Evaluation of Gallium-68 DOTA-TOC Imaging of Somatostatin Receptor Positive Malignancies
Phase: PHASE1
Conditions: Neuroendocrine Tumor, Paraganglioma, Carcinoid Tumors, Neuroblastoma
Sponsor: University of California, San Francisco

Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
Evaluation of Gallium-68 DOTA-TOC imaging of 
somatostatin receptor positive malignancies 
Protocol Number:  CC #  
Study Drug:  Gallium-68 DOTA-TOC 
Version Number:  Version 3.1 
Version Date:  7/28/2015 
IND Number:  122703 
Principal Investigator (Sponsor-Investigator) 
Thomas Hope, MD 
University of California San Francisco 
E-mail:  thomas.hope@ucsf.edu
Co-Investigators 
Dr. Emily Bergsland, MD 
Dr. Henry VanBrocklin, PhD 
Dr. Jim Slater, PhD 
Dr. Carina Mari Aparici, MD 
Dr. Youngho Seo, PhD 
Dr. Paul Fitzgerald, MD 
Clinical Research Coordinator 
NCT#  02177773
14453

Protocol Signature Page 
Protocol No.:   
Version Date: 7/28/2015 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee
(DSMC).
2. I will conduct the study in accordance with applicable CHR requirements, Federal
regulations, and state and local laws to maintain the protection of the rights and welfare of
study participants.
3. I certify that I, and the study staff, have received the requisite training to conduct this
research protocol.
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the
www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with CHR policies,
Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair 
 Thomas A. Hope 
Printed Name 
Signature 
Date 

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Abstract 
Title 
Evaluation of Gallium-68 DOTA-TOC imaging of somatostatin receptor 
positive malignancies 
Patient 
population 
Patients with somatostatin receptor positive malignancies, which includes 
neuroendocrine tumors, paraganglioms/pheochromocytomas and 
neuroblastomas. 
Rationale for 
Study 
Gallium-68 DOTA-TOC has better image sensitivity for somatostatin receptor 
positive tumors compared to conventional imaging, and is more convenient in 
terms of timing of imaging. 
Primary 
Objective 
To determine if Gallium-68 labeled DOTA-TOC results in the delineation of 
more lesions than with conventional imaging. 
Secondary 
Objectives 
To determine if the incorporation of Gallium-68 DOTA-TOC imaging into the 
management decision making process results in a change in stage of the 
patient. 
Study Design 
This is a phase 1-2 single center open label study. 
Number of 
patients 
320 patients over three years. 
Duration of 
Therapy 
The study will involve a single PET/CT imaging study. 
Duration of 
Follow up 
The patients will be followed-up by phone 14 days after the study completion. 
Duration of 
study 
The study will reach completion two years from the time the study opens to 
accrual. 
Study Drugs 
Gallium-68 labeled DOTA-TOC 
Safety 
Assessments 
Patient vital signs will be taken immediately before and after the 
administration of the radiopharmaceutical.  The patients will also be asked to 
report adverse events. 

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List of Abbreviations 
AE 
adverse event 
CHR 
Committee on Human Research (UCSF IRB) 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
Ga-68 
Gallium 68 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IRB 
Institutional Review Board 
IV 
intravenous 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
PK 
pharmacokinetics 
PRC 
Protocol Review Committee (UCSF) 
SD 
standard deviation 

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Table of Contents 
Protocol Signature Page ............................................................................................................ 0 
Abstract 
1 
List of Abbreviations ................................................................................................................... 2 
Table of Contents ....................................................................................................................... 3 
1 
Introduction 5 
1.1 Background on Indication ............................................................................................... 5 
2 
Objectives of the Study ........................................................................................................ 7 
2.1 Primary ........................................................................................................................... 7 
2.2 Secondary ....................................................................................................................... 7 
2.3 Endpoints ........................................................................................................................ 7 
2.3.1 Primary Endpoints .............................................................................................. 7 
2.3.2 Secondary Endpoints .......................................................................................... 7 
3 
Study Design ........................................................................................................................ 7 
3.1 Characteristics ................................................................................................................. 7 
3.2 Number of Subjects ........................................................................................................ 7 
3.3 Eligibility Criteria ........................................................................................................... 7 
3.3.1 Inclusion Criteria ................................................................................................ 8 
3.3.2 Exclusion Criteria............................................................................................... 8 
3.4 Duration of Follow Up .................................................................................................... 8 
3.5 Study Timeline ................................................................................................................ 8 
3.5.1 Primary Completion ........................................................................................... 8 
3.5.2 Study Completion .............................................................................................. 8 
4 
Study Drugs ......................................................................................................................... 9 
4.1 Description, Supply and Storage of Investigational Drugs ............................................ 9 
4.1.1 Investigational Drug #1 ...................................................................................... 9 
5 
Treatment Plan..................................................................................................................... 9 
5.1 Dosage and Administration ............................................................................................ 9 
5.1.1 Other Modality(ies) or Procedures ..................................................................... 9 
5.2 Monitoring and Toxicity Management ........................................................................... 9 
6 
Study Procedures and Observations .................................................................................... 9 
6.1 Schedule of Procedures and Observations ...................................................................... 9 
6.1.2 Treatment Period .............................................................................................. 10 
6.1.3 Post-treatment Follow Up Visits ...................................................................... 10 
6.2 Prohibited Medications ................................................................................................. 12 
7 
Reporting and Documentation of Results ............................................................................12 
7.1 Evaluation of Efficacy (or Activity) ............................................................................. 12 
7.2 Evaluation of Safety ..................................................................................................... 12 
7.3 Definitions of Adverse Events ...................................................................................... 12 
7.3.1 Adverse Event .................................................................................................. 12 
7.3.2 Adverse reaction............................................................................................... 12 
7.4 Recording of an Adverse Event .................................................................................... 13 
7.5 Follow-up of Adverse Events ....................................................................................... 14 
7.6 Expedited Reporting ..................................................................................................... 14 

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Table of Contents 
8 
Statistical Considerations and Evaluation of Results ...........................................................15 
8.1 Study Endpoints ............................................................................................................ 15 
8.1.1 Randomization ................................................................................................. 15 
8.2 Determination of Sample Size and Accrual Rate ......................................................... 15 
8.2.1 Sample Size and Power Estimate ..................................................................... 15 
8.2.2 Accrual estimates ............................................................................................. 15 
8.3 Analyses Plans .............................................................................................................. 16 
8.3.1 Analysis Population ......................................................................................... 16 
8.3.2 Analysis of Primary Endpoints ........................................................................ 16 
8.3.3 Analysis of Secondary Endpoints .................................................................... 16 
9 
Study Management .............................................................................................................17 
9.1 Pre-study Documentation ............................................................................................. 17 
9.2 Institutional Review Board Approval ........................................................................... 17 
9.3 Informed Consent ......................................................................................................... 17 
9.4 Changes in the Protocol ................................................................................................ 17 
10 
Protection of Human Subjects ...........................................................................................17 
10.1 Protection of Privacy .................................................................................................. 17 
References 
19 
Appendices 
20 
Appendix 1 
Performance Status Criteria .............................................................................20 
List of Tables 
Table 1 ............................................................................................................................................ 5 
Table 2 ............................................................................................................................................ 5 
Table 3.1 Schedule of Study Procedures and Assessments ....................................................... 11 

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1 
Introduction 
1.1 
Background on Indication 
Gallium-68 DOTA-TOC is an investigational drug being evaluated for the imaging of 
somatostatin receptor positive malignancies.     
One approach to imaging somatostatin receptor positive malignancies is to label a somatostatin 
analog with a radionuclide and image its distribution within the body.  In the United States, the 
only clinically available agent is Indium-111 labeled pentetreotide (OctreoScan, Covidien), which 
was originally approved in 1994.  Also known as octreotide, this agent is made of 8 amino acids 
that bind to the somatostatin receptor, primarily receptor subtype 2 (see Table 1).   There are 
many issues with octreotide, in particular the long-half life of indium limits the administered 
dose.  Additionally, indium is a gamma emitter and is imaged with using a SPECT scanner that 
inherently has worse spatial resolution than PET imaging.  Lastly due to the required delay 
needed for imaging, there is often significant biliary excretion that interferes with interpretation 
sometimes requiring that the patient return for additional imaging time points.  The first imaging 
time point is usually 24 hours after injection followed by repeat imaging at 48-72 hours. 
Table 1 
Somatostatin receptor binding efficiency (1) 
Compound 
SSR-1 
SSR-2 
SSR-3 
SSR-4 
SSR-5 
DOTA-TATE 
> 10,000
0.2 
> 1,000
300 
377 
DOTA-NOC 
> 10,000
1.9 
40 
260 
7.2 
DOTA-TOC 
> 10,000
2.5 
613 
> 1,000
73 
Octreotide 
> 10,000
7.3 
120 
> 1,000
60 
There are a large number of additional analogs that vary from octreotide by a few amino acids; 
each has a different affinity for the various somatostatin receptor subtypes (Figure 1).  Of note, 
many have a stronger affinity for subtype 2 than octreotide.  This increased affinity allows for an 
earlier imaging time point.  In order to improve the image quality, these compounds are labeled 
with Gallium-68 rather than Indium-111.  Gallium-68 is a PET emitter that has a 68-minute half-
life.   Gallium-68 due to its shorter half-life can be given in a higher dose without increasing the 
patient radiation exposure significantly increasing (Table 2). 
Table 2 
Selected organ and effective dose for Gallium-68 DOTA-TOC and various Gallium-68 labelled 
analogs, Indium-111 Octreotide and Flourine-18 FDG (2) 
Organs 
68Ga-DOTATATE 
68Ga-DOTATOC 
68Ga-DOTANOC 
111In-DTPA-
octreotide 
18F-FDG
Kidneys (mSv/MBq) 
9.21E-02 
2.2E-01 
8.97E-02 
4.5E-01 
1.7E-02 
Liver 
4.50E-02 
7.4E-02 
3.38E-02 
7.0E-02 
2.1E-02 
Spleen 
2.82E-01 
2.4E-01 
7.25E-02 
3.2E-01 
1.1E-02 
Urinary bladder wall 
1.25E-01 
7.0E-02 
8.36E-02 
1.8E-01 
1.3E-01 
ED (mSv/MBq) 
2.57E-02 
2.3E-02 
1.67E-02 
8.0E-02 
1.9E-02 
Typical injected activity 
 MBq 
 mCi 
185 
5 
185 
5 
185 
5 
74 
2 
370 
10 
Estimated effective 
dose per exam (mSv) 
4.8 
4.3 
3.1 
5.9 
7.0 

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Combined with the increased affinity and the better image characteristics, patients are able to 
undergo a diagnostic study all within two hours during one visit that is of higher quality than prior 
octreotide studies.  There is extensive experience using these agents in Europe (3,4) where 
these compounds have replaced octreotide for clinical imaging.   These compounds have 
shown a significant increase in sensitivity compared to In-111 Octreoscan (Figure 1) (5). 
Figure 1 
Estimated sensitivity of various imaging techniques (5).  SRS refers to gamma 
emitting somatostatin receptor imaging techniques such as In-111 Octreotide 
which has a lower sensitivity compared to PET based somatostatin receptor 
imaging techniques. 
In the United States, no company has taken on the investment required to bring an agent to 
market.  In the vacuum of availability, multiple academic groups are currently joining together in 
order to develop a group FDA submission in the hopes of attaining approval.  Through the help 
of the Society of Nuclear Medicine and Molecular Imaging, a joint IND process has been 
developed in order to increase the number of institutions involved.   
A the same time, a phase III clinical trial has begun in the United States using Lutetium-177 
labeled DOTA-TATE for the treatment of midgut neuroendocrine tumors with metastasis.  This 
trial began patient enrollment in the summer of 2013.  If this therapy becomes approved, it will 
be important to have an imaging study that will appropriately evaluate DOTA-TATE positive 
tumors prior to therapy. 
There are a number of malignancies that express the somatostatin receptor.  The 
neuroendocrine family of tumors is the most common, although 
pheochromocytomas/paragangliomas, medulloblastomas and neuroblastomas all express 
somatostatin receptors to varying degrees.   
Unlike neuroendocrine tumors and octreotide, MIBG and DOTA-TOC are imaging different 
aspects of the tumor physiology.  MIBG images norepinephrine reuptake of the cells while 
DOTA-TATE binds to somatostatin receptors.  It has been demonstrated that octreotide does 
bind somatostatin receptors on neuroblastoma cells (6), and receptor subtypes 1 and 2 are 
upregulated in neuroblastoma  (7).   There has been no comparison between Gallium-68 DOTA-
TATE and I-123 MIBG imaging for neuroblastoma imaging, although a comparison of Gallium-
68 DOTA-TOC did show an increased sensitivity for lesions compared to I-123 MIBG (8). 

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Because of the dosimetry, convenience and image quality benefits, we intend to study the utility 
of Gallium-68 DOTA-TOC in the imaging of somatostatin receptor positive malignancies in order 
provide further clinical data to support a group FDA submission. 
2 
Objectives of the Study 
2.1 
Primary 

To determine if Gallium-68 labeled DOTA-TOC results in the delineation of more lesions
than with conventional imaging.
2.2 
Secondary

To determine if the incorporation of Ga-68 DOTA-TOC PET/CT into the management
decision making process results in a change in stage of the patient.
2.3 
Endpoints 
2.3.1 Primary Endpoints 

The 5 largest lesions in each of eight body regions (head and neck, mediastinum, lung,
liver, pancreas, the remaining abdomen and pelvis, bone and lymph nodes) will be
measured by size (short and long axis) as well as SUVmax on conventional imaging and
the Ga-68 DOTA-TOC PET/CT.

Additionally the confidence that each lesion represents a metastasis will be recorded.
2.3.2 Secondary Endpoints 

Clinical stage will be determined based upon conventional imaging, and then be re-
determined incorporating the Ga-68 DOTA-TOC PET/CT.
3 
Study Design 
3.1 
Characteristics 
This is a prospective, Phase 1-2, single center, open-label study in patients with somatostatin 
receptor positive malignancies. Eligible participants will undergo baseline assessments at 
enrollment. Study participants will receive a one-time administration of Ga-68 DOTA-TOC and 
undergo a PET/CT imaging study.  
3.2 
Number of Subjects 
It is anticipated that 320 patients over three years will be enrolled in this study, split between 
neuroendocrine tumors and paragangliomas.   
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the administration of the 
radiopharmaceutical and must meet all inclusion and exclusion criteria.  In addition, the patient 
must be thoroughly informed about all aspects of the study, including the study visit schedule 
and required evaluations and all regulatory requirements for informed consent.  The written 
informed consent must be obtained from the patient prior to enrollment.  The following criteria 
apply to all patients enrolled onto the study unless otherwise specified. 

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3.3.1 Inclusion Criteria 
1. Known or suspected somatostatin receptor positive tumor such as carcinoid;
neuroendocrine tumor; neuroblastoma; pheochromocytoma.  Supporting evidence may
include MRI, CT, biochemical markers, and or pathology report.
2. Age > 18.
3. Karnofsky performance status of > 50 (or ECOG/WHO equivalent).
4. Not pregnant. A negative serum pregnancy test is required for all female subjects with
child-bearing potential.
5. Ability to understand a written informed consent document, and the willingness to sign it
3.3.2 Exclusion Criteria 
1. Hepatic enzymes 5 times greater than the upper limits of normal, serum creatinine > 3.0
mg/dL (270 uM/L)
2. Patients exceeding the weight limitations of the scanner  or are not able to enter the bore
of the PET/CT scanner due to BMI
3. Inability to lie still for the entire imaging time (e.g. cough, severe arthritis, etc.)
4. Inability to complete the needed investigational and standard-of-care imaging
examinations due to other reasons (severe claustrophobia, radiation phobia, etc.)
5. Any additional medical condition, serious intercurrent illness, or other extenuating
circumstance that, in the opinion of the Investigator, may significantly interfere with study
compliance
6. Recognized concurrent active infection
7. Previous systemic or radiation treatment for another cancer of any type within the last 2
months
8. Use of any other investigational product or device within 30 days prior to dosing, or
known requirement for any other investigational agent prior to completion of all
scheduled study assessments.
3.4 
Duration of Follow Up 
Patients will be followed for 14 days after the administration of the radiopharmaceutical. 
3.5 
Study Timeline 
3.5.1 Primary Completion 
The study will reach primary completion 24 months from the time the study opens to accrual. 
3.5.2 Study Completion 
The study will reach study completion 36 months from the time the study opens to accrual. 

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4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug #1 
Ga-68 DOTA-TOC is a radiopharmaceutical that will be produced under cGMP by a research 
pharmacists certified and highly experienced in the Department of Radiology and Biomedical 
Engineering, Jim Slater, PhD. The radiopharmaceutical will be made in the same facility in 
which the injection and imaging will take place, the China Basin Imaging Center.  
5 
Treatment Plan 
5.1 
Dosage and Administration 
The imaging agent (Ga-68 DOTA-TOC) will be administered on an outpatient basis.  It will be 
administered a single time intravenously prior to the PET/CT imaging.  The one-time nominal 
injected dose will be 5 to 7 mCi in a volume of 3 - 5 ml containing 10 - 25 μg Ga-68 DOTA-TOC. 
5.1.1 Other Modality(ies) or Procedures 
5.1.1.1 PET/CT imaging 
Study participants will undergo the Ga-68 DOTA-TOC PET/CT after all screening and baseline 
assessments have been completed.  Prior to imaging, participants will be asked to drink water 
as a “negative” oral contrast since many NETs involve the GI tract.  Patient shall begin imaging 
between 55 and 70 minutes after the injection of the radiopharmaceutical.  Intravenous 
iodinated contrast will be administered depending on the clinical need. For example if the 
patient’s referring oncologist requests a contrast enhanced CT, this will be performed 
concurrently with the study in place of the convention low dose CT acquired for attenuation 
correction purposes only.  Coverage for the scan will extend from the patients vertex through 
the mid thighs. 
The Ga-68 DOTA-TOC PET/CT will be read by a board certified nuclear medicine physician 
within two working days of the completion of the study in line with the Department of Radiology 
policy.  This initial read will be performed by a single nuclear medicine physician. 
5.2 
Monitoring and Toxicity Management 
Each patient receiving Ga-68 DOTA-TOC PET/CT will be evaluable for safety.  The safety 
parameters include physical findings and spontaneous reports of adverse events reported to the 
investigator by patients. 
6 
Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
Screening assessments must be performed within 30 days prior to the first dose of 
investigational product.  Any results falling outside of the reference ranges may be repeated at 
the discretion of the investigator.  Treatment or visit delays for public holidays or weather 
conditions do not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   

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6.1.1.1 Screening Assessments 
The Screening procedures and assessments must be completed within 30 days of the day 1 
Visit.  

Vital signs

Physical examination, medical history

Serum or urine pregnancy test

Performance status
6.1.2 Treatment Period 
6.1.2.1 Study Procedures, Imaging Day 1 

Vital signs

Evaluation of adverse events
6.1.3 Post-treatment Follow Up Visits 
Patients will be followed for two weeks after enrollment, by phone.  The following procedure will 
be performed at two weeks: 

Evaluation of adverse events

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Table 3.1 
Schedule of Study Procedures and Assessments 
Period/ 
Procedure 
Screening 
Imaging day 1 
Two weeks post imaging 
Study Day/Visit Day 
-30 to 1
1 
14 
Informed consent 
X 
Medical History 
X 
Physical examination 
X 
Performance status 
X 
Blood Pressure, HR 
X 
X 
Pulse Oximetry 
X 
X 
Pregnancy Test 
X 
Imaging procedure 
Ga-68 DOTA-TATE 
administration 
X 
PET/CT imaging 
X 
Follow-up 
Adverse event reporting 
X 
X 

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6.2 
Prohibited Medications 
There are no prohibited medications. 
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
7.1.1.1 Definitions 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of Ga-68 DOTA-TOC. 
7.2 
Evaluation of Safety 
Analyses will be performed for all patients receiving Ga-68 DOTA-TOC.  The study will use the 
CTCAE v4.0 for reporting of adverse events. 
7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
7.3.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
7.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 

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as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  

Death

Life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
7.4 
Recording of an Adverse Event 
All grade 3 and above adverse events will be recorded using the NCI CTCAE v4.0.   The 
Investigator will assign attribution of the possible association of the event with use of the 
investigational drug.  
Relationship 
Attribution 
Description 
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention 

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Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
7.5 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
7.6 
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions:  

Suspected adverse reaction (as defined in 6.1.30)

Unexpected (as defined in 0)

Serious (as defined in 6.1.5)

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If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Endpoints 
Primary endpoint: The 5 largest lesions in each of eight body regions (head and neck, 
mediastinum, lung, liver, pancreas, the remaining abdomen and pelvis, bone and lymph nodes), 
will be measured by size (short and long axis) as well as SUVmax on conventional imaging and 
the Ga-68 DOTA-TOC PET/CT.  Additionally the confidence that each lesion represents a 
metastasis will be recorded. 
Secondary Endpoint:  Clinical stage will be determined based upon conventional imaging, and 
then be re-determined incorporating the Ga-68 DOTA-TOC PET/CT.   
8.1.1 Randomization 
There will be no randomization performed.  There for there will be no blinding performed. 
8.2 
Determination of Sample Size and Accrual Rate 
The sample size will be determined by the number of patients enrolled in the trial.  As the goal 
of this trial is to pool data with multiple centers to submit for FDA approval of the imaging agent, 
our goal is to enroll as many patients as possible, rather than power the study for a particular 
endpoint.    
8.2.1 Sample Size and Power Estimate 
If you were to look at a comparison of number of lesions identified using conventional imaging 
compared to the Ga-68 DOTA-TOC PET/CT. Using 60 pairs of observations with a difference of 
one lesion between the pairs and a standard distribution of 2, we would be able to reject the null 
hypothesis that the difference is zero with a probability of (ie power) 0.967 given a type I error 
probability of 0.05. 
8.2.2 Accrual estimates 
We anticipate enrolling 320 patients over three years through this protocol. 

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8.3 
Analyses Plans 
8.3.1 Analysis Population 
There will only be one population.  The total cohort of imaged patients. 
8.3.2 Analysis of Primary Endpoints 
Interpreting physicians will be board-certified in nuclear medicine and experienced in 
interpretation of PET/CT scans.  At least 2 nuclear medicine physicians will independently 
interpret the examinations blinded to each other’s interpretation but otherwise fully cognizant of 
other clinical, imaging and laboratory data. Discrepancies will be resolved by consensus 
between the two imaging physicians, or, if not resolved, by a third similarly qualified physician. 
Discrepancies and concurrences will be recorded. 
Eight body regions are defined: head and neck, mediastinum, lung, liver, pancreas, the 
remaining abdomen and pelvis, bone and lymph nodes. The five largest lesions will be 
measured in each region in long and short axis as well as the SUVmax values for each lesion, 
in accordance with RECIST 1.1 and PERCIST criteria (10).  Additionally the confidence that 
each lesion represents a primary or metastatic lesion will be recorded (1 = benign, 2 = likely 
benign, 3 = indeterminant, 4 = likely malignant, 5 = malignant). 
Comment will be made as to whether or not areas of tumor involvement are visible on the 
investigational Ga-68 DOTA-TOC PET/CT scan that are not otherwise visible prospectively on 
conventional imaging (conventional imaging, CI, is defined as any US FDA approved imaging 
means for diagnosis, staging, restaging or accessing treatment response for malignancy). CI 
used for comparison include contrast enhanced CT and MRI scans, Indium-111 octreotide 
scans, ultrasounds and x-ray plain films. 
The number of positive body regions using conventional imaging and Ga-68 DOTA-TOC 
PET/CT will be compared using a paired t-test (or Wilcoxon signed-rank test if the data appear 
to be non-normally distributed). The Wilcoxon signed-rank test will also be used to compare 
reader confidence of paired lesions between conventional imaging and Ga-68 DOTA-TOC 
PET/CT.  Inter-reader variability for the number of positive regions will be compared using 
Kappa statistics.  In all cases we will provide point estimates and 95% confidence intervals for 
effects along with p-values. 
8.3.3 Analysis of Secondary Endpoints 
In discussion with clinical staff, impact on care will be accessed for value added by the 
investigational Ga-68 DOTA-TOC PET/CT scan similar to assessment for impact on care as in 
the National Oncology PET registry, such as: 
1. Change in stage
A percentage will then be calculated for both “Change in stage” with a 95% confidence interval 
determined. 

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9 
Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.   
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation.  The Study Chair and the UCSF study team will be responsible for updating any 
participating sites. 
10 
Protection of Human Subjects 
10.1 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 

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become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 

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References 
1.
Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, et al. Are radiogallium-labelled
DOTA-conjugated somatostatin analogues superior to those labelled with other
radiometals? Eur J Nucl Med Mol Imaging. 2007 Jan 16;34(7):982–93.
2.
Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured human dosimetry of
68Ga-DOTATATE. J Nucl Med. 2013 Jun;54(6):855–60.
3.
Poeppel TD, Binse I, Petersenn S, Lahner H, Schott M, Antoch G, et al. 68Ga-DOTATOC
versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J Nucl
Med. 2011 Dec;52(12):1864–70.
4.
Yang J, Kan Y, Ge BH, Yuan L, Li C, Zhao W. Diagnostic role of Gallium-68 DOTATOC
and Gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis.
Acta Radiol. 2013 Aug 8.
5.
Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, et al.
Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008 Jan;9(1):61–72.
6.
O'Dorisio MS, Chen F, O'Dorisio TM, Wray D, Qualman SJ. Characterization of
somatostatin receptors on human neuroblastoma tumors. Cell Growth Differ. 1994
Jan;5(1):1–8.
7.
Albers AR, O'Dorisio MS, Balster DA, Caprara M, Gosh P, Chen F, et al. Somatostatin
receptor gene expression in neuroblastoma. Regul. Pept. 2000 Mar 17;88(1-3):61–73.
8.
Kroiss A, Putzer D, Uprimny C, Decristoforo C, Gabriel M, Santner W, et al. Functional
imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr 3-octreotide
positron emission tomography and 123I-metaiodobenzylguanidine. Eur J Nucl Med Mol
Imaging [Internet]. 2011 Jan 29;38(5):865–73. Available from:
http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=21279352&retmod
e=ref&cmd=prlinks

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Appendices 
Appendix 1 Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance without 
restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead