A Pilot Study of 64Cu-DOTA-Trastuzumab Positron Emission Tomography in Treatment of Advanced HER2 Positive Breast Cancer With the Antibody Drug Conjugate Ado-trastuzumab Emtansine
Phase: NA
Conditions: Bone Metastases, HER2-positive Breast Cancer, Liver Metastases, Lung Metastases, Recurrent Breast Cancer, Soft Tissue Metastases, Stage IV Breast Cancer
Sponsor: City of Hope Medical Center

 
IRB 14099 
 
07/18/2018 
Packet: 19 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH  
 
 
TITLE:  
A Pilot Study of 64Cu-DOTA-Trastuzumab Positron Emission Tomography in 
Treatment of Advanced HER2 Positive Breast Cancer with the Antibody Drug 
Conjugate Ado-Trastuzumab Emtansine  
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 14099  
      PROTOCOL DATED: 07/18/18 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
COH Initial Approval 
Protocol Dated 08/01/14 
Version: 00 
COH Amendment A 
Protocol Dated 08/11/14 
Version: 00 
COH Amendment 01 
Protocol dated 12/18/14 
Version: 01 
COH Amendment 02 
Protocol dated 2/25/15 
Version: 02 
COH Amendment 03 
Title page dated 08/03/2015 
Version: 03 
COH Amendment 04 
Protocol dated 09/21/15 
Version: 04 
COH Amendment 05 
Protocol dated 01/04/16                                                            Version: 05 
COH Amendment 06 
Title page dated 04/08/2016 
Version: 06 
COH Amendment 07 
Title Page dated 04/28/2016 
Version: 07 
COH Amendment 08 
Protocol dated 06/02/2016                                                        Version: 08 
COH Amendment 09 
Title Page/Personnel Update, dated 07/15/2016                        Version: 
09 
COH Amendment 10 
Title page dated 8/8/2016 
Version: 10 
COH Amendment 11 
Title Page dated 09/10/16 
Version: 11 
COH Amendment 12 
Title Page dated 10/24/16 
Version: 12 
COH Amendment 13 
Title Page dated 01/31/2017 
Version: 13 
COH Amendment 14 
Title Page dated 10/24/2017 
Version: 14 
COH Amendment 15 
Protocol dated 11/02/17 
Version: 15 
COH Amendment 16 
Protocol dated 07/18/18 
Version: 16 
COH Amendment 17 
Title Page dated 01/22/19 
Version: 17 
COH Amendment 18 at Continuation Title Page dated 12/17/19 
Version: 18 
COH Amendment 19 at Continuation Protocol Dated 07/18/18 (TP) 
Packet: 19 
 
SITE:  
 
 
 
 
Breast 
STAGE (If applicable): 
 
 
IV 
MODALITY:  
 
 
 
Treatment/Imaging 
TYPE:  
 
 
 
 
Pilot 
 
PRINCIPAL INVESTIGATOR: 
 
Joanne Mortimer, M.D. 
 
COLLABORATING INVESTIGATOR(S): 
David Colcher, PhD, 
Paul Frankel, PhD, Dave Yamauchi, M.D., Rita Gidwany, M.D., 
Russell Rockne, PhD, E. Kofi Poku, Pharm.D., Mary Carroll, NP 
 
PARTICIPATING CLINICIANS: 
 
Joseph Chao, M.D., Jana Portnow, M.D.,., Yuan Yuan, M.D., 
Ph.D., Daneng Li, M.D., Ravi Salgia, M.D., Mina Sedrak, M.D.,  

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A Pilot Study of 64Cu-DOTA-Trastuzumab Positron Emission Tomography in Treatment of 
Advanced HER2 Positive Breast Cancer with the Antibody Drug Conjugate Ado-Trastuzumab 
Emtansine  
 
Principal Investigator: 
 
Joanne Mortimer, MD 
 
Vice Chair, Medical Oncology and Therapeutics 
 
City of Hope  
 
1500 East Duarte Road 
 
Duarte, CA 91010 
 
 
(626) 256-4673 ext 61218 
 
(626) 471-5362 (FAX) 
 
 
jmortimer@coh.org 
 
 
Collaborating Investigators: 
James Bading, PhD 
 
Research Professor (retired) 
Cancer Immunology and Tumor Immunotherapeutics 
City of Hope  
 
David Colcher, PhD 
 
Professor  
Cancer Immunology and Tumor Immunotherapeutics 
City of Hope 
 
 
 
 
 
 
Susan Kane, PhD 
 
 
 
 
 
Professor 
 
 
 
 
 
Tumor Cell Biology 
 
Paul Frankel, PhD 
Section Head, Solid Tumors 
Division of Information Sciences 
 
 
Dave Yamauchi, M.D.  
Department of Radiology 
City of Hope 
Jinha Park, MD, PhD 
Assistant Professor 
Department of Radiology 
City of Hope 

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Rita Gidwany, MD 
Assistant Professor 
Department of Radiology 
City of Hope 
 
 
Participating Investigators:  
Joseph Chao, MD 
 
Assistant Professor 
 
Medical Oncology and Therapeutics 
 
 
Arti Hurria, MD 
 
Associate Professor 
 
Medical Oncology and Therapeutics 
 
 
Jana Portnow, MD  
 
Associate Professor 
 
Medical Oncology and Therapeutics 
 
 
George Somlo, MD  
 
Professor 
 
Medical Oncology and Therapeutics 
 
 
Yuan Yuan, MD, PhD 
 
Assistant Professor 
 
Medical Oncology and Therapeutics 
 
Research Nurse/Study Coordinator: Mary Carroll, RN 
 
Phyllis Broene, RN 
 
Clinical Research Assistant: 
Mario Dimacali, CRA 
 
Study Location: 
City of Hope National Medical Center 
 
1500 East Duarte Rd, 
 
Duarte, CA 91010 
 
Study Laboratories: 
Arnold and Mabel Beckman Center for  
 
Cancer Immunotherapeutics & Tumor Immunology, 
 
Room 5312 
 
 
Federal-Wide Assurance Number: FWA 00000692 

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Table of Contents 
Section  
Pages 
______________________________________________________________________ 
1.0 Background 
5-7 
2.0 Study Objectives 
7- 
3.0 Research Design 
6 
4.0 Eligibility 
7 
5.0 Ineligibility 
8 
6.0 Recruitment Process 
8 
7.0 Informed Consent Process 
8-9 
8.0 Study Procedures/Research Interventions 
9 
9.0 Study Calendar 
9-10 
10.0 Protocol Drug and Radiolabeled Imaging Agent 
10-17 
11.0 Positron Emission Tomography (PET) 
17 
12.0 Image Analysis 
17-18 
13.0 Response Assessment 
18-19 
14.0 Laboratory Evaluations 
19 
15.0 Statistical Analysis 
19-21 
16.0 Toxicity Assessment 
21 
17.0 Data Management 
21-22 
18.0 Data Safety Monitoring 
22-23 
19.0 Protocol Deviations 
24 
20.0 References 
25-26 

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1.0 
Background 
HER2-Positive Breast Cancer 
The term “breast cancer” encompasses a number of different diseases that are clinically defined by 
hormone receptor status and HER2 expression. HER2 is a transmembrane protein in the epidermal 
growth factor family. HER2 has tyrosine kinase activity that results in intracellular signaling and 
activation of genes for cell growth and survival. Women whose cancers overexpress the HER2 protein 
have a distinct natural history and are candidates for treatment with trastuzumab. Trastuzumab is a 
humanized IgG-1 antibody that binds to the ectodomain of HER2. When combined with chemotherapy, 
trastuzumab significantly improves the survival of women with both early stage and advanced disease. 
[1-3]  
The pathologic assessment of HER2 status is made on the primary tumor or metastatic foci. HER2 
overexpression and candidacy for trastuzumab have been defined as 3+ staining by 
immunohistochemistry (IHC) or gene amplification by fluorescence in situ hybridization (FISH). [4, 5] 
The American Society of Clinical Oncology and American College of Pathology have recently updated 
the guidelines for measurement of HER2. The new definition requires that the area of tumor contain at 
least 10% contiguous and homogeneous tumor cells which are identified as having protein over 
expression by IHC (3+) or gene amplification in a sample of 20 cancer cells.[6] 
Trastuzumab in combination with chemotherapy improves the overall survival for women with early 
stage and metastatic HER2-positive breast cancers. However, the activity of trastuzumab as a single 
agent in metastatic disease is modest. Objective tumor responses are reported in 35% of women treated 
with trastuzumab as first-line therapy and 18% in those who have been previously treated.[7, 8] Thus, 
trastuzumab therapy does not benefit all patients with HER2-positive breast cancers. Given the cost 
and potential toxicity of trastuzumab, an assessment is needed that predicts benefit from trastuzumab.  
A central pathology review of HER2 tumor status from NSABP B31, a controlled trial of adjuvant 
trastuzumab, identified 103 women whose tumors were HER2 negative. Women with HER2-negative 
disease who received adjuvant trastuzumab experienced fewer breast cancer recurrences than HER2-
negative women who did not receive adjuvant trastuzumab.[5, 9] The CLEOPATRA trial tested the 
addition of pertuzumab to docetaxel and trastuzumab in women with metastatic HER2-positive breast 
cancers. A central pathology review identified HER2-negative patients who benefited from the addition 
of pertuzumab (personal communication, Genentech). These observations suggest that the use of 
trastuzumab-based therapy should be broadened to include at least some nominally HER2-negative 
women and confirm the discordance in results from different institutions. Counterbalancing the potential 
benefit, however, is the fact that treatment with trastuzumab is expensive and may cause cardiac 
toxicity. 
 
Trastuzumab Emtansine (ado-trastuzumab emtansine – TDM1)  
Antibody-drug conjugates (ADCs) are effective in the treatment of leukemia.[10] Ado-trastuzumab 
emtansine is a novel ADC specifically designed for the treatment of HER2-positive cancer. It is 
composed of the following: trastuzumab, a humanized antibody directed against the extracellular region 
of HER2; DM1, an anti-microtubule agent derived from maytansine; and succinimidyl 4-[N-
maleimidomethyl] cyclohexane-1-carboxylate (SMCC), a thioether linker molecule used to conjugate 
DM1 to trastuzumab.[11, 12] Ado-trastuzumab emtansine binds to HER2 with an affinity similar to that 
of unconjugated trastuzumab.[13] It is hypothesized that after binding to HER2, ado-trastuzumab 
emtansine undergoes receptor-mediated internalization, resulting in intracellular release of DM1 and 
subsequent cell death. DM1 is an inhibitor of tubulin polymerization; it binds to tubulin competitively with 
vinca alkaloids.[12] Ado-trastuzumab emtansine has been shown in preclinical studies to retain the 
activities of unconjugated trastuzumab including inhibition of HER2 shedding, inhibition of PI3K/AKT 
signaling pathways, and antibody dependent cellular cytotoxicity.[13]  
Ado-trastuzumab emtansine is the first ADC to be used in breast cancer. EMELIA was a randomized, 
Phase III study of ado-trastuzumab emtansine versus lapatinib + capecitabine for the treatment of 

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patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer previously 
treated with trastuzumab and a taxane.[14] Patients received ado-trastuzumab emtansine (3.6 mg/kg 
IV on Day 1 of a 21-day cycle) or lapatinib (1250 mg orally once per day) plus capecitabine (1000 mg/m2 
orally twice daily on Days 1−14 of a 21-day cycle) until PD or unmanageable toxicity. Eligible patients 
had confirmed HER2-positive metastatic breast cancer (IHC 3+ and/or FISH positive) and had received 
prior therapy with trastuzumab and a taxane. Primary endpoints were progression-free survival (PFS) 
by independent review, overall survival (OS), and safety.  
From February 2009 through October 2011, a total of 991 patients were enrolled; 496 were assigned 
to lapatinib + capecitabine, and 495 were assigned to ado-trastuzumab emtansine. Median duration of 
follow-up for the first and second interim analysis was approximately 13 months and 19 months, 
respectively. Baseline patient demographics, prior therapy, and disease characteristics were balanced. 
The study met the primary endpoint with an improvement in PFS by independent review with a hazard 
ratio (HR) of 0.65, [95% confidence interval (CI) 0.55 to 0.77, p<0.001]. The median PFS was 9.6 
months in the ado-trastuzumab emtansine arm and 6.4 months in the lapatinib + capecitabine arm. A 
strong trend in OS was observed in favor of the ado-trastuzumab emtansine arm [HR = 0.62, (95% CI 
0.48-0.81), p = 0.0005]. At the first interim analysis, median OS was not reached in the ado-trastuzumab 
emtansine arm and was 23.3 months for lapatinib + capecitabine; the interim efficacy stopping boundary 
for OS was not crossed. However, at the second interim analysis, OS data crossed the pre-specified 
boundary that showed patients receiving ado-trastuzumab emtansine (median OS = 30.9 months) 
survived significantly longer than the control group (median OS=25.1 months), with a HR=0.68, 95% CI 
0.55-0.85, p<0.001). The objective response rate (ORR) was 43.6% for the ado-trastuzumab emtansine 
arm versus 30.8% for the lapatinib + capecitabine arm, with a median duration of objective response 
(DOR) of 12.6 months versus 6.5 months, respectively. 
Ado-trastuzumab emtansine was well tolerated, with no unexpected safety signals. The most 
common Grade ≥3 adverse events (AEs) in the ado-trastuzumab emtansine arm were 
thrombocytopenia (12.9% vs. 0.2%), increased AST (4.3% vs. 0.8%), and increased ALT (2.9% vs. 
1.4%); the most common Grade ≥3 AEs in the lapatinib + capecitabine arm were diarrhea (20.7% vs. 
1.6%) palmar plantar erythrodysesthesia (16.4% vs. 0), and vomiting (4.5% vs. 0.8%). The incidence 
of Grade 3/4 AEs in the ado-trastuzumab emtansine arm was 40.8% versus 57.0% in the lapatinib + 
capecitabine arm.   
On the basis of this trial, ado-trastuzumab emtansine is now FDA approved as second line therapy 
in women with metastatic HER2 positive breast cancer who have undergone prior therapy with 
trastuzumab and a taxane. 
 
Molecular Imaging in HER2 Positive Breast Cancer 
PET provides a non-invasive way of studying tumor location, metabolic function, and response to 
therapy. In breast cancer, PET imaging with 18F-flourodeoxyglucose (FDG) has been used to stage 
women with advanced disease and to assess response to chemotherapy and endocrine therapy before 
tumor regression can be documented by clinical examination or anatomical imaging.[15-17] The ability 
to identify patients who may benefit from systemic therapy is critically important to their quality of life; 
toxicities from ineffective therapies are prevented and medical costs are contained.  
In a previous study, we developed a novel functional imaging approach using 64Cu-DOTA-
trastuzumab and PET to characterize the biodistribution and tumor uptake of trastuzumab 24-48 hours 
after systemic intravenous administration. We showed that, with pre-infusion of non-labeled 
trastuzumab (45 mg) to suppress liver uptake, this approach produces high-quality images and detects 
tumors with exquisite sensitivity in patients with HER2-positive metastatic breast cancer. [18] More 
recently, we extended the study to include patients with advanced HER2-negative disease. We found 
that tumor uptake as measured with 64Cu-DOTA-trastuzumab/PET-CT is generally higher in patients 
classified as HER2-positive vs. HER2-negative, but with a good deal of inter- and intra-patient variability 
[19]. The observations were consistent between tumors that were biopsied and histopathologically 

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assessed for HER2 expression and those that were not. This suggests that, while 64Cu-DOTA-
trastuzumab uptake is positively correlated with tumor HER2 expression, other factors such as blood-
tissue transport also have significant effect on tumor uptake of intravenously administered trastuzumab 
and therefore on response to trastuzumab-based therapy. 
The underlying hypothesis of our project is that tumor uptake of 64Cu-DOTA-trastuzumab as 
measured by PET-CT can be used to predict response to ado-trastuzumab emtansine. 
 
2.0 
Study Objectives 
We propose to evaluate the potential of 64Cu-DOTA-trastuzumab/PET-CT to identify women with 
advanced HER2-positive breast cancers who are likely to benefit from treatment with ado-trastuzumab 
emtansine. Because trastuzumab targets both ado-trastuzumab emtansine and 
64Cu-DOTA-
trastuzumab to tumors, we hypothesize that 64Cu-DOTA-trastuzumab uptake can be used as a 
surrogate for relative tumor uptake of ado-trastuzumab emtansine during treatment. Thus, we expect 
that 64Cu-DOTA-trastuzumab/PET-CT can be used to identify HER2-positive disease that is unlikely to 
benefit from ado-trastuzumab emtansine therapy due to inadequate uptake of the ADC. Conversely, 
the current study of women whose disease is classified as HER2-positive, combined with prior 
observations of 64Cu-DOTA-trastuzumab tumor uptake in HER2-negative patients, may engender 
evaluation of 64Cu-DOTA-trastuzumab/PET-CT for identifying patients classified as HER2-negative who 
might nonetheless have adequate tumor uptake to benefit from ado-trastuzumab emtansine. 
While our ultimate goal is to utilize 64Cu-DOTA-trastuzumab/PET-CT to aid “individualized” selection 
of HER2-directed therapies in general, the proposed pilot study will focus only on treatment with ado-
trastuzumab emtansine. Patients entered in the trial will have experienced disease progression after 
prior taxane and trastuzumab chemotherapy.  The fact that trastuzumab is rarely used as a single agent 
presents an obstacle in the evaluation of 64Cu-DOTA-trastuzumab/PET-CT for prediction of response. 
In contrast, treatment with ado-trastuzumab emtansine as a single agent affords a unique opportunity 
for evaluating 64Cu-DOTA-trastuzumab/PET-CT. While emtansine delivery to tumor is of primary 
interest, 64Cu-DOTA-trastuzumab uptake is also relevant to potential effectiveness of the trastuzumab 
component of the ADC. Success in the proposed trial would have implications regarding the potential 
use of 64Cu-DOTA-trastuzumab/PET-CT to aid patient selection for any treatment regimen that includes 
trastuzumab. 
The goal of this pilot study is to correlate 64Cu-DOTA-trastuzumab/PET-CT tumor uptake 
measurements with response both at the patient and individual tumor levels. In addition to inadequate 
tumor uptake, another potential cause of non-response is biological or “molecular” mechanisms of 
resistance (MMRs) to ado-trastuzumab emtansine. Consistent with our prior study protocol, all patients 
will undergo a pretreatment biopsy to ensure positive HER2 status. Residual tumor will be stored for 
future studies that examine the role of putative MMRs in determining response to ado-trastuzumab 
emtansine.  
The Specific Study Objectives are: 
2.1  
Correlated uptake of 64Cu-DOTA-trastuzumab PET by individual tumors with subsequent 
tumor response to ado-trastuzumab emtansine as assessed by serial 18F-FDG/PET-CT. 
2.2  
Compare tumor uptake of 64Cu-DOTA-trastuzumab PET between patients who do and 
patients who do not respond to ado-trastuzumab emtansine.  
2.3  
Obtain tumor tissue for subsequent assessment of the presence of putative MMRs to 
ado-trastuzumab emtansine. When funding becomes available, those samples will be 
used to explore the correlation between the presence of MMRs as assessed by 
histopathology and tumor response to ado-trastuzumab emtansine both in univariate 
analysis and in combination with tumor uptake of 64Cu-DOTA-trastuzumab as measured 
with PET/CT. 
 

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3.0 
Research Design 
This prospective clinical pilot trial will enroll 10 women with metastatic HER2 positive breast cancer 
who will be treated with ado-trastuzumab emtansine. Patients will undergo 
64Cu-DOTA-
trastuzumab/PET-CT just prior to initiation of therapy with ado-trastuzumab emtansine. The objective 
is to examine, both at the patient and individual tumor levels, the relationship between tumor uptake of 
64Cu-DOTA-trastuzumab and response to ado-trastuzumab emtansine. 
 
4.0 
Eligibility 
Women with metastatic HER2-positive breast cancers whose disease will be treated with ado-
trastuzumab emtansine will be considered eligible for study participation if they meet the following 
criteria: 
4.1. 
Participants must be women who have histological confirmation of metastatic invasive 
breast cancer that has metastasized outside the region of the primary tumor and axilla. 
Biopsy must be obtained prior to initiation of chemotherapy.  It should be performed 
within 28 days prior to enrollment (Patients with a biopsy of recurrent disease that is 
HER2-positive and have not received HER2-directed therapy since the biopsy can 
exceed the 28-day windowup to 6 months. Patients must have metastatic disease in 
lung, liver, soft-tissue or bone to qualify for the study (more than one site is permissible). 
4.2 
At least 1 site of metastasis  20 mm in mean diameter must be identified.  
4.3 
The cancer must over express HER2 as determined by IHC and/or FISH. 
4.4 
Patients may not have received trastuzumab within 6 weeks of projected 64Cu-DOTA-
trastuzumab/PET-CT. 
4.5 
Participants must have normal cardiac ejection fraction. 
4.6 
Ability to provide informed consent. 
4.7 
Patients >18 years of age  
4.8 
Patients that may need dose reduction to commence Cycle 1 treatment. 
4.9       ECOG Performance status of 0-2 
4.10     Negative serum pregnancy test (female patient of childbearing potential only) 
4.11     Patients must have adequate cardiac function. Left ventricular ejection fraction (LVEF) 
            ≥ 50% as determined by MUGA scan or echocardiogram. 
 
5.0 
Ineligibility 
5.1 
Participants who have received trastuzumab within the prior 36 days. 
5.2 
Participants who are not considered candidates for ado-trastuzumab emtansine. 
5.3 
No metastatic sites >20 mm. 
5.4 
Concurrent malignancy other than skin cancer. 
5.5 
Inability to provide informed consent. 
 
6.0 
Recruitment Process 
6.1 
Participants will be recruited by the treating Medical Oncologists from patients receiving 
breast cancer treatment at City of Hope and its community practice sites. All imaging will 
occur on the main Duarte campus. 
 

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7.0 
Informed Consent Process and Patient Registration Procedures  
7.1 
The Principal Investigator or IRB-approved named designate will explain to prospective 
enrollees the nature, duration, purpose of the study, potential risks, alternatives and 
potential benefits, and all other information contained in the informed consent document 
as well as their rights as a research subject (Experimental Subjects Bill of Rights) and 
the HIPAA research authorization form. Research participants will be informed that they 
may withdraw from the study at any time and for any reason without jeopardizing (include 
as applicable) their future care,  their employment at City of Hope or any relationship 
they have with City of Hope. After signing the study consent form, HIPAA authorization 
form and the Experimental Subject’s Bill of Rights, research subjects will undergo an 
assessment of their understanding of the study by the Research Subject Advocate, 
followed by eligibility testing. Should sufficient doubt be raised regarding the adequacy 
of comprehension, further clarifications will be made and the consent comprehension 
assessment may be repeated until a satisfactory result is obtained. Prospective research 
subjects who cannot adequately comprehend the fundamental aspects of the research 
study with a reasonable amount of discussion, education and proctoring will be ineligible 
for enrollment. Following this procedure, the protocol management team will review the 
results of eligibility testing and determine if the research subject is a candidate for study 
enrollment.  
 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center 
(DCC) at City of Hope.  Staff (including physicians, protocol nurses and/or CRCs) should 
call the DCC at (626) 256-4673, ext. 64267 if there are any questions regarding subject 
registration.  
 
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a subject does not receive protocol therapy within two weeks following 
registration, the subject’s registration on the study may be canceled. The Data 
Coordinating Center should be notified of cancellations as soon as possible. 
 
Once the signed informed consent has been obtained, all pretreatment evaluations have 
been performed, and subject’s eligibility has been confirmed by the Data Coordinating 
Center, a subject will be registered on study. 
 
To register a subject, the treating physician should contact the protocol nurse or the 
responsible Clinical Research Coordinator (CRC) in the Clinical Trial Office (CTO) to 
complete the eligibility checklist.  
 
The protocol nurse or CRC will contact the Data Coordinating Center at City of Hope 
(626-256-4673, ext. 64267 or via e-mail at dcc@coh.org), scan and EMAIL a copy of the 
completed and signed eligibility checklist, a copy of the signed Informed Consent 
(including a copy of signed subject’s bill of Rights and HIPAA authorization form) and 
copies of any required pre-study test results that are not readily available in the COH 
electronic medical record to dcc@coh.org.  
 
The protocol nurse or CRC may then call the Data Coordinating Center (626-256-4673 
ext. 64267) to confirm receipt of all registration documents. To complete the registration 
process, the Data Coordinating Center will: 
 

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 
Verify and confirm the subject’s eligibility. 
 
Assign a subject accession number (RPN or for example, COH-001, COH-002, etc.). 
 
Register the subject on study centrally (the City of Hope CRC assigned to the trial 
will still be responsible for accessioning via MIDAS).   
 
Complete and email a Confirmation of Registration form within 24 hours to include 
the COH subject study number to the study team, which will include the Principal 
Investigator, treating physician, protocol nurse, CRC and COH IDS Pharmacy. 
 
Call the protocol nurse and/or CRC to verbally confirm registration. 
 
Enter the subject into Medidata RAVE. 
 
A subject failing to meet all protocol requirements will not be registered. 
 
8.0 
Study Procedures/Research Interventions 
8.1 
Use of PET imaging to predict response to ado-trastuzumab emtansine 
8.1.1 Ten women with metastatic breast cancer that is HER2 positive by IHC and/or 
FISH will be recruited from the Medical Oncology Clinics at City of Hope. 
8.1.2 As patients will ultimately receive ado-trastuzumab emtansine therapy, a 
baseline cardiac ejection fraction, by MUGA or ECHO cardiogram, will be 
performed. 
8.1.3 All participants will undergo a history and physical exam and radiographic staging 
workup with whole body 18F-FDG/PET-CT.  
8.1.4 All subjects will receive an IV dose of trastuzumab (45 mg) immediately before 
infusion of 64Cu-DOTA-trastuzumab (≤15 mCi; protein dose 5 mg). Venous blood 
samples (each sample to be 7ml in red top tubes will be drawn just prior to the 
trastuzumab pre-infusion, 1 h after administration of 64Cu-DOTA-trastuzumab, 
and shortly before each of the two PET scans of 64Cu-DOTA-trastuzumab. The 
pre-infusion sample will be used both to determine levels of residual circulating 
trastuzumab from prior treatment and to obtain background measurements for 
radioactivity assays performed on the subsequent blood samples. The samples 
taken at 1 h and later are used to measure the blood clearance of 64Cu-DOTA-
trastuzumab. 
8.1.5 A PET scan of regions of interest will be performed 24 and 48 hours after injection 
of 64Cu-DOTA-trastuzumab. Systemic therapy with ado-trastuzumab emtansine 
will be initiated after completion of the 64Cu-DOTA-trastuzumab PET-CT imaging. 
The conventional dose of ado-trastuzumab emtansine is 3.6 mg/kg every 3 
weeks until disease progression or at the discretion of the treating oncologist. 
8.1.6 Participants will be observed for toxicity for one year. 
8.1.7 Subjects will undergo restaging by whole body18F-FDG/PET-CT every 6 weeks 
for one year after initiation of treatment until disease progression.  After one year 
a PET/CT or CT scan can be performed at the discretion of the treating physician. 
8.1.8 An algorithm for the administration of ado-trastuzumab will be dosed according 
to the package insert. 
8.1.9 Rules for dose modification of ado-trastuzumab are listed according to package 
insert 
 
8.2 
Handling of specimens: All specimens will be handled in accordance with RSC 09001 
and OSBC 90029. 
 

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9.0 
Study Calendar 
 
Treatment with ado-trastuzumab emtansine is administered every 21 days (+/- 7 days) until complete 
response or disease progression 
¹Pretreatment PET/CT and biopsy may be performed between 28 days and up to 6 months prior to 
study treatment for patients that have not received systemic therapy. 
 
< 28¹ 
days 
prior 
to 
study 
entry 
14 
days 
prior to 
[18F]FDG 
PET-CT 
Days 
-16  
to 
-3 
Day 
-2 
Day  
-1 
Day 
0 
Day 
7 
Day 
14 
Day 
21 
Day 
28 
Day 
42 
Day 
63 
Day 
84 
Day 
105 
 
 
Every 21 
Days (+/- 7 
days) 
Until 
Complete 
Response 
or Disease 
Progression 
Biopsy of 
metastasis for 
diagnosis and 
HER2 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and 
Physical Exam 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Cardiac 
ejection 
fraction 
(by MUGA or 
ECHO) q3 
months 
 
X 
 
 
 
 
X2 
X2 
 
 
 
 
X 
 
 
CBC, CMP, 
Tumor markers 
 
X 
 
 
 
X 
X3 
X3 
X 
 
X 
X 
X 
X 
X 
Pregnancy test 
if 
premenopausal 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
[18F]FDG/PET-
CT2 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X2 
Trastuzumab 
serum level 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Cold 
trastuzumab 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
64Cu-DOTA-
trastuzumab 
injection 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
2PET-CT 
Imaging 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Ado-
trastuzumab 
emtansine 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Toxicity 
assessment 
and conmeds 
 
 
 
X 
X 
 
X 
 
 
X 
X5 
 
 
 
 
 
Hematocrit4 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 

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2Re-staging with 18F-FDG/PET-CT is performed every 6 weeks for one year after 1st ado-trastuzumab 
emtansine dose.  After one year a PET/CT or CT scan can be performed at the discretion of the 
treating physician. 
3Participants will be examined by the treating physician on days 7 and 14, and a CBC will be obtained.  
If there are any clinical concerns about cardiac toxicity, a MUGA will be obtained. 
4Blood sample for hematocrit will be collected just prior to the trastuzumab pre-infusion. 
5AEs/SAEs, toxicities and conmeds will only be gathered for 30 days post cold trastuzumab/Cu-DOTA 
injection. 
 
 

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10.0 
Protocol Drugs and Radiolabeled Imaging Agent 
10.1 
Trastuzumab (for “cold” trastuzumab infusions) 
10.1.1 Drug description: Trastuzumab is a recombinant humanized monoclonal 
antibody that binds to the extracellular domain of the HER2. Trastuzumab is a 
sterile, white to pale yellow, preservative-free lyophilized powder for IV 
administration. The nominal content of each trastuzumab vial is 440mg 
trastuzumab, 440mg ,-trehalose dehydrate, 9,9mg L-histidine HCl, 6.4mg L-
histidine, and 1.8mg polysorbate 20, USP. Reconstitution with 20mL of the 
supplied Bacteriostatic Water for Injection (BWFI), USP, containing 1.2% benzyl 
alcohol as a preservative, yields a multi-dose solution containing 21mg/mL 
trastuzumab, at a pH of approximately 6. 
10.1.2 Procurement of trastuzumab: The research participant/research participant’s 
insurance carrier will be responsible for the cost of Trastuzumab.  
10.1.3 Storage/stability: Vials of trastuzumab are stable at 2-8C (36-46 F) prior to 
reconstitution. Do not use beyond the expiration date stamped on the vial. A vial 
of trastuzumab reconstituted with BWFI, as supplied, is stable for 28 days after 
reconstitution when stored refrigerated at 2-8C (36-46 F), and the solution is 
preserved for multiple use. Discard any remaining multi-dose reconstituted 
solution after 28 days. If unpreserved Sterile Water for Injection (SWFI) (not 
supplied) is used, the reconstituted trastuzumab solution should be used 
immediately and any unused portion must be discarded. Do not freeze 
trastuzumab that has been reconstituted. The solution of trastuzumab for infusion 
diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium 
Chloride Injection, USP, may be stored at 2-8C (36-46 F) for up to 24 hours at 
room temperature 2-25C. However, because diluted trastuzumab contains no 
effective preservative, the reconstituted and diluted solution should be stored 
refrigerated 2-8C (36-46 F). 
10.1.4 Reconstitutions and administration 
10.1.4.1. 
Reconstitution 
10.4.1.1.1 
The diluent provided has been formulated to maintain the 
stability and sterility of trastuzumab for up to 28 days. 
Other diluents have not been shown to contain effective 
preservatives for trastuzumab. Each vial of trastuzumab 
should be reconstituted with 20mL of BWFI, USP, 1.1% 
benzyl alcohol preserved as supplied, to yield a multi-dose 
solution containing 21mg/mL trastuzumab.  
10.1.4.1.2 
Immediately upon reconstitution with BWFI, the vial of 
trastuzumab must be labeled in the area marked “Do not 
use after:” with the future date that is 28 days from the date 
of reconstitution. 
Note: When administering trastuzumab to a patient with a 
known hypersensitivity to benzyl alcohol, trastuzumab 
must be reconstituted with SWFI, and only one dose per 
trastuzumab vial should be used. Trastuzumab which has 
been reconstituted with SWFI must be used immediately 
and any unused portion must be discarded. Use of other 
reconstitution diluents should be avoided. 

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Shaking the reconstituted trastuzumab or causing 
excessive foaming during the addition of diluent may result 
in problems with dissolution and the amount of 
trastuzumab that can be withdrawn from the vial. Use 
appropriate aseptic technique when performing the 
following reconstitution steps: 
 
Using a sterile syringe, slowly inject the 20mL of 
diluent into the vial containing the lyophilized cake of 
trastuzumab. The stream of diluent should be 
directed into the lyophilized cake. 
 
Swirl 
the 
vial 
gently 
to 
aid 
reconstitution. 
Trastuzumab may be sensitive to shear-induced 
stress, e.g., agitation or rapid expulsion from a 
syringe. Do not shake. 
 
Slight foaming of the product upon reconstitution is 
not unusual. Allow the vial to stand undisturbed for 
approximately 5 minutes. The solution should be 
essentially free of visible particulates, clear to slightly 
opalescent and colorless to pale yellow. 
10.4.1.2 
Administration: The recommended 45 mg cold infusion dose of 
trastuzumab is administered intravenously over 15 minutes. The 
cold trastuzumab will be injected prior to the injection of 64Cu-
DOTA-trastuzumab. Patients need to stay for 2 hours post 64Cu-
DOTA-trastuzumab administration with vital signs (Temp, Pulse, 
BP, Resp.) to be done at: Pre-start, 15 min post start, 30 min post 
start, 45 min post start , 60 min post start and 2 hours post start of 
64Cu-DOTA-trastuzumab. After measurement of the vital signs 
have been completed, discharge patient home if stable. If 
unstable, notify MD. 
10.1.5 Drug accountability: Trastuzumab will be purchased by the City of Hope 
Pharmacy, which will store and control the drug. It will be prepared for 
administration in the outpatient pharmacy.  
10.1.6 Discard of unused agent: Unused trastuzumab will be discarded in the 
chemotherapy discard containers within the outpatient pharmacy. 
10.1.7 Warnings and Contraindications 
10.1.7.1 
Cardiotoxicity: Administration of trastuzumab can result in the 
development of ventricular dysfunction and congestive heart 
failure. Signs and symptoms of cardiac dysfunction, such as 
dyspnea, increased cough, paroxysmal nocturnal dyspnea, 
peripheral edema, S3 gallop, or reduced ejection fraction have 
been observed in patients treated with trastuzumab. Congestive 
heart failure associated with trastuzumab therapy may be severe 
and has been associated with disabling cardiac failure, death, and 
mural thrombosis leading to stroke. 
10.1.7.1 
Hypersensitivity 
reactions 
including 
anaphylaxis; 
severe 
hypersensitivity reactions have been infrequently reported in 
patients treated with trastuzumab. Signs and symptoms include 
anaphylaxis, urticaria, bronchospasm, angioedema, and/or 
hypotension. In some cases, the reactions have been fatal. 
Trastuzumab infusion should be interrupted in all patients with 

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severe hypersensitivity reactions. In the event of a hypersensitivity 
reaction, appropriate medical therapy should be administered, 
which 
may 
include 
epinephrine, 
corticosteroids, 
diphenhydramine, bronchodilators, and oxygen. Patients should 
be evaluated and carefully monitored until complete resolution of 
signs and symptoms. 
10.1.7.3 
Infusion reactions: In the post-marketing setting, rare occurrences 
of severe infusion reactions leading to fatal outcome have been 
associated with the use of trastuzumab. In clinical trials, infusion 
reactions consisted of a symptom complex characterized by fever 
and chills, and on occasion included nausea, vomiting, pain, 
headache, dizziness, dyspnea, hypotension, rash, and asthenia. 
These reactions were usually mild to moderate in severity. 
However, in post-marketing reports, more severe adverse 
reactions to trastuzumab infusion were observed and included 
bronchospasm, hypoxia, and severe hypotension.  These severe 
reactions were usually associated with the initial infusion of 
trastuzumab and generally occurred during or immediately 
following the infusion. However, the onset and clinical course were 
variable. Delayed post-infusion events with rapid clinical 
deterioration have also been reported.  Rarely, severe infusion 
reactions culminated in death within hours or up to one week 
following an infusion. 
10.7.1.4 
Pulmonary events: Severe pulmonary events leading to death 
have been reported rarely with the use of trastuzumab in the post-
marketing setting. Signs, symptoms, and clinical findings include 
dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic 
pulmonary edema, pulmonary insufficiency and hypoxia, and 
acute respiratory distress syndrome. These events may or may 
not occur as a sequelae of infusion reactions. Patients with 
symptomatic intrinsic lung disease resulting in dyspnea at rest 
may be at greater risk of severe reactions.  
10.1.7.5 
Other severe events reported rarely in the post-marketing setting 
include pneumonitis and pulmonary fibrosis. 
10.2 
Preparation of 64Cu-DOTA-trastuzumab  
10.2.1 All procedures are performed as specified in FDA-approved IND #109971. 
Trastuzumab is purchased from the City of Hope pharmacy and conjugated with 
active ester of DOTA (1,4,7,10-tetraazadodecane-1,4,7,10-tetracetic acid) in the 
City of Hope biologics production facility (CBG) under cGMP compliant 
conditions. Each lot of trastuzumab-DOTA underwent testing for sterility, 
potency, purity and lack of pyrogenicity. Vialing of the conjugated materials will 
be done in City of Hope biologics production facility Fill and Finish area. 
Radiolabeling with 64Cu will be carried out in the City of Hope Radiopharmacy 
under the direction of David Colcher, PhD. The 64Cu will be purchased from the 
Mallinckrodt Institute of Radiology at the Washington University School of 
Medicine, which is preparing the radiolabel for clinical use. Labeling will be 
accomplished by incubating conjugated antibody with the 64Cu for 45 minutes at 
43C, followed by a chase with DTPA and subsequent purification on a size 
exclusion preparative grade Superdex-200 column. Appropriate fractions will be 
pooled and filtered to make up the patient dose, which will be formulated with 
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of 64Cu-DOTA-trastuzumab. The total trastuzumab content per 64Cu-DOTA-
trastuzumab injected dose is less than 5 mg.  
 
We have estimated radiation dose from 64Cu-DOTA-trastuzumab based on our 
previous work with 64Cu-DOTA-trastuzumab and 111In-MxDTPA-
trastuzumab.[18, 20] The study protocol also requires 18F-fluorodeoxyglucose 
(FDG)/PET-CT scans prior to 64Cu-DOTA-trastuzumab/PET-CT and performed 
every 6 weeks after 1st ado-trastuzumab emtansine dose.   
The FDG scans are used to assess treatment response and thus are standard of 
care. Patients will be imaged twice following injection of 
64Cu-DOTA-
trastuzumab. We have used estimated CT radiation dose to arrive at the following 
estimates of overall radiation equivalent and effective doses from the 64Cu-
DOTA-trastuzumab/PET-CT research procedure. The following table compares 
that procedure with 18F-FDG/PET-CT. 
 
 

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Organ/Tissue 
Estimated Equivalent or Effective Dose (mSv)* 
   64Cu-Trastuzumab              CT**        64Cu-Trastuzumab      18F-FDG/PET-CT              
          (15 mCi)                                                 PET-CT                      (15 mCi) 
Heart wall 
88 
6 
94 
9 
Spleen 
55 
6 
61 
9 
Liver 
65 
6 
71 
9 
Bladder wall 
10 
6 
16 
93 
Kidneys 
52 
6 
58 
9 
Red marrow 
21 
6 
27 
9 
Other 
12 
6 
18 
9 
Effective dose 
15 
6 
21 
14 
* Values for 18F-FDG and CT were obtained from Brix, 2005.[21] 
**Low-dose CT procedure; 2 scans. 
10.3 
Ado-trastuzumab emtansine  
10.3.1 Drug description: Ado-trastuzumab emtansine is a novel ADC specifically 
designed for the treatment of HER2-positive cancer. It is composed of (i) 
trastuzumab, a humanized antibody directed against the extracellular region of 
HER2, (ii)  DM1, an anti-microtubule agent derived from maytansine; and (iii) 
succinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (SMCC), a 
thioether linker molecule used to conjugate DM1 to trastuzumab.[11, 12] 
Ado-trastuzumab emtansine binds to HER2 with an affinity similar to that of 
unconjugated trastuzumab.[13] It is hypothesized that after binding to HER2, 
ado-trastuzumab emtansine undergoes receptor-mediated internalization, 
resulting in intracellular release of DM1 and subsequent cell death. DM1 is an 
inhibitor of tubulin polymerization; it binds to tubulin competitively with vinca 
alkaloids. Ado-trastuzumab emtansine also has been shown in preclinical studies 
to retain the activities of unconjugated trastuzumab, including inhibition of HER2 
shedding, inhibition of PI3K/AKT signaling pathways, and antibody dependent 
cellular cytotoxicity.[13] 
10.3.2 Procurement of ado-trastuzumab emtansine: Because this is a standard-of-care 
treatment for recurrent HER2-positive breast cancer, we anticipate that the cost 
of the drug will be provided by insurance. 
10.3.3  Storage/stability: The diluted ado- trastuzumab emtansine infusion solution 
should be used immediately. If not used immediately, the solution may be stored 
in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use. This 
storage time is additional to the time allowed for the reconstituted vials. Do not 
freeze or shake. 
10.3.4 Reconstitutions and administration 
10.3.4.1 
Reconstitution: Using a sterile syringe, 5mL of Sterile Water 
should be injected into the 100mg ado-trastuzumab emtansine 
vial, or 8mL of Sterile Water should be injected into the 160mg 
ado-trastuzumab emtansine vial to yield a solution containing 
20mg/ml. The reconstituted solution should be clear to opalescent 
and free of visible particulates. The reconstituted solution should 
be colorless to pale brown. The reconstituted, lyophilized vials 
should be used immediately or stored for up to 4 hours in a 
refrigerator at 2-8C (36-46F); discard unused ado-trastuzumab 

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emtansine after 4 hours. Do not freeze. The reconstituted product 
contains no preservative and is intended for single-use only. 
10.3.5. Administration: Ado-trastuzumab emtansine is administered as an IV infusion 
using a 0.22 micron in-line non-protein adsorptive polyethersulfone (PES) filter. 
It should be administered as an IV infusion never as a bolus. The drug should not 
be mixed or administered as an infusion with other medical products. The 
recommended dose is 3.6 mg/kg as an IV infusion every 21 days until disease 
progression or unacceptable toxicity. 
10.3.6 Drug accountability: Ado-trastuzumab emtansine will be purchased by the City 
of Hope Pharmacy, which will store and control the drug. It will be prepared for 
administration in the outpatient pharmacy.  
10.3.7 Discard of unused agent: Unused ado-trastuzumab emtansine will be discarded 
in the chemotherapy discard containers within the outpatient pharmacy. 
10.3.8 Warnings and Contraindications 
10.3.8.1 
Pulmonary Toxicity: Cases of interstitial lung disease (ILD), 
including pneumonitis, some leading to acute respiratory distress 
syndrome or fatal outcome have been reported in clinical trials 
with ado-trastuzumab emtansine. Pneumonitis at an incidence of 
0.8% (7 out of 884 treated patients) has been reported, with one 
case of grade 3 pneumonitis. Signs and symptoms include 
dyspnea, cough, fatigue, and pulmonary infiltrates. These events 
may or may not occur as sequelae of infusion reactions. In the 
randomized trial TDM 4370g/BO21977 (EMILIA) the overall 
frequency of pneumonitis was 1.2%. Treatment included 
administration of steroids, oxygen, and study drug discontinuation 
(Data on File. Genentech, Inc). Permanently discontinue 
treatment with ado-trastuzumab emtansine in patients diagnosed 
with ILD or pneumonitis Patients with dyspnea at rest due to 
complications of advanced malignancy and co-morbidities may be 
at increased risk of pulmonary toxicity. 
10.3.8.2 
Hepatotoxicity: Hepatotoxicity, predominantly in the form of 
asymptomatic transient increases in the concentrations of serum 
transaminases (Grade 1-4 transaminitis), has been observed 
while during treatment with ado-trastuzumab emtansine in clinical 
trials . A cumulative effect of ado-trastuzumab emtansine on 
transaminases has been observed (Data on File. Genentech, 
Inc.). Cases of severe hepatotoxicity, including death due to drug-
induced liver injury (DILI) and hepatic encephalopathy, have been 
observed in patients treated with ado-trastuzumab emtansine. 
While 
there 
is 
evidence 
of 
drug-induced 
liver 
toxicity 
(predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases) in patients treated with 
ado-trastuzumab emtansine, its potential to cause liver injury with 
clinically meaningful changes in liver function is unclear, as the 
observed cases were confounded by concomitant medications 
with known hepatotoxic potential and/or underlying conditions. 
Nevertheless, a contributory role of ado-trastuzumab emtansine 
in these cases cannot be excluded. 
10.3.8.3 
Cardiotoxicity: Patients treated with ado-trastuzumab emtansine 
are at increased risk of developing left ventricular dysfunction. A 

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decrease of LVEF to <40% has been observed in patients treated 
with ado-trastuzumab emtansine. In the randomized trial, TDM 
4370g/BO21977 (EMILIA). Left ventricular dysfunction occurred in 
1.8% of patients in the ado-trastuzumab emtansine -treated group 
and 3.3% of patients in the lapatinib plus capecitabine-treated 
group.  
10.3.8.4 
Infusion Reaction: Treatment with ado-trastuzumab emtansine 
has not been studied in patients who had trastuzumab 
permanently discontinued due to infusion-related reactions (IRR) 
and/or 
hypersensitivity; 
treatment 
with 
ado-trastuzumab 
emtansine is not recommended for these patients. Infusion-
related reactions, characterized by one or more of the following 
symptoms - flushing, chills, pyrexia, dyspnea, hypotension, 
wheezing, bronchospasm, and tachycardia have been reported in 
clinical trials of ado-trastuzumab emtansine. In the randomized 
trial, TDM 4370g/BO21977 (EMILIA), the overall frequency of 
IRRs in patients treated with ado-trastuzumab emtansine was 
1.4%. In most patients, these reactions resolved over the course 
of several hours to a day after the infusion was terminated. Ado-
trastuzumab emtansine treatment should be interrupted in 
patients with severe IRR. Ado-trastuzumab emtansine treatment 
should be permanently discontinued in the event of a life-
threatening IRR. Patients should be observed closely for IRR 
reactions, especially during the first infusion. One case of a 
serious, allergic/anaphylactic-like reaction has been observed in 
clinical trials of single-agent ado-trastuzumab emtansine. 
Medications to treat such reactions, as well as emergency 
equipment, should be available for immediate use. 
10.3.8.5 
Thrombocytopenia: Thrombocytopenia was reported in clinical 
trials of ado-trastuzumab emtansine (103 of 884 treated patients 
with Grade ≥3; 283 of 884 treated patients with any Grade). The 
majority of these patients had Grade 1 or 2 events (<LLN to 
≥50,000/mm3) with the nadir occurring by day 8 and generally 
improving to Grade 0 or 1 (≥75,000 /mm3) by the next scheduled 
dose. In clinical trials of ado-trastuzumab emtansine, the 
incidence and severity of thrombocytopenia were higher in Asian 
patients. Independent of race, the incidence of severe 
hemorrhagic events in patients treated with ado-trastuzumab 
emtansine was low. 
10.3.8.6 
Neurotoxicity: Peripheral neuropathy, mainly as Grade 1 and 
predominantly sensory, was reported in clinical trials of ado-
trastuzumab emtansine (14 of 884 treated patients with Grade ≥3; 
196 of 884 treated patients with any Grade). In the randomized 
trial (Study 1), the overall frequency of peripheral neuropathy was 
21.2% in the ado-trastuzumab emtansine-treated group and 
13.5% in the lapatinib plus capecitabine-treated group. The 
incidence of Grade ≥3 peripheral neuropathy was 2.2% in the ado-
trastuzumab emtansine-treated group and 0.2% in the lapatinib 
plus capecitabine-treated group. Ado-trastuzumab emtansine 
should be temporarily discontinued in patients experiencing 
Grade 3 or 4 peripheral neuropathy until resolution to Grade ≤2. 

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Patients should be clinically monitored on an ongoing basis for 
signs or symptoms of neurotoxicity. 
10.3.8.7 
Extravasation: In ado-trastuzumab emtansine clinical studies, 
reactions secondary to extravasation have been observed. These 
reactions, frequently observed within 24 hours of infusion, were 
usually mild and comprised erythema, tenderness, skin irritation, 
pain, or swelling at the infusion site. Specific treatment for ado-
trastuzumab emtansine extravasation is unknown. The infusion 
site should be closely monitored for possible subcutaneous 
infiltration during drug administration. 
 
11.0 
Positron Emission Tomography (PET) 
11.1  Imaging will be performed on a GE Discovery 16 Ste PET-CT scanner (axial field of view 
15.4 cm). PET images will be acquired in 3D mode (septa retracted) and corrected for 
tissue attenuation based on co-registered CT acquired during the same examination. 
PET images will be reconstructed with spatial resolution of approximately 9 mm full-
width-at-half maximum (FWHM) using an iterative algorithm (OSEM).  
11.2 
18F-Fluorodeoxyglucose (18F-FDG): Standard 18F-FDG PET-CT examinations will be 
performed prior to the 64Cu-DOTA-trastuzumab PET-CT research procedure and every 
6 weeks during treatment with ado-trastuzumab emtansine. Patients will be injected via 
a peripheral vein with ≤ 15 mCi of 18F-FDG. Large-area (eyes to mid-thigh) PET-CT 
scans will be obtained beginning at 1 hour post-injection; time per bed position during 
the PET scan will be 2-3 minutes, depending on patient body habitus. 
11.3 
64Cu-DOTA-trastuzumab: Patients will be injected via a peripheral vein with ≤ 15 mCi 
of 64Cu-DOTA-trastuzumab. In order to allow the antibody to accumulate in tumor, PET-
CT scanning of 64Cu will be delayed until 18-24 hours post injection (Day 1). A second 
scan will be obtained 42-48 hours post injection (Day 2). Because of the limited amount 
of activity to be injected and the fact that only 18% of 64Cu decays produce a positron, 
the count rates will be low. To compensate, time per bed position will be relatively long 
and the axial field of view relatively short. (Day 1: 2 or 3 bed positions encompassing 
known tumors; 30 minutes per bed position if 2 bed positions, 20 minutes per bed 
position if 3 bed positions; Day 2: 1 or 2 bed positions, 60 or 30 minutes per bed position). 
Based on our prior clinical study, we know the scanning protocol defined above will yield 
adequate tumor visualization and signal-to-noise ratio in measurements of tumor uptake. 
For tumors at least 2 cm in diameter and average SUV (= tumor activity 
concentration/injected activity per unit body weight) of at least 3 in body regions for which 
tumor: background contrast is at least 4, the precision (coefficient of variation) of tumor 
SUV and tumor: background contrast measurements are expected to be about 10% and 
15%, respectively.  
 
12.0 
Image Analysis 
The 
64Cu-DOTA-trastuzumab and baseline 
18F-FDG PET-CT examinations will be 
interpreted by Dr. Park. Baseline and follow-up 18F-FDG PET-CT examinations will be 
interpreted for the purpose of evaluating tumor response by Dr. Gidwany who is blinded to the 
64Cu-DOTA-trastuzumab examinations.  
Tumor uptake of 18F-FDG will be measured in terms of SULpeak for evaluation of response, 
as prescribed by PERCIST [21]. In order to avoid potential bias, those measurements will be 
performed by the “second” radiologist, who will not have knowledge of the 64Cu-DOTA-
trastuzumab scans. In a separate analysis performed by Dr. Bading, we will also evaluate 
baseline SUVwt for  18F-FDG within a 3D isocontour half way between the image intensity of 

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adjacent background and the maximum voxel.[22] For each baseline FDG-positive tumor, SUVwt 
for 64Cu-DOTA-trastuzumab will be determined by applying the FDG whole-tumor volume of 
interest (VOI) to the CT-coregistered 64Cu image set. We denote to this metric of 64Cu-DOTA-
trastuzumab as SUVwt(FDG-matched).  Tumor sizes (product of maximum mutually 
perpendicular transaxial diameters as well as maximum axial diameter) will be estimated from 
coregistered CT. 
Tumor uptake will be evaluated in terms of standardized uptake values (SUV or SUL = tumor 
activity concentration decay-corrected to time of injection x body weight or lean-body mass 
/injected activity). The standard protocol for metabolic response assessment [PET Response 
Criteria in Solid Tumors (PERCIST)] employs SUL as the metric for tumor uptake of 18F-FDG. 
However, because ado-trastuzumab-emtansine dose is prescribed in terms of mg/body weight, 
we will use SUV for 64Cu-DOTA-trastuzumab.  
For 64Cu, SUVs will be evaluated in tumors, adjacent non-tumor tissue and selected non-
tumor organs and tissues [heart, blood (cardiac ventricles), liver, skeletal muscle]. PET 
quantification for 64Cu will be validated by comparing image-derived measurements of blood 
activity concentrations from the Day 1 and Day 2 scans with direct assays performed on whole 
blood samples taken just prior to each of those scans. Tumor uptake of 64Cu-DOTA-trastuzumab 
will be parameterized in terms of single-voxel maximum values SUVmax, “peak” values SUVpeak 
(defined as the maximum average value within a 1.2 cm diameter sphere scanned over the PET 
image of the tumor), and whole-tumor volumes of interest (SUVwt).[23]  
Tumor uptake of 18F-FDG will be measured in terms of SUVpeak for evaluation of response, 
as prescribed by PERCIST [23]. We will also evaluate SUVwt for  18F-FDG within a 3D isocontour 
half way between the image intensity of adjacent background and the maximum voxel.[22] For 
each baseline FDG-positive tumor, SUVwt for 64Cu-DOTA-trastuzumab will be determined by 
applying the FDG whole-tumor volume of interest (VOI) to the CT-coregistered 64Cu image set. 
We denote to this metric of 64Cu-DOTA-trastuzumab as SUVwt(FDG-matched). 
Relative ado-trastuzumab emtansine dose to individual tumors will be equated with 64Cu-
DOTA-trastuzumab SUVmax, SUVpeak or SUVwt for those tumors. Overall relative ado-
trastuzumab emtansine dose to tumor (DT) for a given patient will be equated with the 64Cu-
DOTA-trastuzumab VOI volume-weighted average SUVwt over all evaluated tumors. 
 
13.0 
Response Assessment 
Patient and individual tumor response to ado-trastuzumab emtansine will be determined 
from serial 18F-FDG/PET-CT, using the specifications prescribed in PERCIST regarding patient 
preparation, scan acquisition, tumor selection for response assessment, and measurement of 
tumor uptake.[23] The relatively coarse image resolution of PET can lead to errors in uptake 
measurements. PERCIST seeks to limit such “partial volume effect” errors by requiring a 
minimum tumor size of 2 cm for quantitative assessment of response. An ad hoc compensation 
for statistical noise and variations in the18F-FDG integral blood curve is made by comparing 
tumor uptake with liver uptake and the amount of random noise in the liver image.  
Response assessment is based on the single evaluable tumor (“target lesion”) with highest 
FDG uptake in the baseline and follow-up scans.  Note that different tumors may qualify as the 
target lesion in the baseline and follow-up scans. Complete metabolic response (CMR) is 
defined as target lesion SULpeak < liver SUL and no tumors (including the target lesion) with 
visually higher uptake than surrounding background in the follow-up scan. Partial metabolic 
response (PMR) is defined as reduction of target lesion SULpeak by at least 30% with no increase 
>30% in the size or SULpeak of any other lesion, and no new FDG-avid lesions. Progressive 
metabolic disease (PMD) is >30% increase in target lesion SULpeak, or visible increase relative 
to baseline in the volumetric extent of FDG tumor uptake with no decline in SUL, or any new 

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FDG-avid lesions. Stable metabolic disease (SMD) is the absence of any of the other 3 possible 
responses. 
PERCIST is designed to support response assessment at the patient level. Patients with 
metastatic breast cancer typically have multiple quantifiable lesions. (We evaluated as many as 
10/patient in our preliminary study.) In order to leverage the statistical power inherent in that 
multiplicity, we will extend PERCIST to individual tumors by applying the rules as they would be 
were the patient to have only one evaluable tumor. Thus, an individual tumor will be classified 
as (i) CMR if its image intensity on follow-up is < liver and not > its surroundings; (ii) PMR if its 
SULpeak declines more than 30% and its size does not increase more than 30% relative to 
baseline, (iii) PMD if its SULpeak and/or size increases more than 30% relative to baseline, and 
(iv) SMD if not CMR, PMR or PMD.  
Patients will be considered responders if they achieve CMR or PMR while on protocol 
therapy (prior to progressive disease or subsequent therapy). Patients with confirmed responses 
(meeting the criteria for response on two consecutive measurements) will be classified as being 
confirmed responders. 18F-FDG PET-CT performed prior to 64Cu-DOTA-trastuzumab PET-CT 
will provide the baseline scan for response assessment. Follow-up 18F-FDG PET-CT will be 
obtained at 6-week intervals for one year, i. e., after each two cycles of ado-trastuzumab 
emtansine.  After one year a PET/CT or CT scan can be performed at the discretion of the 
treating physican. 
 
14.0 
Laboratory Evaluations  
14.1 
Biomarker assessment: Although analysis of biomarkers is not included in the current 
pilot study, left over tumor from the required biopsy will be stored in Pathology for future 
analysis. We anticipate that high uptake of 64Cu-DOTA-trastuzumab will not predict 
response in some tumors and patients due to the presence of molecular mechanisms of 
resistance (MMRs) to ado-trastuzumab emtansine. A core biopsy or an excisional biopsy 
will be performed to confirm recurrent disease within 28 days of ado-trastuzumab 
emtansine infusion. After the diagnosis and HER2 status have been determined, residual 
tumor tissue will be stored in Pathology for future assessment of putative biomarkers of 
DM1 and trastuzumab resistance by IHC staining and/or genomic analysis.  
14.2 
Residual circulating trastuzumab from prior treatment: Patients will have recently 
been treated with trastuzumab and chemotherapy. Residual trastuzumab from those 
treatments could interfere with tumor uptake of 64Cu-DOTA-trastuzumab, although prior 
experience suggests that will not be the case. We address this issue in the study protocol 
by (i) restricting time since last trastuzumab administration to  6 wk prior to the 64Cu-
DOTA-trastuzumab procedure, and (ii) collecting blood samples which could be 
analyzed for residual trastuzumab. 1 Red-top tube (7 ml) will be collected, kept at room 
temperature and sent to Dr. Colcher’s lab for processing and storage each time. We will 
store venous blood taken from patients just prior to infusion of the trastuzumab pre-dose 
and compare tumor uptake of 64Cu-DOTA-trastuzumab with our prior results in HER2-
positive patients.[18] If uptake is, on average, lower than expected, we will attempt to 
account for that by measuring trastuzumab concentrations in the blood samples and 
correlating those data with tumor uptake in the respective patients. 
 
15.0 
Statistical Analysis  
    This is a pilot study of 10 patients to explore the relationship between tumor uptake of 
64Cu-DOTA-trastuzumab as measured by PET-CT and metabolic tumor response to 
ado-trastuzumab emtansine as assessed by 18F-FDG/PET-CT.  Results from this study 
will help guide future evaluations of 64Cu-DOTA-trastuzumab/PET-CT for use in 

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individualizing treatment of metastatic breast cancer with ado-trastuzumab emtansine or 
other trastuzumab-antibody drug conjugates.  
 
Specifically, we are seeking to:  
1. Correlate uptake of 64Cu-DOTA-trastuzumab by individual tumors with subsequent 
tumor response to ado-trastuzumab emtansine as assessed by serial 18F-FDG/PET-
CT. We expect an average of 5 evaluable tumors per patient. Thus, we expect to 
have an initial evaluation of 50 tumors. This will provide sufficient power to detect a 
correlation between pre-treatment tumor uptake of  64Cu-DOTA-trastuzumab and 
change in tumor uptake of  18F-FDG.  
Percentage change in SULpeak [%SULpeak(FDG) = 100 x (follow-up – 
baseline)/baseline] will be used as the metric for change in tumor uptake of 18F-FDG.  
We will evaluate  %SULpeak(FDG) vs. several alternative metrics of 64Cu-DOTA-
trastuzumab uptake [SUVmax, SUVpeak, SUVwt(FDG-matched) and the ratio 
SUVwt(FDG-matched)/ SUVwt(FDG)]. If we observe appreciable changes in tumor 
size between baseline and follow-up, we will also correlate the various metrics of 
64Cu uptake with percentage change in 18F-FDG “total lesion glycolysis” [23] [TLG =  
SUVwt(FDG) x volume within which SUVwt(FDG) is evaluated]. 
With approximately 50 lesions, we will have 90% power to detect a difference 
between a null hypothesis regression slope of 0 (comparing selected 64Cu-DOTA-
trastuzumab metric and change in FDG SULpeak or TLG and an alternative regression 
slope of 0.47, assuming that the standard deviation of the predictor variable is 4.3 
(the observed standard deviation from preliminary data on SUVmax for 64Cu-DOTA-
trastuzumab/PET-CT) and the standard deviation of the residuals equal that of the 
predictor variable, using a t-test with a 0.05 two-sided significance level. 
 
In addition, we will also compare 64Cu-DOTA-trastuzumab uptake metrics between 
“responding” (i. e. CMR + PMR) and “non-responding” (SMR + PMD) tumors. We 
expect about 40% (i. e. about 20) of the 50 tumors to respond [14].  With 20 
responding tumors and 30 non-responding tumors, using a t-test with 0.05 one-sided 
significance level, there is 85% power to detect a difference in means between 
responding and non-responding tumors, assuming a common standard deviation of 
4.3.   
A hierarchical model will be also be explored to evaluate the role of tumor-within-
patient effects. 
Assuming that correlation is observed, the metric(s) of 64Cu-DOTA-trastuzumab 
tumor uptake that best correlates with change in FDG uptake and/or best separates 
responding from non-responding tumors will be used in studies going forward.  
 
2. Compare tumor uptake of 64Cu-DOTA-trastuzumab PET between patients who do 
and patients who do not respond to ado-trastuzumab emtansine.  
We will compare 64Cu-DOTA-trastuzumab uptake between “responding” (i. e. CMR 
+ PMR) and “non-responding”  (SMR + PMD) patients. Metrics of overall upake will 
include (i) VOI volume-weighted average SUVwt(FDG-matched) over all evaluated 
tumors (a putative measure of relative overall ado-trastuzumab emtansine dose per 
unit tumor volume); and (ii) VOI volume-weighted average SUVwt(FDG-
matched)/SUVwt(FDG) over all evaluated tumors (a putative measure of relative 
overall ado-trastuzumab emtansine dose per viable tumor cell). We will also explore 
the response criteria based on the single tumor with max uptake (per PERCIST).  

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We expect 4 responders among the 10 patients [14]. Although such a small sample 
is unlikely to yield a significant difference between the 2 groups, we may see a trend 
(responders substantially > non-responders or vice-versa) that either encourages or 
discourages further investigation. This comparison is aimed at all responders, but we 
will also separately evaluate confirmed responders, and responders at the first 
evaluation. 
 
Further analysis on cut-points, ROC analysis, considering patients as responders or 
not, will also be analyzed in an exploratory fashion.  
 
3  Obtain tumor tissue for subsequent assessment of the presence of putative 
molecular mechanisms of resistance (MMRs) to ado-trastuzumab emtansine.  
Tumor biopsy material will be evaluated when funding becomes available, to help 
reduce the variability in response by adjusting for putative MMRs to ado-trastuzumab 
emtansine. The samples will be used to explore the correlation between the presence 
of MMRs as assessed by histopathology and tumor response to ado-trastuzumab 
emtansine both in univariate analysis and in combination with tumor uptake of 64Cu-
DOTA-trastuzumab as measured with PET/CT. 
 
    The information gained from this pilot study will determine whether 64Cu-DOTA-
trastuzumab/PET-CT warrants further evaluation for individualizing treatment with ado-
trastuzumab emtansine. If so, the pilot study will provide measures of variability and 
help select the proper metrics) for larger studies. 
 
16.0 
Toxicity Assessment / Follow Up 
16.1 
Patients will be monitored for toxicity during and immediately after infusion of the 
trastuzumab imaging pre-dose and 64Cu-DOTA-trastuzumab according to the study 
calendar. 
16.2 
Participants will begin ado-trastuzumab emtansine therapy within 3 days after 
completion of 64Cu-DOTA-trastuzumab/PET-CT. Side effects not known to be related to 
ado-trastuzumab emtansine therapy will be recorded.  
16.3 
Participants will be examined by the treating physician on days 7 and 14, and a 
complete blood count will be obtained. If there are any clinical concerns about cardiac 
toxicity, a MUGA will be obtained.  
16.4     Adverse events, serious adverse events, toxicities, conmeds, will be collected for 30 
days post cold trastuzumab/Cu-DOTA injection. 
 
17.0 
Data Management 
17.1 
Methods used for data collection: All clinical data is captured from the patient’s 
medical record. 
17.2 
Volunteer Identification: Participants identity will be linked to unique patient numbers 
(UPN). 
17.3 
Confidentiality: This research will be conducted in compliance with federal and state of 
California requirements relating to protected health information (PHI). The study will 
record individual imaging results and any side effects, and this will be linked to the 
subject’s identity using a UPN. The Protocol Management Team (PMT) consisting of the 
PI (Joanne Mortimer), , statistician (Paul Frankel PhD), and study nurses (Mary Carroll 

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RN, Phyllis Broene RN) are eligible to review research records, but all information will 
be treated confidentially. No identifiers will be used in any publication of the study results. 
17.4 
Data Reporting 
17.4.1 Confidentiality and Storage of Records: Data will be stored in encrypted, 
password protected, secure computers that meet all HIPAA requirements.   
When results of this study are reported in medical journals or at meetings, 
identification of those taking part will be withheld. Medical records of subjects will 
be maintained in strictest confidence, according to current legal requirements. 
They will be made available for review, as required by the FDA, HHS, or other 
authorized users such as the NCI, under the guidelines established by the 
Federal Privacy Act and rules for the protection of human subjects.   
17.4.2 Subject Consent Form:  
At the time of registration, the original signed and dated Informed Consent form, 
HIPAA research authorization form, and the California Experimental Subject’s Bill 
of Rights (for the medical record) and three copies (for the subject, the research 
record, and the Coordinating Center) must be available.  All Institutional, NCI, 
Federal, and State of California requirements will be fulfilled. 
 
64Cu-DOTA trastuzumab is administered under IND #109971, which is approved 
by and subject to the regulations of the FDA. 
17.4.3 Data Collection Forms and Submission Schedule:   All data will be collected using 
COH data collection forms via an electronic data capture system, Medidata 
RAVE.  Any original data collections forms will reside in the Clinical Trials Office.   
17.4.3.1 
The Eligibility Checklist must be completed by a protocol nurse or 
clinical research coordinator  and signed by a participating 
investigator prior to registering the patient. See Appendix 1. 
17.4.3.2 
Within two weeks of registration, the clinical research coordinator 
will submit all baseline forms located in Medidata RAVE.    
17.4.3.3 
Within two weeks of imaging or end of cycle, the clinical research 
coordinator will submit the following forms: 
 
Treatment Form  
 
Response/Follow-Up  
 
Adverse Events Collection Form  
 
Please refer to Medidata RAVE for a complete listing of all 
case report forms associated with this protocol. 
17.4.4 Results Reporting: City of Hope, as sponsor of IND #109971, will submit reports 
annually to the FDA within 60 days of the anniversary date that the IND went into 
effect (December 27, 2010) in accordance with 21 CFR 312.33. 
17.5 
Sharing results with participants: Information from the 64Cu-DOTA trastuzumab PET-
CT images will be shared with the patient and the treating physician if that information 
may impact the patient’s medical care. 
 
18.0 
Data Safety Monitoring Plan 
18.1 
Definition of Risk Level  
 

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This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety Monitoring 
Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx involving COH as 
IND holder. 
 
18.2 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, 
Collaborating Investigator, CRA/protocol nurse, and statistician is 
responsible for monitoring the data and safety of this study, including 
implementation of the stopping rules for safety and efficacy 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
Data and safety will be reported to the COH DSMC using the PMT 
report and submitted quarterly from the anniversary date of 
activation.  Protocol specific data collection will include the following 
items: tumor uptake on Cu-DOTA trastuzumab PET and infusion 
reactions.  
. 
18.3 
Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or 
change of an existing condition that occurs during or after treatment, whether or not it 
is considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if 
it is not listed in the investigator’s brochure and/or package insert; is not listed at the 
specificity or severity that has been observed; is not consistent with the risk information 
described in the protocol and/or consent; is not an expected natural progression of any 
underlying disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
 

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Expected Adverse Event - Any event that does not meet the criteria for an 
unexpected event OR is an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing 
the adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected adverse event that results in any of the following outcomes: 
 
Death 
 
Is life-threatening experiences (places the subject at immediate risk of death 
from the event as it occurred) 
 
Unplanned hospitalization equal or greater than 24 hours)) or prolongation of 
existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Secondary Malignancy 
 
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience or outcome that meets all 
three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcomes 
may have been caused by the drugs, devices or procedures involved in the 
research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously known 
or recognized. 
 
 
18.4  Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the 
COH DSMC and IRB within 5 calendar days according to definitions and guidelines 
at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem 
that occurs during the study conduct will be reported to the DSMC and IRB by 
submitting electronically in iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed 
by the physician, nurse, or reported by the patient, will be reported according to 
definitions and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and 

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Table 2 below.  Those SAEs that require expedited reporting will be submitted 
electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events 
that do not meet the criteria of serious OR are not unanticipated problems will be 
reported only in the continuation reports and PMT reports (see Table 2 below). 
 
Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting 
Timelines for the DSMC and IRB 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
 
 
 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of 
last day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of 
"serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
 
 
 
 
 

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

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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a 
UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a 
UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
ADDITIONAL REPORTING REQUIREMENTS  
 
SAEs meeting the requirements for expedited reporting to the FDA, as defined in 21 CFR 
312.32, will be reported as an IND safety report using the MedWatch Form FDA 3500A for 
Mandatory Reporting which can found at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  
OIDRA will assist the PI with the preparation of the report and submit the report to the FDA 
in accordance with the following: 
 
any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(2)]; 
 
 
any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of the 
information [21 CFR 312.32(c)(1)] 
 
 
any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
 
 
 

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19.0 
Protocol Deviations 
Protocol deviations using the Protocol Deviation Form must be submitted by the protocol nurse or the 
clinical research coordinator to the Coordinator (cccp@coh.org) for distribution. The clinical research 
coordinator at City of Hope will also submit copies to the Protocol Management Team and the City of 
Hope Data and Safety Management Board. 
19.1 
In accordance with the City of Hope Policy on Clinical Research Protocol Deviation, there 
will be a “no deviations” rule for this protocol. However, for subject safety or unforeseen 
scheduling problems, planned deviations from this protocol will be permitted with 
approval from the IRB in the form of a Single Subject Amendment. In addition, the 
sponsor (the CDMRC) must also approve any planned deviations. 
19.2 
All unplanned deviations will be reported to the City of Hope DSMC. 
19.3 
If there is a dispute among the persons involved in the provision of research treatment, 
in regard to whether a treatment deviates from the protocol, the facts of the case will be 
reported to the DSMC which will be serve as the arbiter of whether a deviation exists.   
19.4 
Study attrition: Participants who withdraw from study before completion of both imaging 
procedures will be replaced by another study participant.   

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