64 Cu-DOTA-Trastuzumab Positron Emission Tomography in Women With Advanced HER2 Positive Invasive Breast Cancer
Phase: NA
Conditions: Breast Cancer, Stage IV Breast Cancer
Sponsor: City of Hope Medical Center

Packet: 15 
 
11/14/2013 
IRB #09101 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND EXPERIMENTAL THERAPEUTICS 
 
TITLE: 
64Cu-DOTA-trastuzumab Positron Emission Tomography in Women with Advanced HER2 
Positive Invasive Breast Cancer 
 
CITY OF HOPE PROTOCOL NUMBER: 
IRB # 09101  
 
 
PROTOCOL 
DATED: 11/14/13 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
Initial Submission 
Protocol Dated 02/01/10 
Version:  00 
COH Amendment 01 
Protocol Dated 10/15/10 
Version:  01 
COH Amendment 02 
Protocol Dated 12/14/2010 
Version:  02 
COH Amendment 03 
Protocol Dated 03/25/2011                               Version: 03  
COH Amendment 04 
Protocol Dated 05/09/2011 
Version: 04 
 COH Amendment 05 
Title Page Dated 08/15/2011                             
Version: 
05 
COH Amendment 06 
Protocol Dated 12/21/11 
Version: 06 
COH Amendment 07 
Protocol Dated 02/13/12 
Version: 07 
COH Amendment 08 
Add Jinha Park,MD 
Version: 08 
COH Amendment 09 
Personnel Changes 
Version: 09 
COH Amendment 10 
Personnel Changes 
Version: 10 
COH Amendment 11 
Title Page Dated 05/23/2013                             
Version: 
11 
COH Amendment 12 
Protocol Dated 11/14/13 
Version: 12 
COH Amendment 13 
Title Page Dated 06/25/2014 
Version: 13 
COH Amendment 14 
Title page dated 08/03/2015 
Version: 14 
COH Amendment 15 at Continuation 
Protocol dated 11/14/13 (tp) 
Packet: 15 
 
 
 
DISEASE SITE:     
Breast Cancer 
STAGE (If applicable): 
Locally Advanced Breast Cancer 
MODALITY: 
Chemotherapy 
TYPE: 
Pilot Project 
 
CO-PRINCIPAL INVESTIGATORS:  
Joanne Mortimer MD 
 
COLLABORATING INVESTIGATOR(S): 
David Colcher, PhD 
 
Paul Frankel, PhD 
 
Dave Yamauchi, MD 
 
Russell Rockne, PhD 
 
 
PARTICIPATING INVESTIGATORS: 
Joseph Chao, MD 
 
Jana Portnow, MD 
 
Yuan Yuan, MD 
 
James Waisman, MD 

 
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Arti Hurria, MD 
 
Associate Professor 
 
Medical Oncology and Therapeutics 
 
 
TheHang Luu, MD  
 
Assistant Professor 
 
Medical Oncology and Therapeutics 
 
 
Jana Portnow, MD  
 
Associate Professor 
 
Medical Oncology and Therapeutics 
 
 
George Somlo, MD  
 
Professor 
 
Medical Oncology and Therapeutics 
 
Research Nurse/Study Coordinator: Mary Carroll, RN 
 
Lois Wright, RN 
 
Phylllis Broene, RN 
 
Clinical Research Assistant: 
Dorie Garcia, CRA 
 
Study Location: 
City of Hope National Medical Center 
 
1500 East Duarte Rd, 
 
Duarte, CA 91010 
 
Study Laboratories: 
Arnold and Mabel Beckman Center for  
 
Cancer Immunotherapeutics & Tumor Immunology, 
 
Room 5312 
 
 
Federal-Wide Assurance Number: 
FWA 00000692 
 
 
 

 
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Table of Contents 
 
 
Section  
Pages 
______________________________________________________________________ 
1.0 Background 
4-8 
2.0 Study Objectives 
8 
3.0 Research Design 
9 
4.0 Eligibility – Part 1 
9 
5.0 Eligibility – Part 2 
10 
6.0 Ineligibility 
10 
7.0 Recruitment Process 
10 
8.0 Informed Consent Process 
11 
9.0 Study Procedures/Research Interventions 
11-13 
10.0 Study Calendar 
13 
11.0 Protocol Drug and Radiolabeled Imaging Agent 
13-19 
12.0 Positron Emission Tomography (PET) 
19-20 
13.0 Imaging Analysis 
21 
14.0 Laboratory Evaluations 
22 
15.0 Statistical Analysis 
22-23 
16.0 Toxicity Assessment 
24 
17.0 Data Management 
24-26 
18.0 Data Safety Monitoring 
26-28 
19.0 Protocol Deviations 
29 
20.0 References 
30-31 
 

 
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1.0 
Background 
The term “breast cancer” encompasses a number of different diseases that are clinically 
defined by hormone receptor status and HER2 expression.  HER2 is a transmembrane protein 
in the epidermal growth factor family.  HER2 has tyrosine kinase activity that results in 
intracellular signaling and activation of genes for cell growth and survival.  Women whose 
cancers overexpress the HER2 protein have a distinct natural history and are candidates for 
treatment with trastuzumab. Trastuzumab is at humanized IgG-1 antibody that binds to the 
ectodomain of HER2. When combined with chemotherapy, trastuzumab significantly improves 
the survival of women with both early stage and advanced disease.[1-3]  The pathologic 
assessment of HER2 status is made on the primary tumor or metastatic foci.  HER2 
overexpression and candidacy for trastuzumab is defined as 3+ staining by 
immunohistochemistry (IHC) or gene amplification by fluorescence in situ hybridization 
(FISH).[4, 5]  Recently, trastuzumab has been shown to be of benefit also in patients whose 
cancers are HER2 negative by IHC and have low level amplification of HER2 when associated 
with chromosome 17 polysomy. Additional data from the NSABP B31 trial suggest that some 
women with HER2 negative disease benefit from adjuvant trastuzumab.[5, 6]  The American 
Society of Clinical Oncology and American College of Pathology convened a panel of experts 
to define guidelines for the pathologic assessment of HER2. In these recently published 
guidelines 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%. While 
assessment of HER2 by FISH is considered to be the “gold standard” for measuring HER2, 
this panel of experts concluded that FISH (ratio of HER2 gene signals to chromosome 17 
signals) amplification level of less that 1.8 was “negative” and that levels greater than 2.2 were 
positive.  An “indeterminate” level of HER2 was defined between 1.8 and 2.2. [7]  The impact 
of trastuzumab on disease outcome is considerable.  However, the cost, potential risk of 
cardiac toxicity, and inconvenience of intravenous administration make it imperative that an 

 
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accurate assessment of HER2 be made in all women with breast cancer.   We hypothesize 
that a functional assessment of HER2 will be more accurate than pathologic assessment. 
 
At initial diagnosis, the HER2 status of the primary tumor and axillary nodes is generally 
concordant.[8]  Similarly, when HER2 assessment is performed on multiple sites of metastatic 
disease in the same patient, the concordance among different sites is 95%. [9-11] Such data 
suggest that the HER2 status is consistently positive or negative.  However, the majority of 
women develop metastatic disease after having been treated for early stage breast cancer.  
Following systemic treatment of early stage disease, the HER2 status may change from being 
HER2 positive to HER2 negative or from HER2 negative to HER2 positive.  In women whose 
disease recurs after treatment for early stage disease, the HER2 status in the metastases may 
differ from that of the primary tumor as often as 40%. [8, 11, 12] These data suggest that 
systemic treatment may have an effect on the HER2 status.   Neoadjuvant chemotherapy plus 
trastuzumab was administered to 141 women with HER2 positive breast cancers.  A complete 
pathologic response rate was achieved in 72 (51%) women.  The primary tumor was HER2  
negative in one third of patients with residual cancer after neoadjuvant chemotherapy and 
trastuzumab.[13]   Such data support a role for the serial assessment of HER2 status across 
the continuum of the breast cancer disease process.  The assessment of HER2 status from a 
metastatic focus requires a biopsy procedure and the location of the metastasis may be 
technically difficult to access with a needle biopsy.  A less invasive measurement of HER2 
would allow treating physicians to repeatedly assess the status of HER2 before and after 
therapeutic interventions.   We believe that positron emission tomography (PET) using 
radiolabeled trastuzumab will provide such an assessment. 
 
Trastuzumab in combination with chemotherapy improves the overall survival for women with 
early stage and metastatic HER2 positive breast cancers.  However, the activity of 
trastuzumab as a single agent in metastatic disease is modest.  Objective tumor responses 
are reported in 35% of women treated with trastuzumab as first-line therapy and 18% in those 

 
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who have been previously treated. [14, 15]  This raises the possibility that trastuzumab is not 
of benefit to all HER2 positive breast cancers.  Given the cost and potential toxicity of 
trastuzumab, an assessment of the HER2 status that predicts for benefit to trastuzumab is 
needed.  
 
Positron emission tomography (PET) provides a non-invasive way of studying tumor location, 
metabolic functions, and response to therapy. In breast cancer, PET imaging is used to stage 
women with advanced disease and to assess response to chemotherapy and endocrine 
therapy before tumor regression can be documented on clinical or radiological exam [16-18]. 
The ability to identify patients who may benefit from systemic therapy is critically important to 
the quality of life of patient; toxicities from ineffective therapies are prevented and medical 
costs are contained.    
 
Radiolabeled trastuzumab has effectively been used to study HER2 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.[19-21] Researchers at City of Hope 
have utilized 111In-DOTA-trastuzmab to image women with advanced HER2 positive invasive 
breast cancer.  The agent has variable accuracy in identifying HER2 positive disease on 
planar and SPECT scans.[22]  In the City of Hope experience, 111In-DOTA-trastuzmab 
identified areas of known metastasis in 4 of 7 patients.[23]   The positron emitting isotope 64Cu 
has a number of potential advantages over 111In including: improved image resolution with 
PET 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.[21, 24]  Therefore, it is likely that 64Cu-DOTA-trastuzumab-
PET will be a superior imaging agent to 111In-DOTA-trastuzmab.   We propose to utilize 64Cu-
DOTA-trastuzumab-PET to image women with metastatic HER2 positive breast cancer. We 
anticipate that the agent will be well tolerated and that the radiation absorbed doses to normal 

 
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tissues using 64Cu-DOTA-trastuzumab will be much lower than the doses incurred with 111In-
DOTA-trastuzmab.    
 
HER2 is expressed on a number of normal tissues such as the heart and kidney.  Some 
investigators have reported that 111In-trastuzumab uptake in the heart predicts for potential 
cardiac toxicity from trastuzumab, while others have not. [22, 25]  
 
Because normal tissues that express HER2 will bind the radioabeled (hot) antibody, 
administration of a “cold dose” of antibody might improve the tumor specificity of the 
radiographic image. The studies that have utilized radiolabeled trastuzumab as an imaging 
agent have consistently administered a large “cold dose” of trastuzumab prior to radiographic 
imaging.  We hypothesize that the dose of “cold antibody” is critical for image quality.  We 
believe that too high a dose of “cold antibody” will reduce tumor uptake and thereby 
compromise the quality of the radiographic image.   In the clinical trial of 111In-DOTA-
trastuzmab at City of Hope, a high dose of “cold” trastuzumab (4mg/kg) was administered prior 
to imaging.  This may explain why 111In-DOTA-trastuzmab failed to image disease in 3 of 7 
women with metastatic HER2 positive breast cancer.    
 
The primary objective of this pilot study is to determine the optimal dose of cold antibody 
required for 64Cu-DOTA-trastuzumab PET to produce a high image quality in women with 
metastatic HER2 positive breast cancer.   In addition, we will assess the impact of the cold 
antibody dose on cardiac uptake of 64Cu-DOTA-trastuzumab.   To establish the optimal dose 
of cold antibody, we will image women with documented metastatic breast cancer with 3 
different protein (trastuzumab) doses - 5 mg, 50 mg, and 4 mg/kg.   
As of February 10, 2012, we have imaged 7 women; two received the 5 mg dose and 5 with 
50 mg.   The 50 mg trastuzumab dose had a marked effect on liver uptake of 64Cu [SUV = 
23±3 (mean±sd) and 6.3±0.6 for 5 and 50 mg tras, respectively; p < 0.05]. 72 CT+ lesions (32 
bone, 28 nodal, 9 liver, 2 breast, 1 lung) were included in Day 1 and/or Day 2 scans. Of these, 

 
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66 of 72 (92%), 48 of 63 (76%) and 36 of 44 (82%) were detected on FDG, D1 and D2 scans, 
respectively. Lesion SUVmax was 9±5 (n=37, range 3-23) on D1 and 11±6 (n=27, range 1-29) 
on Day 2. 64Cu-DOTA-trastuzumab-to-18FDG SUVmax ratios were 1.0±0.8 (range 0.2-4.3) and 
1.3±1.1 (range 0.2-3.5) for Days 1 and 2.  The uptake by 64Cu trended to be greatest in the 
liver, then bones, then lymph nodes.  
 
64Cu-DOTA-trastuzumab PET has been studied by investigators at Memorial Sloan Kettering 
Cancer Center.  Women with advanced HER2 positive breast cancer, who were receiving 
either trastuzumab 2 mg/kg weekly or 6 mg/kg every 21 days were considered for the imaging 
study.   The data is only published in abstract form with data from the first 9 women studied.  
The authors reported that the imaging was feasible and safe.  However, they identified a low 
sensitivity of tumor detection with Cu-64 trastuzumab and hypothesize that the concurrent use 
of therapeutic doses of trastuzumab may have saturated tumor sites and compromised the 
image quality.  Given this experience, we do not believe that the highest planned dose of cold 
trastuzumab (4 mg/kg) in our initial study design would be a wise use of patient resources.  
We have demonstrated that the 50 mg preimaging dose of cold trastuzumab overcomes non-
specific tissue binding of HER2 and provides excellent image quality.  To test the superiority of 
a slightly higher dose of cold trastuzumab would require many additional patients.  We are 
thus satisfied by the image quality obtained with the pre-imaging dose of 50 mg of 
trastuzumab, Aim 1.  We will therefore proceed to the second series of experiments which will 
test whether tumor uptake on 64Cu-DOTA-trastuzumab PET imagine correlated with tumor 
expression of HER2.   To accomplish this goal, we will perform 64Cu-DOTA-trastuzumab PET 
imaging in an additional 15 patients with advanced cancer that are HER2 1+ (5 patients), 
HER2  2+  (5 patients), and HER2 3+. (5 patients). 
 
In preclinical models, resistance to trastuzumab is associated with cellular changes that 
amplify the PI3K pathway. For example, low levels of PTEN, increased IGF1 and increased 
HER2 heterodimerization have been shown to activate the PI3K pathway and decrease the 

 
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effectiveness of trastuzumab.[24]  Because of the importance of the EGFR pathway in 
preclinical models of trastuzumab resistance, we will perform an exploratory analysis of 
biomarkers for the PI3K/Akt pathway.  We know that 64Cu-DOTA-trastuzumab is internalized.  
Therefore we hypothesize that a negative 64Cu-DOTA-trastuzumab PET in a patient whose 
tumor is HER2 positive suggests resistance to trastuzumab.  In this setting, biomarkers that 
are consistent with amplification of the EGFR pathway provide support for trastuzumab 
resistance.      
 
We believe that functional imaging with 64Cu-DOTA-trastuzumab PET has the potential to 
improve the accuracy of HER2 assessment.  Future studies will address tumor biomarker 
assessment with serial 64Cu-DOTA-trastuzumab PET and [18F]FDG/PET before and after 
treatment with trastuzumab to determine which patients are likely to benefit from the drug.   
 
2.0 
Study Objectives 
2.1 
Determine the dose of pre-administered cold antibody that optimizes image quality of 
64Cu-DOTA-trastuzumab PET without increasing the radiation dose to the heart in 
women with metastatic HER2 positive breast cancer. 
2.2 
Determine whether tumor uptake on 64Cu-DOTA-trastuzumab PET correlates with 
tumor expression of HER2 in women with metastatic disease. 
2.3 
Perform an exploratory analysis of the relationship between uptake on 64Cu-DOTA-
trastuzumab PET, HER2 overexpression, and inactivation of the PI3K/Akt pathway. 
 
3.0 
Research Design 
This is a prospective clinical trial in two parts. The initial study enrolled 7 women with 
metastatic HER2 positive breast cancer who will receive one of 3 different protein doses of 
trastuzumab to determine the dose that provides the optimal 64Cu-DOTA-trastuzumab PET 
image quality.  The optimal “cold dose” of trastuzumab has been determined to be 50 mg. This 
dose will be used to image an additional 15 women whose cancers stain 1+, 2+, or 3+ by IHC.  

 
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Five women with each level of IHC staining will undergo 64Cu-DOTA-trastuzumab PET 
imaging and the intensity of 64Cu-DOTA-trastuzumab PET uptake will be correlated with the 
IHC measurement of HER2.  
 
4.0 
Eligibility Part I  (Determination of the cold dose) 
4.1 
Participants must be women who have histological confirmation of metastatic invasive 
breast cancer that has metastasized outside the region of the primary tumor and axilla.  
Biopsy must be obtained within 28 days prior to study. Patients must have metastatic 
disease in lung, liver, soft-tissue or bone to qualify for the study (more than one site is 
permissible). 
4.2 
At least 1 non-hepatic site of metastasis  > 2 cm in mean diameter must be identified in 
addition to the site that was biopsied.   
4.3 
The cancer must over express HER2 as determined by IHC and FISH. 
4.4 
Patients may have received trastuzumab in the adjuvant, neoadjuvant, or metastatic 
setting, but cannot have received the drug within the prior 2 months.  
4.5 
Participants must have normal cardiac ejection fraction. 
 

 
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5.0 
Eligibility Part 2 (correlation of HER2 expression with PET uptake) 
5.1 
Participants must be women who have histological confirmation of metastatic invasive 
breast cancer that has metastasized outside the region of the primary tumor and axilla.  
Biopsy must be obtained within 28 days prior to study. Patients must have metastatic 
disease in lung, liver, soft-tissue or bone to qualify for the study (more than one site is 
permissible). 
5.2 
At least 1 non-hepatic site of metastasis site > 2 cm in mean diameter must be 
identified in addition to the site that was biopsied. 
5.3 
Participants with HER2 1+, 2+ and 3+ by IHC are eligible. 
5.4 
Patients may have received trastuzumab in the adjuvant, neoadjuvant, or metastatic 
setting, but cannot have received the drug within the prior 2 months.  
5.5 
Participants must have normal cardiac ejection fraction. 
 
6.0 
Ineligibility 
6.1 
Participants who have received trastuzumab and/or lapatinib within the prior2 months 
6.2 
Participants who are not considered candidates for trastuzumab 
6.3 
Metastatic disease in a single site 
6.4 
No metastatic site >  2 cm 
 
6.5 
Concurrent malignancy other than skin cancer 
6.6 
Inability to provide informed consent 
6.7 
Participants who are pregnant 
 
7.0 
Recruitment Process 
7.1 
Participants will be recruited by the treating Medical Oncologists from patients 
receiving their breast cancer treatment at City of Hope. 
7.2 
Recruitment letters or advertisements will be reviewed and approved by the IRB prior 
to their use to recruit potential study subjects. 
   

 
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8.0 
Informed Consent Process  
8.1 
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 as well as their rights 
as a research subject (Experimental Subjects Bill of Rights) and the HIPAA research 
authorization form.  Research participants will be informed that they may withdraw from 
the study at any time and for any reason without jeopardizing, include as applicable, 
their future care or their employment at City of Hope or any relationship they have with 
City of Hope.  After signing the study consent form, HIPAA authorization form and the 
Experimental Subject’s Bill of Rights, research subjects will undergo an assessment of 
their comprehension of the study by the Research Subject Advocate, followed by 
eligibility testing.    Should sufficient doubt be raised regarding the adequacy of 
comprehension, further clarifications will be made and the consent comprehension 
assessment may be 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.  Following this procedure, the protocol management team 
will review the results of eligibility testing and determine if the research subject is a 
candidate for study enrollment.  
 
9.0 
Study Procedures/Research Interventions 
9.1 
Treatment Plan for determination of the “Cold dose” 
9.1.1 Fifteen women with metastatic breast cancer that is HER2 positive by IHC and 
FISH will be recruited from the Medical Oncology Clinics at City of Hope. 
9.1.2 As patients will ultimately receive trastuzumab-based therapy, a baseline 
cardiac ejection fraction, by MUGA or ECHO cardiogram, will be performed. 

 
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9.1.3 All participants will undergo a history and physical exam and radiographic 
staging workup, including whole body CT [18F]FDG/PET.  
9.1.4 Five women will receive a total protein dose of trastuzumab of 5 mg, five will 
receive a total protein dose of 50 mg of trastuzumab and five will receive a total 
protein dose of 4 mg/kg of trastuzumab.   Assignment of dose will be by 
stratification by site of metastatic disease (bone, lung, liver) so that an 
approximate balance in metastatic sites is achieved for each group (see 
statistics). 
9.1.5 A PET scan of the regions of interest will be performed 24 and 48 hours after 
injection of 64Cu-DOTA-trastuzumab. 
9.1.6 Systemic therapy with trastuzumab-based therapy may be initiated one week 
after completion of the 64Cu -DOTA-trastuzumab PET imaging, 
9.1.7 Participants will be observed for toxicity for 1 year. 
9.1.8 Antibodies to DOTA and trastuzumab will be assessed at 1, 3, 6, and 12 
months after imaging. 
As of February 10, 2012, part I of this study has been prematurely terminated early as  the 
optimal dose of cold antibody was determined to be 50 mg of trastuzumab. 

 
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9.2 
Treatment Plan to correlate HER2 positivity by IHC with of 64Cu-DOTA-trastuzumab 
PET uptake 
9.2.1 Fifteen women with metastatic breast cancer that is HER2 1+, 2+, and 3+ 
positive by will be recruited from the Medical Oncology Clinics at City of Hope.   
9.2.2 As patients will ultimately receive trastuzumab-based therapy, a baseline 
cardiac ejection fraction, by MUGA or ECHO cardiogram, will be performed. 
9.2.3 All participants will undergo a history and physical exam and radiographic 
staging workup, including whole body CT [18F]FDG/PET.  
9.2.4 We will image 5 women whose metastatic cancer is 1+; 5 whose metastatic 
cancer is 2+, and 5 whose metastatic cancer is 3+ by IHC.  
9.2.5 A PET scan of the regions of interest will be performed 24 and 48 hours after 
injection of 64Cu -DOTA-trastuzumab. 
9.2.6 Systemic therapy with trastuzumab-based therapy may be initiated one week 
after completion of the 64Cu -DOTA-trastuzumab PET imaging. 
9.2.7 Participants will be observed for toxicity for 1 year. 
9.2.8 Antibodies to DOTA and trastuzumab will be assessed at 1, 3, 6, and 12 
months after imaging. 
9.3 
Handling of specimens:  All specimens will be handled in accordance with RSC 09001 
and OSBC 90029  
10.0 
Study Calendar 
 
< 28 
days 
14 days 
Prior to 
imaging 
Day 0 
Day 1 
Day 2 
Day 
7+ 
Day 
14 
1, 3, 6 
mo 
1 year 
Biopsy of metastasis 
for diagnosis and 
HER2  
assessment 
X 
 
 
 
 
 
 
 
 
History and Physical 
Exam  
 
X 
 
 
 
 
 
 
 
Cardiac ejection 
fraction 
(by MUGA or ECHO) 
X** 
 
 
 
 
 
 
 
 

 
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Pregnancy Test 
 
 
X$ 
 
 
 
 
 
 
Bone Scintigraphy 
X 
 
 
 
 
 
 
 
 
[18F]FDG/PET/CT 
 
X 
 
 
 
 
 
 
 
Cold trastuzumab  
 
 
X+ 
 
 
 
 
 
 
64Cu-DOTA-
trastuzumab   
 
 
X* 
 
 
 
 
 
 
PET imaging 
 
 
 
X 
X 
 
 
 
 
Trastuzumab-based 
therapy 
 
 
 
 
 
X 
 
 
 
Toxicity assessment** 
 
 
 
 
 
X 
X  
X 
X 
CBC 
 
 
 
 
 
X 
X  
 
 
Antibodies to DOTA 
and trastuzumab 
 
 
X 
 
 
 
 
X  
X 
Pharmacokinetics# 
 
 
X 
X 
X 
 
 
 
 
$Pregnancy test should be done may be done one day prior to the scan 
+Research participants on 5 mg dose will not get additional cold dose herceptin 
*Injection only 
** If research participant has history of cardiac disease or possible cardiac toxicity, a MUGA should be obtained 
within 14 days of treatment.  
#  Participants will have one PK just prior to the Cu-OTA injection, one hour after the Cu-DOTA injection, one at 
the time of the first scan and one at the time of the second scan. (one red top tube to be delivered to Nicole in 
the Beckman Building, room 5212. No special handling needed) 

 
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11.0 
Protocol Drug and Radiolabeled Imaging Agent 
11.1 
Trastuzumab 
11.1.1 Drug 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. 
11.1.2 Procurement of trastuzumab:   Trastuzumab will be supplied free of charge as 
part of the study to the patients receiving doses less than the conventional 
loading dose of 4 mg/kg.  Lower doses will be charged to the grant. 
11.1.3 Storage/stability: Vials of trastuzumab are stable at 2 o -8 o C (36 o -46 o F) prior 
to reconstitution.  Do not use 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 2 o-8 o C (36 o-46 o F), and the 
solution is preserved for multiple use. The 50mg dose will be taken from one 
440mg vial into WebIDS (drug accountability system) at the time that a patient 
is treated vial, and the remainder of the vial will be used for non-study patients. 
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. Do not freeze trastuzumab that has been 
reconstituted. The solution of trastuzumab for infusion diluted in 
polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride 

 
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Injection, USP, may be stored at 2o -8o C (36 o -46 o F) for up to 24 hours at 
room temperature 2 o-25 o C.  However, because diluted trastuzumab contains 
no effective preservative, the reconstituted and diluted solution should be 
stored refrigerated 2o-8 o C. 
11.1.4 Reconstitutions and administration 
11.1.4.1 
Reconstitution   
11.1.4.1.1 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.  
11.1.4.1.2 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. 
11.1.4.2 
Administration 
The recommended loading dose of trastuzumab of 4 mg/kg is 
administered intravenously over 90 minutes.  For participants in 
the arm assigned 50 mg, the trastuzumab will be administered 
over 15 min.  For those assigned 5 mg, trastuzumab will be 
administered with the 64Cu -DOTA-trastuzumab. The cold 
trastuzumab will be injected prior to the injection of 64Cu-DOTA-
trastuzumab. Trastuzumab will be administered by the research 
nurse in the Phase I unit of the hospital. Patients will be 

 
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monitored by the study nurse for any symptoms suggestive of an 
infusion reaction.  If a patient experiences a reaction, the infusion 
is immediately discontinued and the treating physician is 
contacted.  Benadryl and/or hydrocortisone may be administered 
before resuming the infusion at a slower infusion rate. If a patient 
continues to have reactions despite these interventions, the 
trastuzumab will be discontinued and the patient will be taken off 
study. 
11.1.5 Drug accountability:  Trastuzumab will be purchased by the City of Hope 
Pharmacy, which will store and control the drug.   It will be prepared for 
administration in the outpatient pharmacy.  
11.1.6 Discard of unused agent:  Unused trastuzumab will be discarded in the 
chemotherapy discard containers within the outpatient pharmacy after 28 days. 
11.1.7 Warnings and Contraindications 
11.1.7.1 
Cardiotoxicity:  Administration of trastuzumab can result in the 
development of ventricular dysfunction and congestive heart failure. 
Signs and symptoms of cardiac dysfunction, such as dyspnea, 
increased cough, paroxysmal nocturnal dyspnea, peripheral edema, 
S3 gallop, or reduced ejection fraction, have been observed in 
patients treated with trastuzumab. Congestive heart failure 
associated with trastuzumab therapy may be severe and has been 
associated with disabling cardiac failure, death, and mural 
thrombosis leading to stroke. 
11.1.7.2 
Hypersensitivity reactions including anaphylaxis; severe 
hypersensitivity reactions have been infrequently reported in patients 
treated with trastuzumab. Signs and symptoms include anaphylaxis, 
urticaria, bronchospasm, angioedema, and/or hypotension. In some 

 
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cases, the reactions have been fatal. Trastuzumab infusion should 
be interrupted in all patients with severe hypersensitivity reactions.  
In the event of a hypersensitivity reaction, appropriate medical 
therapy should be administered, which may include epinephrine, 
corticosteroids, diphenhydramine, bronchodilators, and oxygen.  
Patients should be evaluated and carefully monitored until complete 
resolution of signs and symptoms. 
11.1.7.3 
Infusion reactions:  In the postmarketing setting, rare occurrences of 
severe infusion reactions leading to fatal outcome have been 
associated with the use of trastuzumab. In clinical trials, infusion 
reactions consisted of a symptom complex characterized by fever 
and chills, and on occasion included nausea, vomiting, pain, 
headache, dizziness, dyspnea, hypotension, rash, and asthenia. 
These reactions were usually mild to moderate in severity. However, 
in postmarketing reports, more severe adverse reactions to 
trastuzumab infusion were observed and included bronchospasm, 
hypoxia, and severe hypotension.  These severe reactions were 
usually associated with the initial infusion of trastuzumab and 
generally occurred during or immediately following the infusion. 
However, the onset and clinical course were variable. Delayed post-
infusion events with rapid clinical deterioration have also been 
reported.  Rarely, severe infusion reactions culminated in death 
within hours or up to one week following an infusion. 
11.1.7.4 
Pulmonary events:  Severe pulmonary events leading to death have 
been reported rarely with the use of trastuzumab in the 
postmarketting setting. Signs, symptoms, and clinical findings 
include dyspnea, pulmonary infiltrates, pleural effusions, non-

 
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cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, 
and acute respiratory distress syndrome. These events may or may 
not occur as a sequelae of infusion reactions. Patients with 
symptomatic intrinsic lung disease resulting in dyspnea at rest, may 
be at greater risk of severe reactions.  
11.1.7.5 
Other severe events reported rarely in the postmarketing setting 
include pneumonitis and pulmonary fibrosis. 
11.2 
Preparation of 64Cu -DOTA-trastuzumab 
11.2.1 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. 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.  
Patients will be injected via a peripheral vein with 15 mCi of 64Cu-DOTA-
trastuzumab; the protein dose of t he radiolabel given to the patient will be 
approximately 5 mg. The total trastuzumab content per 64Cu -DOTA-

 
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trastuzumab injected dose is less than 5 mg. All procedures will be done as 
specified in an FDA-approved IND.   
We have estimated radiation dose from 64Cu -DOTA-trastuzumab based on our 
previous work with 111In-DOTA-trastuzumab [23] and anticipating that the 
normal tissue biodistribution will be the same for the 64Cu radiolabel as for 111In.  
The study protocol also requires an 
18F-fluordeoxyglucose (FDG) scan.  
Patients will be imaged once and twice following injection of 18F-FDG and  
64Cu -DOTA-trastuzumab, respectively, for a total of three PET-CT  scans.  We 
have used estimated radiation doses from 18F-FDG and CT to arrive at the 
following estimates of overall radiation absorbed dose: 
 
 
 
 
Organ/Tissue 
Estimated Total Absorbed Dose (cGy)* 
 
   64Cu-Trastuzumab         18F-FDG                 CT                         Total 
          (15 mCi)                  (15 mCi)             3 scans 
Heart wall 
12.6 
0.6 
0.8 
14 
Spleen 
10.5 
0.6 
0.8 
12 
Liver 
9 
1 
1 
11 
Bladder wall 
1 
9 
1 
11 
Kidneys 
6.9 
0.6 
0.8 
8 
Red marrow 
2.8 
0.6 
0.8 
4 
Other 
 3.5 
0.6 
0.8 
 5 
*Values for 18F-FDG and CT (specific for PET-CT to be used in the proposed study) were obtained 
from [ref]. 
Brix G, et al. Radiation exposure to patients undergoing whole-body dual-modality 18F-FDG PET/CT 
examinations.  J Nucl Med 2005;46:608-613. 
 
12.0 
Positron Emission Tomography (PET) 
12.1 
Imaging will be performed on a GE Discovery 16 Ste PET-CT scanner (axial field of 
view 15.4 cm).  PET 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 images will be reconstructed with spatial resolution of approximately 
9 mm full-width-at-half maximum (FWHM) using an iterative algorithm (OSEM).  
12.2 
18F-Fluorodeoxyglucose ([18F]FDG).  Standard [18F]FDG PET-CT examinations will be 
performed prior to initiation of treatment. Patients will be injected via a peripheral vein 

 
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with 15mCi of [18F]FDG. Large-area (eyes to mid-thigh) PET-CT scans will be obtained 
beginning at 1 hour post-injection; time per bed position during the PET scan will be 3 
minutes. 
12.3 
64Cu -DOTA-trastuzumab. For patient convenience, the 64Cu-antibody (64Cu half life 
12.7 h) will be injected immediately following the baseline [18F]FDG-PET scan (18F half 
life 1.8 h). Patients will be injected via a peripheral vein with 15 mCi of 64Cu-DOTA-
trastuzumab. In order to allow the 18F to decay and the antibody to accumulate in 
tumor, PET-CT scanning of 64Cu will be delayed until 18 to 24 hours post injection (Day 
1).  A second scan will be obtained 42-48 hours post injection (Day 2).  Because of the 
limited amount of activity to be injected and the fact that only 20% of 64Cu decays 
produce a positron, the count rates will be low. To compensate, time per bed position 
will be relatively long and the axial field of view relatively short. (Day 1: 2-3 bed 
positions encompassing known tumors; 30 min per bed position if 2 bed positions, 20 
min per bed position if 3 bed positions; Day 2: 1 bed position, 60 min).  Based on prior 
phantom studies, we expect the scanning protocol defined above to yield adequate 
tumor visualization as well as measurements of tumor uptake and tumor: adjacent 
background activity concentration ratios ("tumor:bdg contrast") for tumors of at least 2 
cm in diameter and average SUV (= tumor activity concentration/injected activity per 
unit body weight) of at least 3 in body regions for which tumor:bdg contrast is at least 4. 
The precision (coefficient of variation) of tumor SUV and tumor:bgd contrast 
measurements is expected to be about 10% and 15%, respectively.  
 
13.0 
Image Analysis 
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 [18F]FDG PET-CT examination.  “PET –positive” lesions, defined as those clearly 
visualized by [18F]FDG-PET, will be selected for analysis by the IRAT radiologist.  Due to 

 
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possible non-specific antibody uptake secondary to biopsy, the tumor site biopsied for 
pathologic confirmation of HER2 positivity will not be used as an index lesion.   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.” Ratios of 
tumor 64Cu to 18F SUVs will also be computed and used to examine the relative effects of 
receptor expression and cellular viability as determinants of 64Cu-DOTA-trastuzumab uptake in 
tumors.  The selected cold antibody dose will be chosen to minimize the dose to the heart with 
the best ratio of tumor to heart.   If multiple doses meet that criterion, (simulations suggest all 
doses will meet that criterion), the selected dose will be one with the highest image quality as 
defined by the ratio of tumor SUV to heart SUV.  Specifically, for each of the five patients, the 
median tumor SUV (or the tumor SUV if there is only one non-biopsied lesion under 
consideration), will be divided by the heart SUV. This ratio will be obtained for all 5 patients. 
The main comparison will be the median of the five ratios (one value per dose level), 
compared across dose levels, to select the cold dose for future patients on this protocol. 
 
14.0 
Laboratory Evaluation 
14.1 
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.  Biomarker assessment: A core biopsy or an 

 
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excisional biopsy will be performed to confirm recurrent disease within 28 days of study 
initiations.  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.  A pathologic assessment of HER2 is required for 
study participation.  To ensure that the patient is HER2 positive, assessment of HER2 
status will be performed by both IHC and FISH.  The analyses of biomarkers of the 
EGFR pathway are not included in the grant proposal. Left over tumor from the 
required biopsy will be stored in pathology for future analysis. 
14.2 
Pharmacokinetic samples will be brought to Beckman Research Building, room 5212 
and given to Nicole for processing. 
 
15.0 
Statistical Analysis  
15.1 
During study part I, no new patients will be enrolled until the previous patient has been 
imaged and observed for one week post 64Cu-DOTA-trastuzumab PET imaging.   If any 
adverse event (other than a grade 1 injection site reaction) is observed that is possibly 
related to the 64Cu-DOTA-trastuzumab injection, the study will halt pending review at 
the DSMB. After each patient, a decision will be made regarding modification of the 
suggested scan times based on pharmacokinetics, biodistribution, and image quality.   
15.2 
Study Part I:  Fifteen HER2 positive patients with metastatic disease will be enrolled, 
with 5 patients treated with 5mg of antibody, 5 patients treated with 50mg of antibody, 
and 5 patients treated with 4mg/kg of antibody.  This will provide initial estimates of the 
biodistribution of the 64Cu-DOTA-trastuzumab and the preferred dose of cold antibody. 
Patients will be assigned to a cold antibody dose group, with assignment based on 
dynamic balancing to minimization of unbalance in site of metastatic disease between 
the different doses.  Patients with multiple sites will be considered in the strata that 
allows for best balancing (and as such can be re-classified). The information so derived 

 
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will also provide initial guidance on scan times and utility of 64Cu-DOTA-trastuzumab as 
an imaging agent in HER2 positive invasive breast cancer. 
15.3 
Study part 2 The HER2 expression (biopsy) must  be obtained on a different lesion 
than is evaluated with the 64Cu -DOTA-trastuzumab PET, and, in fact, the 64Cu -DOTA-
trastuzumab PET may be discordant with the pathology findings. It is however, 
hypothesized that the mean PET score for HER2+  pathology tumors will be higher 
than HER2- pathology tumors.  5 HER2+ (3+) patients, 5 HER2(+/-)  2+ (may be 
HER2+ or HER2- depending on FISH), and 5 HER2 1+ patients (generally considered 
HER2-). will be enrolled. As HER2+ patients (approximately 30% in the COH patient 
population) have a disproportionate incidence of metastatic disease to the liver, we will 
require at least 3 patients in each group to have liver involvement to help insure that 
differences in PET imaging between the different HER2 status groups are not 
confounded with site of disease.  Patient selection will be used to ensure that the three 
groups are similar with respect to sites of metastasis. Peak SUV value will be plotted 
(y-axis) against HER2+ status. With 9 patients, there is approximately 80% power to 
detect a linear correlation coefficient of 0.7, with a type I error of 5% (1-sided) 
assuming normally distributed covariates. Using a one-way ANOVA, there is 80% 
power to detect an effect size of 1.8 with a type I error of 5%. Finally, by considering all 
patients, with approximately 8 patients in HER2- group, and 7 in the HER+ group, there 
is 80% power to detect an effect size difference of 1.36 (1.36 x the common standard 
deviation in PET scores), using a two group t-test with a 0.05 one-sided significance 
level. We will also be examining for a trend in PET scores across the HER2 IHC 
scoring range for all patients. 
 
16.0 
Toxicity Assessment 
16.1 
Antibodies to DOTA and trastuzumab will be assessed at 1, 3, 6, and 12 months after 
imaging 

 
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16.2 
 Participants may begin trastuzumab-based therapy as early as 7 days after injection of 
64Cu -DOTA-trastuzumab.  Patients will be monitored for 1 year.  Side effects that are 
unrelated to trastuzumab or concurrent chemotherapy will be recorded.  
16.3 
Participants will be examined by the treating physician on days 7 and 14 and a 
complete blood count will be obtained. If there are any clinical concerns about cardiac 
toxicity, a MUGA will be obtained.  
17.0 
Data Management 
17.1 
Methods used for data collection: 
17.2 
Volunteer Identification: Participants identity will be linked to unique patient numbers 
(UPN) 
17.3 
Confidentiality: This research will be conducted in compliance with federal and state of 
California requirements relating to protected health information (PHI). The study will 
record individual imaging results and any side effects, and this will be linked to the 
subject’s identity using a UPN. The Protocol Management Team (PMT) consisting of 
the PI (Joanne Mortimer), Andrew Raubitschek MD, statistician (Paul Frankel PhD), 
and study nurses (Mary Carroll RN, Lois Wright RN, Phyllis Broene RN) and 
representatives of the USAMRMC are eligible to review research records, but all 
information will be treated confidentially.  No identifiers will be used in any publication 
of the study results. 
17.4 
Data Reporting 
17.4.1 Confidentiality of Records 
The original data collection forms will be stored at the originating institution.  At 
COH, the forms will be kept in secure cabinets by Clinical Research Informatics 
Management CRIM.  All records will be retained for a minimum of 2 years. 
 
When results of this study are reported in medical journals or at meetings, 
identification of those taking part will be withheld.  Medical records of patients 

 
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will be maintained in strictest confidence, according to current legal 
requirements.  However, they will be made available for review, as required by 
the FDA or other authorized users such as the NCI, under the guidelines 
established by the Federal Privacy Act. 
17.4.2 Patient Consent Form 
At the time of registration, the original signed and dated patient’s Informed 
Consent with the Experimental Subject’s Bill of Rights (for the medical record) 
and three copies (for the patient, the research record, and the Coordinating 
Center) must be available. All Institutional, NCI, Federal, and State of California 
regulations concerning the Informed Consent form will be fulfilled.  64Cu-DOTA 
trastuzumab is administered under IND 109,971 which is approved by and 
subject to the regulations of the FDA. 
17.4.3 Data Collection Forms and Submission Schedule  
All data will be collected using COH Biostatistics data collection forms. Copies 
of the completed forms will be sent to the City of Hope Department of 
Biostatistics for data entry and stored in a secure location.  The original data 
collection forms will reside at the originating institution in secure location.  
 
17.4.3.1 
The Eligibility Checklist must be completed by a protocol nurse or 
clinical research associate and signed by a participating investigator 
prior to registering the patient.   
17.4.3.2 
Within two weeks of registration, the clinical research associate will 
submit Prior Therapy forms (Prior Therapy Summary – COH1987 
and supplemental forms, as necessary) and On-Study forms (On-
Study Hematology/Other – COH2658 and supplemental forms, as 
necessary). 

 
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17.4.3.3 
Within 1 week of imaging, the clinical research associate will submit 
the following forms: 
 
Protocol Treatment – Drug Agent (COH2698) 
 
Monitoring & Follow-Up Summary (COH2001) 
 
Adverse Events Collection Form (COH2000) 
17.4.4 Results Reporting  
The COH, as sponsor of IND 109,971, will submit reports annually to the FDA within 60 
days of the anniversary date that the IND went into effect (Month DD) in accordance 
with 21 CFR 312.33. 
 
17.5 
Sharing results with participants:  Information from the 64Cu-DOTA trastuzumab PET 
image will be shared with the patient and the treating physician if that information will 
impact on the patient’s medical care. 
 
17.6 
Continuing Review and Final Report: As soon as approval notification is available from 
the IRB, a copy of the approved continuing review report with approval will be 
submitted to the HRPO for review. 
 
18.0 
Data Safety Monitoring Plan 
18.1 
 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: investigational imaging.  
18.2 
:  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. 

 
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Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and 
Compassionate Use 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 
 
 
 
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: antibody levels to 
DOTA and trastuzumab. 
 
 
18.3  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] is 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 

 
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 
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 dyscrasisas 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 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. 
 
 
 
18.4 
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/hrpp/Pages/hrpp-policies.aspx.  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). 
 
Serious Adverse Events - 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/hrpp/Pages/hrpp-policies.aspx 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). 
 

 
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Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for the 
DSMC and IRB 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
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 
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 
  
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 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 

 
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Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days 
of last day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations Director. 
The DSMC will review the case and make a determination as to whether the study will be 
suspended, terminated, amended, or allowed to continue without amendment. 
 
 

 
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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a 
UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
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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19.0 
Protocol Deviations 
Protocol deviations using the Protocol Deviation Form in IRIS must be submitted by the 
protocol nurse or the clinical research associate. The clinical research associate at COH will 
also submit copies to the Protocol Management Team and the COH Data and Safety 
Management Board. 
 
19.1 
In accordance with the COH Policy on Clinical Research Protocol Deviation, there will 
be a “no deviations” rule for this protocol.  However, for subject safety or unforeseen 
scheduling problems, planned deviations from this protocol will be permitted with 
approval from the IRB in the form of a Single Subject Amendment.  In addition, the 
sponsor (the CDMRC) must also approve any planned deviations. 
 
19.2 
All unplanned deviations will be reported to the COH DSMB. 
 
19.3 
If there is a dispute among the persons involved in the provision of research treatment, 
in regard to whether a treatment deviates from the protocol, the facts of the case will be 
reported to the DSMB which will be serve as the arbiter of whether a deviation exists.   
19.4 
Study attrition:  Participants who withdraw from study before completion of both 
imaging procedures will be replaced by another study participant.   
 
 
 

 
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20. 
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