64Cu-DOTA-trastuzumab Positron Emission Tomography in Patients With Gastric Cancer
Phase: NA
Conditions: Adenocarcinoma of the Gastroesophageal Junction, Diffuse Adenocarcinoma of the Stomach, Intestinal Adenocarcinoma of the Stomach, Mixed Adenocarcinoma of the Stomach, Recurrent Gastric Cancer, Stage IA Gastric Cancer, Stage IB Gastric Cancer, Stage IIA Gastric Cancer, Stage IIB Gastric Cancer, Stage IIIA Gastric Cancer, Stage IIIB Gastric Cancer, Stage IIIC Gastric Cancer, Stage IV Gastric Cancer
Sponsor: City of Hope Medical Center

Study Title: 64Cu-DOTA-trastuzumab Positron Emission Tomography in Patients with 
Gastric Cancer  
NCT01939275 
Protocol dated 04/26/2017 
 
 

 
 
 
 
IRB Protocol No. 13229 
 
Version Date:  04/26/2017  
Version: 11 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF SURGERY 
 
TITLE: 64Cu-DOTA-trastuzumab Positron Emission Tomography in Patients with Gastric Cancer 
CITY OF HOPE PROTOCOL NUMBER: 
13229 
VERSION:  
11 
DATE(S) OF AMENDMENT(S)/REVISIONS: 
Inital Approval 
Protocol dated 12/13/13 
 
 
Version 00 
COH Amendment 
Title Page dated 6/24/14 (Personnel Update)  
Version 01 
COH Amendment 
Protocol Amendment dated 7/31/14 
 
 
Version 02 
COH Amendment 
Protocol Amendment dated 10/22/14 
 
 
Version 03 
             COH Amendment 
PI Change dated 07/17/15                  
                      Version 04 
COH Amendment 
Protocol Amendment dated 09/03/15 
 
 
Version 05 
COH Amendment  
Title Page dated 4/22/16 (Personnel Update)  
Version 06 
COH Amendment 
Protocol Amendment dated 04/28/16 
 
 
Version 07 
COH Amendment 
Protocol Amendment dated 08/05/16 
 
 
Version 08 
COH Amendment 
Title Page Dated 12/27/2016 
 
 
Version 09 
COH Amendment 
Title Page Dated 04/07/2017 
 
 
Version 10 
COH Amendment 
Protocol Amendment dated 04/26/17 
 
 
Version 11 
 
 
SPONSOR/IND NUMBER: Amending current IND 
DISEASE SITE: 
Gastric Cancer 
STAGE (if applicable): 
I-IV 
MODALITY: 
Intravenous 
PHASE/TYPE: 
Pilot 
PRINCIPAL INVESTIGATOR: 
City of Hope 
Yanghee Woo, MD 
Dept of Surgery 
COLLABORATING INVESTIGATORS: 
 
City of Hope 
 
City of Hope 
 
E. Kofi Poku, Pharm.D. 
Radiopharmacist 
Van Biglang-awa, Pharm.D. 
Radiopharmacist 
City of Hope 
Juan Mas, CNMT 
Radiation Safety 
City of Hope 
David Colcher, PhD 
Cancer Immunotherapeutics and Tumor 
Immunology 

 
 
 
 
IRB Protocol No. 13229 
 
Version Date:  04/26/2017  
Version: 11 
City of Hope 
Peiguo Chu, MD 
Dept of Pathology 
City of Hope 
Joanne Mortimer, MD 
Dept of Medical Oncology 
City of Hope 
 
City of Hope 
 
City of Hope 
 
 
CONSULTANT: 
 
Dave Yamauchi, MD 
Diagnostic Radiology 
 
Byrne Lee, MD 
Dept of Surgery 
Yuman Fong, MD 
Department of Surgery 
 
James Bading, PhD 
 
STUDY STATISTICIAN: 
City of Hope 
Paul Frankel, PhD 
Division of Information Sciences 
PARTICIPATING CLINICIANS: 
 
City of Hope 
Joseph Chao, MD 
City of Hope 
Marwan Fakih, MD 
 
 
City of Hope 
Dean Lim, MD 
City of Hope 
City of Hope 
Gagandeep Singh, MD 
Vincent Chung, MD 
City of Hope 
Maria Parayno, MD 
 
 
 
PARTICIPATING SITES: 
City of Hope 
 
STUDY SPONSOR AND MONITOR: 
City of Hope 
 

Page 1 of 36 
IRB Protocol No. 13229 
 
Version Date:  04/26/2017 
Version: 11 
  
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF SURGERY 
 
TITLE: 64Cu-DOTA-trastuzumab Positron Emission Tomography in Patients with Gastric Cancer 
CITY OF HOPE PROTOCOL NUMBER: 
13229 
 
 
 
 
SPONSOR/IND NUMBER: Amending current IND 
DISEASE SITE: 
Gastric Cancer 
STAGE (if applicable): 
I-IV 
MODALITY: 
Intravenous 
PHASE/TYPE: 
Pilot 
PRINCIPAL INVESTIGATOR: 
City of Hope 
Yanghee Woo, M.D. 
Dept of Surgery 
 
STUDY SPONSOR AND MONITOR: 
City of Hope 
 
 

Page 2 of 36 
IRB Protocol No. 13229 
 
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Investigators 
 
PRINCIPAL INVESTIGATOR: 
Yanghee Woo, MD 
Associate Clinical Professor  
Department of Surgery 
1500 East Duarte Road 
Duarte, CA 91010 
Phone: 626-218-0220 
Fax: 
626-301-8855 
e-mail: ywoo@coh.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY STATISTICIAN: 
Paul Frankel, PhD 
 
Division of Information Sciences 
 
1500 East Duarte Road 
 
Duarte, CA 91010 
 
Fax: 
626-471-7106 
 
e-mail: pfrankel@coh.org  
 
 
 
AGENT NSC# AND IND#: 
 
IND#109971  
 
COORDINATING CENTER: 
N/A 
 
 

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IRB Protocol No. 13229 
 
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Experimental Design Schema 
 
 
 
 
 
 
 
 

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IRB Protocol No. 13229 
 
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Protocol Synopsis 
Protocol Title: 
64Cu-DOTA-trastuzumab Positron Emission Tomography in Patients with Gastric Cancer 
Brief Protocol Title for the Lay Public (if applicable): 
 
Study Phase: 
Pilot 
Participating Sites: 
City of Hope 
Rationale for this Study: 
 
Recently, in a Phase III randomized trial on patients with HER2 positive gastric cancer, 
trastuzumab was shown to significantly improve survival for patients with locally advanced or 
metastatic disease(1).  Notably, the percent of HER2 positive disease in the literature ranges from 
~7% to 34% depending on the clinical study and methodology used to assess HER2 status.  
Surgical blocks have established that, on a microscopic scale, gastric cancer is heterogeneous, 
making it more difficult to establish HER2 positivity when compared to breast cancer.  This has 
resulted in recommendations ranging from the use of multiple blocks(2), to the use of bright-field 
methodologies(3) and larger tissue samples(4).  Each of these approaches has limitations.   
 
Our research team has developed radiolabeled trastuzumab to study HER-2/neu positive breast 
cancers in animal models and in humans using PET, in part because trastuzumab has a high rate 
of internalization, which results in trapping of radiometals within the cell. We have used 
radiolabeled trastuzumab for PET imaging in women with advanced HER2 positive invasive 
breast cancer and shown that tumor uptake of the radiotracer correlates with pathologic HER2 
positivity/negativity. We hypothesize that 64Cu-DOTA-trastuzumab PET can be used to improve 
assessment of HER2 status in gastric cancer by providing non-invasive, macroscopic 
measurements of average receptor expression (on a scale of approximately 4 cc).   Our long term 
goal is to use functional imaging with 64Cu-DOTA-trastuzumab PET to better predict which 
gastric patients will benefit from HER2-targeted therapy.   This pilot study represents the first 
imaging of gastric cancer with 64Cu-DOTA-trastuzumab PET.   It will allow us (1) To compare 
tumor uptake of  64Cu-DOTA-trastuzumab in gastric cancer patients with pathologic evaluation of 
tumor HER2/neu expression; and (2) To compare 64Cu-DOTA-trastuzumab-PET scan with 
standard radiographic imaging for staging patients with gastric cancer. 
  
Objectives: 
1. To compare tumor uptake of  64Cu-DOTA-trastuzumab in gastric cancer patients with 
pathologic evaluation of tumor HER2/neu expression 
2. To compare 64Cu-DOTA-trastuzumab-PET-CT scan with standard radiographic imaging 
for staging patients with gastric cancer 

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IRB Protocol No. 13229 
 
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Study Design: 
Pilot trial: see study schema 
Endpoints: 
 64Cu-DOTA-trastuzumab-PET-CT image assessment; 
HER2/neu assessment by pathology 
Sample Size: 
22 
Estimated Duration of the Study 
35months 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria 
1.1.1 
Histologic diagnosis of gastric or gastroesophageal junction adenocarcinoma 
(Two of the 22 enrolled patients must be HER2 3+ by IHC or FISH positive) 
1.1.2 
Either the primary tumor or at least one of the metastatic lesions must be >2cm 
1.1.3 
Normal cardiac ejection fraction 
1.1.4     Ability to provide informed consent 
 
 
 
Exclusion Criteria 
1.1.1 
Impaired cardiac function as evidenced by ejection fraction below institutional 
normal limits 
1.1.2 
Uncontrolled hypertension (mmHg >160 systolic or >90 diastolic) 
1.1.3     Participants who have reached trastuzumab within the prior 36 days 
1.1.4     Patients who are pregnant 
 
Investigational Product Dosage and Administration: 
64Cu -DOTA-trastuzumab 
 
Clinical Observations and Tests to be Performed: 
After the diagnosis and HER 2 status have been determined, additional tumor will be stored in 
pathology for future assessment of PI3K, PTEN, IGF1-R, EGFR, and phospho-S6 by 
immunohistochemical staining. The DNA Sequencing Core will assess mutations in PI3K and 
PTEN. 
Statistical Considerations: 
Sample Size Determination: 

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IRB Protocol No. 13229 
 
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As most of the objectives can obtain sufficient information for a pilot study with fewer patients, 
we powered this study to insure sufficient number of HER2 positive patients by IHC to serve as a 
positive control. 
 
Specifically, with 22 patients, there is an 80% chance we’d enroll at least one HER2 positive 
patient by IHC if the true incidence of HER2 positivity is the lowest end of the reported rate of 
7%. If the incidence is 16% (5), we would expect to observe 2 or more HER2+ patients with 89% 
probability.  
 
Additional analysis:  
1. In breast cancer, 64Cu-DOTA-trastuzumab-PET-CT) (Cu-PET-CT) was able to identify 
the tumors with low HER2 expression.  Gastric cancer has different adjacent tissue to 
provide a background noise comparison. As a result, with 22 patients, we will be able to 
determine the percent of patients whose tumors image with Cu-PET-CT with a 95% CI 
half-width of 21%.  
2. A subset of patients will have tumors of sufficient size to have Cu-PET-CT SUV 
variation over the tumor.  For patients with metastatic disease who have Cu-PET-CT 
positivity but negative initial testing for HER2 expression, additional image-directed 
biopsy of the Cu-PET-CT positive area will be performed for analysis prior to their 
destination systemic treatments (Track A on schema).  In those cases when subjects 
undergo surgical resection (Track B on schema), the, positive and negative areas of the 
tumor will be sent to pathology for confirmation.  These will be exploratory. 
3.  A subset of patients will receive neoadjuvant chemotherapy or chemotherapy and 
radiation as part of their standard of care treatment as determined by the surgeon. Once 
their neoadjuvant treatment is complete, they will undergo resection and pathologic 
correlation with the Cu-PET-CT. (Track C on Schema). 
4.  Correlation of Cu-PET-CT SUV (measured as peak SUV) and pathology will be 
explored. As correlation requires a continuous measure from pathology, and some 
pathology will use FISH and/or IHC, this will be exploratory.  Comparing Cu-PET-CT in 
positive cases versus negative by pathology will depend on the percent of patients 
deemed positive. This is an exploratory aim. 
5. Patients who are deemed negative by pathology, but appear positive by Cu-PET-CT is 
exploratory, as further evaluation will be needed to determine positivity by Cu-PET-CT. 
Sponsor/Licensee: 
City of Hope 
Case Report Forms 
Medidata Rave Electronic Data Capture 
Study Design 

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IRB Protocol No. 13229 
 
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We will enroll patients with gastric adenocarcinoma diagnosed either with endoscopic biopsy of 
the primary tumor or transcutaneous biopsy of a metastatic focus. After consenting and 
enrollment, the patient will have 64Cu-DOTA-trastuzumab-PET-CT scan prior to any treatment. If 
the 64Cu-DOTA-trastuzumab-PET-CT scan is negative and it correlates with a negative HER2 
evaluation of the biopsied tissue then utility of scan is verified (E on Schema). If the 64Cu-DOTA-
trastuzumab-PET-CT scan is positive and correlates with positive HER2 staining of biopsied 
tissues then, again the utility of scan is verified (C2 and B2 on Schema). If the scan is positive but 
the staining of HER2 is negative, the hypothesis is that this discrepancy is due to the 
heterogeneity of the tumor (A, B1, C1 on Schema). Therefore these patients will undergo scan 
directed biopsy or scan directed evaluation of the surgical specimen after resection.  

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IRB Protocol No. 13229 
 
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Table of Contents 
 
SECTION .............................................................................................................................. PAGE 
1.0 
Goals and Objectives (Scientific Aims) ............................................................................ 11 
2.0 
Background ....................................................................................................................... 11 
2.1 
Introduction/Rationale for Development ............................................................. 11 
2.2 
Overview of Proposed Study ............................................................................... 11 
2.3 
Human Studies ..................................................................................................... 12 
3.0 
Patient Eligibility .............................................................................................................. 14 
3.1 
Inclusion Criteria ................................................................................................. 14 
3.1.1 
Disease Status ......................................................................................... 14 
3.1.2 
Age Criteria, Performance Status and Life Expectancy ......................... 14 
3.1.3 
Child Bearing Potential ........................................................................... 15 
3.1.4 
Protocol-Specific Criteria ....................................................................... 15 
3.1.5 
Informed Consent/Assent ....................................................................... 15 
3.1.6 
Prior Therapy .......................................................................................... 15 
3.2 
Exclusion Criteria ................................................................................................ 15 
3.2.1 
Study-Specific Exclusions ...................................................................... 15 
3.2.2 
Non-Compliance ..................................................................................... 15 
3.3 
Inclusion of Women and Minorities .................................................................... 16 
4.0 
Screening and Registration Procedures............................................................................. 16 
4.1 
Screening Procedures ........................................................................................... 16 
4.2 
Informed Consent ................................................................................................ 16 
4.3 
Registration Requirements/Process ..................................................................... 16 
5.0 
Treatment Program ........................................................................................................... 17 
5.1 
Treatment Overview ............................................................................................ 17 
5.2 
Planned Duration of Therapy ............................................................................... 18 
5.3 
Criteria for Removal from Treatment .................................................................. 18 
5.4 
Subject Follow-Up ............................................................................................... 18 
5.5 
Supportive Care, Other Concomitant Therapy, Prohibited Medications ............. 18 
5.6 
Additional Studies ................................................................................................ 18 
5.6.1 
Laboratory Studies .................................................................................. 18 
6.0 
Dose Delays/Modifications for Adverse Events ............................................................... 19 
7.0 
Data and Safety Monitoring, Unanticipated Problems and Adverse Event Reporting ..... 19 

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7.1 
Data and Safety Monitoring ................................................................................. 16 
7.2 
Monitoring and Personnel Responsible for Monitoring ...................................... 19 
7.3 
Definitions ........................................................................................................... 20 
7.4 
Reporting of Unanticipated Problems and Adverse Events Error! Bookmark not 
defined. 
8.0 
Agent Information and Risks ............................................................................................ 26 
8.1 
64Cu-DOTA  ......................................................................................................... 22 
8.1.1 
Description .............................................................................................. 27 
8.1.2 
Pharmacology – Handling, Storage, Dispensing and Disposal ............... 27 
8.2 
Herceptin .............................................................................................................. 23 
9.0 
Correlative/Special Studies ............................................................................................... 28 
10.0 
Study Calendar .................................................................................................................. 29 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect....................................................... 31 
11.1 
Response Criteria ................................................................................................. 31 
12.0 
Data Reporting/Protocol Deviations ................................................................................. 31 
12.1 
Data Reporting ..................................................................................................... 31 
12.1.1 Confidentiality and Storage of Records .................................................. 31 
12.1.2 Subject Consent Form ............................................................................. 31 
12.1.3 Data Collection Forms and Submission Schedule .................................. 31 
12.2 
Protocol Deviations .............................................................................................. 32 
12.2.1 Deviation Policy ..................................................................................... 32 
12.2.2 Reporting of Deviations .......................................................................... 32 
12.2.3 Resolving Disputes ................................................................................. 32 
13.0 
Statistical Considerations .................................................................................................. 33 
13.1 
Study Design ........................................................................................................ 33 
13.2 
Sample Size Accrual Rate .................................................................................... 33 
14.0 
Human Subject Issues ....................................................................................................... 33 
14.1 
Institutional Review Board .................................................................................. 33 
14.2 
Recruitment of Subjects ....................................................................................... 33 
14.3 
Advertisements .................................................................................................... 34 
14.4 
Study location and Performance Sites ................................................................. 34 
14.5 
Confidentiality ..................................................................................................... 34 
14.6 
Financial Obligations and Compensation ............................................................ 34 
14.7 
Informed Consent Processes ................................................................................ 34 
15.0 
References ......................................................................................................................... 35 

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IRB Protocol No. 13229 
 
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Abbreviations 
Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCE 
Dynamic Contrast Enhanced 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
DWI 
Diffusion-weighted Image 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 

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IRB Protocol No. 13229 
 
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1. Goals and Objectives (Scientific Aims) 
1. 
To compare tumor uptake of  64Cu-DOTA-trastuzumab in gastric cancer patients with 
pathologic evaluation of tumor HER2/neu expression 
2. 
To compare 64Cu-DOTA-trastuzumab-PET-CT scan with standard radiographic imaging 
for staging patients with gastric cancer 
2. Background 
2.1  Introduction/Rationale for Development 
Gastric cancer remains the 2nd most frequent cause of cancer-related death worldwide(6). Although the 
incidence of gastric cancer is relatively low in the United States, it is a major cause of cancer-related 
deaths in California because of the state’s high numbers of Asian and East European immigrants(7). 
Despite multimodality treatment approaches, the prognosis of patients with advanced gastric cancers has 
remained quite poor with median rates of overall survival approximately 7 months. Targeted therapies 
have been identified and tested in many cancers; and recently, the evaluation of HER2/neu in gastric 
cancer has resulted in treatment advances. As a member of the epidermal growth factor receptor family, 
HER-2/neu (c-erb-B2, ERBB2) is a transmembrane tyrosine kinase receptor that plays a key role in 
growth factor signal transduction regulating cell growth, survival, and differentiation.(8) It has been 
shown to be overexpressed in 15-40% of tumors evaluated.(9)  
 
Trastuzumab is a humanized IgG-1 antibody that binds to the ectodomain of HER2. When combined with 
chemotherapy, trastuzumab significantly improves the survival of patients with biopsy-proven HER2 
overexpression. In the recent trastuzumab in gastric cancer (TOGA) Phase III randomized trial, the 
addition of trastuzumab to standard chemotherapy was shown to significantly improve survival. HER2 
overexpression and candidacy for trastuzumab is defined as 3+ staining by immunohistochemistry (IHC) 
or gene amplification by fluorescence in situ hybridization (FISH).(1) The greatest benefit appeared to 
occur in patients with 3+ overexpression on IHC, leading to median overall survival rates close to 18 
months. However, significant problems exist with HER2. Unlike breast cancers which are largely 
homogeneous, the task of identifying HER2 expression in gastric cancers is more difficult because of 
tumor heterogeneity. Although HER2 overexpression in the TOGA trial was reported to be 22% 
(consistent with breast cancer), our City of Hope institutional data shows a rate closer to 10-15%. 
Therefore, the diagnostic workup for HER2 overexpression must be improved, so that we can determine 
whether patients are eligible to receive trastuzumab which improves survival in patients with advanced 
gastric cancer.  
 
Interestingly, trastuzumab has been shown to be of benefit even in patients whose cancers are HER2 
negative by IHC and have low amplification of HER2 when associated with chromosome 17 polysomy. 
Additionally, data from NSABP B31 trial suggest that select women with HER2 negative breast cancer 
may benefit from trastuzumab therapy.(10) Finally, it is noted that when multiple measures of HER2 are 
performed at different institutions, the discordance rate (positive versus negative) may be as high as 20%. 
Taken together, the current measures of HER2 in clinical practice for patients with gastric cancer (and 
breast cancer) remain inaccurate which may preclude the administration of an effective targeted agent.   
 
2.2 Overview of Proposed Study 
Positron emission tomography (PET) provides a non-invasive way of studying tumor metabolic functions 
and response to therapy. In gastric cancer, PET-CT imaging is used in staging patients to evaluate 
metastatic disease and to assess response to chemotherapy before tumor regression can be documented on 

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IRB Protocol No. 13229 
 
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clinical or radiological exam.(11-13) Our research team has developed radiolabeled trastuzumab to study 
HER-2/neu positive breast cancers in animal models and in humans, in part because trastuzumab has a 
high rate of internalization, which results in trapping of radiometals within the cell.(14, 15) We have used 
radiolabled trastuzumab to image women with advanced HER2 positive invasive breast cancer. 64Cu-
DOTA-trastuzumab, first developed at City of Hope, accurately identified HER2 positive breast cancer in 
nude mice bearing an MCF7 HER2 overexpressing xenograft.(16, 17) We hypothesize that functional 
imaging with 64Cu-DOTA-trastuzumab PET-CT will improve the accuracy of HER2 assessment in 
patients with gastric cancer.  
 
An accurate assessment of HER2 status is essential to select patients who would benefit the most from the 
targeted therapy with trastuzumab. However, tumor heterogeneity of HER2 gene amplification has been 
reported between 5-53%.(4)  Although other published studies report overexpression of HER-2/neu in 15-
40% of gastric cancers, our institution has had a much lower HER-2/neu  overexpression rate at 
approximately 10% in biopsy-proven gastric cancer.  We hypothesize that imaging with 64Cu-DOTA-
trastuzumab-PET-CT can provide a non-invasive approach to more accurately evaluate HER2 status in 
gastric cancer.  Our proposed study is also highly innovative in three ways: (1) We will compare HER2 
expression in gastric cancers in vivo with 64Cu-DOTA-trastuzumab-PET-CT; (2) the 64Cu-DOTA-
trastuzumab-PET-CT and the IHC and/or FISH expressions of HER2 will be correlated; (3) the 
possibility of 64Cu-DOTA-trastuzumab-PET-CT directed identification of HER2 positive areas will be 
explored in both the biopsy of metastatic and resection of primary lesions; and (4) the effect of 
neoadjuvant treatment of gastric cancer on HER2 expression will be tested.    
 
2.3 Human Studies 
Trastuzumab, a recombinant humanized antibody that binds to the extracellular domain of HER2 protein, 
was conjugated to the active ester of DOTA (Macrocyclics).  64Cu, provided by the Mallinckrodt Institute 
of Radiology, Washington University School of Medicine, was incubated with DOTA-conjugated 
antibody and purified on a size exclusion preparative column.  Radiolabeled trastuzumab has been used 
safely and effectively to study HER2 positive breast cancers in animal models and in humans.  
Researchers at City of Hope have utilized 111In-DOTA-trastuzmab to image women with advanced HER2 
positive invasive breast cancer.  In the City of Hope experience, 111In-DOTA-trastuzmab identified areas 
of known metastasis in 4 of 7 patients; however, this agent has variable accuracy in identifying HER2 
positive disease on planar and SPECT scans. The positron emitting isotope 64Cu has a number of potential 
advantages over 111In including: improved image resolution with PET-CT and lower doses of radiation to 
the patient. 64Cu-DOTA-trastuzumab, first developed at City of Hope, accurately identified HER2 positive 
breast cancer in nude mice bearing an MCF7 HER2 overexpressing xenograft.  Because normal tissues 
that express HER2 will bind the radioabeled (hot) antibody, administration of a “cold dose” of 
trastuzumab improved the tumor specificity of the radiographic image.  Dr Joanne Mortimer (PI) recently 
completed a clinical trial with 64Cu-DOTA-trastuzumab in patients with metastatic HER2 positive breast 
cancer. The optimal dose of cold antibody required for 64Cu-DOTA-trastuzumab PET-CT to produce a 
high image quality was determined to be 50 mg.   

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As 64Cu-DOTA-trastuzumab is a radiolabeled conjugated ester analogue of trastuzumab, it is expected 
that it will have similar risks as the standard trastuzumab.  Additional risks will include the radiation 
absorbed per dose (reference Table A for the estimated absorbed dose vs. the radiation from the standard 
PET-CT tracer molecule F18 Glucose [FDG] which has a low dose of radiation equivalent to a bone 
scan). 
Table A: Estimated Radiation per Absorbed Dose 
64Cu Herceptin Absorbed Dose (AD) per 20 mCi injection 
Organ/Tissue 
AD (cGy) 
STD (cGy) 
Heart Wall 
17 
2 
Spleen 
14 
2 
Liver 
12 
1 
Kidneys 
9.2 
2 
Red Marrow 
3.8 
0.2 
Osteogenic cells 
4.6 
0.2 
Other 
< 2.2 
 
Total Body  
1.8 
0.2 
 
 
Currently, Dr. Mortimer is correlating tumor uptake of 64Cu-DOTA-trastuzumab PET-CT with the degree 
of immunopositivity of HER2 in women with metastatic disease.  Patients with metastatic HER2+ breast 
cancer that had not received HER2 directed therapy in the last 4 months were considered eligible.  The 
64Cu-DOTA-trastuzumab was infused intraveneously in 25 ml of saline over 10 minutes and patients were 
50 mg  dose 
pretreatment 
 5 mg  dose 
pretreatment 
FDG PET-CT 
 

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watched closely for any adverse reactions.  Eight patients were treated on study and tolerated it well 
without any unexpected adverse events.  64Cu-DOTA-trastuzumab is a radiolabelled conjugate so any 
toxicities are expected from the trastuzumab. The estimated radiation dose was within the range of those 
established for radionuclear imaging procedures.  The purpose of this study was to confirm the safety of 
this imaging technique which was shown.  In addition as demonstrated in the following figure, FDG-PET-
CT was able to visualize the rib lesion; however, the spinal metastasis was not obvious. With the 64Cu-
DOTA-trastuzumab PET-CT, the spinal lesion was clearly visible for up to 48 hours later. 
 
 
3. Patient Eligibility 
 
3.1 Inclusion Criteria  
3.1.1  Disease Status 
Patient must have a histologic diagnosis of gastric or gastroesophageal junction 
adenocarcinoma.  Two patients must be HER2 3+ by IHC or FISH positive 
Either the primary tumor or at least one of the metastatic lesions must be >2cm 
 
3.1.2 
Age Criteria 
Patients must be ≥ 18 years old 
ECOG performance status of 0-2 
   Life expectancy of > 3 months 
 
 
18FDG-PET 
64Cu-DOTA –Trastuzumab PET-CT 
(at 23 h)  
64Cu-DOTA –Trastuzumab PET-CT 
(at 48 h)  

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3.1.3 
Child Bearing Potential 
Women of childbearing potential must have a negative serum pregnancy test within 14 
days of 64Cu-DOTA administrations and must have agreed to use an effective 
contraceptive method 
The effects of 64Cu-DOTA on the developing fetus are unknown.  For this reason, women 
of child-bearing potential and men must agree to use adequate contraception (hormonal 
or barrier method of birth control or abstinence} prior to study entry and for four months 
following duration of study participation.  Should a woman become pregnant or suspect 
that she is pregnant while participating on the trial, she should inform her treating 
physician immediately. 
 
3.1.4 
Protocol-Specific Criteria 
 
CT/MRI scan must be obtained within 4 weeks prior to study entry 
 
Patients must have normal cardiac ejection fraction 
3.1.5 
Informed Consent/Assent 
All subjects must have the ability to understand and the willingness to sign a written 
informed consent. 
3.1.6 
For patients that have received prior therapy 
All toxicities should recover to grade 0 or 1 prior to day 1. 
3.2 Exclusion Criteria 
3.2.1 
Study-Specific Exclusion 
Impaired cardiac function including any one of the following: 
Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital 
long QT syndrome, presence of ventricular tachyarrhythmias, clinically significant 
resting bradycardia (<50 beats per minute), QTcF > 450 msec on screening ECG, or right 
bundle branch block + left anterior hemiblock (bifascicular block) 
Presence of atrial fibrillation 
Previous history angina pectoris or acute MI within 6 months 
Congestive heart failure (New York Heart Association functional classification III-IV) 
Uncontrolled hypertension (mmHg >160 systolic or >90 diastolic) 
Patients should not have active infections or concurrent neoplastic disease except for skin 
cancer. 
Patients may not be receiving any other investigational agents 
At the time of enrollment, patients may not have received any biological, chemotherapy, 
or radiation therapy.  
Patients may not have received trastuzumab within the prior 6 months for any other 
reason.  
 
 
Patients who are pregnant 
 
 
3.2.2 
Non-Compliance 

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Subjects, who in the opinion of the investigator, may not be able to comply with the 
safety monitoring requirements of the study. 
 
3.3 Inclusion of Women and Minorities 
The study is open to anyone regardless of gender or ethnicity.  Efforts will be made to extend the accrual 
to a representative population, but in a trial which will accrue approximately 20 subjects, a balance must 
be struck between subject safety considerations and limitations on the number of individuals exposed to 
potentially toxic or ineffective treatments on the one hand and the need to explore gender, racial, and 
ethnic aspects of clinical research on the other.  If differences in outcome that correlate to gender, racial, 
or ethnic identity are noted, accrual may be expanded or additional studies may be performed to 
investigate those differences more fully. 
4. Screening and Registration Procedures 
4.1 Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values, even if the studies were 
done before informed consent was obtained.  Reference is made to Section 10.0 – Study Calendar. 
4.2 Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
subject and a signed informed consent will be obtained.  Documentation of informed consent for 
screening will be maintained in the subject’s research chart and medical record.   
4.3 Registration Requirements/Process 
To register a patient, the treating physician should contact the protocol nurse or the responsible Clinical 
Research Associate (CRA) in Clinical Trial Office (CTO) to complete the eligibility/registration form. 
The protocol nurse or CRA will contact the Data Coordinating Center at the City of Hope (626-256-4673, 
ext. 64267 or e-mail dcc@coh.org), EMAIL a copy of the completed eligibility checklist, required pre-
study tests (per protocol – and may include laboratory, CT and pathology reports), signed Informed 
Consent, signed Patients' Bill of Rights and HIPAA authorization form to dcc@coh.org.  
The patient registration process will be handled by the Department of  Clinical Research Information 
Support (CRIS) Data Coordinating Center (DCC) at City of Hope. Documentation of current IRB 
approval must be on file with the DCC prior to registration of patients on this study for participating 
institution.  
 
The steps below are to be taken when registering a patient: 
 
The research staff must assure they have the most current and updated version of the protocol 
and informed consent prior to enrolling a patient.  If a question arises, please contact the Data 
Coordinating Center at 626-256-4673 extension 64267 or via email at  dcc@coh.org.   
 
The study staff must assure that all prestudy laboratory tests, scans and x-rays have been 
completed prior to registration according to the study calendar 
 
The  study staff must assure that the patient has signed an approved informed consent prior to 
registration/randomization, including the Experimental Subject Bill of Rights and appropriate 
HIPAA authorization. 

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 
The study staff must confirm that the patient meets all inclusion and exclusion eligibility 
criteria for the protocol.  The eligibility checklist (provided by the COH DCC) must be 
completed in its entirety. 
 
Patients must be registered prior to initiation of treatment but no more than 5 working days 
prior to planned start of treatment.  A patient failing to meet all protocol requirements may 
not be registered.   
 
Once a patient is eligible, all the pre-study requirements have been fulfilled, and the informed 
consent obtained, the research nurse or the data manager (study coordinator) will inform the 
COH Data Coordinating Center at (626) 256-4673, extension 64267; email dcc@coh.org and 
FAX (fax number 626 256-8794) a copy of the patient’s signed informed consent, , 
completed eligibility checklist and corresponding source documentation confirming 
eligibility (including pathology reports, lab reports, x-ray reports, etc.). 
 
The City of Hope Data Coordinating Center will: 
 
Review all materials/source documentation to ensure the patient is eligible.   
 
Ensure the consent form is valid and is signed correctly by all parties.  If additional 
information is needed or should there be any questions, the Data Coordinating Center will 
immediately contact the study staff and registration will not occur until all issues are 
resolved.   
 
If there are questions regarding exceptions to the eligibility criteria, please contact he study 
Principal Investigator, as well as the COH DCC.  Documentation of IRB approval of 
exception will need to be submitted as well as the COH DCC. 
 
Confirmation of Registration will be emailed/faxed to the  study staff noting the patient’s 
study number within 24 hours post receipt of a complete eligibility packet. 
 
The COH DCC will call the research nurse or data manager (study coordinator) and verbally 
confirm the registration (if needed). 
 
If the patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled.  The COH DCC should be notified of 
cancellations as soon as possible. 
5. Treatment Program 
5.1 Treatment Overview 
Patients with histology confirmed gastric or gastroesophageal junction adenocarcinoma are eligible for 
the study.  Informed consent will be obtained and patients screened.   If eligibility criteria are met, patient 
will be enrolled in the trial and undergo 64Cu -DOTA-trastuzumab PET CT scan. 
 
Treatment Plan 
Patients will receive 45 mg trastuzumab over 15 minutes prior to the administration of 64Cu -DOTA-
trastuzumab, which includes 5 mg of trastuzumab. See section 8.1 for information regarding preparation 
of 64Cu -DOTA-trastuzumab.  Imaging will be performed on a GE Discovery 16 Ste PET-CT scanner 
(axial field of view 15.4 cm).  PET-CT images will be performed in 3D mode (septa retracted) and 
corrected for tissue attenuation based on co-registered CT acquired during the same examination. PET-CT 
images will be reconstructed with spatial resolution of approximately 9 mm full-width-at-half maximum 
(FWHM) using an iterative algorithm (OSEM).  Patients will be injected via a peripheral vein with 15 

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mCi of 64Cu-DOTA-trastuzumab. PET-CT scanning of 64Cu will be peformed between 24 and  48 hours 
post injection (Day 2 or Day 3). At 24 hours, the concentration of 64Cu-DOTA-trastuzumab will allow for 
whole body PET-CT imaging within the same amount of time required to image the abdomen and pelvis 
at 48 hours due to the half life of the radiotracer.  PET-CT images will be compared to standard MRI or 
CT scans. 
 
5.2 Planned Duration of Therapy 
This is a nontherapeutic study and patients will be on study for the duration of screening and then PET-
CT imaging with 64Cu -DOTA-trastuzumab.  If a patient experiences any adverse events related to the 
administration of 64Cu -DOTA-trastuzumab, their medical condition will continue to be followed until 
resolution of the adverse effects.  Participants requiring additional study related treatment such as the 
image directed transcutanteous biopsy of the area of PET and IHC/FISH discordance will continued to be 
monitored as part of the study until first postprocedure follow-up or until any complications from the 
study related procedures are resolved.  Those who undergo surgical resection will be followed until the 
first postoperative clinic appointment or until any complications from the study related procedures are 
resolved.   
5.3 Criteria for Removal from Treatment 
This is a nontherapeutic trial. Patients will be removed from the trial if they experience an infusion 
reaction or are unable to comply with the research visits. 
5.4 Subject Follow-Up 
There is no formal follow-up after 15 days.  Progress notes on the patient’s condition with standard 
therapy may be collected for data up to 6 months after the completion of the trial. 
5.5 Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Patients will be instructed not to take any additional medications (including over-the-counter products) 
during the course of the study without prior consultation with the investigator. At each visit, the 
investigator will ask the patient about any new medications he/she is or has taken after the start of the 
study drug. 
All concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and after start 
of study drug, including physical therapy and blood transfusions, should be recorded. 
The following restrictions apply during the entire duration of the study (Days 1-15): 
No other investigational therapy should be given to patients.  The patient may proceed with 
therapeutic treatment after day 15.   
No anticancer agents should be given to patients. If such agents are required for a patient then the 
patient must first be withdrawn from the study. 
 
5.6 Additional Studies 
5.6.1 
Laboratory Studies 
Prestudy laboratory tests to determine eligibility should be done within 30 days of day 1 
on protocol. 
 

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6. Dose Delays/Modifications for Adverse Events 
N/A 
7. Data and Safety Monitoring  
7.1 Definition of Risk Level 
This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety Monitoring Plan”, 
http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx involving COH as IND holder and the 
first-in-human use in gastric patients of 64Cu-DOTA.  
 
  
7.2 Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, CRA/protocol 
nurse, and statistician is responsible for monitoring the data and safety of this study, including 
implementation of the stopping rules for safety and efficacy.   
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the 
frequency prescribed in the City of Hope Institutional Data and Safety Monitoring Plan [policy 
dated 07/09/2014].  Important decisions made during PMT meetings (i.e., dose escalation, de-
escalation, etc.) only need to be noted in the PMT Report submitted to the Data and Safety 
Monitoring Committee (DSMC). 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting Requirement 
RL 1, RL2, and Expanded 
Access Studies 
No reports required 
3 
I 
Every 3 months from activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from activation date, as 
indicated in MIDAS 
 
 

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Data and safety will be reported to the COH DSMC using the PMT report and submitted quarterly from 
the anniversary date of activation.  Protocol specific data collection will include the following items: any 
UPs or AEs that occur on this study along with any treatment related deaths.  
7.3 Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change 
of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if 
it is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event OR is an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
Serious Adverse Event (SAE) [21 CFR 312.32] - defined as any expected or unexpected adverse 
event that results in any of the following outcomes: 
 Death 
 Is life-threatening experiences (places the subject at immediate risk of death 
from the event as it occurred) 
 Unplanned hospitalization equal or greater than 24 hours)) or prolongation of 
existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasias of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) - Any incident, experience or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 

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approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
 
Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the 
study agent or study procedure. 
 
Definite - The AE is clearly related to the investigational agent or study procedure and 
unrelated to any other cause. 
 
Probable - The AE is likely related to the investigational agent or study procedure and 
unlikely related to other cause(s). 
 
Possible -The AE may be related to the investigational agent or study procedure and may be 
related to another cause(s). 
 
Unlikely -The AE is doubtfully related to the investigational agent or study procedure and 
likely related to another cause(s). 
 
Unrelated -The AE is clearly not related to the investigational agent or study procedure and 
is attributable to another cause(s). 
 
The PI will be responsible for determining the event name, assessing the severity (grade), 
expectedness, and attribution of all adverse events using the CTCAE version 4. 
 
7.4 Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems - Most unanticipated problems must be reported to the COH 
DSMC and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/policy/Policies%20and%20Procedures/REVIEWING_AND_REPORTING
_UNANTICIPATED_PROBLEMS.pdf.  Any unanticipated problem that occurs during the 
study conduct will be reported to the DSMC and IRB by submitting electronically in 
iRIS (http://iris.coh.org). 

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Serious Adverse Events - Begins after study treatment or any study related procedures.  All 
SAEs occurring during this study, whether observed by the physician, nurse, or 
reported by the patient, will be reported according to definitions and guidelines at 
http://www.coh.org/policy/Policies%20and%20Procedures/REVIEWING_AND_REPORTING
_UNANTICIPATED_PROBLEMS.pdf and Table 2 below.  Those SAEs that require 
expedited reporting will be submitted electronically in iRIS (http://iris.coh.org). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that 
do not meet the criteria of serious OR are not unanticipated problems will be reported 
only in the continuation reports and PMT reports (see Table 2 below). 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
DSMC Risk Level 3 and Risk Level 4 Protocol Reporting Timelines 
 
 
 
Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Death while on active treatment or within 30 days of last day of treatment 
Possibly, Probably, Definitely 
5 calendar days 
Unlikely, Unrelated 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
Within 30 days of last active treatment/therapy 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
 
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 

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Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
After 30 days of last active treatment/therapy 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 

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DSMC Risk Level 1 and Risk Level 2 Protocol Reporting Timelines 
Required Reporting Timeframe to DSMC 
Attribution 
Unexpected 
Expected 
  
Death while on active treatment or within 30 days of last day 
of treatment 
Possibly, Probably, Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
 
 
COH IRB Adverse Event Reporting Timelines  
 

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Required Reporting Timeframe to COH IRB  
Attribution 
Unexpected 
Expected 
 
Death while on active treatment/therapy or within 30 days 
of the last day of active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 
Possibly, Probably, Definitely 
5 calendar days1 
Annual2 
Unlikely, Unrelated 
Annual2 
Annual2 
1 These events must be reported in the time frame if they meet the definition of an unanticipated problem. 
2 For studies that are not first in human, Phase I and first in pediatric trials, only grades 3-5 must be reported at annual review.  
 
ADDITIONAL REPORTING REQUIREMENTS  
 
SAEs meeting the requirements for expedited reporting to the FDA, as defined in 21 CFR 
312.32, will be reported as an IND safety report using the MedWatch Form FDA 3500A for 
Mandatory Reporting which can found at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  
OIDRA will assist the PI with the preparation of the report and submit the report to the FDA in 
accordance with the following: 
 
any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(2)] 
 
 
any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(1)] 
 
 
any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 

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8. Agent Information and Risks 
8.1 Preparation of 64Cu -DOTA-trastuzumab  
8.1.1 Description 
Trastuzumab will be purchased from the City of Hope pharmacy and conjugated with active ester of 
DOTA (1,4,7,10-tetraazadodecane-1,4,7,10-tetracetic acid) in the COH biologics production facility 
(CBG) under cGMP compliant conditions. Each lot of trastuzumab-DOTA will undergo testing for 
sterility, potency, purity and lack of pyrogenicity. Vialing of the conjugated materials will be done 
in COH biologics production facility Fill and Finish area.  An IND application will be filed with the 
FDA. Radiolabeling with 64Cu will be carried out in the City of Hope Radiopharmacy under the 
direction of David Colcher, PhD. The 64Cu will be purchased from the Mallinckrodt Institute of 
Radiology at the Washington University School of Medicine, which is preparing the radiolabel for 
clinical use under a separate NCI grant. Labeling will be accomplished by incubating conjugated 
antibody with the 64Cu for 45 minutes at 43o C, followed by a chase with DTPA and subsequent 
purification on a size exclusion preparative grade Superdex-200 column. Appropriate fractions will 
be pooled and filtered to make up the patient dose, which will be formulated with human serum 
albumin. Protein dose to the patient will be approximately 50 mg. The total trastuzumab content per 
64Cu -DOTA-trastuzumab injected dose is less than 50 mg. All procedures will be done as specified 
in an IND that will be filed with the FDA to cover the studies proposed in the protocol. Based on our 
previous work with 111In-DOTA-trastuzumab and anticipating that the normal tissue biodistribution 
of 64Cu -DOTA-trastuzumab will be the same as that of 111In-DOTA-trastuzumab, we calculate that 
the radiation doses to normal tissues will be:  
 
64Cu Herceptin Absorbed Dose (AD)* per 15 mCi injection 
estimated  from 111In-DOTA-trastuzumab in 8 patients (18)  
Organ/Tissue 
AD (cGy) 
Heart Wall 
12  1 
Spleen 
10  3 
Liver 
9  1 
Kidneys 
7  1 
Red Marrow 
2.8  0.3 
Osteogenic cells 
3.5  0.5 
Other 
< 3.5 
Total Body  
1.4  0.1 
* Values are mean  standard deviation. 

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8.2 Herceptin 
8.2.1 
Description Trastuzumab is a recombinant humanized monoclonal antibody that binds to 
the extracellular domain of the HER2. Trastuzumab is a sterile, white to pale yellow, 
preservative-free lyophilized powder for intravenous (IV) administration. The nominal 
content of each trastuzumab vial is 440 mg trastuzumab, 440 mg ,-trehalose 
dehydrate, 9,9 mg L-histidine HCl, 6.4 mg L-histidine, and 1.8 mg polysorbate 20, USP.  
Reconstitution with 20 mL of the supplied Bacteriostatic Water for Injection (BWFI), 
USP, containing 1.2% benzyl alcohol as a preservative, yields a multi-dose solution 
containing 21 mg/mL trastuzumab, at a pH of approximately 6. 
8.2.2 
Pharmacology – Handling, Storage, Dispensing and Disposal 
Storage/stability: Vials of trastuzumab are stable at 2o-8o C (36o-46o F) prior to 
reconstitution. They will not be used beyond the expiration date stamped on the vial. A 
vial of trastuzumab reconstituted with BWFI, as supplied, is stable for 28 days after 
reconstitution when stored refrigerated at 2o-8o C (36o-46o F), and the solution is 
preserved for multiple use. We will discard any remaining multi-dose reconstituted 
solution after 28 days. If unpreserved Sterile Water for Injection (SWFI) (not supplied) is 
used, the reconstituted trastuzumab solution should be used immediately and any unused 
portion must be discarded. We will not freeze trastuzumab that has been reconstituted. 
The solution of trastuzumab for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% Sodium Chloride Injection, USP, may be stored at 2o-8o C (36o-46o 
F) for up to 24 hours at room temperature 2o-25o C.  However, because diluted 
trastuzumab contains no effective preservative, the reconstituted and diluted solution 
should be stored refrigerated 2o-8o C. 
 
8.2.3 
Reconstitutions and administration 
 
The diluent provided has been formulated to maintain the stability and sterility of 
trastuzumab for up to 28 days. Other diluents have not been shown to contain effective 
preservatives for trastuzumab. Each vial of trastuzumab should be reconstituted with 20 
mL of BWFI, USP, 1.1% benzyl alcohol preserved as supplied, to yield a multi-dose 
solution containing 21 mg/mL trastuzumab. Immediately upon reconstitution with BWFI, 
the vial of trastuzumab must be labeled in the area marked “Do not use after:” with the 
future date that is 28 days from the date of reconstitution. 
Note: When administering trastuzumab to a patient with a known hypersensitivity 
to benzyl alcohol, trastuzumab must be reconstituted with SWFI, and only one dose 
per trastuzumab vial should be used. Trastuzumab which has been reconstituted 
with SWFI must be used immediately and any unused portion must be discarded. 
Use of other reconstitution diluents should be avoided. 

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Shaking the reconstituted trastuzumab or causing excessive foaming during the addition 
of diluent may result in problems with dissolution and the amount of trastuzumab that can 
be withdrawn from the vial.  Use appropriate aseptic technique when performing the 
following reconstitution steps: 
 
Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing 
the lyophilized cake of trastuzumab. The stream of diluent should be directed into 
the lyophilized cake. 
 
Swirl the vial gently to aid reconstitution. Trastuzumab may be sensitive to shear-
induced stress, e.g., agitation or rapid expulsion from a syringe.  Do not shake. 
 
Slight foaming of the product upon reconstitution is not unusual.  Allow the vial to 
stand undisturbed for approximately 5 minutes.  The solution should be essentially 
free of visible particulates, clear to slightly opalescent and colorless to pale yellow. 
 
Administration 
 
The cold trastuzumab will injected prior to the injection of 64Cu -DOTA-
trastuzumab.   
 
9. 
Correlative/Special Studies 
 
Specimen Collection / Documentation 
Antibody assessment will be performed in the laboratory of Dr. Colcher.  Left over serum from 
the antibody assessment will be stored in the Translational Research Core of the Cancer Center 
for future research.  After the diagnosis and HER 2 status have been determined, additional tumor 
will be stored in pathology for future assessment of PI3K, PTEN, IGF1-R, EGFR, and phospho-
S6 by immunohistochemical staining. The DNA Sequencing Core will assess mutations in PI3K 
and PTEN. Both IHC and FISH assessment of HER2 status will be performed by both IHC and 
FISH. Left over tumor will be stored in pathology for future analysis. 

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10. 
Study Calendar 
FOR ALL PATIENTS 
Pre-Study 
Day 1 
Day 2 
or 3 
 
Within  
one month 
Informed consent 
R 
 
 
 
 
Demographics 
R 
 
 
 
 
Medical history 
R 
 
 
 
 
Concurrent meds 
R 
 
 
 
 
Pretreatment Biopsy of Tumor  
R 
 
 
 
 
Staging EUS 
S 
 
 
 
 
Staging CT AP Chest 
S 
 
 
 
 
“Cold” Trastuzumab 
 
R 
 
 
 
64Cu -DOTA-trastuzumab a  
 
R 
 
 
 
64Cu -DOTA-trastuzumab PET/CT 
 
 
R 
 
 
Antibodies to DOTA 
 
 
 
 
R 
Cardiac ECHOc 
R 
 
 
 
 
Start Neoadjuvant Treatment* 
 
 
 
 
*S 
Surgical Resection* 
 
 
 
 
*S 
Correlation analysis 
 
 
 
 
R 
Image directed biopsy of tumord 
 
 
 
 
R 
DATA COLLECTION 
 
Physical exam 
S 
S 
 
 
S 
Vital signs 
S 
S 
S 
 
S 
Height 
S 
 
 
 
S 
Weight 
S 
 
 
 
S 
Performance Status 
S 
S 
 
 
S 
CBC w/diff. Plateletsb 
S 
S 
S 
 
S 
Serum chemistryb 
S 
S 
S 
 
S 
B-HCGe 
S 
 
 
 
 
Diagnostic Pathology 
S 
 
 
 
 

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HER2 Testing on tumor 
S 
 
 
 
R 
Adverse event evaluation 
R 
R 
 
 
 
 
 
 
 
 
 
a: 
 Dose as assigned 
b: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, LDH, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
c:    Cardiac ECHO will be done prestudy 
d.    More frequent evaluations and laboratory tests will be done at the discretion of the treating 
physician.    
e:    Serum pregnancy test (women of childbearing potential). 
*:    For certain patients, surgery upfront will be standard; others will require neoadjuvant treatment prior 
to surgery.  The initial treatment whether surgery or neoadjuvant chemotherapy will receive their planned 
treatment as determined by the surgeon or medical oncologist within the month after enrollment in the 
study 
R:  Represents tests that are done purely for research purposes 
S:   Indicates tests that are done for standard of care. If these tests are done for standard of care purposes, 
the data from these tests will be collected, however they are not required for research purposes. If they 
are not done, it will not exclude the patient from participation on the trial, and will not constitute a 
protocol deviation. 

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11. Endpoint Evaluation Criteria/Measurement of Effect 
 
11.1 
Response Criteria 
The PET-CT examinations will be analyzed and interpreted by the City of Hope Image Response 
Assessment Team (IRAT). Tumors will be selected for analysis on the basis of the pretreatment 
CT examination and pathological analysis of the surgical specimen.  The Cu64 SUVs will be 
evaluated in tumors, adjacent non-tumor tissue and selected non-tumor organs and tissues (heart, 
extracardiac mediastinum, liver, skeletal muscle). Tumor sizes (product of maximum mutually 
perpendicular transaxial diameters as well as maximum axial diameter) will be estimated from 
coregistered CT. Tumor uptake of 64Cu-DOTA-trastuzumab will be parameterized in terms of 
single-voxel maximum values SUVmax and whole-tumor volumes of interest (SUVwhtum) as 
defined from the coregistered CT images. Ratios of tumor to non-tumor activity concentration 
will also be calculated for adjacent tissue, extracardiac mediastinum, liver, and skeletal muscle.  
Receiver-operator curve (ROC) analysis will be performed to estimate optimal cutoff values of  
SUVmax, SUVwhtum, tumor:background and tumor:organ ratios for classifying tumors as 
“HER2 positive” or “HER2 negative.” The optimal cold antibody dose required for 64Cu -DOTA-
trastuzumab to produce high quality images was determined to be 45 mg. 
 
12. Data Reporting/Protocol Deviations 
12.1 
Data Reporting 
12.1.1 Confidentiality and Storage of Records 
The original data collection forms will be submitted into electronic data capture (EDC) system Medidata 
Rave. Data will be stored in a encrypted, password protected, secure computers that meet all the HIPAA 
requirements.  When results of this study are reported in medical journals or at meetings, identification of 
those taking part will not be disclosed.  Medical records of subjects will be securely maintained in the 
strictest confidence, according to current legal requirements.  They will be made available for review, as 
required by the FDA, HHS, or other authorized users such as the NCI, under the guidelines established by 
the Federal Privacy Act and rules for the protection of human subjects. 
12.1.2 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA research 
authorization form, and the California Experimental Subject’s Bill of Rights (for the medical record) and 
three copies (for the subject, the research record, and the Coordinating Center) must be available.  All 
Institutional, NCI, Federal, and State of California requirements will be fulfilled. 
12.1.3 Data Collection Forms and Submission Schedule  
All data will be collected on the case report forms in Medidata Rave. The CRFs will be submitted within 
1 week from baseline, completion of each treatment and each subsequent follow-up visit.  Data will be 
sent to the location identified in Section 12.1.1 and stored in a secure location. 
12.1.3.1 Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research associate and signed 
by an authorized investigator prior to registering the subject.  See Section 4.3 for the registration 
procedure. 

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12.1.3.2 Prior Therapy Forms and On-Study Forms 
Within one week of registration, the clinical research associate will submit baseline Case Report Forms to 
Medidata EDC. 
 
12.2 
Protocol Deviations 
12.2.1 Deviation Policy 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred without prior 
IRB approval.  Investigators may deviate from the protocol to eliminate immediate hazard(s) for the 
protection, safety, and well-being of the study subjects without prior IRB approval.  For any such 
deviation, the PI will notify the COH DSMC and IRB within 5 calendar days of its occurrence via iRIS in 
accordance with the Clinical Research Protocol Deviation policy [policy effective date:  11/07/11].   
 
This protocol will be conducted in accordance with COH’s “Clinical Research Protocol Deviation Policy” 
located at http://www.coh.org/dsmc/Documents/Institutional%20Deviation%20Policy.pdf. 
Deviations from the written protocol that could increase patient risk or alter protocol integrity require 
prior IRB approval of a single subject exception (SSE) request.  In addition, if contractually obligated, the 
sponsor must also approve the deviation.  IRB pre-approved SSE protocol modifications are considered 
an amendment to the protocol and not a deviation.  The submission of a deviation report is not required. 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 
inclement weather, family responsibilities, security alerts, government holidays, etc.  This can also extend 
to complications of disease or unrelated medical illnesses not related to disease progression.  The PI has 
the discretion to deviate from the protocol when necessary so long as such deviation does not threaten 
patient safety or protocol scientific integrity.  Examples include, but are not limited to:  a) dose 
adjustments based on excessive patient weight; b) alteration in treatment schedule due to non-availability 
of the research participant for treatment; c) laboratory test results which are slightly outside the protocol 
requirements but at levels that do not affect participant safety.  These instances are considered to be 
deviations from the protocol.  A deviation report will be submitted to the DSMC/IRB within five days. 
12.2.2 Reporting of Deviations 
Protocol deviations using the Protocol Deviation Form must be submitted by the protocol nurse or the 
clinical research associate to the Coordinator (cccp@coh.org) for distribution. The clinical research 
associate at City of Hope will also submit copies to the Protocol Management Team and the City of Hope 
Data and Safety Management Board.  All deviations will be reported to the COH DSMC within five days.  
The DSMC will forward to report to the IRB following review. 
 
12.2.3  Resolving Disputes 
The COH Investigational Drug Service (IDS) cannot release a research agent that would cause a protocol 
deviation without approval by the PI.  Whenever the protocol is ambiguous on a key point, the IDS 
should rely on the PI to clarify the issue. 
In situations where there is misperception or dispute regarding a protocol deviation among the persons 
involved in implementing the protocol, it is the responsibility of the PI to resolve the dispute and the PI 
may consult with the DSMC chair (or designee) to arrive at resolution. 
 

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13. Statistical Considerations 
13.1  
Study Design 
As most of the objectives can obtain sufficient information for a pilot study with fewer patients, we 
powered this study to insure sufficient number of HER2 positive patients by IHC to serve as a positive 
control. 
 
Specifically, with 22 patients, there is an 80% chance we’d enroll at least one HER2 positive patient by 
IHC if the true incidence of HER2 positivity is the lowest end of the reported rate of 7%. If the incidence 
is 16% (Marx, et al, 2009), we would expect to observe 2 or more HER2+ patients with 89% probability.  
 
For the other objectives:  
1. In breast cancer, Cu-PET-CT (64Cu-DOTA-trastuzumab-PET-CT) was able to identify the tumors 
with low HER2 expression.  Gastric cancer has different adjacent tissue to provide a background 
noise comparison. As a result, with 22 patients, we will be able to determine the percent of 
patients whose tumors image with Cu-PET-CT with a 95% CI half-width of 21%.  
2. A subset of patients will have tumors of sufficient size to have Cu-PET-CT SUV variation over 
the tumor. For patients with metastatic disease who have Cu-PET-CT positivity but negative 
initial testing for HER2 expression, additional image-directed biopsy of the Cu-PET-CT positive 
area will be performed for analysis prior to their destination systemic treatments (Track A on 
schema).  In those cases when subjects undergo surgical resection (Track B and C on schema), 
the positive and negative areas of the tumor will be sent to pathology for confirmation.  These 
will be exploratory. 
3. Correlation of Cu-PET-CT SUV (measured as peak SUV) and pathology will be explored. As 
correlation requires a continuous measure from pathology, and some pathology will use FISH 
and/or IHC, this will be exploratory.  Comparing Cu-PET-CT in positive cases versus negative by 
pathology will depend on the percent of patients deemed positive. This is an exploratory aim. 
4. Patients who are deemed negative by pathology, but appear positive by Cu-PET-CT is 
exploratory, as further evaluation will be needed to determine positivity by Cu-PET-CT. 
13.2 
Sample Size Accrual Rate 
22 patients 
Accrual rate 1-2 patients per month 
14. Human Subject Issues 
14.1 
Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17, must review and approve this protocol and the informed consent form prior to initiation of the study.  
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
14.2  
Recruitment of Subjects 
The gastric cancer team, most often the gastric surgeon who is the PI of this study or the medical 
oncologist who is a co-investigator of this study will screen patients for this study.  From analysis of the 
gastric cancer patient volume at City of Hope in the previous three years, 65-67 gastric cancer patients 
underwent surgery for gastric cancer and another similar volume non-surgical patients seen by medical 

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oncologists.  The inclusion criteria should allow for majority of these patients to be eligible to this study 
and both the surgical and medical oncologists treating gastric cancer patients at COH will be recruiting to 
this study.   
14.3  
Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to 
be posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and 
approved by the IRB prior to their use to recruit potential study subjects. 
14.4  
Study location and Performance Sites 
This study will be performed at COH.  
14.5  
Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating 
to protected health information (PHI).  The principal investigator, co-investigators, and laboratory 
technicians will have access to this information, but all information will be treated confidentially.  No 
identifiers will be used in any subsequent publication of these results. 
14.6 
Financial Obligations and Compensation 
The investigational drug, 64Cu-DOTA-trastuzumab , will be provided free of charge by City of Hope.  The 
standard of care procedures provided will be the responsibility of the research participant and/or the 
insurance carrier.  The research participant will be responsible for all copayments, deductibles, and other 
costs of treatment and diagnostic procedures as set forth by the insurance carrier.  The research participant 
and/or the insurance carrier will be billed for the costs of treatment and diagnostic procedures in the same 
way as if the research participant were not in a research study.  However, neither the research participant 
nor the insurance carrier will be responsible for the research procedures related to this study. 
In the event of physical injury to a research participant, resulting from research procedures, appropriate 
medical treatment will be available at the City of Hope to the injured research participant, however, 
financial compensation will not be available. 
The research participant will not be paid for taking part in this study. 
14.7  
Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without prejudice, including as applicable, their current or future 
care or employment at City of Hope or any relationship they have with City of Hope.  Research subjects 
will be afforded sufficient time to consider whether or not to participate in the research. 
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those subjects who 
do comprehend the fundamental aspects of the study, consent will be obtained and documented, followed 
by eligibility testing.  The research team will review the results of eligibility testing and determine if the 
subject is a candidate for study enrollment.  

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15. References 
 
1. 
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2. 
Asioli S, Maletta F, Verdun di Cantogno L, Satolli MA, Schena M, Pecchioni C, et al. Approaching 
heterogeneity of human epidermal growth factor receptor 2 in surgical specimens of gastric cancer. Hum Pathol. 
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gastric cancer: a practical approach. Mod Pathol. 2012;25:637-50. 
4. 
Lee HE, Park KU, Yoo SB, Nam SK, Park DJ, Kim HH, et al. Clinical significance of intratumoral HER2 
heterogeneity in gastric cancer. Eur J Cancer. 2012. 
5. 
Marx AH, Tharun L, Muth J, Dancau AM, Simon R, Yekebas E, et al. HER-2 amplification is highly 
homogenous in gastric cancer. Hum Pathol. 2009;40:769-77. 
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Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 
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Kunz PL, Gubens M, Fisher GA, Ford JM, Lichtensztajn DY, Clarke CA. Long-term survivors of gastric 
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Bang YJ. Advances in the management of HER2-positive advanced gastric and gastroesophageal junction 
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Lub-de Hooge MN, Kosterink JG, Perik PJ, Nijnuis H, Tran L, Bart J, et al. Preclinical characterisation of 
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Olafsen T, Kenanova VE, Sundaresan G, Anderson AL, Crow D, Yazaki PJ, et al. Optimizing radiolabeled 
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Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells 
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Herceptin in metastatic breast cancer patients receiving cold Herceptin therapy. 12th Conference on Cancer Therapy 
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