Clinical trial NCT02065609
Conditions: Breast Cancer
Keywords: Trastuzumab
Sponsor: Washington University School of Medicine
Start date: 2014-02-01; Completion date: 2018-02-13
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to see if Positron Emission Tomography (PET-Imaging) with 89Zr labeled trastuzumab can detect trastuzumab (HER2) positive breast cancer.

Detailed description:

Arms: arm 1: 89Zr-Trastuzumab Human Dosimetry and Safety arm 2: HER2 Positive Lesion Detection and Safety
Interventions: intervention 1: 89Zr-Trastuzumab Human Dosimetry and Safety intervention 2: HER2 Positive Lesion Detection and Safety
Intervention descriptions: intervention 1: PET Imaging following administration of 89Zr labeled Trastuzumab for calculation of human dosimetry and overall safety intervention 2: Detection of HER2 Positive Breast Cancer with 89Zr Labeled Trastuzumab and PET imaging

Protocol documents:
Prot_SAP_ICF_000.pdf: 
VI. PROTOCOL  
Assessment of HER2 Receptors in Breast Carcinoma by Positron Emission Tomography 
(PET) using 89Zr-Trastuzumab 
 
HRPO #: 201307037 
Version #15: 06/16/2017 
IND#: 118029 
Clinical Trials.gov #:  NCT#02065609 
 
Principal Investigator 
Farrokh Dehdashti, M.D. 
Washington University School of Medicine 
660 S. Euclid, Campus Box 8223 
St. Louis, MO  63110 
Telephone: 314-362-1474 
E-mail: dehdashtif@mir.wustl.edu 
 
Sub-Investigators 
Michael J. Naughton 
Department of Medical Oncology 
Telephone: (314) 362-9115 
Fax: 314-996-8277 
email: mnaughto@wustl.edu 
 
Richard Laforest, Ph.D. 
Department of Radiology 
Tel: (314) -362-8427 
Fax: (314) -362-5428 
Email: laforestr@mir.wustl.edu 
 
Ron Bose, M.D., Ph.D. 
Department of Medical Oncology  
Telephone: (314) 362-8903 
Fax: (314) 747-9320 
Email: rbose@wustl.edu 
 
Ningying Wu, Ph.D. 
Division of Biostatistics 
Telephone: (314) 362-8762 
Email: ningying@wubios.wustl.edu 
 
Buck E. Rogers, Ph.D. 
Department of Radiation Oncology 
Telephone: (314) 362-9787 
Email: brogers@radonc.wustl.edu 
 
 
 
Souzan Sanati, M.D. 
Department of Pathology 
Phone: (314) 747-5648 
Email: ssanati@path.wustl.edu 
Barry A. Siegel, M.D. 
Department of Radiology 
Telephone: (314) 362-2809 
Email: siegelb@mir.wustl.edu 
 
 
 


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Page 2 
Study Coordinators 
Jennifer Frye, CNMT, CCRC 
Department of Radiology 
Ph: (314) -747-1604 
Fax: (314) -362-5428 
PAGER: (314)-407-4643 
Email: fryej@mir.wustl.edu 
 
Jill Anderson  
Departmentof Medical Oncology 
Telephone : (314) 747-5209 
Fax : (314) 362-0206 
PAGER : (314) 294-3009 
            Email : janders1@dom.wustl.edu 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 1 
 
Protocol Revision History 
 
10/29/2012 
Initial PRMC Submission  
11/15/2012 
PRMC suggested changes 
 
Section 6.4 clarified eligibility criterion #6 
 
Section 6.5.3 added clarification for use of small dose of 
unlabeled antibody  
 
Section 6.5.5 added clarification to revising dose of unlabeled 
antibody 
 
Section 6.5.9 corrected mistake in QT interval 
 
Section 6.11 updated table for data submission 
07/01/2013 
Updated protocol to match FDA submission 
 Title Page updated sub-investigators and study team members 
 Section SCHEMA – removed reference to pilot study and 
updated to 2 cohorts  and removed references to testing for 
trastuzumab resistance 
 Updated table of contents 
 6.1.0 Background removed references to testing for trastuzumab 
resistance.  Added references to Washington University’s 
experiences with HER2 positive and HER2 negative cell lines.    
 6.2.0 Objectives:  study objectives updated 
 6.4.0 Inclusion Criteria/ Exclusion Criteria updated to include 2 
cohorts of subjects and statement on women and minority 
recruitment  
 6.5.2 Patient Population: updated to include 2 cohorts of 
subjects.  Total number of subjects increased from 15 to 52  
 6.5.4 PET Imaging:  updated to include 2 cohorts of subjects 
 6.5.5 PET Image Processing and Analysis: updated to include 2 
cohorts of subjects  
 Removed section 6.5.6 “Analysis of markers of Trastuzumab 
Resistence” updated remaining sections for numbering.   
 6.7.0 Statistics: updated to include 2 cohorts of subjects 
 6.8.0 Risks and Benefits: updated to include radiation dosimetry 
for 2 cohorts of subjects  
 6.11 Data Forms and Submission Schedule: updated to include 2 
cohorts of subjects  
 6.12 References: updated 
07/24/2013 
 
Title Page updated to current version number and date.  Added IND 
#, clarified registration to Clinical trials.gov is not applicable to this 
phase I study.  Updated study team members 
 
6.1.0 Background :updated maximum injected dose from 4 mCi to 2.5 
mCi revised total mass of trastuzumab based on revised maximum 


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Page 2 
injected dose, updated table 1 maximum human absorbed radiation 
dosimetry based on revised maximum injected dose 
 
6.2.0 Objectives: updated maximum injected dose to 2.5 mCi 
 
6.5.4 PET Imaging: updated maximum injected dose to 2.5 mCi, 
revised CT for attenuation correction imaging parameters to a 
maximum effective mAs of 30 
 
6.8.0 Risks and Benefits: updated radiation dosimetry based on 
revised maximum injected dose and CT for attenuation correction 
imaging parameters.   
08-22-2013 
 
6.4.0 Inclusion Criteria/ Exclusion Criteria: clarified HER2 positive and 
negative patients are included as stratified by cohort 1 vs cohort 2. 
 
Fixed spelling and grammar errors.   
12-27-2013 
 
Title Page updated to current version number and date.  Added 
HRPO#, Corrected formatting, Added study coordinator pager 
numbers  
 
6.5.4 PET Imaging clarification added to imaging time points to allow 
a window of ± 6 hours around each imaging time point.   
 
6.5.7  Clinical Laboratory Testing revised window for obtaining 
baseline laboratory samples 
 
6.11 Data Forms and Submission Schedule updated to clarify timing 
for baseline lab and urine samples.   
 
06-27-2014 
 
Title Page added NCT# updated version date to IRB renewal date  
 
6.1.0 Background Dosimetry table corrected error in column 3 
rad/2.5mCi injection.  Recorded dose was falsely elevated because it 
included radiation dosimetry from CT scanning and did not accurately 
represent the column title.   
 
12-10-2014 
 
Title Page updated version number and date and footer date 
throughout entire document  
 
6.4.0 Inclusion Criteria/Exclusion Criteria added Cohort 2 HER2 
negative subjects must have normal baseline ejection fraction to be 
eligible for study participation 
 
6.5.6 Vital Signs:  fixed inconsistency in protocol vital signs will be 
obtained 3 times on injection day  
 
6.5.6, 6.5.7 & 6.5.8 Vital Signs, Lab Testing and ECG testing:  clarified 
where clinically significant findings are recorded and when they are 
also recorded on the adverse event log 
 
6.8.0 Risks and Benefits:  Added risks for baseline cardiac function 
testing (ECHO or RVG) for cohort 2 HER2 negative subjects 
 
6.10.1 Adverse Events (AEs):  clarified AE assessments are made to 
assess relationship to 89Zr-Trastuzumab injection and PET/CT imaging   


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 
6.10.5 Protocol Exceptions:  Clarified that due to the nature of 
radioactivity and imaging, some protocol exceptions may occur.   
 
6.11 Data Forms and Submission Schedule:  Updated footnotes in 
cohort 1 and cohort 2 schedule to clarify number and timing of ECG 
and Vital sign measurements.  
05-18-2015 
 
Title Page updated version number and date and footer date 
throughout entire document to match renewal request 
02-03-2016 
 
Title Page updated version number and date and footer date 
throughout entire document  
 
SCHEMA - Continued added schema for cohort 3 
 
6.1.0 Background updated to include TDM1 
 
6.2.0 Objectives updated to include cohort 3 
 
6.4.0 Inclusion Criteria/ Exclusion Criteria updated to include cohort 3 
and to clarify stable disease is eligible  
 
6.5.0 METHODS updated all sections to include cohort 3 
 
6.7.0 Statistics updated to add cohort 3 
 
6.8.0 Risks and Benefits updated to add risks for cohort 3 including 
biopsy and additional radiation exposure if CT guided biopsy is 
needed 
 
6.9.0 Record Keeping add up to 2 year follow up for cohort 3 subjects 
 
6.11 Data Forms and Submission Schedule add cohort 3 submission 
schedule 
 
6.12 References add cohort 3 references  
03-04-2016 
 
Title Page updated version number and date and footer date 
throughout entire document  
 
6.8.0 Risks and Benefits updated to revise the radiation dosimetry 
from CT guided biopsy if applicable to cohort 3 subjects  
04/12/2016 
CHANGES MADE AT ANNUAL RENEWAL  
 
Title Page updated version number and date and footer date 
throughout entire document  
 
NOTE THESE CHANGES WERE REVIEWED BY PRMC ONLY 
 
 
 


Version: 06/16/2017 
Page 4 
 
12/12/2016 
Amendment for Cohort 3 Subjects 
 
Protocol Page – update study coordinators 
 
Footer updated date  
 
SCHEMA – Updated Schema for cohort 3 
 
Table of Contents- updated page numbers 
 
6.1.0 Background- add FDG-PET/CT and breast cancer 
 
6.1.0 Background- update human dosimetry tables 
 
6.2.0 Objectives add FDG-PET/CT imaging for cohort 3 
 
6.4.0 Inclusion Criteria/ Exclusion Criteria clarified cohort 3 
procedures which must be completed prior to start of T-DM1 
therapy 
 
6.5.2 Patient Population – added FDG-PET/CT to cohort 3 
study patient description 
 
6.5.4 PET Imaging updated number of cohort 3 subjects to be 
studied added FDG-PET/CT imaging parameters and how 
results will be used 
 
6.5.5 PET Image Processing and Analysis Added FDG-PET/CT 
information  
 
6.7.0 Statistics updated to include FDG-PET/CT 
 
6.8.0 Risks and Benefits updated to include FDG-PET/CT 
 
6.11 Data Forms and Submission Schedule added FDG-PET to 
cohort 3 and clarified foot notes.   
 
6.12 References Updated to include published human 
dosimetry and other information  
03/28/2017 
Renewal Request update footer and version to date of request 
 
Footer updated date  
 
SCHEMA –updated to indicate cohort 1 and cohort 2 closed 
to enrollment 12/31/2016 
 
SCHEMA – Continued Cohort 3 updated to clarify cohort 3 
specific study schema 
 
Table of Contents- updated page numbers 
06/16/2017 
Protocol Amendment  
 
Footer updated date  
 
6.5.4 PET Imaging revised to indicate that FDG-PET/CT 
imaging results after the 2nd cycle of therapy will be included 
in the subject’s medical record.   
 
 
 
 


Version: 06/16/2017 
Page 5 
 
SCHEMA -  
 
Assessment of HER2 Receptors in Breast Carcinoma by Positron Emission Tomography 
(PET) using 89Zr-Trastuzumab 
NOTE Cohort 1 and Cohort 2 closed to enrollment 12/31/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary or Metastatic/Recurrent Breast 
Cancer with Lesion Size ≥ 1.5 cm by 
Standard Radiological Procedures: 
Mammography, Ultrasound, CT or MRI or 
Physical Examination 
 
89Zr-Trastuzumab-PET Imaging  
Correlation of tumor uptake of 89Zr-Trastuzumab 
with HER2 evaluated by in vitro assay  
Cohort 1: Biopsy-Proven Breast Cancer with 
Human epidermal growth factor receptor 2 
(HER2)-positive Dosimetry imaging  
(n=12) 
Cohort 2:  Biopsy-Proven Breast Cancer with 
Human epidermal growth factor receptor 2 
(HER2)-positive OR HER2-Negative 
(n=40) 


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SCHEMA – Continued Cohort 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary or Metastatic/Recurrent Breast Cancer 
with Lesion Size ≥ 1.5 cm by Standard 
Radiological Procedures: Mammography, 
Ultrasound, CT or MRI or Physical Examination 
who are going to be treated with T-DM1 and have 
at least one lesion amenable to biopsy 
Correlation of tumor uptake of 89Zr-Trastuzumab with 
HER2 resistance markers evaluated by in vitro assay and 
response to T-DM1 
Research tumor biopsy for analysis of HER2 
resistance markers, Baseline FDG-PET/CT and 
89Zr-Trastuzumab-PET Imaging  
Cohort 3: Biopsy-Proven Breast Cancer with Human 
epidermal growth factor receptor 2 (HER2)-positive - 
T-DM1 imaging (n=10) 
Repeat FDG-PET/CT scan after 2 cycles of T-DM1 (Day 
14-28 of Cycle 2 of T-DM1 Therapy or immediately prior 
to Cycle 3 administration) 


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Page 7 
Table of Contents 
SCHEMA -...................................................................................................................................... 5 
SCHEMA – Continued Cohort 3 .................................................................................................... 6 
Table of Contents ............................................................................................................................ 7 
6.1.0 Background ......................................................................................................................... 8 
6.2.0 Objectives ......................................................................................................................... 13 
6.3.0 Statement of Qualifications............................................................................................... 14 
6.4.0 Inclusion Criteria/ Exclusion Criteria ............................................................................... 14 
6.5.0 METHODS ....................................................................................................................... 15 
6.5.1 Study Design ................................................................................................................. 15 
6.5.2 Patient Population ......................................................................................................... 15 
6.5.3 Infusion of Trastuzumab and 89Zr-Trastuzumab........................................................... 16 
6.5.4 PET Imaging ................................................................................................................. 17 
6.5.5 PET Image Processing and Analysis ............................................................................ 18 
6.5.6 Vital Signs ..................................................................................................................... 20 
6.5.7  
Clinical Laboratory Testing ...................................................................................... 21 
6.5.8 Electrocardiograms (ECGs) .......................................................................................... 22 
6.5.9  
Cohort 3 Research Biopsy Procedure ....................................................................... 22 
6.6.0 Drug Preparation ............................................................................................................... 23 
6.7.0 Statistics ............................................................................................................................ 23 
6.8.0 Risks and Benefits............................................................................................................. 24 
6.9.0 Record Keeping ................................................................................................................ 26 
6.10.0 
Regulatory and Reporting Requirements ...................................................................... 26 
6.10.1 
Adverse Events (AEs) ............................................................................................... 26 
6.10.2 
Unanticipated Problems ............................................................................................ 26 
6.10.3 
Noncompliance ......................................................................................................... 27 
6.10.4 
Serious Noncompliance ............................................................................................ 27 
6.10.5 
Protocol Exceptions .................................................................................................. 27 
6.10.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington University .............. 27 
6.10.7 
Reporting to the FDA................................................................................................ 28 
6.10.8 
Timeframe for Reporting Required Events............................................................... 29 
6.12 References6.11 Data Forms and Submission Schedule ..................................................... 30 
6.12 
References ......................................................................................................................... 33 
 
 


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6.1.0 Background  
Breast cancer remains the leading cause of cancer mortality among women in Western 
countries. Current estimates suggest one in eight American women will be diagnosed with breast 
cancer during their lifetime. Distinct characteristics of breast cancer can be exploited to help 
determine the overall prognosis and the likelihood of response to specific therapy. It is well 
established that several factors including steroid receptors, peptide growth factors, oncogenes, and 
tumor suppressor genes play a crucial role in the transformation of breast cancer.   
Human epidermal growth factor receptor 2 (HER2) has an important role in cell survival, cell 
proliferation, cell maturation, metastasis and angiogenesis, as well as exerting antiapoptotic effects 
(1)  HER2-positive breast cancer accounts for approximately 25% of all cases of breast cancer.  In 
the setting of HER2 gene amplification or high levels of HER2 expression, the HER family of 
receptors and their associated signal transduction pathways play a dominant role in cell growth 
and survival.  These tumors have a distinct natural history that, in the absence of HER2-directed 
therapy, is characterized by short disease-free survival and an aggressive course in the metastatic 
setting.  Trastuzumab is monoclonal antibody directed against HER2.  Its anti-tumor activity is 
likely attributable to several different effects. Trastuzumab downregulates HER2 expression on 
cell surface and activates p27 and p130.  Trastuzumab also sensitizes tumor cells to TNF and 
inhibits tumor angiogenesis by decreasing the production of VEGF.  In patients with HER2-
amplified tumors, the overall response rate to single-agent trastuzumab as a first-line therapy for 
metastatic breast cancer is approximately 34%.  In a randomized study, Slamon et al.have shown 
that the addition of trastuzumab improves survival in the adjuvant treatment of HER-positive 
breast cancer, although combined therapy with anthracycline-based regimens has been associated 
with cardiac toxicity (2).  However, the non anthracycline-based regimens combined with 
trastuzumab have been associated with fewer acute toxic effects, and lower risks of cardiotoxicity 
and leukemia.  Thus while trastuzumab therapy results in a significant improvement of disease free 
survival and overall survival, it is associated with cardiac toxicity resulting in symptomatic 
congestive heart failure and a significant drop in left ventricular ejection function (3).  Identifying 
patients who are going to benefit from trastuzumab therapy will be of critical importance. 
Markers of Trastuzumab Resistance: Multiple trastuzumab resistance mechanisms have 
been identified, including alternation of the of the HER2 protein that prevent trastuzumab binding 
and activation of downstream or parallel signaling pathways that support HER2+ breast cancer 
cell growth even in the presence of trastuzumab.  A shorted isoform of HER2, called p95-HER2, 
lacks the trastuzumab binding site but is able to still promote breast cancer tumorigenesis(4).  The 
frequency of p95-HER2 expression in patient samples has been reported to be up to 30% (5, 6).  
Loss of the trastuzumab binding site will result in loss of 89Zr-trastuzumab binding by the tumor 
and this would be detectable by PET imaging. 
Most studies to date have used Western blot, which has limited clinical utility, to identify 
the p95HER fragments. There is evidence that HER2 status may change during the course of the 
disease and after chemotherapy (7). In addition, discordance in HER2 expression across tumor 
lesions in the same patient has been reported (8-11). Thus, the use of repeated biopsies during the 
course of the disease is encouraged (12, 13). However, repeated biopsies are not clinically feasible 
due to their invasiveness and not all lesions are readily accessible to be biopsied (14). Therefore, 
a method that can reliably determine both the quantity and the functional status of tumor HER2 in 
individual lesions would be of critical importance in identifying patients who would benefit from 
HER2-targeted therapy. 


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Additional mechanisms for trastuzumab resistance include activation of pSrc or activation 
of PI3-kinase signaling either by PIK3CA gene mutation or deletion of PTEN and upregulation of 
signaling from other receptor tyrosine kinases, IGF1R, EGFR, HER3, MET and pMAPK (15, 16, 
33) .  These mechanisms of trastuzumab resistance would not be expected to alter trastuzumab 
binding.   
Assessment of HER2: In order to select the patients that are likely to benefit from HER-2-
targeted therapy, it is important to determine the status of HER-2 in breast cancer.  Currently, two 
types of tests, i.e. immunohistochemistry (IHC) that detects receptor overexpression and 
fluorescence in situ hybridization (FISH) that identifies HER-2 gene amplification, are used for 
the purpose (17-19).  Protein expression levels are scored as 0 or 1+ (zero or low), 2+ 
(intermediate) or high 3+.  Recent reports indicate a considerable degree of concordance between 
the two methods of detection on same tumor specimens.  While 100% concordance was observed 
in IHC 3+ readings when compared with FISH, cases with 2+ IHC score were not very 
reproducible (20)  It is common practice to send scores of 2+ on IHC for FISH analysis, and 
patients whose tissue is positive on FISH (i.e. amplification >2.0) are offered trastuzumab.  Thus, 
such patients must have a confirmatory FISH test before administration of trastuzumab therapy.  
Though detection of HER-2 by FISH is more accurate, it requires special equipment that make it 
more expensive.  When compared to IHC, FISH test is also found to be a better predictor of 
response to trastuzumab therapy and overall prognosis.   
Recently, ado-Trastuzumab Emtansine (T-DM1), a HER2-targeted ADC consisting of an 
antimicrotubule agent (DM1) linked to trastuzumab, has shown to be active in patients with 
trastuzumab and lapatinib refractory metastatic breast cancer. (34, 35, 36)   As the mechanism for 
this therapy is via binding to the extracellular domain of HER2, the presence of this receptor is 
vital for this therapy to be efficacious.  
There is evidence that HER2 status may change during the course of the disease and after 
chemotherapy (7).  In addition, discordance in HER2 expression across tumor lesions in the same 
patient has been reported (8-11).  Thus, the use of repeated biopsies during the course of the disease 
is encouraged (12, 13).  However, repeated biopsies are not clinically feasible due to their 
invasiveness and not all lesions are readily accessible to be biopsied (14).  Therefore, a method 
that can reliably determine both the quantity and the functional status of tumor HER2 in individual 
lesions would be of critical importance in identifying patients who would benefit from HER2-
targeted therapy.  
In vivo measurement of the HER2 expression in breast cancer could offer several 
advantages over current in vitro methods. These include assessing the HER2 expression of the 
entire tumor volume rather than just a part of the tumor (addressing the intrinsic heterogeneity of 
receptor expression), assessing the biologic availability of HER2 in vivo, and evaluating the effects 
of therapy on HER2 expression of the tumor. In addition, in vivo imaging can simultaneously 
assess HER2 expression of the primary and metastatic lesions, many of which may be inaccessible 
to biopsy.  Efforts have been made to develop imaging agents for HER2 labeled with single photon 
radionuclides and positron emitting radionuclides for noninvasive in vivo evaluation of HER2 
expression and localization of HER2-overexpressing tumor lesions including inaccessible 
metastatic foci.  111In-trastuzumab, a single photon emission radiopharmaceutical, has been 
developed and tested in patients with breast cancer (21).  Perik et al. have shown HER2-specific 
uptake in patients with HER2-positive metastatic breast cancer. 111In-trastuzumab imaging 
discovered unsuspected HER2-positive lesions in 13 of 15 patients and was therefore considered 
to be of potential value as a clinical diagnostic tool in patients with metastatic breast cancer (21).  
In addition, there are several other radiopharmaceuticals that have been used for clinical HER2 
imaging, such as 99mTc-labeled anti-HER2 rat antibody ICR12.  99mTc-ICR12 was administered to 
8 patients with breast cancer, which suggested that this radiopharmaceutical could be used for 
imaging of HER2-positive disease (22).  Currently, there are on-going clinical studies with both 


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gamma-emitting and positron emitting radiopharmaceuticals, such as 111In- and 64Cu-trastuzumab 
and with 68Ga-trastuzumab F(ab′)2 fragments (23, 24).  
HER2 Imaging with PET: Positron emission tomography (PET) has been shown to have 
the ability to image radioligand binding quantitatively at tracer concentrations.  This is a distinct 
advantage over conventional nuclear medicine using planar or SPECT imaging.  This has 
encouraged considerable efforts to develop positron emitting radionuclides such as 64Cu-
trastuzumab and 68Ga-trastuzumab F(ab′)2 fragments, 68Ga-ABY-002 and 89Zr-trastuzumab (25).  
Limited clinical studies with 68Ga-ABY-002 have shown that high liver and renal uptake interferes 
with lesion detection in patients with metastatic lesions in the abdomen (26).  89Zr-trastuzumab 
using intact antibodies has the advantage over the smaller HER2-directed F(ab′)2 fragments, as 
generally, large intact monoclonal antibodies penetrate slowly but constantly into solid tumor 
tissue, ultimately resulting in higher accumulation in the tumor than is the case with small proteins 
when antibody fragments penetrate faster into tumor tissue but show less tumor uptake because of 
more rapid clearance from the blood  (10).  In addition, for immunoPET imaging, positron-emitting 
radiometals such as 89Zr have an advantage over radiohalogens such as 124I because they are 
residualizing and are therefore retained within the target cell after internalization and intracellular 
degradation of the tracer.  This results in higher uptake in the tumor when an internalized antibody 
such as trastuzumab is used (10).  Of the positron-emitting radiometals, 89Zr has the longest and 
therefore most favorable half-life (78.4 h), allowing antibody imaging up to 7 days after the 
injection, the time needed for in vivo circulation, optimal biodistribution and tumor targeting.  
Preclinical evaluation of 89Zr-trastuzumab showed that it displays superior image quality as 
compared to 111In-trastuzumab, given the high spatial resolution and sensitivity of PET (27).  At 
Washington University, we have evaluated MDA435/LCCHER2/GFP/Luc (HER2-positive) and 
MDA435/Lcc6Vector (HER2-negative) cell lines, which overexpress and minimally express 
HER2, 
respectively, 
with 
89Zr-trastuzumab. 
 
Using 
flow 
cytometry, 
MDA435/LCC6HER2GFP/Luc cells demonstrated elevated levels of HER2 expression in 
comparison to MDA435/LCC6Vector cells, which demonstrated minimal expression.  Both cell 
lines also express luciferase for bioluminescence imaging to confirm tumor growth.  In in vitro 
studies, the uptake of 89Zr-trastuzumab was 8.5 fold greater in HER2-positive cells compared to 
HER2-negative cells (p < 0.01).     
Dijkers et al. studied 14 patients with HER2-positive metastatic breast cancer with 89Zr-
trastuzumab-PET (28).  These patients received 37 MBq of 89Zr-trastuzumab at one of three doses 
(10 or 50 mg for those who were trastuzumab-naive and 10 mg for those who were already on 
trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5 after 
89Zr-trastuzumab injection.  The results of the study showed that the best time for assessment of 
89Zr-trastuzumab uptake by tumors was 4–5 days after the injection.  The accumulation of 89Zr-
trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been 
undetected earlier.  The relative uptake values (RUVs) (mean ± standard error of mean [SEM]) 
were 12.8 ± 5.8, 4.1 ± 1.6, and 3.5 ± 4.2 in liver, bone, and brain lesions, respectively, and 5.9 ± 
2.4, 2.8 ± 0.7, 4.0 ± 0.7, and 0.20 ± 0.1 in normal liver, spleen, kidneys, and brain tissue, 
respectively.  This first-in-human 89Zr-trastuzumab HER2-PET imaging study showed excellent 
tumor uptake and visualization of HER2-positive metastatic liver, lung, bone, and even brain 
tumor lesions, when an adequate trastuzumab protein dose was administered.  In trastuzumab-
naive patients with HER2-positive metastatic breast cancer, 50 mg of trastuzumab was the dose 
that resulted in optimal biodistribution characteristics under the test conditions and proved 
adequate for 89Zr-trastuzumab-PET imaging.  The 50-mg trastuzumab dose in naive patients is a 
good starting point for further optimization in future studies.  In patients undergoing treatment 
with trastuzumab at the time of tracer injection, 10 mg trastuzumab was adequate for PET imaging.  
Higher doses of trastuzumab were not expected to improve 89Zr-trastuzumab-PET imaging; 
trastuzumab clearance was already minimal, and therefore a further increase in the dose of 


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Page 11 
trastuzumab could induce target saturation.  Quantification of the PET images confirmed the dose-
dependency of trastuzumab clearance and revealed a significantly higher uptake in metastatic 
tumor lesions as compared to corresponding normal tissue.  In this study, lesions with HER2 
overexpression can be distinguished from those without HER2 overexpression based on 89Zr-
trastuzumab uptake.  However, further studies are needed to determine the exact amount of HER2 
expression required for adequate imaging.  Thus, due to these advantages, we have chosen 89Zr-
trastuzumab with PET to study HER2 expression in patients with breast cancer.   
FDG-PET/CT Imaging:  The use of PET imaging with 18F-fluorodeoxyglucose (FDG) for 
restaging breast cancer patients who have progressed on currently therapy and in predicting 
response to therapy in breast cancer is well documented and beneficial (37,38).  FDG is transported 
into the cell via glucose transporters, but unlike glucose, FDG is not metabolized but is irreversibly 
phosphorylated by hexokinase and trapped within the cell. Glucose transport is upregulated in most 
cancers and the use of FDG PET imaging for restaging breast cancer patients who have progressed 
on current therapy is routinely used at our institution.  Biologic correlates of FDG uptake in breast 
cancer include mitotic activity index, histologic grade, tumor cell density, as well as other markers 
of aggressiveness.  FDG-PET imaging has also proven useful in monitoring response to 
chemotherapy in the metastatic setting.    
Animal Toxicity Study 
Animal Toxicity studies were conducted at Memorial Sloan Kettering Cancer Center   The 
objective of the study was to evaluate the acute toxicity of a single high dose intravenous infusion 
of cold Zr-DFO-Trastuzumab in mice 250 times higher than the proposed clinical PET imaging 
dose for 89Zr-DFO-Trastuzumab. 
Zr-DFO-Trastuzumab was tested at a dose level of 10 mg/kg in B6D2F1mice (32 male and 
32 female).  No unacceptable adverse events were observed for the test article during acute dosing 
or the following 14-day observation period.  The study concluded that 10 mg/kg 89Zr-
DFOtraztuzumab  administered i.v. as a single dose is the No Observed Adverse Effect Level 
Dosimetry (NOAEL in B6D2F1 mice):  
The human radiation dosimetry estimates for the imaging agent 89Zr-trastuzumab was 
calculated from mice dissection biodistribution data and from human S-values for 89Zr. Radiation 
dose estimates were calculated using the MIRD methodology. The human female and male adult 
model was used with the program OLINDA/EXM to calculate the normal organ radiation dose 
estimates. A dosage of maximum of 2.5 mCi is proposed for human studies.  Assuming a worst 
case specific activity of 0.2 mCi/mg, the 89Zr-trastuzumab mass injected for a 2.5 mCi dosage 
would be 12.5 mg. The dosage given to mice and hamsters in the toxicity study was more than 30 
times the mass (10 mg/kg) as the proposed dosage to humans. Thus, favorable binding 
characteristics, animal biodistribution, dosimetry, and our ability to produce high-specific-activity 
product combine to make 89Zr-trastuzumab a candidate for human breast cancer imaging.   
 
 


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Table 1.  Extrapolated human radiation dose estimates for 89Zr-
Herceptin per unit of administered activity. (Cohort 1 and 
Cohort 2 Study Subjects) 
Organ 
Dose (rad/mCi) 
 
Dose (rad/ 2.5 mCi) 
 
Adrenals 
1.99 
4.98 
Brain 
0.53 
1.33 
Breasts 
1.21 
3.03 
Gallbladder 
1.66 
4.15 
LLI Wall 
1.70 
4.25 
Small Intestines 
1.61 
4.03 
Stomach 
1.54 
3.85 
ULI Wall 
1.74 
4.35 
Heart muscle 
2.93 
7.33 
Kidneys 
1.98 
4.95 
Liver 
2.07 
5.18 
Lungs 
2.23 
5.58 
Muscle 
1.26 
3.15 
 
Ovaries 
1.85 
4.63 
Pancreas 
1.71 
4.28 
Red Marrow 
1.45 
3.63 
Bones 
1.86 
4.65 
Skin 
0.94 
2.35 
Spleen 
1.59 
3.98 
Thymus 
1.73 
4.33 
Thyroid 
1.43 
3.58 
Urinary Bladder 
1.37 
3.43 
Uterus 
2.36 
5.90 
Total Body 
1.39 
3.48 
 
 
 
Effective Dose (rem) 
1.63 
4.08 
We are planning to inject 2.5 mCi in order to provide images of sufficient quality for analysis and 
interpretation. For dosimetry patient, imaging is performed over 6-7 bed positions and at 5-8 
minutes per bed position, resulting in an imaging duration of approximately 1 hour. We judge that 
1 hour is the longest imaging duration a patient can tolerate in the scanner. 
 
 


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Page 13 
 
Based on dosimetry results from cohort 1 and the associated publication (39) the maximum 
injected dose to cohort 3 patients will be 1. 5 mCi  
 
Table 2.  Human Radiation Dosimetry for 89Zr-Herceptin per unit of 
administered activity. (Cohort 3 Study Subjects)  
Organ 
Dose (rad/mCi) 
 
Dose (rad/ 1.5 mCi) 
 
Adrenals 
2.96 
4.44 
Brain 
1.44 
2.16 
Breasts 
1.55 
2.33 
Gallbladder 
3.18 
4.77 
LLI Wall 
2.15 
3.22 
Small Intestines 
2.11 
3.16 
Stomach 
2.33 
3.50 
ULI Wall 
2.41 
3.61 
Heart muscle 
4.11 
6.16 
Kidneys 
4.55 
6.83 
Liver 
6.03 
9.05 
Lungs 
2.18 
3.27 
Muscle 
1.81 
2.72 
 
Ovaries 
2.18 
3.27 
Pancreas 
2.89 
4.33 
Red Marrow 
2.55 
3.83 
Bones 
2.92 
4.38 
Skin 
1.26 
1.89 
Spleen 
3.18 
4.77 
Thymus 
2.11 
3.16 
Thyroid 
1.59 
2.39 
Urinary Bladder 
1.55 
2.33 
Uterus 
2.15 
3.22 
Total Body 
2.04 
3.05 
 
 
 
Effective Dose (rem) 
2.26 
3.39 
 
6.2.0 Objectives 
We are planning to perform a trial with goals to demonstrate the feasibility of imaging 
breast cancer patients with 89Zr-trastuzumab-PET, to evaluate preliminarily the relationship 
between tumor 89Zr-trastuzumab uptake and in vitro positivity of HER2, to assess the safety of 
89Zr-trastuzumab and human dosimetry of this tracer. In a pilot study, we are planning to study the 
correlation between 89Zr-trastuzumab uptake and known markers of resistant to Her2-targeted 
therapies (such as PTEN, pAkt, pMAPK, and pSrc) and to assess whether 89Zr-trastuzumab-PET 
can assist in identifying patients with HER2-positive breast cancer who are resistant to HER2-
targeted therapy with T-DM1.  This is to obtain pilot data for planning a future trial to more 
definitively evaluate the role of 89Zr-trastuzumab in predicting response, assessed according to 
standard clinical response criteria, to anti HER2 therapies.  
Study objectives:  
6.2.1 To determine the diagnostic quality and lesion detection rate of 89Zr-trastuzumab-
PET images.  


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6.2.1.1 
To assess the diagnostic quality and lesion detectability of 89Zr-
trastuzumab-PET images at a maximum of 2.5 mCi dose.  Also to 
determine the imaging time after injection of 89Zr-trastuzumab that yields 
best image quality and lesion detection rate. 
6.2.2 To calculate human dosimetry of 89Zr-trastuzumab and assess the safety 89Zr-
trastuzumab administration. 
6.2.3 To evaluate the relationship between tumor 89Zr-trastuzumab uptake and in vitro 
status of HER2.   
6.2.4 To evaluate preliminary if the degree 89Zr-trastuzumab uptake (and intra-patient 
lesion heterogeneity in uptake) can predict patient response to the T-DM1 antibody 
drug conjugate.   
6.2.5 To identify metabolically active disease to map HER2+ disease and to predict 
response to T-DM1 therapy. 
6.265 To evaluate if loss of tumor binding of trastuzumab is the mechanism for acquired 
resistance to T-DM1. The tumor uptake of 89Zr-trastuzumab will be correlated with 
markers of HER2 resistance on patient’s biopsy tissue obtained at the time of 
resistance to trastuzumab-targeted therapy prior to T-DM1 therapy initiation. 
6.3.0 Statement of Qualifications  
The FDA 1572 Form is provided in the IND submission along with curriculum vitae for 
the study’s Principal Investigator, Farrokh Dehdashti, M.D. Washington University School of 
Medicine, St. Louis, Missouri.   
 
6.4.0 Inclusion Criteria/ Exclusion Criteria 
Adult women with biopsy- proven breast cancer who have undergone HER2-testing and 
who will be treated according to standard of care are eligible to participate in this study.   
 
Inclusion Criteria:  
 Female patients 18 years of age or older 
 Cohort 1: Her2-positive (defined as 3+) or FISH HER2:CEP17 ratio > 2 biopsy-
proven breast cancer 
 Cohort 2: Her2-positive (defined as 3+) or FISH HER2:CEP17 ratio > 2 OR HER2-
negative (0 or 1+, 2+ and FISH negative) biopsy-proven breast cancer 
 Cohort 2 HER2 negative subjects must have normal baseline ejection fraction (as 
determined by standard echocardiogram (ECHO) or radionuclide ventriculogram 
(RVG) obtained within 3 months of 89Zr-Trastuzumab infusion.  If not performed as 
standard of care, a study specific ECHO or RVG may be scheduled after informed 
consent has been obtained as part of baseline screening.    
 Cohort 3: Her2-positive (defined as 3+) or FISH HER2:CEP17 ratio > 2 biopsy-
proven breast cancer who are going to be treated with T-DM1 and have at least one 
lesion amenable to biopsy.  Biopsy, FDG-PET/CT prior to and after 2 cycles of T-DM1 
and 89Zr-Trastuzumab-PET/CT imaging must be completed prior to starting TDM-1 
therapy.   


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Page 15 
 Primary or recurrent/metastatic lesion size ≥ 1.5 cm as determined by imaging studies 
(ultrasonography, mammography, CT or MRI) or physical examination. Subjects with 
stable disease whose lesion size meets criteria are also eligible to participate.   
 Able to give informed consent 
 Not currently pregnant or nursing:  Subject must be surgically sterile (has had a 
documented bilateral oophorectomy and/or documented hysterectomy), post-
menopausal (cessation of menses for more than 1 year), non-lactating, or of 
childbearing potential for whom a urine pregnancy test (with the test performed within 
the 24 hour period immediately prior to administration of 89Zr-trastuzumab) is negative  
 Cohort 1 and cohort 2 patients currently receiving trastuzumab therapy with or without 
other types of systemic therapy can participate during therapy provided lesion size 
criteria is met, or if their disease progresses (development of new lesion(s) or 
worsening of known lesion(s) based on imaging modalities or physical examination.  
 Cohort 3 patients must complete all study related procedures (biopsy, injection of 89Zr-
Trastuzumab and imaging 5-7 days later) prior to starting treatment with TDM-1  
 
Exclusion Criteria: 
 Patients with other invasive malignancies, with the exception of non-melanoma skin 
cancer, who had (or have) any evidence of the other cancer present within the last 5 
years 
 Unable to tolerate up to 60 min of PET imaging per imaging session 
 
6.4.1  Inclusion of Women and Minorities 
Only women will be enrolled due to the anatomical specificity of breast cancer. 
Members of all races and ethnic groups are eligible for this trial. 
6.5.0 METHODS  
6.5.1 Study Design  
A single center, open-label, baseline-controlled diagnostic imaging study designed to 
assess the diagnostic quality of 89Zr-trastuzumab imaging with PET.     
6.5.2 Patient Population  
Cohort 1: 12 adult women with Her2-positive primary, recurrent/metastatic breast 
cancer with lesion size ≥ 1.5 cm by standard radiological procedures: mammography, 
ultrasound, CT or MRI or physical examination will be studied once with 89Zr-
trastuzumab-PET imaging..  Patients who are on trastuzumab based therapy can also 
participate.  Patients with recurrent/metastatic disease are required to have at least one 
measurable lesion (as defined by RECIST 1.1).. Written informed consent will be 
obtained prior to the PET imaging session.  89Zr-trastuzumab-PET images at 2 times 
points in each patient will be compared to identify the time point that yields the best 
lesion detection rate.  89Zr-trastuzumab-PET images also will be correlated with all 
available imaging studies to assess lesion detection rate.  .  Cohort 1 subjects entered 
on study will be asked to undergo total body 89Zr-trastuzumab-PET imaging at two 
separate time points for purposes of calculating human dosimetry.   
 


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Cohort 2: To evaluate whether tumor uptake 89Zr-trastuzumab correlates with tumor 
expression of HER2, only adult women with at least one measurable (based on RECIST 
1.1) primary or metastatic lesions, which has known HER2 status will be evaluated. 
HER2-negative (0 or 1+, 2+ and FISH negative) and HER2-positive lesions (3+ by IHC 
and FISH positive) will be evaluated. A total of 40 patients will yield a minimum of 40 
evaluable lesions, 20 HER2-negative and 20 HER2-positive. Patients will undergo only 
one PET imaging study after 89Zr-trastuzumab injection similar to the imaging protocol 
used Specific Aim 1, but at the best time established from Cohort 1. 
Cohort 3: To evaluate preliminarily if 89Zr-trastuzumab can predict patient response to 
the T-DM1 antibody drug conjugate.  To evaluate if loss of tumor binding of 
trastuzumab is the mechanism for acquired resistance to T-DM1. Also, to identify 
metabolically active tumor by FDG-PET/CT in order to map HER2+ metabolically 
active disease sites by 89Zr-trastuzumab.  In this Cohort, only adult women with at least 
one measurable (based on RECIST 1.1) HER2-positive primary or metastatic/recurrent 
lesion which is amenable to biopsy will be evaluated. A total of 5 patients will be 
evaluated. Patients will undergo FDG-PET/CT followed by 89Zr-trastuzumab injection 
and imaging at the best time established from Cohort 1 (5 to 7 days post 89Zr-
trastuzumab injection). These patients will also undergo a research tumor biopsy for in 
vitro analysis of known markers of resistant to HER2-targeted therapies (such as PTEN, 
pAkt, pMAPK, and pSrc) prior to starting T-DM1-therapy. Optimal pre-therapy 
scheduling will be FDG-PET/CT, biopsy, followed by injection, and imaging 5 to 7 
days later.  However, due to anticipated scheduling conflicts other scheduling options 
will also be acceptable.  In addition, cohort 3 subjects will undergo FDG-PET/CT an 
day 14-28 of cycle 2 of T-DM1 therapy or immediately prior to administration of cycle 
3 of therapy.    
 
6.5.3 Infusion of Trastuzumab and 89Zr-Trastuzumab 
As suggested by Dijkers et al. (28).  To minimize uptake of the radiotracer in normal 
tissues, trastuzumab-naïve patients (OR patients who have received their last dose of 
transtuzumab therapy ≥ 4 weeks prior to planned 89Zr-trastuzumab injection will receive a 
50 mg dose of trastuzumab and patients already on trastuzumab treatment will receive a 10 
mg dose, typically 30 min to 2 hours, prior to 89Zr-trastuzumab injection.  For subjects who 
are currently receiving trastuzumab therapy a standard of care therapy dose can be 
substituted for the 10 mg dose if scheduling permits.  The administration of a fixed small 
dose of unlabeled antibody to improve tumor-to-normal-tissue (T/N) uptake of the 
radiolabeled antibody is standard in this type of imaging procedure.  Infusion of 
trastuzumab will be prepared and administered in the treatment area of the Siteman Cancer 
Center according to normal treatment protocol by personnel appropriately trained and 
certified to administer chemotherapeutic agents.  Following the infusion of trastuzumab 
subjects will be monitored for approximately 30 minutes for infusion reactions and side 
effects 
Because the dose of trastuzumab being administered is a very small fraction of the 
dose normally administered as standard treatment to this patient population and it is being 
administered one time on study, no dose modifications for trastuzumab are allowed. We 
do not expect any side effects as a result of the administration of the small dose of 
trastuzumab for this study. However, as it is suggested for therapeutic dose, subjects who 
experience serious infusion reaction (i.e., dyspnea, chest tightness, fever, rigors or 
hypotension) during trastuzumab administration will have the infusion stopped.  
Continuation of dosing and continuation on study will be based on the severity and 


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resolution of the event and will be at the discretion of the investigator and the 
referring/treating physician. Any treatment for an infusion reaction should be administered 
per institutional practices.   
Immediately following release from the treatment area subjects will be transported 
to the clinical nuclear medicine facility or the CCIR for administration of 89Zr-trastuzumab.  
A maximum of 2.5 mCi (range 1-2.5 mCi) of 89Zr-trastuzumab will be injected 
intravenously over a period of at least 60 seconds.  Injection will be followed by a normal 
saline flush of 20-30 ml.  Patients will be monitored for 30 min after injection to detect any 
infusion-related anaphylactic reactions or adverse events.  Whenever possible and as 
applicable, the injection site should be on the arm opposite of the known breast lesion 
 
6.5.4 PET Imaging  
A total of 42 adult women with Her2-positive breast cancer and 20 adult women 
with HER2-negative breast cancer will be studied with 89Zr-trastuzumab-PET imaging in 
cohorts 1 and 2.  An additional 5 subjects will be scanned in cohort 3.  In all cases subjects 
will have a minimum of 24 hours to review the consent form before agreeing to participate 
in this research project. All PET imaging will be performed with a CTI/Siemens Biograph 
40 PET/CT scanner, located on the 10th floor West Pavilion of Barnes-Jewish Hospital in 
the Center for Clinical Research Imaging (CCIR). The Biograph 40 is a 4-ring PET scanner 
made up of a multi-LSO-detector ring system with 3D acquisition and reconstruction and 
109 image planes with an extended 21.6 cm axial field of view, enabling the detection of 
78% more photons (compared with a conventional-field-of-view scanner). The scanner 
features high spatial resolution (less than 5 mm in transaxial and axial dimensions) with 
Pico 3D ultra fast electronics for decreased dead-time and high signal-to-noise ratio.  
All patients will undergo routine clinical staging as dictated by the treating medical 
oncologist or surgeon. The results of 89Zr-trastuzumab-PET will not be provided to the 
patient or the treating oncologist/surgeon unless, in the judgment of the principal 
investigator, the images demonstrate an unsuspected abnormality that may warrant further 
evaluation.  The results of baseline FDG-PET/CT for cohort 3 subjects will be reported 
clinically and made a part of a subject’s medical record as this information is considered 
useful and relevant to patient management.  The results of the FDG-PET/CT scan 
performed after 2 cycles of T-DM1 therapy will also be reported due to the fact FDG-
PET/CT imaging which clearly shows progression after two cycles of therapy should be 
known so that the treating physician can make an informed decision about continuing on 
therapy.  .   
 
6.5.4.1 PET Imaging Procedure 
All subjects entered on study will be asked to undergo total body (brain to 
upper thighs or extended to include metastatic disease in the lower legs) 89Zr-
trastuzumab-PET imaging.  
Subjects who enter on study in Cohort 1 will undergo whole body imaging twice 
within 7 days following administration of 89Zr-trastuzumab to measure HER2 
density and calculate human dosimetry.  4 Subjects will be imaged at each of the 
following time points:  
 
1 and 3 days post injection.   
 
2 and 5 days post injection.  


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4 and 6 days post injection   
A window of ± 6 hours is allowed for all imaging time points 
Subjects who enter on study in cohort 2 or cohort 3 will undergo total body imaging 
a single time at the optimal time point as determined from cohort 1 image 
assessment.    
For all cohorts receiving 89Zr-trastuzumab-PET imaging, the subject will be placed 
supine on the imaging table with arms resting above the head or secured by the 
sides. A spiral CT scan for attenuation correction will be obtained from the top of 
the skull through the upper thighs. The CT will consist of a 10-20 second topogram 
for determining correct anatomical positioning followed by a spiral CT at a 
maximum of 30 mAs (or care dose calculated dose if less than 30 mAs) and 120 
kVp (Biograph 40). Average CT scan time is 15-30 seconds. Scans are acquired 
using a 5-mm-slice thickness. Immediately after the attenuation CT scan, emission 
images beginning at the top of the skull and proceeding down through the upper 
thighs will be obtained (1-10 min per bed position).   
In addition to 89Zr-trastuzumab-PET imaging, Cohort 3 subjects will also undergo 
FDG-PET imaging at two time points.  For FDG-PET imaging patients will fast for 
at least 4 hours and have their glucose checked prior to FDG administration.  
Fasting blood glucose must be ≤ 200 mg/dL (or approved by attending NM 
physician if greater) for FDG administration to occur.  10-15 mCi of FDG will be 
administered intravenously followed by a 50-70 min uptake period.  Oral hydration 
or IV hydration (up to 500 ml) may be given during the uptake period.  Oral and IV 
contrast will not be routinely administered for FDG-PET imaging.   
Cohort 3 FDG scanning parameters will vary depending on timing of scan within 
protocol.   The subject will be placed supine on the imaging table with arms resting 
above the head or secured comfortably by the side.  A spiral CT scan for attenuation 
correction will be obtained from the base of the brain to the upper thighs (or 
adjusted higher or lower to include known sites of disease).  As described above a 
topogram will be obtained followed by a spiral CT scan.  The baseline CT scan 
(done prior to starting TDM-1 therapy) will be a maximum of 111 mAs (or care 
dose if calculated to be less)  the follow up scan performed after 2 cycles of therapy 
will be a maximum of 50 mAs or case dose calculated.  Immediately after the 
attenuation scan emission imaging will be obtained at 2-5 minutes per bed position.    
 
For safety analysis, all subjects will undergo vital sign measurement, 
clinical laboratory testing, and ECG testing as specified in sections 6.5.6, 6.5.7 and 
6.5.8 of the protocol.  No additional safety analysis is needed for FDG-PET/CT.   
 
6.5.5 PET Image Processing and Analysis   
The emission images will be corrected for measured attenuation using CT data 
according to the provided scanner manufacturer software package. PET images will be 
evaluated semiquantitatively by the use of standardized uptake value (SUV) and tumor-to-
normal tissue (T/N) ratio or tumor-to-muscle (T/M) ratio. The SUV is widely used for 
assessment of regional tracer accumulation in oncological studies, is technically simple to 
perform, and makes imaging easier for the patient because longer dynamic imaging is not 
required. SUV is a decay-corrected measurement of activity per volume of tissue (nCi/mL) 
divided by the average activity per unit mass in the entire body.  


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Cohort 1:  Images will be assessed by the principal investigator, who will initially be 
blinded to all clinical information available (tumor size, location, and HER2 status). 
Overall image quality will be graded (using 4-point scale with 1 being the worse and 
poor quality, not acceptable for diagnostic interpretation and 4 being good image 
quality, similar to routine clinical studies), the number of lesions (up to 5 most intense 
lesions and in patients with multiple lesions, 2 in each organ), and the degree of 
confidence for malignancy of each lesion (tumor foci will be graded on a five-point 
scale regarding the presence or absence of abnormal uptake: 1 = definitely normal; 2 = 
probably normal; 3 = equivocal; 4 = probably abnormal; and 5 = definitely abnormal).  
Semiquantitative analysis of the images will also be obtained.  For all tumor foci 
(primary and metastases, if identified and grade 4 or 5 on the malignancy confidence 
scale) and main organs (i.e., blood pool, liver, kidney, bladder, etc.), an SUV 
calculation (or T/N, T/M) will be performed.  
Human Dosimetry (results published (39): Calculation from Cohort 1 images: Using 
our standard image analysis software, regions of interest (ROIs) will be traced on the 
visible organs as visible on the PET/CT whole body images. Average organ activity 
concentration will be measured from large 3D ROI encompassing most of the organ 
volume. Decay corrected to injection time activity concentrations will be expressed as 
fraction of injected activity and plotted as a function of time combing all data points 
from all twelve patients. Activity organ residence times will be calculated by numerical 
or analytical integration of the time-activity curves. Uptake/clearance functional fits of 
mono- or bi-exponential functions will be performed and analytical integration, 
accounted for physical decay, will be performed.   
It will be assumed that the lung and heart chamber residence times to be determined in 
proportion of their respective blood content which will be taken as 300 and 550 mL 
with respect to the whole body blood volume  (29). The blood content of the major 
organ are taken to be: 550mL in heart, 300 mL in the lungs, 250 mL in the liver, 190mL 
in the bone, 77mL in the spleen, and 72 ml in the kidneys for a standard human size of 
70 kg with 5.1 liter of blood (29).  The red marrow residence times will be calculated 
from the formula of Wessels et al. (30) for intact antibody.  
patient
blood
RM
blood
RM
M
M
A
HCT
RMECFF
A









1
 where RMCEFF = 0.19 for the red marrow extra 
cellular fluid fraction (RMECFF), HCT, the hematocrit value taken as 0.39 and MRM 
and Mblood-patient are the mass of red marrow and mass of blood in the patient (31) Since 
activity in the blood is assigned to each major organ, 72% of the blood residence time 
will be assigned to the remainder of the body. All unaccounted for activity will be 
assumed to be excreted. This value is expected to be small due to the long retention 
time of mono-clonal antibodies. 
 
The calculated residence times will be used with the program OLINDA/EXM for 89Zr 
and using the adult human female model to calculate the individual organ radiation 
dose, the whole-body dose and the effective dose. Doses will be reported in rad/rem 
per mCi injected or rad/rem 
Cohort 2: Images will be evaluated by one observer qualitatively (graded on a five-
point scale regarding the presence or absence of abnormal uptake: 1 = definitely 
negative; 2 = probably negative; 3 = equivocal; 4 = probably positive; and 5 = definitely 
positive) and semiquantitatively (SUV and T/N) with the knowledge of the location of 


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the lesion with known HER2 status. The uptake of 89Zr-trastuzumab will be correlated 
to the HER2 status of each lesion. It is expected that a significant difference (p < 0.05) 
in 89Zr-trastuzumab tumor uptake between HER-positive and HER2-negative lesions 
will be seen.  
Cohort 3: 89Zr-trastuzumab images will be evaluated by one observer qualitatively 
(graded on a five-point scale regarding the presence or absence of abnormal uptake: 1 
= definitely negative; 2 = probably negative; 3 = equivocal; 4 = probably positive; and 
5 = definitely positive) and semiquantitatively (SUV and T/N) with the knowledge of 
the location of the lesion with known HER2 status. The uptake of 89Zr-trastuzumab will 
be correlated to response to T-DM1 therapy and the markers of resistant to HER2-
targeted therapies.  FDG-PET/CT images will be evaluated according to standard 
clinical practice with generation of a clinical report, and inclusion of images and report 
to the participant’s medical record (only for the baseline FDG-PET/CT).  The second 
FDG-PET/CT is considered research and the results of the study will not be reported, 
however, the treating oncologist will be informed of the results if there is a finding that 
may impact patient management or is life threatening. Additional study specific 
analysis will consist of SUV measurement of six most intense lesions (not more than 2 
lesions per organ) in order to assess change in FDG uptake after therapy and assess 
metabolic response. 
 
6.5.6 Vital Signs 
All vital signs will be recorded on the case report form. Vital signs may be obtained 
with the subject in the supine or upright position. Care will be taken to obtain subsequent 
recordings with the subject in the same position (supine or upright). Although allergic or 
other immediate adverse reactions are not anticipated, subjects will be monitored for at 
least 30 min post injection in an area where emergency equipment is available. Vital signs 
will be obtained pre-injection (within 30 minutes prior to injection of 89Zr-trastuzumab), 
within 10-15 min post injection, and at study discharge on injection day.  At each imaging 
session vital signs will be obtained prior to placing the subject on the imaging table and at 
discharge after the scan has been completed.  . Vital signs will include the following: heart 
rate, systolic blood pressure, diastolic blood pressure, respiratory rate, and body 
temperature. The following changes from baseline will be considered noteworthy:   
 
Heart rate: 
 
 
> 20 beats per minute 
 
Systolic blood pressure 
> 20 mm Hg 
 
Diastolic blood pressure 
> 10 mm Hg 
Noteworthy changes will be documented on the PI Data Safety Review Form. The 
Principal Investigator will indicate on the form whether or not the changes in vital signs 
are clinically significant. If clinically significant, the principal investigator will assess the 
causality of the change to the injection of 89Zr-trastuzumab. Clinically significant changes 
in vital signs will be followed up hourly until they return to baseline or normal levels, or 
until follow-up is no longer warranted. If a clinically significant change of a vital sign is 
noted and assessed as being attributable to 89Zr-Trastuzumab injection by the PI on the 
Data Safety and Review CRF, it will be reported on the adverse event log.  
 


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6.5.7  Clinical Laboratory Testing 
Laboratory tests will consist of the following: standard CBC, comprehensive 
metabolic panel and urinalysis obtained at the following time points:  
Baseline: Baseline labs may be obtained anytime within 21 days prior to 89Zr-
trastuzumab injection.  .   
Subsequent imaging days up to 7 days (2 time points for cohort 1 subjects and 1 
time point for cohort 2 and cohort 3 subjects): Approximately 14 ml of blood and a urine 
sample will be collected at each imaging time point.   
Additional standard of care laboratory testing obtained up to 30 days post injection 
will be collected and reviewed. Analysis of this will take into account whether or not the 
subject has undergone surgical removal of tumor or neoadjuvant treatment including 
hormonal therapy or chemotherapy.   
The following changes from baseline clinical laboratory values are considered to 
be noteworthy and require assessment as to clinical significance when they fall outside of 
normal limits. Clinically significant changes in laboratory values which are attributed to 
89Zr-Trastuzumab injection should be followed up daily until they return to baseline or 
normal levels, or until follow-up is no longer warranted. Laboratory values that are 
abnormal at baseline but move into normal range will not be considered clinically 
significant.  If a clinically significant change of a laboratory value is noted, it will be 
reported on the PI Data Safety and Review Form so that the PI can assess the change as 
being attributable to 89Zr-Trastuzumab injection.  All clinically significant laboratory 
changes as identified below which are identified by the PI as being attributable to 89Zr-
Trastuzumabwill be recorded on the adverse event log.   
Clinically Significant Laboratory Values 
Analyte 
Change from baseline 
Hemoglobin 
> 2g/dL 
WBCs 
> 1 K/mm3 
Neutrophils  
> 10 % 
Lymphocytes  
> 10% 
Platelets 
> 50 K/mm3 
Creatinine 
> 0.75 mg/dL 
BUN 
> 20 mg/dL 
Calcium 
> 1mg/dL 
Sodium 
> 5 mmol//L 
Potassium 
> 0.5 mmol/L 
CO2 
> 4 mmol/L 
ALT (SGPT)  
> 150 IU/L 
AST (SGOT) 
> 100 IU/L 
Alkaline Phosphatase 
> 150 IU/L 
Total Bilirubin 
> 0.5 mg/dL 
Albumin  
> 1g/dL 
Changes in pre and post injection urinalysis will be noted but due to variability will not 
be used to determine clinical significance for changes due to the injection of 89Zr-
trastuzumab.     
 


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6.5.8 Electrocardiograms (ECGs)  
A standard 12-lead ECG will be obtained on all subjects at baseline (within 30 
minutes prior to injection of 89Zr-trastuzumab), 5-10 min post injection, and prior to 
discharge on injection day.  ECG will also be obtained at both imaging sessions.  
The following table lists criteria for normal limits and clinically notable limits 
for ECGs in adults.  
 
Criteria for Normal Limits and Clinically Notable Limits for ECGs in Adults 
 
Normal Limits (msec) 
Notable Limits (msec) 
ECG Variables 
Low 
High 
Low  
High 
PR interval 
120 
200 
<120 
>200 
QRS interval 
50 
100 
< 50 
>100 
RR interval 
600 
1000 
<600 
>1000 
QT interval 
No lower limit 
≥ 460 
No lower limit 
≥ 460 
ECG’s which have limits noted to be outside of the table above will be recorded on the PI Data 
Safety and Review Form where the PI will review and assess as being attributable to 89Zr-
Trastuzumab injection.  Any ECG recordings identified by the PI as being attributable to 89Zr-
Trastuzumabwill be recorded on the adverse event log 
 
6.5.9  Cohort 3 Research Biopsy Procedure 
 
 
All subjects enrolled in cohort 3 will undergo a biopsy of the suspected primary or 
recurrent/metastatic lesion prior to initiation of T-DM1 therapy.  If a biopsy has already 
been scheduled as part of the subject’s standard of care she will be asked to provide 
additional tissue at the time of biopsy.  If biopsy is not needed per standard of care the 
biopsy will be required for research purposes only.  The type of biopsy (CT guided, 
ultrasound guided, etc) will be determined by the treating physician based on what is 
most likely to yield a diagnostic specimen.  It is preferred that the biopsy be the first 
research procedure followed by baseline FDG-PET/CT, 89Zr-trastuzumab injection and 
imaging 5 to 7 days after injection.  However, other scheduling options will be 
determined based on availability of the various modalities on an individual basis.   
 
Biopsy specimens will be sent to the AMP Core lab at the Washington University School of 
medicine where they will be formalin-fixed paraffin embedded (FFPE).  Upon completion 
samples will be transferred to the secure lab of one of the primary breast oncologists (Dr. Bose or 
Dr. Ma) where they will be securely stored at room temperature until all cohort 3 participants 
have been enrolled and completed study procedures.  Batch processing of all samples for 
phospho-MAPK, phospho-Akt,, phospho-Src, PTEN and HER2 will occur for research purposes 
only.   If applicable and if informed consent for storage of future research was obtained any 
remaining tissue samples will be transferred to the lab manager for enrollment into an applicable 
tissue bank or for use in retrospective or current research projects.  Remaining tissue samples for 
those who did not consent to future use will be destroyed per current lab practices.  
 


Version: 06/16/2017 
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6.6.0 Drug Preparation  
 
89Zr-trastuzumab will be prepared as previously described by Vosjan et al (29).  89Zr-
oxalate will be produced via the 89Y(p,n)89Zr transmutation reaction on the CS-15 cyclotron 
(Cyclotron Corporation, Berkeley, CA) as described previously(30, 31).  The resulting 89Zr-oxalate  
is produced with a specific-activity of 8.1-15.4 GBq/mol (220-418 mCi/mol).  Trastuzumab 
(HerceptinTM, Genentech, South San Francisco, CA) is incubated with Df-Bz-NCS (Macrocyclics, 
Dallas, TX) in 0.1 M NaHCO3 buffer pH 9.0.  The resulting product, Df-Bz-NCS-trastuzumab, is 
purified via Zeba Spin Desalting Columns (Pierce Biotechnology, Rockford, IL).  89Zr is 
complexed with Df-Bz-NCS-trastuzumab in 0.5 M HEPES buffer pH 7.0 at 37oC for 1h with 
constant agitation at 850 RPM.  89Zr-Df-Bz-NCS-trastuzumab is purified with Zeba Spin Desalting 
Columns and radiochemical purity determined by radio-ITLC with 50 mM DTPA and analytical 
size-exclusion chromatography (Superose 12 10/300 GL, GE Healthcare, Piscataway, NJ).   
 
6.7.0 Statistics  
Study Endpoints: 
The primary endpoint of the study is the 89Zr-trastuzumab uptake in tumors and normal 
structures including the blood pool, liver, intestine, kidneys and bladder evaluated by the 
standardized uptake value (SUV) and tumor-to-normal tissue ratio (T/N). The secondary 
endpoint of the study is the tumor expression of HER2 that is HER2-negative (0 or 1+, 2+ 
by IHC and FISH negative) and HER2-positive (3+ by IHC and FISH positive) correlates 
with 89Zr-trastuzumab tumor uptake.  
 
Study Design: 
This is a study aiming to demonstrate the feasibility of using 89Zr-trastuzumab-PET in 
breast cancer patients by identifying HER2-positive tumors. The sampling method is non-
random. For Specific Aim 1, twelve HER-positive patients will be imaged to determine the 
imagining time for optimal image quality based on visual and semi-quantitative analysis of 
the images. Images will be independently evaluated by two readers. Inter-rater reliability 
will be examined. For Specific Aim 2, the differentiating power of 89Zr-trastuzumab-PET 
on HER2 expression will be examined on 20 HER2-negtive and 20 HER2-positive patients 
using the optimal imaging time established by Specific Aim 1. The 5 patients enrolled to 
cohort 3 will be used as pilot data to design a larger trial specific to this patient population 
only.   
 
Accrual:  
The rate of accrual for the study is expected to be about 2-3 patients per month.  It is 
expected that the accrual period of the study will be completed in 24 months with total 52 
patients enrolled to cohorts 1 and 2.  Accrual to cohort 3 is expected to be much slower as 
this is a very specific patient population.  Enrollment is expected to be one patient every 
two to three months.  .  
 
Power Analysis 
There is no power analysis for Specific Aim 1 considering its descriptive nature. For 
Specific Aim 2, using a 2-sample t-test with 80% power at a 2-sided 0.05 significance level, 
the designed sample size (n=20 patients/group) will allow us to detect a minimum of 91% 
SD between-group difference, where SD represents the standard deviation of 89Zr-
trastuzumab uptake in a pooled data. Previous study on 89Zr-trastuzumab-PET and HER2-
positive tumors in breast cancer (29) showed that the coefficients of variance 
(CV=SD/Mean) of relative uptake values (RUVs) on normal tissues ranged from .65 – 


Version: 06/16/2017 
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1.66, assuming similar variability will be seen in this study, this sample size will allow us, 
with 80% power at 2-sided 0.05 significance level, to detect a between group difference of 
60% - 150% normal tissue means.  
 
Data Analysis 
Demographic and clinical characteristics of the sample will be summarized using 
descriptive statistics. For Specific Aim 1, Cohen's kappa coefficient will be calculated to 
measure inter-rater agreement on images quality and lesion detection. For Specific Aim 2, 
the association between 89Zr-trastuzumab uptake values (e.g., SUV, T/N) and HER2 
expression on tumor will be examined via Wilcoxon rank sum tests, Spearman-Brown 
correlation coefficients, and scatter plots. Bootstrapping techniques will be used as a 
method of inference which does not rely on a specific underlying distribution considering 
sample size is small. The changes in vital signs and clinical laboratory tests will be listed 
to evaluate the safety of 89Zr-trastuzumab-PET. 
 
Cohort 3: The association between tumor uptake of 89Zr-trastuzumab and response to T-
DM1 and markers of HER2 resistance will be examined via Pearson and/or Spearman’s 
rank correlation coefficients. Imaging measurements such as SUV for 89Zr-trastuzumab 
and FDG uptake will be collected on all patients at baseline and after 2 cycles of T-DM1. 
Descriptive statistics will be used to summarize each type of measurements at each time 
point, including mean, median, range, overall across all patients and by response.  Given 
40~44% response rate, we may have 3 non-responding patients and 2 responding patients 
and measurements will be compared by response using two sample t-test at each time point. 
 
6.8.0 Risks and Benefits 
The potential risks from this imaging protocol are expected to be very low. Expected risks 
include discomfort from the placement of intravenous catheter(s) for injection of trastuzumab, and 
89Zr-trastuzumab (and FDG for cohort 3), radiation exposure from the injection of 89Zr-
trastuzumab (and FDG for cohort 3) and from low dose CT scan used for attenuation correction 
and discomfort from lying still on the imaging table. Whenever possible, injection site will be 
contra lateral to the known tumor site if a primary breast or axillary lesion is present. Blood 
samples will be obtained for safety analysis. There is a slight risk of bruising and a remote risk of 
infection from the placement of the intravenous catheter(s). Although unlikely, there is a rare 
chance of having patients suffer an allergic or other immediate adverse reaction to trastuzumab or 
89Zr-trastuzumab. To minimize the risks to subjects, intravenous catheters will only be placed by 
trained personnel. All studies will take place under the supervision of the Principal Investigator or 
a collaborating physician. Additionally, the PET scanner is located within the hospital where 
advanced life support personnel and equipment are available for immediate use.  
At standard therapeutic doses Trastuzumab can be cardiotoxic.  HER2 negative subjects 
who enter on study as part of cohort 2 will be required to have a normal ejection fraction as 
determined by cardiac imaging such as ECHO or RVG.  Although, a significantly higher risk of 
congestive heart failure has been reported in regimens in which trastuzumab was given for more 
than six months than in regimens without trastuzumab (risk ratio (RR) 5.39; 90% confidence 
interval (CI) 3.56 to 8.17, p < 0.00001). A shorter treatment period did not appear to be associated 
with an increase in the risk of congestive heart failure (RR 0.50; 90% CI 0.07 to 3.74, p = 0.57) 
(32). In addition, the risk of congestive heart failure has been reported to be significantly higher 
when trastuzumab was given sequentially with chemotherapy (RR 11.05; 90% CI 3.46 to 35.29, p 
< 0.0007) and concurrently (RR 3.90; 90% CI 2.42 to 6.28, p < 0.00001) (32). Establishing baseline 
cardiac function for this subject population is done as a precaution in case abnormal cardiac 


Version: 06/16/2017 
Page 25 
function is suspected after study participation has concluded and subject is receiving standard 
chemotherapy agents which could also be cardiotoxic.  Risks from ECHO include discomfort from 
lying on the imaging table and from the imaging probe which may be pressed firmly into the chest 
during the scan.  Risks from RVG include radiation exposure, discomfort from lying on the 
imaging table and from the IV injection of stannous pyrophosphate and technetium-99m necessary 
to perform the imaging procedure.    
Radiation Exposure: This research project involves radiation exposure to participants from 
the i.v. injection of 89Zr-trastuzumab and 2 whole-body PET/CT scans. The total amount of 
radiation exposure received, when averaged over the entire human body, is equivalent to a uniform 
whole-body exposure of approximately 4.86 rem for cohort 1 subjects and 4.47 rem for cohort 2 
HER2 positive subjects (4.08 rem from 89Zr-trastuzumab and 0.39 rem from one whole-body CT 
and 0.78 rem from two whole-body CT).  Cohort 2 HER2 negative subjects who receive RVG 
imaging at screening to determine study eligibility will receive an additional 0.65 rem of exposure 
for a total of 5.12 rem.  Cohort 3 subjects (with updated radiation dosimetry based on calculations 
and published data from cohort 1 subjects (39) will receive up to 7.83 rem of total exposure (3.39 
rem from 89Zr-trastuzumab, 1.71 rem from 2 FDG injections, 2.44 rem from 3 whole-body CT 
scans, and 0.16 to 0.29 rem additional exposure depending on the type of biopsy procedure 
performed).   . 
Research tumor biopsy: Research biopsy will be performed by surgeon or radiologist under 
imaging-guidance according to standard of care procedure. The risks related to the biopsy are 
described below 
 
Likely/Common 
• 
Pain or discomfort  
• 
Bruising around the biopsy site 
• 
Redness around the biopsy site 
• 
Discomfort from the pressure of the probe during the ultrasound procedure 
• 
Pain, discomfort, bleeding, bruising, and allergic reaction from the numbing 
medication 
• 
Drowsiness, slurred speech, staggering gait (clumsy or uncoordinated walking), poor 
judgment, and poor reflexes from the sedative 
 
Less Likely/Less Common 
• 
Swelling 
• 
Excessive bleeding 
• 
Drainage 
 
Rare 
• 
Infection at the site where the biopsy needle penetrates though the skin 
• 
There is also the possibility that having this procedure may shift some cells from the 
tumor into the surrounding tissues that come in contact with the biopsy needle.  This 
means that if there are cancer cells present there is a slight risk they could spread to 
that area.   
 
Although subjects who participate in this early phase 1 imaging trial are not expected to 
directly benefit from 89Zr-trastuzumab-PET imaging, the overall and long term benefits to future 
women with breast carcinoma far outweigh the minimal risks anticipated.  It is anticipated that this 
study will contribute to the understanding of the performance of the 89Zr-trastuzumab-PET/CT in 
evaluating HER2 status and the interaction of HER2 with trastuzumab based therapy in breast 


Version: 06/16/2017 
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cancer.  Ultimately, 89Zr-trastuzumab-PET/CT may provide clinically important information about 
HER2 expression that can be used to select patients with trastuzumab or T-DM1 therapy and to 
assess the effectiveness of therapeutic strategies targeted to treat HER2-positive cancer. 
6.9.0 Record Keeping 
It is anticipated that 62 subjects will be entered into this pilot study within a 60-month 
period. No long-term follow-up is required for subjects entered into cohort 1 and cohort 2, as the 
primary end point for these subjects do not require it.  Subjects who enter into cohort 3 will be 
followed for a maximum of 2 years or disease progression whichever comes first.  A patient file 
will be kept in the Research Coordinators’ office (Room 1017C) located on the 10th floor of the 
Mallinckrodt Institute of Radiology in Barnes-Jewish Hospital South Campus. Each file will 
contain a copy of the original signed consent form, as well as documentation necessary to prove 
patient eligibility to participate in this research study. Specific documentation of imaging 
procedures will also be maintained in this patient file. Original signed consent forms will be 
maintained in a separate file also located in the coordinators’ office. All digital data associated 
with 89Zr-trastuzumab-PET imaging is maintained on the PET acquisition computer. Raw data 
files are backed up on password protected encrypted external hard drive(s). All imaging data is 
also backed up on DVD after it has been transferred to a desktop PC. Processed data will be stored 
on the Principal Investigator's password protected desktop.  CRF's and patient files will be stored 
in the study coordinators' office. Entrance to the PI's and coordinators' offices requires admission 
through two separate locked doors.    
6.10.0 Regulatory and Reporting Requirements   
6.10.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject who receives 89Zr-
Trastuzumab and PET/CT imaging, including any abnormal sign, symptom, or disease.  
The event does not necessarily have to be causally related to injection of 89Zr-Trastuzumab 
or PET/CT imaging to qualify as an adverse event, just temporally related.   
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP).  A copy of this guidance can 
be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
6.10.2 Unanticipated Problems 
 
Definition: 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 


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experience, or outcome may have been caused by the procedures involved in the 
research); and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
6.10.3 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
 
6.10.4 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
 
6.10.5 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Research imaging protocols which involve the injection of radioactive tracers can produce 
unique situations not common to standard treatment protocols.  In the event a situation 
occurs which requires deviation from this protocol – for example less than expected tracer 
production, problems with the scanner, patient unable to tolerate the imaging protocol as 
described, the principal investigator will have final authority over whether or not a study 
is completed.  Any protocol deviations will be documented on the PET imaging data form.  
Deviation such as less than expected tracer production can be accounted for during data 
analysis and will not necessarily result in cancellation of the scan.  Similarly, adjusting 
imaging procedures to accommodate patient comfort can also be accounted for at the time 
images are reviewed.   
 
Except as described above, pre-approval of all protocol exceptions must be obtained prior 
to the event. 
 
6.10.6 Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 


Version: 06/16/2017 
Page 28 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
6.10.7 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences associated with 
use of the drug (i.e., there is a reasonable possibility that the experience may have 
been caused by the drug) by telephone or fax no later than 7 calendar days after 
initial receipt of the information.  A life-threatening adverse experience is defined 
as any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 Report any serious, unexpected adverse experiences, as well as results from animal 
studies that suggest significant clinical risk within 15 calendar days after initial 
receipt of this information.  A serious adverse drug experience is defined as any 
adverse drug experience occurring at any dose that results in any of the following 
outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
An unexpected adverse drug experience is defined as any adverse drug experience, 
the specificity or severity of which is not consistent with the current investigator 
brochure (or risk information, if an IB is not required or available). 
 
For the purposes of regulatory reporting, a causality assessment of definitely related, 
probably related, or possibly related will be managed as “related,” and unrelated or unlikely 
related will be managed as unrelated.” 
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 


Version: 06/16/2017 
Page 29 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
6.10.8 Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment. 
 
Deaths 
Any reportable death while on study or within 
30 days of study 
Immediately, within 24 hours, to PI, 
Daiichi Sankyo, and the IRB 
Any reportable death while off study  
Immediately, within 24 hours, to PI, 
Daiichi Sankyo, and the IRB 
Adverse Events/Unanticipated Problems 
Any reportable adverse events as described in 
Sections 7.1 and 7.2 (other than death) and 7.9 
Immediately, within 24 hours to PI , 
within 10 working days to the IRB, 
and within 7 or 15 calendar days to 
the FDA and Daiichi Sankyo 
All adverse events regardless of grade and 
attribution should be submitted cumulatively  
Include in DSM report 
Noncompliance and Serious Noncompliance 
All noncompliance and serious noncompliance 
as described in Sections 7.3 and 7.4 
Immediately, within 24 hours, to PI 
and within 10 working days to the 
IRB 
 
 
 


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6.12 References6.11 
Data Forms and Submission Schedule 
Case report forms for PET imaging, image analysis, and laboratory test results are located 
in the appendix 1 
Cohort 1 
Procedure 
Baseline(a) 
Day 0 
First 
Imaging 
Day 2(b) 
Second 
Imaging 
Day(b) 
30 Day follow-
up(c) 
Informed 
Consent 
X 
 
 
 
Medical History 
X 
 
 
X 
Radiology 
Reports 
X 
 
 
X 
Pathology 
Report(s) 
X 
 
 
X 
Blood for 
Laboratory 
Analysis  
X 
X 
X 
 
Urine for 
Laboratory 
Analysis  
X 
X 
X 
 
Vital Signs(d) 
X 
X 
X 
 
ECG(e) 
X 
X 
X 
 
Total Body 
Imaging  
 
X 
X 
 
(a) Baseline is defined as period from initial subject contact until injection of 89Zr-trastuzumab 
Baseline for vital signs and ECG  is within 30 minutes prior to injection of 89Zr-trastuzumab.  
Baseline for blood and urine laboratory samples is within 21 days prior to trastuzumab 
injection.  
(b) Imaging day is defined as period of time from injection of 89Zr-trastuzumab through end of 
last imaging session.    Each subject will be imaged on two separate days. 
(c) Subjects’ medical records are followed for 30 days after study entry to ensure no adverse 
events have occurred. Any standard of care clinical exams obtained during this time period will 
be reviewed to correlate with scan results.  There are no protocol requirements during this time 
frame 
(d) obtained  at each time point ( baseline, within 30 min post injection, and at discharge on 
injection day and at beginning and end of each imaging session) 
(e) obtained at baseline, 5-10 minutes post injection and prior to discharge on 
injection day and at each imaging session   
 
 


Version: 06/16/2017 
Page 31 
Cohort 2 
Procedure 
Baseline(a) 
Day 0 
 Imaging 
Day (b) 
30 Day follow-
up(c) 
Informed 
Consent 
X 
 
 
Medical History 
X 
 
X 
Radiology 
Reports 
X 
 
X 
Pathology 
Report(s) 
X 
 
X 
Blood for 
Laboratory 
Analysis  
X 
X 
 
Urine for 
Laboratory 
Analysis  
X 
X 
 
Vital Signs(d) 
X 
X 
 
ECG(e) 
X 
X 
 
Total Body 
Imaging  
 
X 
 
(a) Baseline is defined as period from initial subject contact until injection of 89Zr-trastuzumab 
Baseline for vital signs and ECG is within 30 minutes prior to injection of 89Zr-trastuzumab.  
Baseline for blood and urine laboratory samples is within 21 days prior to trastuzumab injection 
HER2 negative cohort 2 subjects are allowed to be completed cardiac assessment to confirm 
eligibility on the same day as baseline study drug injection.   
(b) Imaging day as defined from cohort 1.  Imaging day period will be defined as period of time 
beginning after study day 0 procedures are completed (injection of 89Zr-trastuzumab through 
completion of the imaging session).   
(c) Subjects’ medical records are followed for 30 days after study entry to ensure no adverse 
events have occurred. Any standard of care clinical exams obtained during this time period will 
be reviewed to correlate with scan results.  There are no protocol requirements during this time 
frame 
(d) obtained at each time point ( baseline, within 30 min post injection and at study discharge 
on injection day and at beginning and end of the imaging session 
(e) obtained at baseline, 5-10 minutes post injection and at discharge on injection day and once 
on the day of imaging   
 
 


Version: 06/16/2017 
Page 32 
Cohort 3 
Procedure 
Baseline(a) 
 
 89Zr-
Trastuzumab 
Scan (b) 
Post 2 
Cycles 
 T-DM1  
Follow-up at 30 Day 
up to approximately 2 
years(c) 
Informed Consent 
X 
 
 
 
Medical History 
X 
 
 
X 
Radiology Reports 
X 
 
 
X 
Pathology Report(s) 
X 
 
 
X 
Blood for Laboratory 
Analysis  
X 
X 
 
 
Urine for Laboratory 
Analysis  
X 
X 
 
 
Vital Signs(d) 
X 
X 
 
 
ECG(e) 
X 
X 
 
 
89Zr-Trastuzumb PET 
Scan  
 
X 
 
 
FDG-PET Scan  
X 
 
X 
 
Tumor Biopsy  
Xf 
 
 
(a) Baseline is defined as period from initial subject contact until injection of 89Zr-trastuzumab Baseline 
for vital signs and ECG is within 30 minutes prior to injection of 89Zr-trastuzumab.  Baseline for blood 
and urine laboratory samples is within 21 days prior to trastuzumab injection  
(b) Imaging day as defined from cohort 1.  Imaging day period will be defined as period of time 
beginning after study day 0 procedures are completed (injection of 89Zr-trastuzumab through the imaging 
session which will occur 5 to 7 days post 89Zr-Trastuzumab injection).   
(c) Subjects’ medical records are followed for 30 days after study entry to ensure no adverse events have 
occurred.  Follow up will continue for up to two years or disease progression whichever comes first to 
document response and for correlation with HER2 markers of resistance. Any standard of care clinical 
exams obtained during this time period will be reviewed to correlate with scan results.  There are no 
protocol requirements during this time frame 
(d) Obtained at each time point (baseline, within 30 min post injection and at study discharge on injection 
day and at beginning and end of the imaging session) 
(e) Obtained at baseline, 5-10 minutes post injection and at discharge on injection day and once on the 
day of imaging   
 (f) Optimal scheduling will be baseline FDG-PET/CT, biopsy, 89Zr-trastuzumab injection, and imaging 5 
to 7 days later.  However, due to anticipated scheduling conflicts other scheduling options will be 
acceptable 
(g) FDG-PET scan may be performed on days 14-28 of Cycle 2 or immediately before Cycle 3 of T-
DM1 therapy is administered.   
 
 
 


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6.12 
References 
1. 
Gross ME, Shazer RL, Agus DB. Targeting the HER-kinase axis in cancer. Semin Oncol. 
2004;31:9-20. 
2. 
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast 
cancer. N Engl J Med. 2011;365:1273-1283. 
3. 
Lamot C, Rottey S, De Backer T, et al. Cardiac toxicity of trastuzumab: experience at the 
Ghent Unversity Hospital, Belgium. Acta Clin Belg. 2010;65:300-304. 
4. 
Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 
2011;71:1515-1519. 
5. 
Parra-Palau JL, Pedersen K, Peg V, et al. A major role of p95/611-CTF, a carboxy-terminal 
fragment of HER2, in the down-modulation of the estrogen receptor in HER2-positive 
breast cancers. Cancer Res. 2010;70:8537-8546. 
6. 
Scaltriti M, Chandarlapaty S, Prudkin L, et al. Clinical benefit of lapatinib-based therapy 
in patients with human epidermal growth factor receptor 2-positive breast tumors 
coexpressing the truncated p95HER2 receptor. Clin Cancer Res. 2010;16:2688-2695. 
7. 
Pedrini JL, Francalacci Savaris R, Casales Schorr M, Cambruzi E, Grudzinski M, Zettler 
CG. The effect of neoadjuvant chemotherapy on hormone receptor status, HER2/neu and 
prolactin in breast cancer. Tumori. 2011;97:704-710. 
8. 
Solomayer EF, Becker S, Pergola-Becker G, et al. Comparison of HER2 status between 
primary tumor and disseminated tumor cells in primary breast cancer patients. Breast 
Cancer Res Treat. 2006;98:179-184. 
9. 
Wulfing P, Borchard J, Buerger H, et al. HER2-positive circulating tumor cells indicate 
poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res. 
2006;12:1715-1720. 
10. 
Dijkers EC, de Vries EG, Kosterink JG, Brouwers AH, Lub-de Hooge MN. 
Immunoscintigraphy as potential tool in the clinical evaluation of HER2/neu targeted 
therapy. Curr Pharm Des. 2008;14:3348-3362. 
11. 
Lower EE, Glass E, Blau R, Harman S. HER-2/neu expression in primary and metastatic 
breast cancer. Breast Cancer Res Treat. 2009;113:301-306. 
12. 
Carlson RW, Allred DC, Anderson BO, et.al. National Comprehensive Cancer Network 
(NCCN) 
Clinical 
Practice 
Guidelines 
in 
Oncology. 
http://wwwnccnorg/professionals/physician_gls/ PDF/breastpdf. 2009, v.1. 
13. 
Breast 
Cancer 
Treatment 
(PDQ®). 
http://wwwcancergov/cancertopics/pdq/treatment/breast/Healthprofessional/page8#Secti
on_220. 
14. 
Lear-Kaul KC, Yoon HR, Kleinschmidt-DeMasters BK, McGavran L, Singh M. Her-2/neu 
status in breast cancer metastases to the central nervous system. Arch Pathol Lab Med. 
2003;127:1451-1457. 
15. 
Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the 
PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer 
Cell. 2007;12:395-402. 
16. 
Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: 
understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract 
Oncol. 2006;3:269-280. 
17. 
Mack L, Kerkvliet N, Doig G, O'Malley FP. Relationship of a new histological 
categorization of ductal carcinoma in situ of the breast with size and the 
immunohistochemical expression of p53, c-erb B2, bcl-2, and ki-67. Hum Pathol. 
1997;28:974-979. 


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Rosenthal SI, Depowski PL, Sheehan CE, Ross JS. Comparison of HER-2/neu oncogene 
amplification detected by fluorescence in situ hybridization in lobular and ductal breast 
cancer. Appl Immunohistochem Mol Morphol. 2002;10:40-46. 
19. 
Barron JJ, Cziraky MJ, Weisman T, Hicks DG. HER2 testing and subsequent trastuzumab 
treatment for breast cancer in a managed care environment. Oncologist. 2009;14:760-768. 
20. 
Cuadros M, Villegas R. Systematic review of HER2 breast cancer testing. Appl 
Immunohistochem Mol Morphol. 2009;17:1-7. 
21. 
Perik PJ, Lub-De Hooge MN, Gietema JA, et al. Indium-111-labeled trastuzumab 
scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic 
breast cancer. J Clin Oncol. 2006;24:2276-2282. 
22. 
Allan SM, Dean C, Fernando I, et al. Radioimmunolocalisation in breast cancer using the 
gene product of c-erbB2 as the target antigen. Br J Cancer. 1993;67:706-712. 
23. 
Center MS-KC. PET Imaging With Cu-64 Labeled Trastuzumab in HER2+ Metastatic 
Breast Cancer (Cu-64 HER2+). http://clinicaltrialsgov/ct2/show/NCT00605397. 2008. 
24. 
Center MS-KC. Biodistribution and Dosimetry of Serial PET Imaging With Ga-68 Labeled 
F(ab′) 2-Trastuzumab http://clinicaltrialsgov/ct2/show/NCT00613847. 2008. 
25. 
Capala J, Bouchelouche K. Molecular imaging of HER2-positive breast cancer: a step 
toward an individualized 'image and treat' strategy. Curr Opin Oncol. 2010;22:559-566. 
26. 
Baum RP, Prasad V, Muller D, et al. Molecular imaging of HER2-expressing malignant 
tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled affibody 
molecules. J Nucl Med. 2010;51:892-897. 
27. 
Dijkers EC, Kosterink JG, Rademaker AP, et al. Development and characterization of 
clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med. 
2009;50:974-981. 
28. 
Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab 
and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin 
Pharmacol Ther. 2010;87:586-592. 
29. 
Vosjan MJ, Perk LR, Visser GW, et al. Conjugation and radiolabeling of monoclonal 
antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-
isothiocyanatobenzyl-desferrioxamine. Nat Protoc. 2010;5:739-743. 
30. 
Verel I, Visser GW, Boellaard R, Stigter-van Walsum M, Snow GB, van Dongen GA. 89Zr 
immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal 
antibodies. J Nucl Med. 2003;44:1271-1281. 
31. 
Holland JP, Sheh Y, Lewis JS. Standardized methods for the production of high specific-
activity zirconium-89. Nucl Med Biol. 2009;36:729-739. 
32. 
Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast 
cancer. Cochrane Database Syst Rev. 2012;4:CD006243. 
33. 
Castagnoli L1, Iezzi M2, Ghedini GC1, et al. Activated d16HER2 homodimers and SRC 
kinase mediate optimal efficacy for trastuzumab. Cancer Res. 2014 Nov 1;74(21):6248-
59) 
34. 
Krop I, Winer EP. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-
positive breast cancer. Clinical cancer research: an official journal of the American 
Association for Cancer Research. 2014;20(1):15-20 
35. 
Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, et al. A phase II study 
of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-
positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, 
an anthracycline, a taxane, and capecitabine. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2012;30(26):3234-41. 
36. 
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine 
for HER2-positive advanced breast cancer. The New England journal of medicine. 
2012;367(19):1783-91.). 


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37.  
Vercher-Conejero JL1, Pelegrí-Martinez L2, Lopez-Aznar D3, Cózar-Santiago Mdel P4  
Positron Emission Tomography in Breast Cancer.  Diagnostics (Basel). 2015 Mar 
16;5(1):61-83. doi: 10.3390/diagnostics501006 
38. 
Avril S1, Muzic RF Jr2, Plecha D2, Traughber BJ3, Vinayak S4, Avril N5. ¹⁸F-FDG 
PET/CT for Monitoring of Treatment Response in Breast Cancer.  J Nucl Med. 2016 
Feb;57 Suppl 1:34S-9S. doi: 10.2967/jnumed.115.157875. 
39. 
Laforest R, Lapi S, Oyama R, et al. [89Zr] Trastuzumab: Evaluation of Radiation 
Dosimetry, Safety and Optimal Imaging Parameters in Women with HER2-Positive Breast 
Cancer. Mol Imaging Biol (2016) 18:952-959; DOI 10.1007/s11307-016-0951z  
 
 


 
FOR IRB USE ONLY 
 
IRB ID #: 201307037 
APPROVAL DATE: 03/14/18 
RELEASED DATE: 03/14/18 
EXPIRATION DATE: 03/13/19 
 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
Assessment of HER2 Receptors in Breast Carcinoma by Positron Emission 
Tomography (PET) using 89Zr-Trastuzumab (Cohorts 1 & 2) 
 
Principal Investigator: 
Farrokh Dehdashti 
 
Research Team Contact: 
Dr. Farrokh Dehdashti 314-362-1474 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research participant. By signing this form you are 
agreeing to participate in this study. 
 If you have any questions about anything in this form, you should ask the research team for 
more information.   
 You may also wish to talk to your family or friends about your participation in this study. 
 Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study.  We invite you to participate in this research study because you have been 
diagnosed with new or recurrent breast cancer which has been tested for a protein called human 
epidermal growth factor (HER2).  HER2 is a protein which helps cancer cells to grow.  HER2 positive 
breast cancer cells have excess HER2.  Currently, there are treatments approved by the United States 
Food and Drug Administration (FDA) to target HER2.  One approved treatment is a drug called 
trastuzumab (also known as Herceptin).  Trastuzumab targets HER2 and kills the cancer cells.  
Trastuzumab can be used alone or with other drugs in the treatment of breast cancer.   
 
One problem with the current way breast cancers are diagnosed and treatment decisions are made is that 
we must rely on biopsies or small samples of tissue that are taken from the tumor to tell us what types of 
cancer cells are present.  A tumor may not be uniform in the type of cells present so the biopsy sample 
may not accurately represent the actual function of the cells within the tumor.  Additionally, just because 
a tumor was classified as, for example, HER2 positive at initial diagnosis, recurrent or metastatic tumors 
may not have the same characteristics.   
 
The primary goal of this research imaging study is to see if a radioactive labeled form of trastuzumab 
called 89Zr-trastuzumab can provide more information about the location and function of HER 2 positive 
cells within the body.  A radioactive labeled form of trastuzumab is the FDA approved medicine 
trastuzumab which has a very small amount of a radioactive element called zirconium attached to it.  
This labeled form of trastuzumab allows us to image it within the body to confirm it is going to known 
cancer cells within the body. We will also be looking at how accurate 89Zr-trastuzumab imaging is in 
tumors classified has HER-2 negative.  The safety of 89Zr-trastuzumab and the amount of the radioactive 
tracer that is found in normal cells when it is injected into the blood stream and how the amount of 89Zr-
trastuzumab in the tumor cells and normal tissues changes over time is also being studied.   


 
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EXPIRATION DATE: 03/13/19 
 
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89Zr-trastuzumab is considered investigational, which means that it has not been approved by the U.S. 
Food and Drug Administration. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
To participate in this study you will be asked to read and sign this consent form before any study 
procedures are performed.  Your study doctor will determine if you are eligible to participate by 
reviewing your medical history, medical records, current medications, and imaging scans.  
 
Standard medical procedures that are part of your regular cancer care and probably would be done even 
if you do not join the study will be reviewed along with those procedures that are done for research 
purposes only.  
 
If you are one of the first 12 patients to enter on study you will be assigned to cohort 1.  If you enter into 
the study after the 12th patient, you will be in cohort 2.  The only differences between cohort 1 and 
cohort 2 is that cohort 1 subjects will be asked to return on 2 separate times for imaging while those in 
cohort 2 will only be asked to return for imaging once.  The optimal imaging time used in cohort 2 will 
be determined from the cohort 1 images.  HER2 negative patients in cohort 2 will also be asked to 
undergo a test of their heart to confirm study eligibility.   
 
Cohort 2 HER2 negative patients Screening  
If you are a cohort 2 patient who is HER2 negative, you will be asked to undergo a test to evaluate how 
well your heart is functioning before you will be entered on study.  Trastuzumab, when given over a 
period of time at treatment doses (dose much higher than you will receive in this study) can cause heart 
failure (inability of the heart to properly pump blood).  You may receive either a MUGA (multi-gated 
acquisition scan) or an ECHO (echocardiogram).  Both of these tests take pictures of the blood as it 
moves through the heart.  A MUGA scan uses a small amount of a radioactive tracer to label the blood 
cells so the scanner is able to take the pictures.  For the MUGA scan you will receive two injections 
about 20 minutes apart.  The second injection is a small amount of a radioactive material that labels your 
blood cells so the camera can see your heart.  An ECHO uses sound waves to take pictures of your 
beating heart.  If this test has been done within the past 3 months it will not need to be repeated.   
 
All Patients:  Infusion/Injection Visit Day 0 
Your first visit to the hospital will consist of two parts: trastuzumab infusion followed by 89Zr-
trastuzumab injection.  For both parts of the visit an IV will be needed.  The IV will be inserted into an 
upper extremity vein such as one in your arm or hand.  If you are a woman capable of becoming 
pregnant, you will have a blood or urine pregnancy test performed to confirm you are not currently 
pregnant before you will be allowed to receive the infusions. Blood, if not previously obtained in the 
past 21 days, will be drawn from the IV line for standard laboratory testing (routine testing of your 
blood counts and organ function will be obtained.  Standard laboratory testing is used to monitor the 
safety of 89Zr-trastuzumab so these tests will be repeated several times during the study.  Each time, 
approximately 3 teaspoons of blood will be drawn from a vein in your arm or the IV line. If a pregnancy 
test is needed an additional 1 teaspoon of blood may be obtained for this test one time only before you 
receive trastuzumab. 
 You will be asked to provide a urine sample (if not previously obtained in the past 21 days) for 
standard laboratory testing. 


 
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 Your weight will be measured and your vital signs (blood pressure, heart rate, breathing rate and 
temperature) will be collected. 
 You will receive an infusion of trastuzumab into the IV line.  The amount of trastuzumab you 
will receive is less than what is given as a standard treatment dose.  This dose of trastuzumab is 
not intended to treat you but only to saturate or fill up the normal cells in your body so that the 
cancer cells will be ready to receive the 89Zr-trastuzumab.   
 Following the infusion of trastuzumab you will be monitored for approximately 30 minutes to 
ensure you do not have any reactions.  Your vital signs may be checked several times during this 
monitoring period. 
 You will be transported to the positron emission tomography (PET) facility for injection of 89Zr-
trastuzumab.   
 At the PET facility and before the injection of 89Zr-trastuzumab, an electrocardiogram (ECG or 
tracing of your heart) will be obtained along with your vital signs. For this test, up to 12 self-
adhesive electrodes (small blunt pieces of metal) will be attached to your skin on your arms, legs 
and chest.  The areas where the electrodes will be placed will be cleaned and sometimes the area 
may need to be shaved.   
 The injection of 89Zr-trastuzumab will be given to you into your IV line over a period of 1-2 
minutes.  After the injection you will be monitored for approximately 30 minutes.  You vital 
signs will be measured and additional ECG tracings of your heart will be taken during this time.   
 
The total amount of time you will need to be at the hospital on the infusion day is 3 – 3 ½ hours. No 
PET imaging will occur on the infusion day.  You will be transported from the chemotherapy area of 
the hospital after the trastuzumab infusion for the injection of 89Zr-trastuzumab.  This is done so the 
amount of 89Zr-trastuzumab you will receive can be measured in a special counter immediately 
before the injection.   
 
PET Imaging – Days 1-7 
If you are in cohort 1, you will be scheduled to return to the PET facility on 2 separate days for 
imaging.  You will be asked to return at one of the following time points:  1 and 3 days post injection 
OR 2 and 5 days post injection, OR 4 and 6 days post injection.  The best imaging time point will be 
determined from these first set of images.   
 
If you are in cohort 2 you will be scheduled to return for imaging one time 1-7 days after injection.  
The exact imaging time point will be determined from the cohort 1 images. 


 
FOR IRB USE ONLY 
 
IRB ID #: 201307037 
APPROVAL DATE: 03/14/18 
RELEASED DATE: 03/14/18 
EXPIRATION DATE: 03/13/19 
 
Version #  04.18.2016 
Page 4 of 11 
Visual Chart of Study Visits based on cohort 
 
 
 
 
 
 
 
 
 
On each imaging(s) day you will be questioned to see if you have had any changes in your 
medication or health since your last visit.  Your vital signs and an ECG recording of your heart will 
be obtained along with a sample of blood and urine for standard laboratory testing (approximately 3 
teaspoons of blood will be drawn from a vein in your arm).   
 
The scanner will be a combination PET/CT scanner and is used to take pictures of your body.  PET 
scanners allow us to image the function of different cells and organs in the body.  The CT scan 
(computed tomography) is a type of x-ray scan that images the anatomy (size or structure) of the 
body in two dimensions.  The combined PET/CT scanner is a special type of scanner that allows us 
to image both structure (CT) and function (PET) following the injection of 89Zr-trastuzumab.  You 
will be asked to lie on the PET imaging table for the pictures.  Your arms will be positioned to rest at 
your side or comfortably above your head.  Your body will be scanned from your head through your 
upper thighs.  Each scan will take approximately 30-60 minutes to complete.   
 
The total amount of time you will need to be at the PET facility on each of the 2 imaging days is 
approximately 90-120 minutes.   
 
Will you save my samples or research data to use in future research studies?  
As part of this study, we are obtaining PET/CT images of you. By agreeing to be part of this study you 
give up any property rights you may have in the images and the data. We would like to use your 
PET/CT images for other research projects in the future. These future studies may provide additional 
information that will be helpful in understanding your cancer type or how the PET/CT scanner obtains 
and processes the images, but it is unlikely that what we learn from these studies will have a direct 
benefit to you. It is possible that your images might be used to develop tests, determine future 
treatments. There are no plans to provide financial compensation to you should this occur.  This means 
we will store your images and may use it for studies going on right now as well as studies that are 
conducted in the future.  Your images may be used to develop investigational tests, treatments, drugs, or 
devices that are not yet approved by the U.S. Food and Drug Administration. 
 
Cohort 1 Subjects 
Return to PET facility on 2 different assigned 
imaging days  
 day 1 & 3 OR  
 day 2 & 5 OR  
 day 4 & 6 
Infusion / Injection Day 0 for All Participants 
 Trastuzumab infusion 
 Move to PET facility for 89Zr- Trastuzumab injection  
Cohort 2 Subjects 
Return to PET facility for imaging one 
time on day assigned 


 
FOR IRB USE ONLY 
 
IRB ID #: 201307037 
APPROVAL DATE: 03/14/18 
RELEASED DATE: 03/14/18 
EXPIRATION DATE: 03/13/19 
 
Version #  04.18.2016 
Page 5 of 11 
HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 52 people (12 in cohort 1 and 40 in cohort 2) will take part in this study conducted by 
investigators at Washington University.   
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for approximately 6-8 hours spread out 
over two or three different days.   
 The infusion visit will take approximately 3 – 3 ½ hours 
 Each of the PET imaging visits will take approximately 1 ½ - 2 hours.  If you are in cohort 1 you 
will undergo PET imaging on 2 days separate from your injection day.  If you are in cohort 2 you 
will return for imaging once on a day separate from your injection.    
 Your medical records will be followed for approximately 30 days after you complete imaging to 
ensure no problems developed as a result of your participation in this research project.   
 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. Some risks described in this consent document, if severe, may cause death.  
 
MUGA Scan:   
Mild / Likely:  You may feel discomfort from the IV injections and from lying on your backside 
for the pictures.  .   
Life Threatening/Rare:  allergic reaction to the tracer is rare.  The most common symptoms of 
an allergic reaction are rash or hives, tightening of the throat, wheezing, difficulty 
breathing or shortness of breath.   
 
ECHO Scan:   
 
Mild/Likely:  You may feel discomfort from lying on the imaging table or from the 
scanner probe which may be pressed into your skin and moved across your chest while 
the pictures are being taken.   
 
Trastuzumab Infusion: 
The amount of trastuzumab you will be receiving is less than what is normally given for treatment.  The 
followings are side effects collected from patients who receive normal treatment doses of trastuzumab.  
Side effects have been reported during the actual infusion and up to 24 hours following the infusion. 
Mild / Likely: pain at the injection site, generalized feeling of weakness, muscle aches, fever, 
chills, nausea, headaches and coughing 
Serious / Less likely:  back pain, stomach pain, bone or joint pain, vomiting, loss of appetite, 
dizziness 
Life Threatening / Rare:  irregular heartbeat, difficulty breathing and shortness of breath, high 
blood pressure, weakening of the heart muscle, allergic reaction-unexplained rash, 
itching, hives, swelling, low red blood cell counts, which can cause tiredness and 
shortness of breath, and low white blood cell counts, which can increase the  risk of 
infection.   
 


 
FOR IRB USE ONLY 
 
IRB ID #: 201307037 
APPROVAL DATE: 03/14/18 
RELEASED DATE: 03/14/18 
EXPIRATION DATE: 03/13/19 
 
Version #  04.18.2016 
Page 6 of 11 
89Zr-Trastuzumab Injection: because the amount of trastuzumab used in making the radioactive form 
of trastuzumab is even less than what you will receive from the trastuzumab infusion no additional side 
effects other than those listed above are expected.   
 
PET/CT Imaging: 
 
Mild / Likely:    Discomfort from lying still on the imaging table  
Life Threatening / Rare:  Malfunction of worn or implanted electronic medical devices from 
the CT scanner  
 
 
Radiation Exposure:  This study will expose you to radiation from the injection of an investigational 
radioactive drug, 89Zr-Trastuzumab and from CT scanning used as part of each PET/CT scan.  Cohort 2 
HER2 positive patients who receive MUGA testing will have additional exposure from that test.  The 
radiation exposure you will receive is equal to a uniform whole body exposure which is about 97 % 
(cohort 1) or 89% (cohort 2 HER2 positive or cohort 2 HER2 negative patients who receive ECHO or no 
cardiac testing) or 99% (cohort 2 HER2 negative patients who receive MUGA scan) of the allowable 
annual dose for radiation workers.  The risk from this level of radiation exposure is too small to be 
measured and is small when compared with other everyday risks.  If you want to know more about 
radiation exposure, please see the “Radiation Fact sheet” on the Guidelines page of the Human Research 
Protection Office website, at http://hrpo.wustl.edu or ask the study staff for a copy. 
 
Because certain research studies are subject to specific radiation exposure limits, it is important that you 
inform us if you have been in any other research studies in the last 12 months that involved exposure to 
radiation for research purposes (from x-rays, CT scans, PET scans or other nuclear medicine 
procedures).  It is also important that you tell future investigators about your participation in this 
research study if you are asked to participate in another research study. 
 
IV Placement and Blood Drawing: 
Mild / Likely:  discomfort from placement of the IV in your arm or hand or from the needle 
used to draw blood  
Serious /Less Likely:  There is a slight risk of bruising, some people feel dizzy or faint when an 
IV is placed or blood is drawn from them 
Life Threatening / Rare:  There is a rare risk of infection at the site of IV placement or blood 
drawing. 
 
ECG: You may feel discomfort from the placement and removal of the electrode patches from the skin. 
Remaining still while the ECG is taken (less than 1 minute) may cause anxiety.     
 
Vital Signs:  You may feel discomfort from the squeezing of the blood pressure cuff around your arm.   
 
Reproductive Risks: 
If you are a woman of childbearing potential, you will be required to have a pregnancy test before you 
may receive the infusion of Trastuzumab or the 89Zr-Trastuzumab.   
 
 


 
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EXPIRATION DATE: 03/13/19 
 
Version #  04.18.2016 
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Participation in future research studies:  There is a rare risk that you would not be eligible to 
participate in other research or treatment protocols or that you would need to complete a waiting period 
a this study before you would be allowed to participate in other research projects or studies.   
 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure, and we think the risk 
of accidental disclosure is very small.  Please see the section in this consent form titled “How will you 
keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
You will not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because being able to 
accurately identify the active HER2 receptor sites in the body could lead to better and more 
individualized treatment for patients with HER2 positive breast cancer.   
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You may have additional costs for being in this research study.  
 You will be asked to visit the hospital for two or three separate visits.  If you are making the trip 
to the hospital only for the research visits you will have travel related expenses.   
 
You and/or your medical/hospital insurance provider will remain responsible for your regular medical 
care expenses. 
 
WILL I BE PAID FOR PARTICIPATING? 
You will be paid for being in this research study. You will need to provide your social security number 
(SSN) in order for us to pay you. You may choose to participate without being paid if you do not wish to 
provide your social security number (SSN) for this purpose.  You may also need to provide your address 
because payment will be made in the form of a check mailed to you.  It can take up to 4 weeks for 
processing and delivery of the check to the address you provide.   If your social security number is 
obtained for payment purposes only, it will not be retained for research purposes.    
 
We recognize and appreciate the time and effort to participate in a research study.  If you are in cohort 1 
you will receive $350.00.  If you are in cohort 2 and HER2 positive or HER2 negative patient who does 
not need to undergo cardiac assessment, you will receive $250.00.  If you are a HER2 negative patient 
who needs to have cardiac testing done to confirm eligibility you will receive $300.  This is for 
Because PET scans can be harmful to an unborn baby, you should not become pregnant while on 
this study.  There is not enough medical information to know what the risks might be to an unborn 
child in a woman who takes part in this study. It is important that you understand that you need to 
use birth control while on this study. Ask your study doctor about what kind of birth control 
methods to use and how long to use them. If you are a woman who can become pregnant, you must 
agree to a blood or urine pregnancy test on the infusion day.  Please discuss with your research 
physician how long you need to wait before becoming pregnant. 


 
FOR IRB USE ONLY 
 
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APPROVAL DATE: 03/14/18 
RELEASED DATE: 03/14/18 
EXPIRATION DATE: 03/13/19 
 
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additional costs you may encounter, such as meals, extra time at hospital away from work or family, 
and/or other unforeseen expenses related to your participation and completion of the imaging visits of 
study.  The amount you will be compensated is broken down into $150 for the infusion day, $100 for 
each day of imaging and $50 if you need to have cardiac testing done to confirm eligibility.  Overnight 
hotel stay(s) may be available if needed as well.   
 
WHO IS FUNDING THIS STUDY? 
The National Institutes of Health (NIH) is funding this research study.  This means that Washington 
University is receiving payments from the NIH to support the activities that are required to conduct the 
study.  No one on the research team will receive a direct payment or increase in salary from the NIH for 
conducting this study.  
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator Dr. 
Farrokh Dehdashti at 314-362-2809 and/or the Human Research Protection Office at 1-(800)-438-
0445.  
 
Decisions about payment for medical treatment for injuries relating to your participation in research will 
be made by Washington University. If you need to seek medical care for a research-related injury, please 
notify the investigator as soon as possible.  
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
 Government representatives, (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
 The U.S. Food and Drug Administration 
 Your primary care physician if a medical condition that needs urgent attention is discovered 
 Hospital or University representatives, to complete Hospital or University responsibilities 
 Information about your participation in this study may be documented in your health care records 
and be available to your health care providers who are not part of the research team.  
 The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures 
 Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants.) The Institutional Review Board has reviewed and 
approved this study.  
 
New health information will be created as a result of your participation.  The images from the PET scans 
are obtained and stored in a digital format in a computer and kept on protected computer hard drives 
and/or disks.  Study Protected Health Information (PHI) will be kept in your research record and the 
information obtained from your 89Zr-Trastuzumab PET scans will not be shared with your doctor unless 
a life threatening condition is found.  Your research records and images may be kept permanently on file 


 
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RELEASED DATE: 03/14/18 
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at Washington University and may be used for future research.  All personal identifiers are removed and 
replaced with a unique identifying number.  The research that may be done with the information will not 
specifically help you.  But, it might help people who have cancer and other diseases in the future.   
 
The Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital 
is supported by funding from the National Cancer Institute (NCI). To meet NCI requirements, your PHI 
relating to your participation in this study (including your social security number) will be stored in a 
secure database at the Siteman Cancer Center.  This database and also your treatment records may be 
reviewed by Siteman Cancer Center personnel.  All information will be securely and confidentially 
maintained.  
 
To help protect your confidentiality, we will ensure that all patients identified and recruited for this 
study are within the Health Insurance Portability and Accountability Act (HIPAA) protected population 
of the research team at Washington University.  You will have an opportunity to ask questions about this 
study privately.  The research location will be in the clinic and treatment area of the Center for 
Advanced Medicine, the clinical PET facility and in the Center for Clinical Imaging Research where 
precautions are made to protect the privacy of all patients, not only research or non-research patients.  If 
we write a report or article about this study or share the study data set with others, we will do so in such 
a way that you cannot be directly identified. 
 
This consent form or similar documentation that you are participating in a research study may be 
included in your clinical medical record.  Anyone with access to your medical record, including your 
health insurance company may be able to see that you are participating in a research study. 
 
A description of this clinical trial may be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
Are there additional protections for my health information? 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 
The research team will only use and share your information as talked about in this form.  When possible, 
the research team will make sure information cannot be linked to you (de-identified).  Once information 
is de-identified, it may be used and shared for other purposes not discussed in this consent form. If you 
have questions or concerns about your privacy and the use of your PHI, please contact the University’s 
Privacy Officer at 866-747-4975.  
 


 
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Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
 your treatment or the care given by your health provider. 
 your insurance payment or enrollment in any health plans.   
 any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
 You authorize the use of your PHI for this research 
 Your signature and this form will not expire as long as you wish to participate. 
 You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
 To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
http://hrpo.wustl.edu/participants//withdrawing-from-a-study/ or you may request that the 
Investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared if necessary for safety reasons.  
 You will not be allowed to continue to participate in the study. 
 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  If you decide not to be in this 
study, or if you stop participating at any time, you won’t be penalized or lose any benefits for which you 
otherwise qualify. 
 
What if I decide to withdraw from the study? 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
http://hrpo.wustl.edu/participants/ under Withdrawing from a Research Study. 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned.  This might happen because staying in the study would be harmful, you need 
treatment that is not allowed while on the study, you fail to follow instructions, you become pregnant, 
you develop a major side effect, or the study is canceled.  


 
FOR IRB USE ONLY 
 
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APPROVAL DATE: 03/14/18 
RELEASED DATE: 03/14/18 
EXPIRATION DATE: 03/13/19 
 
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WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Dr. Farrokh Dehdashti at 314-362-1474 If you experience a research-related injury, please 
contact: Dr. Dehdashti as well.   
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office, 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research subject or to speak to someone other than the research 
staff, call the Human Research Protection Office at the number above. 
 
 
This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study.  
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 03/13/19. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
Statement of Person Who Obtained Consent 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that he or she understands 
the risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)