Pilot Study: Detection of Carcinomas Using 64Cu-Labeled M5A Antibody to Carcinoembryonic Antigen (CEA)
Phase: NA
Conditions: Breast Cancer, Colon Cancer, Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Gastrointestinal Cancer, Liver and Intrahepatic Biliary Tract Cancer, Lung Cancer, Metastatic Cancer, Pancreatic Cancer, Rectal Cancer, Thyroid Gland Medullary Carcinoma, Unspecified Adult Solid Tumor, Protocol Specific
Sponsor: City of Hope Medical Center

 
IRB 14238 
 
05/03/2018 
Packet : 19 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF RADIATION ONCOLOGY 
 
TITLE:  
Pilot Study: Detection of Carcinomas Using 64Cu-Labeled M5A Antibody to Carcinoembryonic 
Antigen (CEA) 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 14238  
Protocol Version date: 05/03/2018 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
COH Initial Approval 
Protocol Dated 11/17/14 
Version: 00 
Amendment 01 
Protocol Dated 12/19/14 
Version: 01 
Amendment 02 
Protocol Dated 02/24/15 
Version: 02 
Amendment 03 
Protocol Dated 04/13/15 
Version: 03 
Amendment 04 
Protocol Dated 09/30/15 
Version: 04 
Amendment 05 
Title Page Dated 04/21/16 
Version: 05 
Amendment 06 
Protocol Dated 08/11/16 
Version: 06 
Amendment 07 
Title Page Dated 09/09/16 
Version: 07 
Amendment 08 
Title Page Dated 01/24/17 
Version: 08 
Amendment 09 
Title Page Dated 03/01/17 
Version: 09 
Amendment 10 
Protocol Dated 09/27/17 
Version: 10 
Amendment 11 
Title Page Dated 10/25/17 
     Version: 11 
Amendment 12 
Title Page Dated 01/30/18 
     Version: 12 
Amendment 13 
Title Page/Protocol 05/03/18 
     Version: 13 
Amendment 14 
Title Page Dated 07/03/18 
     Version: 14 
Amendment 15 at Continuation Title Page Dated 06/03/19 
     Version: 15 
Amendment 16 at Continuation Title Page Dated 5/18/20 
     Version: 16 
Amendment 17 at Continuation    Protocol Dated 05/03/2018 (tp)                                                  Packet: 17 
Amendment 18 at Continuation    Protocol Dated 05/03/2018 (tp)                                                  Packet: 18 
Amendment 19 at Continuation Protocol Dated 05/03/2018 (tp) 
Packet: 19 
 
 
SITE:  
 
 
 
 
CEA-Producing Malignancies 
STAGE (If applicable): 
 
 
Any 
MODALITY:  
 
 
 
Radioimmunoimaging IV 
TYPE:  
 
 
 
 
Pilot 
 
PRINCIPAL INVESTIGATOR: 
 
Jeffrey Wong, MD 
 
 
COLLABORATING INVESTIGATOR(S): 
Jack Shively, PhD 
Paul Yazaki, PhD 
 
 
David Colcher, PhD 
Dave Yamauchi, MD  
 
Paul Frankel, PhD 
E. Kofi Poku, PharmD 
PARTICIPATING CLINICIANS: 
 
 
 
YiJen Chen, MD, PhD 
Dean Lim, MD 
Vincent Chung, MD 
Kurt Melstrom, MD 
Savita Dandapani, MD 
Maria Parayno, MD 
Marwan Fakih, MD 
 
Fouad Kandeel, MD  
 

 
IRB 14238 
 
05/03/2018 
Packet : 19 
 
Yanghee Woo, MD 
Ammar Chaudhry, MD 
Arya Amini, MD 
Scott Glaser, MD 
 
 

Page 1 of 31 
IRB Protocol No. 14238 
 
Version Date:  05/03/18 
Version:  13 
Protocol Synopsis 
Protocol Title: 
Pilot Study: Detection of Carcinomas Using 64Cu-Labeled M5A Antibody to Carcinoembryonic 
Antigen (CEA) 
Brief Protocol Title for the Lay Public (if applicable): 
Pilot Study: Detection of Carcinomas Using 64Cu-Labeled M5A Antibody to Carcinoembryonic 
Antigen (CEA) 
Study Phase: 
Pilot 
Participating Sites: 
City of Hope 
Rationale for this Study: 
CEA expression in normal tissues is largely restricted to the intestinal epithelium but is also seen 
in other sites, such as the testes.  This very limited normal tissue distribution combined with the 
widespread occurrence of CEA in tumors,  has led CEA to be a prominent target for experimental 
monoclonal antibody based radioisotopic imaging (radioimmunoscintigraphy). 
Objectives: 
The primary objective of this pilot study is to determine the ability of 64Cu labeled M5A antibody 
to localize to CEA positive cancers (such as GI, lung, medullary thyroid and breast cancers), as 
determined by PET imaging.   
Secondary objectives are: 
1. 
To characterize the frequency and titer of the human anti-human antibody (HAHA) 
response to 64Cu labeled M5A antibody. 
2. 
To determine the safety of administration of 64Cu labeled M5A antibody. 
Study Design: 
This is a three-year open-labeled pilot study that will enroll 20 patients with CEA-producing 
malignancies at the City of Hope National Medical Center.  
Endpoints: 
The primary aim of this pilot study is to evaluate the tumor targeting, pharmacokinetic, and 
immunogenicity properties of 64Cu labeled M5A antibody. The results of this pilot study will be 
used to determine if the antibody should be studied in a larger imaging trial. The data for the 20 
patients imaged will be used to summarize the scan results. 
Sample Size: 
20 patients 
 
 
 
 

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IRB Protocol No. 14238 
 
Version Date:  05/03/18 
Version:  13 
 
Estimated Duration of the Study 
3 years 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
Inclusion Criteria  
 Disease Status 
 
Patients must have histologically confirmed primary or metastatic cancer.  If 
biopsies were performed at an outside facility, the histology must be 
reviewed and confirmed by the Department of Pathology at the City of Hope. 
 
Patients must have tumors that produce CEA as documented by a current or 
past history of an elevated serum CEA above the institutional limit of 
normal, or by immunohistochemical methods.  NOTE:  Patients with 
colorectal cancer are exempt from this requirement since >95% are CEA 
positive.   
 Age Criteria, Performance Status and Life Expectancy  
 
Patients must be 18 years of age or older. 
 Child Bearing Potential 
The effects of 64Cu-M5A on the developing fetus are unknown.  For this reason, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control or abstinence) prior to study entry and for six months following duration of study 
participation.  Should a woman become pregnant or suspect that she is pregnant while 
participating on the trial, she should inform her treating physician immediately. 
 Protocol-Specific Criteria 
 
Patients must have a known site of disease. Please note, for patients 
undergoing neoadjuvant therapy, this requirement must be met 
retrospectively prior to the start of neoadjuvant therapy. Patients who are in 
radiological/clinical remission after neoadjuvant therapy, prior to infusion of 
radiolabeled antibody, are still eligible. 
 
Although not mandated by the protocol, the results of the CT scans and labs 
(CBC, CMP) that are performed as part of the standard work up should be 
available and should have been done within 2 months prior to study entry. 
 Informed Consent/Assent 
All subjects must have the ability to understand and the willingness to sign a written informed 
consent. 
 Prior Therapy 
 
Prior therapy (chemotherapy, immunotherapy, radiotherapy) must be 
completed at least 2 weeks prior to infusion of radiolabeled antibody 
 
 

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IRB Protocol No. 14238 
 
Version Date:  05/03/18 
Version:  13 
Exclusion Criteria: 
 
Patients should not have any uncontrolled illness including ongoing or active infection.    
 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to 64Cu-M5A. 
 
Patients must not have received prior chemotherapy or radiation for  2 weeks before study 
enrollment.   
 
Pregnant women are excluded from this study because 64Cu-M5A is an agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with 64Cu-
M5A, breastfeeding should be discontinued if the mother is treated with 64Cu-M5A.   
 Study-Specific Exclusions 
 
Any patient who has had exposure to mouse or chimeric (human/mouse) immunoglobulin 
and has antibody to the M5A. 
 Non-Compliance 
Subjects, who in the opinion of the investigator, may not be able to comply with the safety 
monitoring requirements of the study. 
 
Investigational Product Dosage and Administration: 
15 mCi/5 mg 64Cu-labeled M5A antibody, IV 
Clinical Observations and Tests to be Performed: 
See study calendar, section 10. 
Statistical Considerations: 
The data will be summarized using two methods.  Both methods will examine the efficacy of 
each modality in locating cancer in each of four regions: primary, hepatic, extra-hepatic 
abdominal, and extra-abdominal.  For the first method, referred to as a lesion analysis, the 
efficacy of each modality will be evaluated where a successful outcome will be defined as the 
ability of at least one known tumor identified by conventional imaging modalities to be imaged 
using the M5A antibody.  For the second method, referred to as a region analysis, a successful 
outcome will be defined as the identification of suspicious tissue within a region. 
Sponsor/Licensee: 
City of Hope 

Page 4 of 31 
IRB Protocol No. 14238 
 
Version Date:  05/03/18 
Version:  13 
Table of Contents 
 
SECTION ................................................................................................................................. PAGE 
1 
Goals and Objectives (Scientific Aims) .............................................................................. 8 
2 
Background ......................................................................................................................... 8 
2.1 
Introduction/Rationale for Development ............................................................... 8 
2.2 
Overview of Proposed Study ............................................................................... 10 
2.3 
Preclinical Studies ................................................................................................ 10 
2.4 
Human Studies ..................................................................................................... 15 
3 
Patient Eligibility .............................................................................................................. 16 
3.1 
Inclusion Criteria ................................................................................................. 16 
3.1.1 
Disease Status ......................................................................................... 16 
3.1.2 
Age Criteria, Performance Status and Life Expectancy ......................... 16 
3.1.3 
Child Bearing Potential ........................................................................... 16 
3.1.4 
Protocol-Specific Criteria ....................................................................... 16 
3.1.5 
Informed Consent/Assent ....................................................................... 17 
3.1.6 
Prior Therapy .......................................................................................... 17 
3.2 
Exclusion Criteria ................................................................................................ 17 
3.2.1 
Study-Specific Exclusions ...................................................................... 17 
3.2.2 
Non-Compliance ..................................................................................... 17 
3.3 
Inclusion of Women and Minorities .................................................................... 17 
4 
Screening and Registration Procedures............................................................................. 17 
4.1 
Screening Procedures ........................................................................................... 17 
4.2 
Informed Consent ................................................................................................ 17 
4.3 
Registration Requirements/Process ..................................................................... 18 
4.4 
Randomization and/or Dose Level Assignment................................................... 18 
5 
Treatment Program ........................................................................................................... 18 
5.1 
Treatment Overview ............................................................................................ 18 
5.1.1 
Schedule .................................................................................................. 18 
5.2 
Planned Duration of Therapy ............................................................................... 19 
5.3 
Criteria for Removal from Treatment .................................................................. 19 
5.4 
Subject Follow-Up ............................................................................................... 19 
5.5 
Supportive Care, Other Concomitant Therapy, Prohibited Medications ............. 19 
5.6 
Additional Studies ................................................................................................ 19 

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IRB Protocol No. 14238 
 
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5.6.1 
Laboratory Studies .................................................................................. 19 
6 
Dose Delays/Modifications for Adverse Events ............................................................... 20 
7 
Data and Safety Monitoring, Unanticipated Problems and Adverse Event Reporting ..... 20 
7.1 
Data and Safety Monitoring ................................................................................. 20 
7.2 
Monitoring and Personnel Responsible for Monitoring ...................................... 20 
7.3 
Definitions ........................................................... Error! Bookmark not defined. 
7.4 
Reporting of Unanticipated Problems and Adverse Events Error! Bookmark not 
defined. 
8 
Agent Information and Risks ............................................................................................ 23 
8.1 
DOTA-M5A humanized anti-CEA antibody ....................................................... 23 
8.1.1 
Description .............................................................................................. 23 
8.1.2 
Toxicology .............................................................................................. 23 
8.1.3 
Pharmacology – Handling, Storage, Dispensing and Disposal ............... 23 
8.1.4 
Risks ....................................................................................................... 24 
9 
Correlative/Special Studies ............................................................................................... 24 
10 
Study Calendar .................................................................................................................. 25 
11 
Endpoint Evaluation Criteria/Measurement of Effect....................................................... 26 
11.1 
Response Criteria ................................................................................................. 26 
12 
Data Reporting/Protocol Deviations ................................................................................. 26 
12.1 
Data Reporting ..................................................................................................... 26 
12.1.1 Confidentiality and Storage of Records .................................................. 26 
12.1.2 Subject Consent Form ............................................................................. 26 
12.1.3 Data Collection Forms and Submission Schedule .................................. 26 
12.2 
Protocol Deviations .............................................. Error! Bookmark not defined. 
12.2.1 Deviation Policy ..................................... Error! Bookmark not defined. 
12.2.2 Reporting of Deviations .......................... Error! Bookmark not defined. 
12.2.3 Resolving Disputes ................................. Error! Bookmark not defined. 
13 
Statistical Considerations .................................................................................................. 26 
13.1 
Study Design ........................................................................................................ 26 
13.2 
Sample Size Accrual Rate .................................................................................... 27 
13.3 
Statistical Analysis Plan ....................................................................................... 27 
14 
Human Subject Issues ....................................................................................................... 27 
14.1 
Institutional Review Board .................................................................................. 27 
14.2 
Recruitment of Subjects ....................................................................................... 27 
14.3 
Advertisements .................................................................................................... 27 

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IRB Protocol No. 14238 
 
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14.4 
Study location and Performance Sites ................................................................. 27 
14.5 
Confidentiality ..................................................................................................... 27 
14.6 
Financial Obligations and Compensation ............................................................ 28 
14.7 
Informed Consent Processes ................................................................................ 28 
15 
References ......................................................................................................................... 28 
 

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IRB Protocol No. 14238 
 
Version Date:  05/03/18 
Version:  13 
Abbreviations 
Abbreviation 
Meaning 
AE 
Adverse Event 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
 

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IRB Protocol No. 14238 
 
Version Date:  05/03/18 
Version:  13 
1 Goals and Objectives (Scientific Aims) 
The primary objective of this pilot study is to determine the ability of 64Cu labeled M5A 
antibody to localize to CEA positive cancers (such as GI, lung, medullary thyroid and breast 
cancers), as determined by PET imaging.   
Secondary objectives are: 
 To characterize the frequency and titer of the human anti-human antibody (HAHA) 
response to 64Cu labeled M5A antibody. 
 To determine the safety of administration of 64Cu labeled M5A antibody. 
2 Background 
2.1 
Introduction/Rationale for Development 
Carcinoembryonic antigen (CEA) is a 180 kD glycoprotein that was among the first tumor 
markers to be identified (1).  This antigen is well characterized with respect to both its molecular 
nature and its tissue distribution in man (2-4).  CEA expression in normal tissues is largely 
restricted to the intestinal epithelium but is also seen in other sites, such as the testes (5).  This 
very limited normal tissue distribution combined with the widespread occurrence of CEA in 
tumors,  has led CEA to be a prominent target for experimental monoclonal antibody based 
radioisotopic imaging (radioimmunoscintigraphy) (6-8).   
 
Early work with polyclonal anti-CEA antibodies and 131iodine label (6-8) was sufficiently 
encouraging to prompt further trials using murine monoclonal anti-CEA antibodies labeled with 
the metallic radionuclide 111indium (111In) (9-11). 111In labeled anti-CEA antibody 
radioimmunoscintigraphy clinical trials were initiated by Drs. Beatty and Shively at the City of 
Hope first using the murine anti-CEA monoclonal antibody, designated T84.66 (BB-IND 2014), 
an IgG1 with very high affinity for CEA (K=2.6 x 1010 M-1) and with no cross-reactivity to 
normal tissues (12, 13).  Initial trials used relatively low doses (2 mCi 111In activity/200 µg 
T84.66 antibody) to minimize patient anti-antibody response.  With this agent approximately 
67% (18/27) of primary colorectal carcinomas and 75% (3/4) of extra-abdominal colorectal 
metastases were visualized as hot spots (10, 14-16).  No significant adverse effects were noted.  
This trial also provided correlation of radioimmunoscintigraphy findings with surgical and 
pathologic findings at the time of laparotomy.  This allowed histologic confirmation of tumor in 
the areas of increased antibody uptake and correlation of tumor images with tumor 111In activity, 
tumor CEA content, and tumor histologic characteristics.  Tumors that were imaged had higher 
uptake of 111In (10.7 + 3.5 %ID/kg vs. 3.6 + 1.5 %ID/kg), were larger (38.1 + 17.8 cm3 vs. 6.0 + 
1.7 cm3), were more fungating than ulcerative, suggesting better vascularity, had higher CEA 
content (12.9 + 3.6 µg/gm vs. 3.3 + 1.7 µg/gm), and, by immunohistology, had CEA staining at 
the apical regions of the cells or the intraluminal regions of tumor.  Overall, these results 
suggested that the best imaging results were in tumors that were large, well-vascularized, and 
had large amounts of CEA that was accessible to the antibody.  Although approximately 40% of 
hepatic metastases were detected, almost all were visualized as cold spots due to the relatively 
high non-specific uptake of 111In labeled T84.66 antibody by surrounding normal liver. 
 

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IRB Protocol No. 14238 
 
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Murine antibodies have the disadvantage of being recognized as foreign by the patient’s immune 
system, which can lead to the formation of human anti-mouse antibodies (HAMA) in 30-50% of 
patients (17-20). The formation of HAMA can hasten blood clearance and therefore compromise 
the imaging or therapeutic efficacy of subsequently administered antibody (19, 21). Investigators 
have recently evaluated human/mouse chimeric and humanized antibodies, which have 
demonstrated decreased immunogenicity (22-26). Chimeric T84.66 (cT84.66) is a human/murine 
chimeric IgG1 monoclonal antibody developed at the City of Hope with high affinity (KA = 1.16 
x 1011 M-1) and specificity to CEA (27). Chimeric T84.66 was initially evaluated at this 
institution, conjugated to isothiocyanatobenzyl DTPA and radiolabeled with 111In, in a pilot 
biodistribution trial which entered patients with metastatic CEA-producing malignancies of 
various histologies (28). 111In-DTPA-cT84.66 was further evaluated in an antibody protein dose 
escalation trial in 15 patients with colorectal cancer (29). Results from these two studies 
demonstrated targeting to CEA-producing metastatic sites, imaging sensitivity comparable to 
other intact anti-CEA monoclonals, no allergic reactions, decreased immunogenicity compared 
to murine monoclonals, and no significant changes in biodistribution or tumor localization with 
escalation of antibody protein doses from 5 mg to 105 mg. In addition, antibody uptake 
determined from biopsy samples demonstrated that cT84.66, if labeled with 90yttrium ( 90Y), 
could potentially deliver therapeutic radiation doses to tumor and regional lymph nodes in a 
subset of patients.  
 
M5A is the humanized version of cT84.66 engineered to further reduce the immunogenicity 
compared to cT84.66.  Recently a phase I therapy trial of 111In/90Y labeled M5A was completed. 
Tumor targeting was demonstrated. Eighteen patients received the initial 111In-M5A imaging 
dose of the antibody, with 17 of 18 targeting known sites of disease. Sixteen patients received the 
therapy dose of 90Y radiolabeled M5A of which only two patients demonstrated an anti-antibody 
response suggesting further decrease in immunogenicity compared to chimeric T84.66. No 
allergic reactions were seen. (Wong et al, unpublished results; manuscript in preparation) 
 
Given the experience with M5A to date, M5A may also be a potential imaging agent of CEA+ 
cancers, especially when labeled with a positron emitters such a Cu-64 for PET imaging. PET 
imaging is rapidly becoming an important imaging modality for an increasing number of 
malignancies for its ability to detect and differentiate metabolic and phenotypic differences 
between tumor and normal tissues. The use of positron emitting radionuclides provides 
advantages in imaging quality over traditional imaging using gamma-emitting radionuclides.  
 
Cu-64 is a promising PET radionuclide with a half-life of 12.7 hours. It is currently being 
evaluated in clinic trials, which including 64Cu-ATSM, which targets tumor hypoxia, and 64Cu-
trastuzumab, which targets Her2+ cancers. Images with 64Cu-trastuzmab compare favorably to 
those seen on an earlier COH trial using 111In-trastuzumab in patients with Her2+ breast 
cancer. 
 

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2.2 
Overview of Proposed Study 
This is a three-year open-labeled pilot study that will enroll 20 patients with CEA-producing 
malignancies at the City of Hope National Medical Center.  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
the applicable regulatory requirements. 
 
2.3 
Preclinical Studies 
In-111-DOTA M5A Anti-CEA Antibody 
The pre-clinical characterization of M5A has been published (30). Tumor uptake at 48 hours was 32.65 
%injected dose/gram in LS174T human colon cancer xenograft tumor bearing mice. Murine imaging 
studies with In-111-DOTA M5A are shown below with clearly seen tumor targeting.  
 
 
Tumor imaging by PET and targeting is also seen with 64Cu-DOTA-M5A in the same tumor 
bearing mouse model. (Image at 23 hours in mouse with right and left SQ tumors; see Fig. 3) 
 
The preclinical evaluation of Cu-64 labeled M5A is summarized below: 
Radiolabeling of hT84.66-M5A/NHS-DOTA 
Radiolabeling with Copper-64 
The hT84.66-M5A/NHS-DOTA Final Vialed Product (FVP) was radiolabeled with Copper-64 
(64Cu) obtained from Washington University (St. Louis) in a manner similar to that planned for 
clinical studies.  The radiolabelings was performed on July 23, 2014 to August 6, 2104 according 
to RIT SOP 0311 “Radiolabeling of hT84.66-M5A/NHS-DOTA with Cu-64 for Clinical Use” 

Page 11 of 31 
IRB Protocol No. 14238 
 
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and purified by Size Exclusion Chromatography according to RIT SOP-0322 “HPLC 
Purification of Radiolabeled Antibodies for Clinical Use”.  The 64Cu-labeled hT84.66-
M5A/NHS-DOTA was purified using Superdex 200.  The radioactive trace (red) and the UV 
(A280) trace (blue) from these 3 runs are presented in Error! Reference source not found. and 
showed a single peak with no evidence of aggregates or unincorporated 64Cu.  The peak was 
collected and pooled.  Reference is made to Section 11.4.8 and 11.4.10 for a copy of the noted 
SOPs. 
The 64Cu to be used in the clinical trial proposed under this IND will be purchased from the 
Mallinckrodt Institute of Radiology at the Washington University School of Medicine.  
Radiolabeling will be carried out in the City of Hope Radiopharmacy.  The process entails 
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 human serum albumin (HSA) and dispensed through the radiopharmacy at City 
of Hope.   
 
Figure 1: Purification of 64Cu-hT84.66-M5A/NHS-DOTA by High Performance Liquid 
Chromatography using Size Exclusion (Superdex 200 GL) 
0
1 0
2 0
3 0
4 0
5 0
6 0
T im e  ( m in )
R a d i o a c t i v i t y
( 0 7 2 3 1 4 )
0
1 0
2 0
3 0
4 0
5 0
6 0
T im e  ( m in )
R a d i o a c t i v i t y
( 0 7 3 0 1 4 )
0
1 0
2 0
3 0
4 0
5 0
6 0
T im e  ( m in )
R a d i o a c t i v i t y
( 0 8 0 6 1 4 )
 
Purity of Radiolabeled Product 
Samples of the purified radiolabeled hT84.66-M5A/NHS-DOTA were taken for analysis of 
radiochemical purity and immunoreactivity as well as endotoxin level and sterility. 
Size Exclusion Chromatography 
The purity of the pooled peak preparation was analyzed on an analytical HPLC Size Exclusion 
Chromatograph using Superose-6.  The purified radiolabeled 64Cu-labeled hT84.66-M5A/NHS-

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IRB Protocol No. 14238 
 
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DOTA exhibited a single peak at a size consistent with IgG (Error! Reference source not found. 
[red]). 
The immunoreactivity of the 64Cu-labeled hT84.66-M5A/NHS-DOTA post-labeling was tested 
using human CEA protein in an HPLC SEC shift assay.  The immunoreactivity was expressed as 
a percentage of the CEA -bound 64Cu-labeled hT84.66-M5A/NHS-DOTA vs. unbound 64Cu-
labeled hT84.66-M5A/NHS-DOTA as determined by radioactive monitoring of size exclusion 
HPLC.  The immunoreactivity of this 64Cu-labeled hT84.66-M5A/NHS-DOTA preparation was 
found to be 100% as evidenced by the shift of the radiolabeled product (Error! Reference source 
not found. [blue]).  The final product was of exceptional purity and immunoreactivity as 
demonstrated by SEC-HPLCs of the purified products. 
 
Figure 2: Immunoreactivity of 64Cu-hT84.66-M5A/NHS-DOTA to Carcinoembryonic 
Antigen Analyzed by Size Exclusion Chromatography (Superose 6 GL) 
2 0
3 0
4 0
5 0
T i m e  ( m i n )
R a d i o a c t i v i t y
C o n t r o l
+  C E A
( 0 7 2 3 1 4 )
2 0
3 0
4 0
5 0
T i m e  ( m i n )
R a d i o a c t i v i t y
( 0 7 3 0 1 4 )
C o n t r o l
+  C E A
2 0
3 0
4 0
5 0
T i m e  ( m i n )
R a d i o a c t i v i t y
( 0 8 0 6 1 4 )
C o n t r o l
+  C E A
 
 
Limulus Amoebocyte Lysate (LAL) 
The endotoxin content of the products post-labeling will be determined using the Charles River’s 
Endosafe™-PTS system which is a rapid, point-of-use test system that utilizes FDA-licensed 
LAL formulations loaded into a test cartridge along with a handheld spectrophotometer.  The 
endotoxin concentration is routinely determined to be < 0.05 endotoxin units/mL.  The amount 
of final product administered is 25 mL.  Therefore the administered dose will normally have 
<1.25 EU.  No product will be administered with > 2 EU/mL.  Results from the three lots labeled 
between July 23, 2014 to August 6, 2104 had <0.05 EU/mL. 
Sterility 
Sterility of the radiolabeled products will be tested according to USP 27, Chapter 71 under RIT 
SOP 0501 “Sterility Test”.  This is a 14 day test and the 64Cu has a half-life of approximately 

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12.7 hours.  Therefore, the results of the sterility test will not be obtained until after the drug has 
been administered.  Test labelings of 64Cu-labeled hT84.66-M5A/NHS-DOTA, including those 
of July 23, 2014 to August 6, 2014, has always been shown to be sterile. 
 
Stability of hT84.66-M5A/NHS-DOTA 
Stability Monitoring Program 
A stability monitoring program has been established for the vialed product for radiolabeling.  
The stability of antibody constructs that are radiolabeled prior to patient administration will be 
monitored on a regular basis. 
We will evaluate the purity, sterility and immunoreactivity of the antibody constructs after 
radiolabeling on a schedule to ensure that no more than 6 months has elapsed between stability 
testing and administration to a patient.  The following tests will be performed.   
 
Assay 
Specifications 
Sterility 
Sterile 
Pyrogen Level 
<50 EU per patient dose 
Immunoreactivity 
>80% immunoreactivity 
Size Exclusion 
Chromatography 
IgG Single peak ≥. 95.0% 
Aggregates  5.0% 
 
The testing will be performed using the following SOPs. The data will be reviewed by the 
Director of the Radiopharmacy. 
 
RIT SOP 0501 
Sterility Testing (USP) 
RIT SOP 0503 
Pyrogenicity Testing using Endosafe PTS System 
RIT SOP 0504 
Immunoreactivity by Liquid Phase HPLC Assay* 
* This SOP is based on the use of purified antigen and a shift in the elution of the 
radiolabeled material to a higher molecular weight. 
 
 
In Vivo Studies using 64Cu-labeled hT84.66-M5A/NHS-DOTA. 
Following purification on the TosoHaas G2000SW column, 64Cu–labeled hT84.66– M5A/NHS-
DOTA IgG pooled peak material (≈ 100µCi/mouse) was injected into athymic mice bearing the 

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human xenotransplanted colon carcinoma, LS–174T (≈ 1 × 106 cells s.c. bilaterally).  Tumor 
imaging and biodistribution studies were conducted. 
PET images were taken at 4hrs and at 1 and 2 days (Figure 3).  The blood pool can be seen in 
the early image which clears over time.  The bilateral tumors are detected by 4 hrs and show 
increased uptake at 1 day.  
Figure 3:  PET Imaging of 64Cu-hT84.66-M5A/NHS-DOTA in Mice Bearing Bilateral 
Human Colorectal Cancer Xenografts 
 
 
The animals were euthanized after the 2 day images and the tissues were weighed and counted.  
The tumors retained approximately 40% of the injected dose per gram (Figure 4).  The blood has 
approximately 11%ID/gm while the other major organs retained 3-5%ID/gm. 
 
Figure 4:  Biodistribution of 64Cu-hT84.66-M5A/NHS-DOTA in Mice Bearing Bilateral 
Human Colorectal Cancer Xenografts 
% Injected Dose/Gram
Blood
Heart
Lung
Liver
Spleen
Stomach + Contents
Sm. Int. + Contents
Lg. Int. + Contents
Kidney
Muscle
Right Tumor
Left Tumor
Axial LN
Carcass
0
10
20
30
40
50

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2.4 
Human Studies 
Yttrium-90 labeled Humanized Anti-CEA M5A Antibody 
Initial studies evaluated the antibody as a therapy agent labeled with Y-90. They are summarized 
below and are currently closed to accrual. 
IRB 05198 A Phase I Study of Yttrium-90 labeled Humanized Anti-CEA M5A Antibody in 
Patients with CEA Producing Advanced Malignancies: Recently a phase I therapy trial of 
111In/90Y labeled M5A was completed.  
Originally the study combined Y-90 M5A and Gemcitabine.  Three patients were enrolled at the 
first dose level (12 mCi/m2 Y-90) with Gemcitabine.  Two received 2 cycles and had stable 
disease.  One received 1 cycle and had progressive disease.  One patient was enrolled at the next 
dose level with Gemcitabine and she had stable disease.  The toxicities seen with Y-90 and 
Gemcitabine were more severe, sooner and longer in duration than our previous study; therefore 
we amended the protocol to omit Gemcitabine . 
Since then 6 patients have been treated on the first dose level (12 mCi/m2 Y-90) without 
Gemcitabine.  The 1st and 6th patient had dose limiting toxicities (DLT) (toxicities did not return 
to grade 1 by 10 weeks post RIT), therefore we amended the protocol to state that we would 
enroll 6 patients at a lower dose level (10 mCi/m2 Y-90) without Gemcitabine, and then close the 
trial (Serial No. 0003, submitted August 19, 2008). 
Of the 6 patients who received the 12 mCi/m2 Y-90 without Gem, 2 had SD and 4 had PD.  One 
had a positive anti-antibody result.  None received a 2nd cycle.  
Six patients have been treated on the reduced dose (10 mCi/m2 Y-90) without Gemcitabine.  
Four of the 6 received a second cycle.  Best responses for these 6 patients include 5 with stable 
disease, 1 with progressive disease.  One patient had an antibody response.  None of these 6 
patients experienced a DLT. 
 
IRB 09053 : A Phase II Trial of Radioimmunotherapy (Y-90 M5A) Following Hepatic 
Resection and FOLFOX Chemotherapy (±Bevacizumab) for Metastatic Colorectal 
Carcinoma to the Liver 
We have consented five patients on this trial. Three eventually decided not to participate on the 
trial; another was too ill and has since passed away. The remaining patient was treated on the 
study but progressed 5 months post antibody treatment. We are currently following her for 
survival. 
 
IRB 10038: A Phase I Trial of Radioimmunotherapy (Y-90 M5A) in Combination with 
FOLFIRI and Bevacizumab Chemotherapy for Metastatic Colorectal Carcinoma  
 
Three patients were enrolled on this study. Two had DLTs: one was low ANC requiring 
neupogen support; and the other was grade 4 PLT count with prolonged platelet recovery. All 
patients received only one cycle. Since two out of the first three patients experienced a DLT on 
the first dose level, we closed the study. Best responses were 1 partial response (PRu), 2 stable 

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disease (SD). The patient with PRu has now progressed (8 mo post study therapy) and one 
patient with SD has progressed (4.6 mo post study therapy). The third patient underwent 
debulking surgery. As of this time, all three patients have expired due to disease progression.  
In our previous imaging studies, no significant adverse events have been seen. However, an 
emergency cart will be available near the patient at all times of injection.  Anticipated events and 
management would be:  fever and chills, which will be treated with acetaminophen; hypotension 
or frank anaphylactic shock, which will be treated with intravenous fluids, pressors, and 
corticosteroids; bronchospasm and respiratory distress, which will be treated with 
bronchodilators.  The patients will also be observed for other possible toxicities, including 
pulmonary toxicity, renal toxicity, skin rash, and serum sickness.  Appropriate therapy will be 
instituted if any one or more of these develop.  Adverse reaction form (see Case Report Form) 
will be completed in all patients suffering any potential adverse reaction.  The toxicity will be 
graded using the NCI common toxicity scale CTCAE v4.03.  Any patient developing any chest 
pain, respiratory distress, fever or hypotension with a fall of more than 25mm in systolic blood 
pressure will not be given further injection of antibody. 
 
3 Patient Eligibility 
3.1 
Inclusion Criteria  
3.1.1 
Disease Status 
 
Patients must have histologically confirmed primary or metastatic cancer.  If biopsies 
were performed at an outside facility, the histology must be reviewed and confirmed 
by the Department of Pathology at the City of Hope. 
 
Patients must have tumors that produce CEA as documented by a current or past 
history of an elevated serum CEA above the institutional limit of normal, or by 
immunohistochemical methods.  NOTE:  Patients with colorectal cancer are exempt 
from this requirement since >95% are CEA positive.   
3.1.2 
Age Criteria, Performance Status and Life Expectancy  
 
Patients must be 18 years of age or older. 
3.1.3 
Child Bearing Potential 
The effects of 64Cu-M5A on the developing fetus are unknown.  For this reason, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method of birth control 
or abstinence) prior to study entry and for six months following duration of study participation.  Should a 
woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform 
her treating physician immediately. 
3.1.4 
Protocol-Specific Criteria 
 
Patients must have a known site of disease. Please note, for patients undergoing 
neoadjuvant therapy, this requirement must be met retrospectively prior to the start of 
neoadjuvant therapy. Patients who are in radiological/clinical remission after 
neoadjuvant therapy, prior to infusion of radiolabeled antibody, are still eligible. 
 
Although not mandated by the protocol, the results of the CT scans and labs (CBC, 
CMP) that are performed as part of the standard work up should be available and 
should have been done within 2 months prior to study entry. 

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3.1.5 
Informed Consent/Assent 
All subjects must have the ability to understand and the willingness to sign a written informed consent. 
3.1.6 
Prior Therapy 
 
Prior therapy (chemotherapy, immunotherapy, radiotherapy) must be completed at 
least 2 weeks prior to infusion of radiolabeled antibody 
3.2 
Exclusion Criteria 
 
Patients should not have any uncontrolled illness including ongoing or active infection.   
 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
64Cu-M5A. 
 
Patients must not have received prior chemotherapy or radiation for  2 weeks before study 
enrollment.   
 
Pregnant women are excluded from this study because 64Cu-M5A is an agent with the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for adverse events 
in nursing infants secondary to treatment of the mother with 64Cu-M5A, breastfeeding should be 
discontinued if the mother is treated with 64Cu-M5A.   
3.2.1 
Study-Specific Exclusions 
 
Any patient who has had exposure to mouse or chimeric (human/mouse) immunoglobulin and has 
antibody to the M5A. 
3.2.2 
Non-Compliance 
Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring 
requirements of the study. 
3.3 
Inclusion of Women and Minorities 
The study is open anyone regardless of gender or ethnicity.  Efforts will be made to extend the accrual to 
a representative population, but in a trial which will accrue approximately 10 subjects, a balance must be 
struck between subject safety considerations and limitations on the number of individuals exposed to 
potentially toxic or ineffective treatments on the one hand and the need to explore gender, racial, and 
ethnic aspects of clinical research on the other.  If differences in outcome that correlate to gender, racial, 
or ethnic identity are noted, accrual may be expanded or additional studies may be performed to 
investigate those differences more fully. 
4 Screening and Registration Procedures 
4.1 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values, even if the studies were 
done before informed consent was obtained.  Reference is made to Section 10.0 – Study Calendar. 
4.2 
Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
subject and a signed informed consent will be obtained.  Documentation of informed consent for 
screening will be maintained in the subject’s research chart and medical record.   

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4.3 
Registration Requirements/Process 
Subjects will be registered by the assigned Clinical Research Nurse and Clinical Research Coordinator. 
4.4 
Randomization and/or Dose Level Assignment  
All patients will receive 15 mCi/5 mg 64Cu-labeled M5A Antibody 
5 Treatment Program 
5.1 
Treatment Overview 
Ten patients will be enrolled in this pilot study.  The patients will receive 15 mCi/5 mg 64Cu labeled M5A 
antibody. 
All study treatment will be outpatient. 
5.1.1 
Schedule 
For a tabular view of the treatment, monitoring, and follow-up schedule, see study calendar in Section 10. 
The infusion of the 64Cu-labeled M5A Antibody will be given on “Day 0”, and there will be scans on days 
1 and 2, and blood draws for PK analysis on Day 0, Day 1 and Day 2.  See study calendar in Section 10. 
ANTIBODY ADMINISTRATION 
As in the case of any radioactive material, care will be taken to minimize radiation exposure to the 
patient, consistent with proper patient management, and to ensure minimum radiation exposure to the 
occupational worker.  There will be strict adherence to aseptic technique throughout. 
 
M5A antibody will be labeled with 64Cu.  Activity, volume, date and time of the radiopharmaceutical 
preparation will be recorded on the radiopharmacy CRF.  Fifteen mCi/5 mg of the labeled M5A antibody 
(64Cu labeled M5A antibody) will be brought up to approximately 25 mL of saline with 1% human serum 
albumin (HSA) and mixed prior to infusion. Antibody dose will be given by slow IV push.  
 
After the injection is completed, the patients are then observed per routine.  In addition to routine 
observation, vital signs including pulse, respirations, blood pressure and temperature will be taken prior to 
study drug administration, every 15 minutes for up to one hour following administration, and at 
approximately the 3-4 hour post start of infusion blood draw.  The use of 64Cu labeled M5A antibody will 
be recorded in the drug accountability form. 
 
IMAGING STUDIES 
1. 
PET images will be performed in 3D mode (septa retracted) and corrected for tissue 
attenuation based on co-registered CT acquired during the same examination. PET images 
will be reconstructed with spatial resolution of approximately 9 mm full-width-at-half 
maximum (FWHM) using an iterative algorithm (OSEM). 
 
 
2. 
64Cu -DOTA-M5A. Patients will be injected via a peripheral or central vein with 15 mCi of 
64Cu-DOTA-M5A. Scans will be performed the following day (Day 1) and Day 2. Because of 
the limited amount of activity to be injected and the fact that only 20% of 64Cu decays 
produce a positron, the count rates will be low. To compensate, time per bed position will be 

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relatively long and the axial field of view relatively short. (Day 1: 2-3 bed positions 
encompassing known tumors; 30 min per bed position if 2 bed positions, 20 min per bed 
position if 3 bed positions; Day 2: 1 bed position, 60 min). Based on prior phantom studies, 
we expect the scanning protocol defined above to yield adequate tumor visualization as well 
as measurements of tumor uptake and tumor: adjacent background activity concentration 
ratios ("tumor:bdg contrast") for tumors of at least 2 cm in diameter and average SUV (= 
tumor activity concentration/injected activity per unit body weight) of at least 3 in body 
regions for which tumor:bdg contrast is at least 4. The precision (coefficient of variation) of 
tumor SUV and tumor:bgd contrast measurements is expected to be about 10% and 15%, 
respectively. 
 
3. 
Image Analysis:  The Cu-64 SUVs will be evaluated in tumors, adjacent non-tumor tissue and 
selected non-tumor organs and tissues (heart, extracardiac mediastinum, liver, skeletal 
muscle). Tumor sizes (product of maximum mutually perpendicular transaxial diameters as 
well as maximum axial diameter) will be estimated from coregistered CT. Tumor uptake of 
64Cu-DOTA-M5A will be parameterized in terms of single-voxel maximum values SUVmax 
and whole-tumor volumes of interest (SUVwhtum) as defined from the coregistered CT 
images. Ratios of tumor to non- tumor activity concentration will also be calculated for 
adjacent tissue, extracardiac mediastinum, liver, and skeletal muscle. Receiver-operator curve 
(ROC) analysis will be performed to estimate optimal cutoff values of SUVmax, SUVwhtum, 
tumor:background and tumor:organ ratios for classifying tumors as “CEA positive” or “CEA 
negative.”  Note: the image analysis will be done prior to completion of the study (not in real 
time). 
 
5.2 
Planned Duration of Therapy 
Study duration is 3 months.  See study calendar in section 10.  Each patient will be considered to have 
completed the study three months following antibody infusion with the completion of the HAHA sample 
and provided that all case report forms have been completed to the principal investigator's satisfaction. 
5.3 
Criteria for Removal from Treatment 
Patients may withdraw from the study for personal reasons at any time.  A patient may also be dropped 
from the study by the investigator for other reasons including medical concerns or failure to comply with 
the protocol. 
5.4 
Subject Follow-Up 
See study calendar.  
5.5 
Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Not applicable. 
5.6 
Additional Studies 
Not applicable. 
5.6.1 
Laboratory Studies 
See study calendar section 10. 

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6 Dose Delays/Modifications for Adverse Events 
In our previous imaging studies, no significant adverse events have been seen.  Anticipated events and 
management would be:  fever and chills, which will be treated with acetaminophen; hypotension or frank 
anaphylactic shock, which will be treated with intravenous fluids, pressors, and corticosteroids; 
bronchospasm and respiratory distress, which will be treated with bronchodilators.  The patients will also 
be observed for other possible toxicities, including pulmonary toxicity, renal toxicity, skin rash, and 
serum sickness.  Appropriate therapy will be instituted if any one or more of these develop.  Adverse 
reaction form (see Case Report Form) will be completed in all patients suffering any potential adverse 
reaction.  The toxicity will be graded using the NCI common toxicity scale CTCAE v4.03.  Any patient 
developing any chest pain, respiratory distress, fever or hypotension with a fall of more than 25mm in 
systolic blood pressure will not be given further injection of antibody. 
7 Data and Safety Monitoring Plan  
Definition of Risk Level 
This is a Risk Level 4 study, as defined in the City of Hope Institutional Data and Safety Monitoring 
Plan [policy dated 07/09/2014].  This determination was made because the study involves COH as 
IND holder and radioimmunoimaging with 64Cu-labeled M5A antibody. 
 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) is responsible for monitoring the data and safety of this study.  
The PMT consists of the Principal Investigator (PI), Collaborating Investigator(s), Biostatistician, 
Research Protocol Nurse and Clinical Research Coordinator. 
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the frequency 
prescribed in the City of Hope Institutional Data and Safety Monitoring Plan [policy dated 07/09/2014].  
Important decisions made during PMT meetings (i.e., dose escalation, de-escalation, etc.) only need to be 
noted in the PMT Report submitted to the Data and Safety Monitoring Committee (DSMC). 
 
Adverse Events and Serious Adverse Events 
The PI will be responsible for determining the event name, assessing the severity (i.e., grade), 
expectedness, and attribution of all adverse events. 
 
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.  
 
Reporting Non-serious Adverse Events – Adverse events will be collected after the patient is given the 
study treatment or any study related procedures.  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 PMT Report. 
 

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Serious Adverse Event (SAE) [Modified from the definition of unexpected adverse drug experience in 
21 CFR 312.32] - defined as any expected or unexpected adverse events that result in any of the following 
outcomes: 
 
Death 
 
Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Secondary malignancy 
 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias of convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse). 
 
Reporting Serious Adverse Events - begins after study treatment or any study related procedures.  All 
SAEs occurring during this study, whether observed by the physician, nurse, or reported by the patient, 
will be reported according to the approved City of Hope’s Institutional policy [policy effective date:  
05/14/14].  Serious Adverse Events that require expedited reporting will be submitted electronically using 
iRIS. 
 
Adverse Event Name and Severity 
The PI will determine the adverse event name and severity (grade) by using the CTCAE version 4. 
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. 
 
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. 
 
Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
Definite - The AE is clearly related to the investigational agent or study procedure and unrelated to 
any other cause. 
Probable - The AE is likely related to the investigational agent or study procedure and unlikely 
related to other cause(s). 
Possible -The AE may be related to the investigational agent or study procedure and may be related 
to another cause(s). 

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Unlikely -The AE is doubtfully related to the investigational agent or study procedure and likely 
related to another cause(s). 
Unrelated -The AE is clearly not related to the investigational agent or study procedure and is 
attributable to another cause(s). 
 
COH Held IND  
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (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. 
The criteria that require reporting using the Medwatch 3500A are: 
 
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)] 
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 approved 
City of Hope’s Institutional policy [policy effective date:  05/14/14]. 
 
Deviations and Unanticipated Problems 
 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred without prior 
IRB approval.  Investigators may deviate from the protocol to eliminate immediate hazard(s) for the 
protection, safety, and well-being of the study subjects without prior IRB approval.  For any such 
deviation, the PI will notify the COH DSMC and IRB within 5 calendar days of its occurrence via iRIS in 
accordance with the Clinical Research Protocol Deviation policy [policy effective date:  11/07/11].   
 
Single Subject Exception (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures 
called for in a protocol are not in the best interests of a specific patient.  It is a deviation that is anticipated 
and receives prior approval by the PI and the IRB.  The SSE must be submitted as a “Single Subject 
Exception Amendment Request” via iRIS in accordance with IRB guidelines and the Clinical Research 
Protocol Deviation policy [policy effective date:  11/07/11].  An IRB approved SSE does not need to be 
submitted as a deviation to the DSMC. 
 
Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all three of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 

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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. 
Any UP that occurs during study conduct will be reported to the DSMC and IRB in accordance with the 
City of Hope’s Institutional policy [policy effective date:  05/14/14] using iRIS.   
 
COH Held IND 
The Office of IND Development and Regulatory Affairs (OIDRA) will assist the PI in reporting the event 
to the Food and Drug Administration (FDA). 
 
8 Agent Information and Risks 
8.1 
DOTA-M5A humanized anti-CEA antibody 
8.1.1 
Description 
Chemistry/Mechanism of Action:  M5A is a humanized IgG monoclonal antibody developed at the City 
of Hope National Medical Center.  It recognizes the A3 domain of the CEA molecule and has little cross 
reactivity with other members of the CEA family.  It binds CEA with a high affinity (approximately 2 x 
1010 /M) and is able to bring a bound radioisotope into close proximity.   It is labeled with Cu-64 to form 
the imaging agent.  This will be under COH IND #125855. 
8.1.2 
Toxicology 
A possible complication of treatment is also the development of human anti-human antibody antibodies 
(HAHA). 
8.1.3 
Pharmacology – Handling, Storage, Dispensing and Disposal 
Formulation:  Cu-64-DOTA-M5A anti-CEA antibody is produced and labeled at the City of Hope by the 
Department of Immunology.  See below for details. 
Administration:  See below for details regarding administration and radiation safety. 
Supplier: M5A anti-CEA antibody is an investigational agent produced and labeled at the City of Hope by 
the Department of Immunology. 
Test Preparations:  The DOTA-M5A antibody will be provided as a sterile, apyrogenic solution.  All test 
preparations will be packaged in identical 2 mL CZ plastic vials.  Each vial containing 1 ml of M5A 
antibody at a concentration of 6.78 mg/ml. 
Radiolabeling of the 64Cu labeled M5A antibody will be performed by the Radioimmunotherapy section. 
The 64Cu will be purchased from the Mallinckrodt Institute of Radiology at the Washington University 
School of Medicine, which is preparing the radiolabel for clinical use. Labeling will be accomplished by 
incubating conjugated antibody with the 64Cu for 45 minutes at 43o C, followed by a chase with DTPA 
and subsequent purification on a size exclusion preparative grade Superdex-200 column. Appropriate 
fractions will be pooled and filtered to make up the patient dose, which will be formulated with human 
serum albumin. All preparations will be purified by HPLC. Each administered dose of antibody is also 
tested for endotoxin, sterility, and immunoreactivity. 

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Labeling and Drug Identification 
The drug label is permanently attached to the drug container.  The label contains the name, list, lot 
number of the drug and the words Caution:  New Drug―Limited by Federal (U.S.A.) law to 
investigational use.  All used and unused containers will be accounted for on the Drug Accountability 
Log. 
 
Storage and Disposition of Supplies 
The M5A anti-CEA antibody is stored at 4ºC in the Center for Biomedicine and Genetics (CBG) or 
Investigational Pharmacy.  All drug supplies are kept at 4ºC in a refrigerator that is connected to the 
central alarm system.  The investigator will maintain a current running inventory of drug supplies on the 
form provided (OMB No. 0925-0240). 
8.1.4 
Risks 
In our previous imaging studies, no significant adverse events have been seen.  Anticipated events and 
management would be:  fever and chills, which will be treated with acetaminophen; hypotension or frank 
anaphylactic shock, which will be treated with intravenous fluids, pressors, and corticosteroids; 
bronchospasm and respiratory distress, which will be treated with bronchodilators.  The patients will also 
be observed for other possible toxicities, including pulmonary toxicity, renal toxicity, skin rash, and 
serum sickness.   
9 Correlative/Special Studies 
HAHA (anti-antibody assay):  Approximately 5 ml (1 teaspoon) of blood in a red top tube will be drawn 
for this test at 3 time points (see study calendar, section 10).  It will be delivered at ambient temperature 
to Dr. Colcher’s laboratory for analysis of immunogenicity. 
 
Blood pharmacokinetics:  Approximately 5 cc (1 teaspoon) of blood will be collected for blood analysis 
of radioactivity (approx. 2.5 ml in a red top tube and approx. 2.5 ml in a EDTA tube).  These will be 
drawn at 7 time points (see study calendar, section 10).  These will be delivered at ambient temperature to 
Dr. Colcher’s laboratory for analysis. 
 
 
 
 
 
 
 

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10 Study Calendar 
 
Pre-Study 
Day 0 
Day 1 
Day 2 
1 mo post 
study drug 
(+/- 7 days) 
3 mo post 
study drug 
(+/- 14 days) 
STANDARD OF CARE 
 
 
 
 
 
 
Medical history 
S 
 
 
 
 
 
Physical exam 
S 
 
 
 
 
 
Vital signs (pulse, BP, resp rate, temp) 
S 
 
 
 
 
 
Weight 
S 
 
 
 
 
 
RESEARCH 
 
 
 
 
 
 
Informed consent 
R 
 
 
 
 
 
Urine pregnancy test (if applicable) 
R^ 
 
 
 
 
 
HAHA (Anti-antibody assay)# 
R^ 
 
 
 
R 
R 
64Cu-M5A infusion 
 
R 
 
 
 
 
Vital signs (pulse, BP, resp rate, temp) 
 
R* 
 
 
 
 
Radioactivity 
 
 
 
 
 
 
     Pharmacokinetics 
 
R** 
R 
R 
 
 
Imaging (per section 5) 
 
 
R 
R 
 
 
*    approx every 15 min post start of infusion for 1 hr, then again at approx 3-4 hours. 
**  1 EDTA tube and 1 red top tube drawn at pre-infusion, and at approx 30 min, 1 h, 2 h and 3-4 h post start of infusion 
^   To be completed within 4 weeks prior to antibody infusion 
#   1 red top tube to Dr. Colcher’s lab. 
 
 
STUDY CALENDAR NOTES: 
 “R” represents tests that are done purely for research purposes 
“S” indicates tests that are done for standard of care.  If these tests are done for standard of care purposes, the data from these tests will be 
collected, however they are not required for research purposes.  If they are not done, it will not exclude the patient from participation on 
the trial, and will not constitute a protocol deviation.

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11 Endpoint Evaluation Criteria/Measurement of Effect 
11.1 Response Criteria  
Not applicable. 
12 Data Reporting/Protocol Deviations 
12.1 Data Reporting 
12.1.1 Confidentiality and Storage of Records 
The protocol will uses Electronic Data Collection (EDC) and the 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 not be disclosed.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  They will be made available for review, as required by the FDA, HHS, or other 
authorized users such as the NCI, under the guidelines established by the Federal Privacy Act and rules 
for the protection of human subjects. 
12.1.2 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA research 
authorization form, and the California Experimental Subject’s Bill of Rights (for the medical record) and 
three copies (for the subject, the research record, and the Coordinating Center) must be available.  All 
Institutional, NCI, Federal, and State of California requirements will be fulfilled. 
12.1.3 Data Collection Forms and Submission Schedule  
All data will be collected within approximately 30 days post antibody administration using EDC.  Data 
will be sent to the location identified in Section 12.1.1 and stored in a secure location. 
12.1.3.1 Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research associate and signed 
by an authorized investigator prior to registering the subject.  See Section 4.3 for the registration 
procedure. 
12.1.3.2 Prior Therapy Forms and On-Study Forms 
Within 2 weeks of registration, the clinical research associate will submit baseline data forms within the 
EDC. 
 
 
13 Statistical Considerations 
13.1 Study Design 
The primary aim of this pilot study is to evaluate the tumor targeting, pharmacokinetic, and 
immunogenicity properties of 64Cu labeled M5A antibody. The results of this pilot study will be used to 
determine if the antibody should be studied in a larger imaging trial. The data for the 20 patients imaged 
will be used to summarize the scan results. 

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13.2 Sample Size Accrual Rate 
This is a three-year open-labeled pilot study that will enroll 20 patients with CEA-producing malignancies 
at the City of Hope National Medical Center. 
13.3 Statistical Analysis Plan 
The data will be summarized using two methods.  Both methods will examine the efficacy of each 
modality in locating cancer in each of four regions: primary, hepatic, extra-hepatic abdominal, and 
extra-abdominal.  For the first method, referred to as a lesion analysis, the efficacy of each modality will 
be evaluated where a successful outcome will be defined as the ability of at least one known tumor 
identified by conventional imaging modalities to be imaged using the M5A antibody.  For the second 
method, referred to as a region analysis, a successful outcome will be defined as the identification of 
suspicious tissue within a region. 
For both methods, using the standard statistical formulas, the number of true positives (TP), false 
positives (FP), true negatives (TN), false negatives (FN), as well as the sensitivity and corresponding 95% 
confidence interval will be estimated using the method of Lee and Dubin (31) or Rao and Scott (32), 
which accounts for the correlation between lesions within the same subject.   
General clinical findings and serum concentration data will be tabulated and descriptive statistics 
computed.  Safety data will be displayed and abnormal laboratory values flagged.  The frequency of 
adverse events will be tabulated by body system.   
 
14 Human Subject Issues 
14.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17,  must review and approve this protocol and the informed consent form prior to initiation of the study.  
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
14.2 Recruitment of Subjects 
Subjects will be recruited by the PI, Co-PI and participating clinicians in their respective clinics. 
14.3 Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to 
be posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and 
approved by the IRB prior to their use to recruit potential study subjects. 
14.4  Study location and Performance Sites 
This study will be performed at COH.   
14.5 Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating 
to protected health information (PHI).  The study will record individual demographics, cancer history, 
tumor targeting and any side effects, and this will be linked to the subject’s identity using a coded study 
number.  The principal investigator, co-investigators, clinical research nurses and clinical research 
coordinators will have access to this information, but all information will be treated confidentially.  No 
identifiers will be used in any subsequent publication of these results.   

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14.6 Financial Obligations and Compensation 
The investigational drug, 64Cu-M5A, will be provided free of charge by COH.   
The research participant will not be paid for taking part in this study. 
14.7 Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without prejudice, including as applicable, their current or future 
care or employment at City of Hope or any relationship they have with City of Hope.  Research subjects 
will be afforded sufficient time to consider whether or not to participate in the research. 
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those subjects who 
do comprehend the fundamental aspects of the study, consent will be obtained and documented, followed 
by eligibility testing.  The research team will review the results of eligibility testing and determine if the 
subject is a candidate for study enrollment.  
15 References 
 
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