurance 
 
Regularly scheduled registration reports will be generated to monitor patient accruals and the 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and the extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period, and potential 
problems will be brought to the attention of the principal investigator for discussion and 
action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team at least once a year, more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The data and safety monitoring (DSM) plans at MSKCC were approved by the National 
Cancer Institute in September 2001. The plans address the policies set forth by the NCI in 
the document entitled Policy of the National Cancer Institute for Data and Safety Monitoring 
of Clinical Trials, which can be found at http://cancertrials.nci.nih.gov/clinicaltrials. The DSM 
plans at MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC DSM plans can be found on the MSKCC Intranet at:  
http://mskweb5.mskcc.org/intranet/html/70775.cfm. 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff  
education on clinical research quality assurance) and departmental procedures for quality 
control, and there are two institutional committees that are responsible for monitoring the 
activities of our clinical trials programs. The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the MSKCC Research Council and 
Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, 
and the monitoring procedures will be established at the time of protocol activation. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonization, and the ethical standards set forth in the 
Declaration of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
The proposed patient studies are purely diagnostic in nature and, based on our extensive 
clinical experience with diagnostic radiotracers in general and diagnostic radiolabeled 
peptides in particular, will involve administration of the labeled peptide at mass and activity 
levels far below those which would induce any toxic or other pharmacological effect. 
However, as with any exposure to radiation, even at the diagnostic levels to be used in this 
study, there is a very low, theoretical risk of radiation-induced cancer at some later point in 
life. The projected normal-organ radiation doses to subjects in this study are determined and 
included in our protocols and are well in the range of typical diagnostic imaging tests for 
cancer patients, such as CT. The risk of subsequent radiation-induced cancer is explicitly 
included in the Informed Consent forms for the studies included in this protocol. In addition, 
the subjects who will be enrolled in this clinical investigation will be exclusively patients with 
prostate. The additional radiation doses associated with the PET or PET/CT scans involved 
in this study, will typically represent a small increment in their "lifetime" exposures. The 
typical age of patients with prostate cancer will also decrease the likelihood for radiation 
induced cancer. 
This protocol does not have therapeutic intent and does not offer patients therapeutic benefit. 
This will be clearly conveyed to patients when communicating the potential toxicities/side 
effects of participating in this trial. Participation in the trial is voluntary and there will be no 
financial benefit (or burden) for the patients. Participants will not be charged for 68Ga-RM2 
tracer injections, 68Ga-RM2 PET/CT scans, and research testing on tumor tissue obtained 
from prostatectomy. 
17.1 
Privacy 
 
MSKCC‘s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant‘s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‗Reporting of Serious 
Adverse Events‘, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‘s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‘s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI‘s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
 
17.2.1 
 
This protocol will have an IND. SAE will also be reported to the FDA through the IND 
office and the report will include the FDA assigned IND number and name. 
17.3 
SAE Recording and Grading 
 
17.3.1 
Recording 
 
The investigator must assess each event to determine if it meets the criteria for classification as 
a serious adverse event (SAE) or serious adverse drug reaction (ADR). An SAE/ADR as defined 
in the Code of Federal Regulations (21CFR312.32) is any event that: 
 
• 
Results in death 
• 
Is life-threatening 
• 
Results in inpatient hospitalization or prolongs an existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Results in congenital anomaly/birth defect 
• 
Is medically significant in the opinion of the investigator 
 
 
All SAEs that occur any time a patient is on study (i.e., as soon as the informed consent has 
been signed) or within 30 days of the 68 Ga-RM2 PET/CT scan must be reported, regardless of 
the suspected relationship to the study drug. Any SAE occurring more than 30 days after the 
PET/CT scan must be reported if a causal relationship is suspected. 
 
When accounting for many tests per year, the radiation doses (on the order of 20 mSv) lie well 
within the ―low-dose‖ range—well below the threshold doses (typically on the order of 1000 mSv 
or greater) for any known deterministic effects. A detailed description of the expected dosimetry 
from the 68Ga-RM2 has been published. The dose of 68 Ga-RM2 per administration (150-200 
MBq) gives the lowest amount that would be consistent with the research goal. Lower doses of 
radioactivity would limit image quality and will limit the detectably of prostate cancer on PET. 
17.3.2 
Grading Severity 
 
All adverse events will be graded for intensity on a scale of 0 to 5. Severity grades will be 
recorded and based on the CTCAE v4.0. 
17.3.3 
Attributing Causality 
 
The investigator will evaluate the potential relationship between all clinical AEs, abnormal 
laboratory values, and the 68 Ga-RM2, and categorize the relationship according to the 
descriptions in Table 5. Abnormal laboratory values of clinical significance that were present at 
baseline and did not change in either severity or frequency during the experimental therapy or 
intervention and/or that can obviously be attributed to the underlying disease will be evaluated by 
the investigator and recorded in the ―unrelated‖ category. 
Table 6. 
Relationship of Adverse Event to 68Ga-RM2 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
Relationship 
Description 
Unrelated 
AE is clearly not related to the 68 Ga-RM2 
Unlikely 
AE is unlikely related to the 
68 Ga-RM2 
Possible 
AE may be related to the 68Ga-RM2 
Probable 
AE is likely related to the 68 Ga-RM2 
Definite 
AE is clearly related to the 
68Ga-RM2 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11- 
30. PubMed PMID: 23335087. 
2. 
Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, et al. Radical 
prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011;364(18):1708- 
17. PubMed PMID: 21542742. 
3. 
Eggener SE, Scardino PT, Walsh PC, Han M, Partin AW, Trock BJ, et al. Predicting 15-year 
prostate cancer specific mortality after radical prostatectomy. The Journal of urology. 
2011;185(3):869-75. PubMed PMID: 21239008. 
4. 
Eggener S, Salomon G, Scardino PT, De la Rosette J, Polascik TJ, Brewster S. Focal 
therapy for prostate cancer: possibilities and limitations. Eur Urol. 2010;58(1):57-64. PubMed PMID: 
20378241. 
5. 
Bastian PJ, Carter BH, Bjartell A, Seitz M, Stanislaus P, Montorsi F, et al. Insignificant 
prostate cancer and active surveillance: from definition to clinical implications. Eur Urol. 
2009;55(6):1321-30. PubMed PMID: 19286302. 
6. 
Eggener SE, Mueller A, Berglund RK, Ayyathurai R, Soloway C, Soloway MS, et al. A multi- 
institutional evaluation of active surveillance for low risk prostate cancer. The Journal of urology. 
2013;189(1 Suppl):S19-25; discussion S. PubMed PMID: 23234624. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
7. 
Hovels AM, Heesakkers RA, Adang EM, Jager GJ, Strum S, Hoogeveen YL, et al. The 
diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate 
cancer: a meta-analysis. Clin Radiol. 2008;63(4):387-95. PubMed PMID: 18325358. 
8. 
Smeenge M, Barentsz J, Cosgrove D, de la Rosette J, de Reijke T, Eggener S, et al. Role of 
transrectal ultrasonography (TRUS) in focal therapy of prostate cancer: report from a Consensus 
Panel. BJU Int. 2012;110(7):942-8. PubMed PMID: 22462566. 
9. 
Shukla-Dave A, Hricak H. Role of MRI in prostate cancer detection. NMR Biomed. 2013. 
PubMed PMID: 23495081. 
10. 
Vargas HA, Akin O, Shukla-Dave A, Zhang J, Zakian KL, Zheng J, et al. Performance 
characteristics of MR imaging in the evaluation of clinically low-risk prostate cancer: a prospective 
study. Radiology. 2012;265(2):478-87. PubMed PMID: 22952382. 
11. 
Meirelles GS, Schoder H, Ravizzini GC, Gonen M, Fox JJ, Humm J, et al. Prognostic value 
of baseline [18F] fluorodeoxyglucose positron emission tomography and 99mTc-MDP bone scan in 
progressing metastatic prostate cancer. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2010;16(24):6093-9. PubMed PMID: 20975102. 
12. 
Scher HI, Morris MJ, Larson S, Heller G. Validation and clinical utility of prostate cancer 
biomarkers. Nat Rev Clin Oncol. 2013;10(4):225-34. PubMed PMID: 23459624. 
13. 
Jilg CA, Rischke HC, Schultze-Seemann W. Salvage lymph node dissection with adjuvant 
radiotherapy for Choline-PET-CT positive lymph nodes in patients with nodal recurrence of prostate 
cancer. Journal of Urology. 2012. 
14. 
Rigatti P, Suardi N, Briganti A. Pelvic/Retroperitoneal Salvage Lymph Node Dissection for 
Patients Treated With Radical Prostatectomy With Biochemical Recurrence and Nodal Recurrence 
Detected by [11C]Choline Positron Emission Tomography/Computed Tomography. Eur Urol. 
2011;60(5):935-43. Epub 2011/08/16. doi: 10.1016/j.eururo.2011.07.060. PubMed PMID: 21840116. 
15. 
Souvatzoglou M, Weirich G, Schwarzenboeck S, Maurer T, Schuster T, Bundschuh RA, et al. 
The sensitivity of [11C]choline PET/CT to localize prostate cancer depends on the tumor 
configuration. Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2011;17(11):3751-9. PubMed PMID: 21493868. 
16. 
Poulsen MH, Bouchelouche K, Hoilund-Carlsen PF, Petersen H, Gerke O, Steffansen SI, et 
al. [18F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) 
for lymph node staging of prostate cancer: a prospective study of 210 patients. BJU Int. 
2012;110(11):1666-71. PubMed PMID: 22520686. 
17. 
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. Epub 2007/12/07. doi: 
10.1124/pr.107.07108. PubMed PMID: 18055507; PubMed Central PMCID: PMC2517428. 
18. 
Markwalder R, Reubi JC. Gastrin-releasing peptide receptors in the human prostate: relation 
to neoplastic transformation. Cancer Res. 1999;59(5):1152-9. PubMed PMID: 10070977. 
19. 
Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR. Radiopeptide imaging and therapy in 
Europe. J Nucl Med. 2011;52 Suppl 2:42S-55S. PubMed PMID: 22144555. 
20. 
Yu Z, Ananias HJ, Carlucci G, Hoving HD, Helfrich W, Dierckx RA, et al. An update of 
radiolabeled bombesin analogs for gastrin-releasing peptide receptor targeting. Curr Pharm Des. 
2013;19(18):3329-41. PubMed PMID: 23431995. 
21. 
Bodei L, Ferrari M, Nunn A, Llull J, Cremonesi M, Martano L, et al. 177Lu-AMBA Bombesin 
analogue in hormone refractory prostate cancer patients: a phase I escalation study with single- 
cycle administrations [abstract]. Eur J Nucl Med Mol Imaging. 2007;34 (Suppl 2):S221. 
22. 
Schwartsmann G, DiLeone LP, Horowitz M, Schunemann D, Cancella A, Pereira AS, et al. A 
phase I trial of the bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC3095 in patients with 
advanced solid malignancies. Investigational new drugs. 2006;24(5):403-12. doi: 10.1007/s10637- 
006-6886-5. PubMed PMID: 16505950. 
23. 
Abiraj K, Mansi R, Tamma ML, Fani M, Forrer F, Nicolas G, et al. Bombesin antagonist- 
based radioligands for translational nuclear imaging of gastrin-releasing peptide receptor-positive 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
tumors. J Nucl Med. 2011;52(12):1970-8. doi: 10.2967/jnumed.111.094375. PubMed PMID: 
22080443. 
24. 
Mansi R, Wang X, Forrer F, Kneifel S, Tamma ML, Waser B, et al. Evaluation of a 1,4,7,10- 
tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the 
labeling with single-photon emission computed tomography, positron emission tomography, and 
therapeutic radionuclides. Clinical cancer research : an official journal of the American Association 
for Cancer Research. 2009;15(16):5240-9. doi: 10.1158/1078-0432.CCR-08-3145. PubMed PMID: 
19671861. 
25. 
Mansi R, Wang X, Forrer F, Waser B, Cescato R, Graham K, et al. Development of a potent 
DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours. Eur J Nucl Med Mol 
Imaging. 2011;38(1):97-107. PubMed PMID: 20717822. 
26. 
Roivainen A, Kahkonen E, Luoto P, Borkowski S, Hofmann B, Jambor I, et al. Plasma 
Pharmacokinetics, Whole-Body Distribution, Metabolism, and Radiation Dosimetry of 68Ga 
Bombesin Antagonist BAY 86-7548 in Healthy Men. J Nucl Med. 2013;54(6):867-72. PubMed PMID: 
23564761. 
27. 
Kahkonen E, Jambor I, Kemppainen J, Lehtio K, Gronroos TJ, Kuisma A, et al. In vivo 
imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 2013;19(19):5434- 
43. Epub 2013/08/13. doi: 10.1158/1078-0432.ccr-12-3490. PubMed PMID: 23935037. 
28. 
Wieser G MR, Grosu AL, Schultze-Seeman W, Dumont-Walter RA, Meyer PT, Maecke H, 
Reubi JC, Weber WA. Positron emission tomography (PET) imaging of prostate cancer with a 
gastrin releasing peptide receptor antagonist - from mice to men. Theranostics, In press. 
29. 
Vargas HA, Akin O, Franiel T, Mazaheri Y, Zheng J, Moskowitz C, et al. Diffusion-weighted 
endorectal MR imaging at 3 T for prostate cancer: tumor detection and assessment of 
aggressiveness. Radiology. 2011;259(3):775-84. PubMed PMID: 21436085. 
30. 
Beer M, Montani M, Gerhardt J, Wild PJ, Hany TF, Hermanns T, et al. Profiling gastrin- 
releasing peptide receptor in prostate tissues: clinical implications and molecular correlates. 
Prostate. 2012;72(3):318-25. PubMed PMID: 21739464. 
31. 
Ananias HJ, van den Heuvel MC, Helfrich W, de Jong IJ. Expression of the gastrin-releasing 
peptide receptor, the prostate stem cell antigen and the prostate-specific membrane antigen in 
lymph node and bone metastases of prostate cancer. Prostate. 2009;69(10):1101-8. PubMed PMID: 
19343734. 
32. 
de Visser M, van Weerden WM, de Ridder CM, Reneman S, Melis M, Krenning EP, et al. 
Androgen-dependent expression of the gastrin-releasing peptide receptor in human prostate tumor 
xenografts. J Nucl Med. 2007;48(1):88-93. PubMed PMID: 17204703. 
33. 
Schroeder RP, de Visser M, van Weerden WM, de Ridder CM, Reneman S, Melis M, et al. 
Androgen-regulated gastrin-releasing peptide receptor expression in androgen-dependent human 
prostate tumor xenografts. Int J Cancer. 2010;126(12):2826-34. PubMed PMID: 19876914. 
34. 
Yang JC, Ok JH, Busby JE, Borowsky AD, Kung HJ, Evans CP. Aberrant activation of 
androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer. 
Cancer Res. 2009;69(1):151-60. PubMed PMID: 19117998. 
35. 
Evans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, et al. Noninvasive 
measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that 
targets prostate-specific membrane antigen. Proceedings of the National Academy of Sciences of 
the United States of America. 2011;108(23):9578-82. PubMed PMID: 21606347. 
36. 
Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, et al. PET 
imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: 
biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 
2013;40(4):486-95. PubMed PMID: 23179945. 
37. 
Barrett JA, Coleman RE, Goldsmith SJ, Vallabhajosula S, Petry NA, Cho S, et al. First-in- 
man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer. J Nucl 
Med. 2013;54(3):380-7. PubMed PMID: 23303962. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 14-146 A(5) 
Approval date: 05-Sep-2018 
 
 
 
38. 
Cho SY, Gage KL, Mease RC, Senthamizhchelvan S, Holt DP, Jeffrey-Kwanisai A, et al. 
Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight 
inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J Nucl 
Med. 2012;53(12):1883-91. PubMed PMID: 23203246. 
39. 
Ross JS, Sheehan CE, Fisher HA, Kaufman RP, Jr., Kaur P, Gray K, et al. Correlation of 
primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate 
cancer. Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2003;9(17):6357-62. PubMed PMID: 14695135. 
40. 
Paulo P, Ribeiro FR, Santos J, Mesquita D, Almeida M, Barros-Silva JD, et al. Molecular 
subtyping of primary prostate cancer reveals specific and shared target genes of different ETS 
rearrangements. Neoplasia. 2012;14(7):600-11. PubMed PMID: 22904677. 
41. 
Gopalan A, Leversha MA, Dudas ME, Maschino AC, Chang J, Al-Ahmadie HA, et al. 
TMPRSS2-ERG rearrangement in dominant anterior prostatic tumours: incidence and correlation 
with ERG immunohistochemistry. Histopathology. 2013. PubMed PMID: 23701505. 
42. 
Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, et al. Aberrant ERG 
expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 
2009;41(5):619-24. PubMed PMID: 19396168. 
43. 
Gopalan A, Leversha MA, Satagopan JM, Zhou Q, Al-Ahmadie HA, Fine SW, et al. 
TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. 
Cancer Res. 2009;69(4):1400-6. PubMed PMID: 19190343. 
44. 
Gonen M, Panageas KS, Larson SM. Statistical issues in analysis of diagnostic imaging 
experiments with multiple observations per patient. Radiology. 2001;221(3):763-7. PubMed PMID: 
11719674. 
45. 
Gonen M. Sample size and power for McNemar's test with clustered data. Stat Med. 
2004;23(14):2283-94. PubMed PMID: 15236431. 
 
 
 
20.0 
APPENDICES 
 
Not applicable